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61.
62.
ABSTRACT

Introduction: Ubiquitin-proteasome system (UPS) has been validated as a novel anticancer drug target in the past 20 years. The UPS contains two distinct steps: ubiquitination of a substrate protein by ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3), and substrate degradation by the 26S proteasome complex. The E3 enzyme is the central player in the ubiquitination step and has a wide range of specific substrates in cancer cells, offering great opportunities for discovery and development of selective drugs.

Areas covered: This review summarizes the recent advances in small molecule inhibitors of E1s, E2s, and E3s, with a focus on the latest patents (from 2015 to 2018) of E3 inhibitors and modulators.

Expert opinion: One strategy to overcome limitations of current 20S proteasome inhibitors is to discover inhibitors of the upstream key components of the UPS, such as E3 enzymes. E3s play important roles in cancer development and determine the specificity of substrate ubiquitination, offering novel target opportunities. E3 modulators could be developed by rational design, natural compound or library screening, old drug repurposes, and application of other novel technologies. Further understanding of mechanisms of E3–substrate interaction will be essential for discovering and developing next-generation E3 inhibitors as effective anticancer drugs.  相似文献   
63.
IntroductionSildenafil is the first effective oral treatment for male erectile dysfunction. Although it is generally accepted that its action is peripheral, it has been suggested that it influences central neural pathways that are involved in male sexual arousal. Recently, it was shown that local sildenafil administration enhances extracellular dopamine (DA) in the nucleus accumbens (NAcc).AimThe aim of this study was to determine whether sildenafil administration alters dopaminergic and serotonergic activity in the NAcc and the medial preoptic area (mPOA) during a model of sexual arousal.MethodsAn acute (2 days) or chronic (21 days) sildenafil regimen (1 mg/kg) was administered intraperitoneally to male rats. Thirty minutes after the last sildenafil injection, all males were exposed to noncontact erection sessions by the presentation of inaccessible estrous females. Half of the males had previous experience of noncontact sexual encounter and the other half were exposed for the first time.Main Outcome MeasuresTissue levels of DA and its metabolites, 3,4‐Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), as well as serotonin (5‐HT) and its metabolite 5‐HIAA, were measured in the mPOA and NAcc with high‐performance liquid chromatography with electrochemical detector. Dopamine ([DOPAC+HVA]/DA) and serotonin (5‐HIAA/5‐HT) turnovers were also calculated as indices of neurotransmission.ResultsIn nontrained males, acute and chronic sildenafil treatment increased DA and 5‐HT turnover rates in the mPOA and NAcc. In trained rats, acute sildenafil also increased DA and 5‐HT turnover rates in both structures, whereas chronic treatment enhanced 5‐HT turnover rate only in the mPOA and DA turnover rate only in the NAcc.ConclusionsOur data confirm that sildenafil enhances dopaminergic activity in the NAcc, extend these findings to the mPOA and furthermore, reveal sildenafil‐induced effects on serotonergic activity in these brain regions as well. Therefore, present findings support an effect of sildenafil on central neural pathways that are involved in the control of sexual arousal. Kyratsas C, Dalla C, Anderzhanova E, Polissidis A, Kokras N, Konstantinides K, and Papadopoulou‐Daifoti Z. Experimental evidence for sildenafil's action in the central nervous system: Dopamine and serotonin changes in the medial preoptic area and nucleus accumbens during sexual arousal. J Sex Med 2013;10:719–729.  相似文献   
64.
Since their discovery in 1940, it has been well established that gangliosides are associated with a number of biological pathways and cellular processes such as growth, differentiation and toxin uptake. Gangliosides are glycosphingolipids containing neuraminic acid which are expressed on the plasma membrane of cells particularly in the nervous system. Heterogeneity and structural variation in the carbohydrate chains of gangliosides contributes to unique features of each of these molecules. Thirty five years ago it was discovered that aberrant glycosylation occurs in a variety of human cancers, including aberrant glycosylation of gangliosides. Ganglioside expression in terms of quality and quantity varies in different cancers and different roles may be played. Gangliosides, by affecting the immune system, including esxpression of cytokines and adhesion molecules, may inhibit anti-tumor mechanisms, as well as having direct impact on angiogenesis, cell movement and metastasis. It should be noted that different kinds of gangliosides do not all act by the same mechanisms.  相似文献   
65.
Endorphins are the body’s natural opioids that are created and released by the central nervous system, hypothalamus and pituitary gland. Endorphins have a reputation for pain reduction, enhancing excitement or satisfaction, boosting confidence, enabling control of emotions and generating feelings of euphoria, and are involved in the natural reward cycle. There is also evidence in the literature suggesting the role of endorphins in sexuality (including sexual function and sexual behaviours), as they may regulate the release of sex hormones, prolactin and growth hormone, which are involved in sexual function and love. Endogenous oxytocin is another intrinsic hormone whose role in inducing labour contractions, the delivery of the baby and stimulating lactation has been well studied. However, the potential impact of endorphins and oxytocin on sexuality and romantic relationships is not well understood. This article reviews the research on endorphins and endogenous oxytocin and how they relate to human sexuality and romantic relationships. Some animal studies report the effect of endorphin and oxytocin on sex hormones and mating behaviours, but these findings have not been supported by research into human behaviour, indicating many gaps in knowledge relating to the association between these hormones and human sexuality.  相似文献   
66.

Objective

Umbilical cord abnormalities increase fetal morbidity and mortality. This study was designed to compare antenatal umbilical coiling index (aUCI) in gestational diabetes mellitus (GDM) and non-gestational diabetes mellitus (non-GDM) pregnancy, considering uncertainties about the best time to perform antenatal ultrasonography scan.

Materials and Methods

In this prospective study, 246 parturients were included, 123 with GDM and 123 with non-GDM pregnancy. Gestational diabetes was confirmed at 24–28 weeks of gestation (WG) using one-step strategy. An anatomical ultrasound survey of placenta and umbilical cord was performed at 18–23 as well as 37–41 weeks of gestational age.

Results

At 18–23 WG, the frequency distribution (10th, 90th percentiles, mean ± SD) of the aUCI in the GDM and non-GDM groups were (0.13,0.66,0.32 ± 0.19) and (0.18,0.74, 0.4 ± 0.31) respectively. These values were (0.12,0.4, 0.25 ± 0.11) in the GDM group at 37–41 WG and (0.17,0.43, 0.29 ± 0.11) in the non-GDM group. A significant relationship was detected between UCI value and GDM/non-GDM groups at both antenatal evaluations (18–23 WG; P = 0.002, 37–41WG; P < 0.001). A significant association at 18–23 WG was found between GDM/non-GDM groups and aUCI categorization (hypocoiling <10th, normocoiling 10th–90th and hypercoiling >90th) (P = 0.001). However, hypocoiling were significantly more frequent in GDM than non-GDM in both antenatal evaluations (P < 0.001, P = 0.006).

Conclusion

Antenatal UCI in pregnancy complicated by GDM were lower in comparison with non-GDM pregnancy. The most abnormal pattern of coiling in gestational diabetes was hypocoiling in both trimesters. In addition, 18–23 WG is the best time to perform ultrasound scan to detect aUCI and umbilical cord pattern.  相似文献   
67.
The aim of this study was to evaluate the effect of three methods of fiber insertion on fracture resistance of endodontically treated maxillary premolars in vitro. Sixty extracted human maxillary premolars received endodontic treatment followed by mesioocclusodistal (MOD) cavities with 2.5 ± 0.2 mm thicknesses of buccal and lingual cusps at height of contour. The gingival cavosurface margin was 1.5 mm coronal to the cementoenamel junction (CEJ). Subsequently, the teeth were randomly divided into four groups. In the no-fiber group, the cavities were restored with composite, and in other groups, composite impregnated glass fibers were placed in the gingival, middle, and occlusal third surfaces of the cavities, respectively, and were restored similar to the no-fiber group. Subsequent to thermocycling and exertion of compressive forces, statistical analysis showed that the fracture resistance in the occlusal fiber group was significantly higher than that in other groups (p < 0.0005). In addition, the highest favorable fracture and the lowest cusp detachment rates were observed in the occlusal fiber group.  相似文献   
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69.
We present a clinical case of a young woman who underwent splenectomy for thrombocytopenic splenomegaly at the age of 7 years. An acute diagnostic picture of splenosis of the left epigastric region and chronic non‐cirrhotic portal vein thrombosis with cavernous transformation was found 20 years later.  相似文献   
70.
We report a case of a 48-year-old male patient with “krokodil” drug-related osteonecrosis of both jaws. Patient history included 1.5 years of “krokodil” use, with 8-month drug withdrawal prior to surgery. The patient was HCV positive. On the maxilla, sequestrectomy was performed. On the mandible, sequestrectomy was combined with bone resection. From ramus to ramus, segmental defect was formed, which was not reconstructed with any method. Post-operative follow-up period was 3 years and no disease recurrence was noted. On 3-year post-operative orthopantomogram, newly formed mandibular bone was found. This phenomenon shows that spontaneous bone formation is possible after mandible segmental resection in osteonecrosis patients.  相似文献   
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