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61.
Yokoyama K Ishikawa N Igarashi S Kawano N Hattori K Miyazaki T Ogino S Matsumoto Y Takeuchi M Ohta M 《Bioorganic & medicinal chemistry》2008,16(14):7021-7032
A new series of quinazolines that function as CCR4 antagonists were discovered during the screening of our corporate compound libraries. Subsequent compound optimization elucidated the structure-activity relationships and led the identification of 2-(1,4'-bipiperidine-1'-yl)-N-cycloheptyl-6,7-dimethoxyquinazolin-4-amine 14a, which showed potent inhibition in the [(35)S]GTPgammaS-binding assay (IC(50)=18nM). This compound also inhibited the chemotaxis of human and mouse CCR4-expressing cells (IC(50)=140nM, 39nM). 相似文献
62.
Qin B Polansky MM Sato Y Adeli K Anderson RA 《The Journal of nutritional biochemistry》2009,20(11):901-908
We have reported previously that a cinnamon extract (CE), high in type A polyphenols, prevents fructose feeding-induced decreases in insulin sensitivity and suggested that improvements of insulin sensitivity by CE were attributable, in part, to enhanced insulin signaling. In this study, we examined the effects of CE on postprandial apolipoprotein (apo) B-48 increase in fructose-fed rats, and the secretion of apoB48 in freshly isolated intestinal enterocytes of fructose-fed hamsters. In an olive oil loading study, a water-soluble CE (Cinnulin PF, 50 mg/kg body weight, orally) decreased serum triglyceride (TG) levels and the over production of total- and TG-rich lipoprotein-apoB48. In ex vivo 35S labeling study, significant decreases were also observed in apoB48 secretion into the media in enterocytes isolated from fructose-fed hamsters. We also investigated the molecular mechanisms of the effects of CE on the expression of genes of the insulin signaling pathway [insulin receptor (IR), IR substrate (IRS)1, IRS2 and Akt1], and lipoprotein metabolism [microsomal TG transfer protein (MTP), sterol regulatory element-binding protein (SREBP1c) in isolated primary enterocytes of fructose-fed hamsters, using quantitative real-time polymerase chain reaction. The CE reversed the expression of the impaired IR, IRS1, IRS2 and Akt1 mRNA levels and inhibited the overexpression of MTP and SREBP1c mRNA levels of enterocytes. Taken together, our data suggest that the postprandial hypertriglycerides and the overproduction of apoB48 can be acutely inhibited by a CE by a mechanism involving improvements of insulin sensitivity of intestinal enterocytes and regulation of MTP and SREBP1c levels. We present both in vivo and ex vivo evidence that a CE improves the postprandial overproduction of intestinal apoB48-containing lipoproteins by ameliorating intestinal insulin resistance and may be beneficial in the control of lipid metabolism. 相似文献
63.
Satoshi Yokoshima Yuzo Abe Naoto Watanabe Yoichi Kita Toshiyuki Kan Takeshi Iwatsubo Taisuke Tomita Tohru Fukuyama 《Bioorganic & medicinal chemistry letters》2009,19(24):6869-6871
We have developed photoaffinity probes for γ-secretase with a nitrobenzenesulfonamide-type linker that can be cleaved with 2-mercaptoethanol under physiological conditions. 相似文献
64.
65.
Ryuichiro Mizuno Teruyuki Kawabata Yuichi Sutoh Yuzo Nishida Shigeru Okada 《Biometals》2006,19(6):675-683
Oxidative renal tubular injuries and carcinogenesis induced by FeIII-nitrilotriacetate (NTA) and FeIII–ethylenediamine-N,N′-diacetate (EDDA) have been reported in rodent kidneys, but the identity of iron coordination structure essential for renal carcinogenesis, remains to be clarified. We compared renal tubular injuries caused by various low molecular weight aminocarboxylate type chelators with injuries due to NTA and EDDA. We found that FeIII-iminodiacetate (IDA), a novel iron-chelator, induced acute tubular injuries and lipid peroxidation to the same extent. We also prepared FeIII-IDA solutions at different pHs, and studied resultant oxidative injuries and physicochemical properties. The use of FeIII-IDA at pH 5.2, 6.2, and 7.2 resulted in renal tubular necrosis and apoptotic cell death, but neither tubular necrosis nor apoptosis was observed at pH 8.2. Spectrophotometric data suggested that FeIII-IDA had the same dimer structure from pH 6.2 to 7.2 as FeIII-NTA; but at a higher pH, iron polymerized and formed clusters. FeIII-IDA was crystallized, and this was confirmed by X-ray analysis and magnetic susceptibility measurements. These data indicated that FeIII-IDA possessed a linear μ-oxo bridged dinuclear iron (III) around neutral pH. 相似文献
66.
Mitzi M. Gonzales Takashi Tarumi Steven C. Miles Hirofumi Tanaka Furqan Shah Andreana P. Haley 《Obesity (Silver Spring, Md.)》2010,18(11):2131-2137
Midlife obesity is associated with cognitive deficits and cerebral atrophy in older age. However, little is known about the early signs of these deleterious brain effects or the physiological mechanisms that underlie them. Functional magnetic resonance imaging (fMRI) allows us to detect early changes in brain response to cognitive challenges while behavioral performance is still intact. Accordingly, we examined the impact of obesity on functional activation during a 2‐Back task in 32 cognitively normal middle‐aged adults, who were classified into normal, overweight, and obese groups according to BMI. Additionally, we examined insulin sensitivity as a potential mediator of the relationship between BMI and brain activation. Insulin sensitivity is of special interest because insulin is strongly associated with both obesity and central nervous system functioning. Group differences in task‐related brain activation were examined in a priori regions of interest (ROIs) using ANOVA. The obese BMI group displayed significantly lower task‐related activation in the right parietal cortex, BA 40/7, (F(2,29) = 5.26, P = 0.011) than the normal (P = 0.016) and overweight (P = 0.047) BMI groups. Linear regression and bootstrapping methods for assessing indirect effects indicated that insulin sensitivity fully mediated the relationship between task‐related activation in the right parietal cortex and BMI ((F(3,28) = 9.03, P = 0.000), β = 0.611, P = 0.001, 95% confidence interval: ?2.548 to ?0.468). In conclusion, obesity in middle age was related to alterations in brain activation during a cognitive challenge and this association appeared to be mediated by insulin sensitivity. 相似文献
67.
Devan AE Umpierre D Harrison ML Lin HF Tarumi T Renzi CP Dhindsa M Hunter SD Tanaka H 《American journal of physiology. Heart and circulatory physiology》2011,300(3):H813-H819
Advancing age is a major risk factor for coronary artery disease. Endothelial dysfunction accompanied by increased oxidative stress and inflammation with aging may predispose older arteries to greater ischemia-reperfusion (I/R) injury. Because coronary artery ischemia cannot be induced safely, the effects of age and habitual endurance exercise on endothelial I/R injury have not been determined in humans. Using the brachial artery as a surrogate model of the coronary arteries, endothelial function, assessed by brachial artery flow-mediated dilation (FMD), was measured before and after 20 min of continuous forearm occlusion in young sedentary (n = 10, 24 ± 2 yr) and middle-aged (n = 9, 48 ± 2 yr) sedentary adults to gain insight into the effects of primary aging on endothelial I/R injury. Young (n = 9, 25 ± 1 yr) and middle-aged endurance-trained (n = 9, 50 ± 2 yr) adults were also studied to determine whether habitual exercise provides protection from I/R injury. Fifteen minutes after ischemic injury, FMD decreased significantly by 37% in young sedentary, 35% in young endurance-trained, 68% in middle-aged sedentary, and 50% in middle-aged endurance-trained subjects. FMD returned to baseline levels within 30 min in young sedentary and endurance-trained subjects but remained depressed in middle-aged sedentary and endurance-trained subjects. Circulating markers of antioxidant capacity and inflammation were not related to FMD. In conclusion, advancing age is associated with a greater magnitude and delayed recovery from endothelial I/R injury in humans. Habitual endurance exercise may provide partial protection to the endothelium against this form of I/R injury with advancing age. 相似文献
68.
Niki M Takai S Kusuhara Y Ninomiya Y Yoshida R 《Cellular and molecular neurobiology》2011,31(7):1033-1040
In taste bud cells, glutamate may elicit two types of responses, as an umami tastant and as a neurotransmitter. Glutamate
applied to apical membrane of taste cells would elicit taste responses whereas glutamate applied to basolateral membrane may
act as a neurotransmitter. Using restricted stimulation to apical or basolateral membrane of taste cells, we examined responses
of taste cells to glutamate stimulation, separately. Apical application of monosodium glutamate (MSG, 0.3 M) increased firing
frequency in some of mouse fungiform taste cells that evoked action potentials. These cells were tested with other basic taste
compounds, NaCl (salty), saccharin (sweet), HCl (sour), and quinine (bitter). MSG-sensitive taste cells could be classified
into sweet-best (S-type), MSG-best (M-type), and NaCl or other electrolytes-best (N- or E/H-type) cells. Furthermore, S- and
M-type could be classified into two sub-types according to the synergistic effect between MSG and inosine-5′-monophosphate
(S1, M1 with synergism; S2, M2 without synergism). Basolateral application of glutamate (100 μM) had almost no effect on the
mean spontaneous firing rates in taste cells. However, about 10% of taste cells tested showed transient increases in spontaneous
firing rates (>mean + 2 standard deviation) after basolateral application of glutamate. These results suggest the existence
of multiple types of umami-sensitive taste cells and the existence of glutamate receptor(s) on the basolateral membrane of
a subset of taste cells. 相似文献
69.
Chieko Kurihara Hideo Kusuoka Shunsuke Ono Naoko Kakee Kazuyuki Saito Kenji Takehara Kiyokazu Tsujide Yuzo Nabeoka Takuya Sakuhiro Hiroshi Aoki Noriko Morishita Chieko Suzuki Shigeo Kachi Emiko Kondo Yukiko Komori Tetsu Isobe Shigeru Kageyama Hiroshi Watanabe 《PloS one》2014,9(1)
Introduction
International norms and ethical standards have suggested that compensation for research-related injury should be provided to injured research volunteers. However, statistical data of incidence of compensation claims and the rate of awarding them have been rarely reported.Method
Questionnaire surveys were sent to pharmaceutical companies and medical institutions, focusing on industry-initiated clinical trials aiming at new drug applications (NDAs) on patient volunteers in Japan.Results
With the answers from pharmaceutical companies, the incidence of compensation was 0.8%, including 0.06% of monetary compensation. Of the cases of compensation claims, 99% were awarded. In turn, with the answers from medical institutions, the incidence of compensation was 0.6%, including 0.4% of serious but not death cases, and 0.04% of death cases. Furthermore, most claims for compensation were initiated by medical institutions, rather than by the patients. On the other hand, with the answers from clinical trial volunteers, 3% of respondents received compensations. These compensated cases were 25% of the injuries which cannot be ruled out from the scope of compensation.Conclusion
Our study results demonstrated that Japanese pharmaceutical companies have provided a high rate of compensation for clinical trial-related injuries despite the possibility of overestimation. In the era of global clinical development, our study indicates the importance of further surveys to find each country''s compensation policy by determining how it is being implemented based on a survey of the actual status of compensation coming from statistical data. 相似文献70.
Joji Sasaki Makoto Murakami Yuzo Yamada 《Bioscience, biotechnology, and biochemistry》2013,77(10):3017-3022
A type II restriction endonuclease, designated as GceGLI, was purified from cells of Gluconobacter cerinus IFO 3285. The purified enzyme was found to be homogeneous on Polyacrylamide gel disc electrophoresis. The enzyme worked best at 37°C and pH 7.5 and required 7 mM MgCl2 and 100 mM NaCl. The purified enzyme was stable when preincubated over a pH range of 7.5 to 9.5 for 12 hr at 4°C and a temperature range of 37 to 40°C for 5 min at pH 7.5. The enzyme was shown to cleave λ φX174 RF, SV40, pBR322, M13 mp7 RF and Ad2 DNAs at 4, 1,0, 0, 0 and 25 or more sites, respectively, and to recognize the DNA sequence of 5′-C-C-G-C-G-G-3′ and to cut between C and G on the right side of the sequence, being an isoschizomer of SacII of Streptomyces achromogenes ATCC 12767. 相似文献