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1.
Yoshiko Ogata Yoshihiro Mori Hikari Koga Kazuya Awai Yukako Arakawa Norihiko Nakanishi Mikio Kataoka Fumikazu Kohi 《Nihon Kokyūki Gakkai zasshi》2004,42(9):837-841
A 22-year-old man was urgently admitted for pneumothorax. He continued complaining of exertional dyspnea and dry cough after the pneumothorax healed. About three months later, an atypical pulmonary mycobacteriosis by mycobacterium kansasii was identified. Exertional dyspnea increased after chemotherapy was administered, and the patient was readmitted because of difficulty in daily life activities. Chest radiographs and CT scans showed bilateral pulmonary hyperinflation and a narrowed heart shadow. There was also marked combined ventilatory impairment, as identified by a respiratory function test. Furthermore, the histological findings of surgically removed lung tissue revealed accumulation of lymphocytes in the wall of a small bronchus. Idiopathic bronchiolitis obliterans was diagnosed from the clinical course and clinical findings. The patient is now being monitored and is awaiting lung transplantation. 相似文献
2.
3.
Cháriston André Dal Belo Gildo Bernardo Leite Marcos Hikari Toyama Sergio Marangoni Alexandre Pinto Corrado Marcos Dias Fontana Andy Southan Edward G Rowan Stephen Hyslop Léa Rodrigues-Simioni 《Toxicon》2005,46(7):736-750
We have isolated a new phospholipase A2 (MiDCA1) from the venom of the coral snake Micrurus dumerilii carinicauda. This toxin, which had a molecular mass of 15,552Da, shared high sequence homology with the PLA2 toxins MICNI A and B from Micrurus nigrocinctus venom (77.7% and 73.1%, respectively). In chick biventer cervicis preparations, MiDCA1 produced concentration- and time-dependent neuromuscular blockade that reached 100% after 120 min (2.4 microM, n = 6); contractures to exogenously applied carbachol (8 microM) and KCl (13 mM) were still seen after complete blockade. In mouse phrenic-nerve diaphragm preparations, MiDCA1 (2.4 microM; n = 6) caused triphasic changes followed by partial neuromuscular blockade. Intracellular recordings of end-plate potentials (EPPs) and miniature end-plate potentials (MEPPs) from mouse diaphragm preparations showed that MiDCA1 increased the quantal content by 386+/-12% after 10 min (n = 14; p<0.05) and caused a triphasic change in the frequency of MEPPs. MiDCA1 also decreased the resting membrane potential, an effect that was prevented by tetrodotoxin and/or low extracellular calcium, but not by d-tubocurarine. The toxin increased the amplitude of mouse sciatic-nerve compound action potentials by 30+/-9% (0.6 microM; p<0.05). Potassium currents elicited in freshly dissociated dorsal root ganglia neurones were blocked by 31+/-1% (n = 4; p<0.05) in the presence of 2.4 microM MiDCA1. These results show that MiDCA1 is a new presynaptic phospholipase A2 that produces neuromuscular blockade in vertebrate nerve-muscle preparations. The triphasic effects seen in mammalian preparations and the facilitatory response were probably caused mainly by the activation of sodium channels, complemented by the blockade of nerve terminal potassium channels. The inability of d-turocurarine to prevent the depolarization by MiDCA1 indicated that cholinergic nicotinic receptors were not involved in this phenomenon. 相似文献
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5.
Kotani A Takahashi A Koga H Morita R Fukuyama H Ichinohe T Ishikawa T Hori T Uchiyama T 《European journal of haematology》2002,69(5-6):318-320
A patient who developed myasthenia gravis (MG) 25 months after allogeneic bone marrow transplant was immunologically analyzed. OX40+CD4+ T cells in the peripheral blood prominently increased one month before the onset of MG. CD4/CD8 ratios, usually abnormally inverted in patients with chronic graft-vs.-host disease (cGVHD), showed pseudonormalization during the course of MG. We succeeded in uneventful rapid tapering of prednisolone (PSL) using mycophenolate mofetil (MMF). Monitoring of OX40+CD4+ T cells supported the tapering of PSL and MMF as a marker of cGVHD activity. This case suggested the utility of MMF and monitoring of OX40+CD4+ T cells in the management of cGVHD-associated autoimmune diseases. 相似文献
6.
Nozomi Asaoka Masakazu Ibi Hikari Hatakama Koki Nagaoka Kazumi Iwata Misaki Matsumoto Masato Katsuyama Shuji Kaneko Chihiro Yabe-Nishimura 《The Journal of neuroscience》2021,41(12):2780
Repetitive behavior is a widely observed neuropsychiatric symptom. Abnormal dopaminergic signaling in the striatum is one of the factors associated with behavioral repetition; however, the molecular mechanisms underlying the induction of repetitive behavior remain unclear. Here, we demonstrated that the NOX1 isoform of the superoxide-producing enzyme NADPH oxidase regulated repetitive behavior in mice by facilitating excitatory synaptic inputs in the central striatum (CS). In male C57Bl/6J mice, repeated stimulation of D2 receptors induced abnormal behavioral repetition and perseverative behavior. Nox1 deficiency or acute pharmacological inhibition of NOX1 significantly shortened repeated D2 receptor stimulation-induced repetitive behavior without affecting motor responses to a single D2 receptor stimulation. Among brain regions, Nox1 showed enriched expression in the striatum, and repeated dopamine D2 receptor stimulation further increased Nox1 expression levels in the CS, but not in the dorsal striatum. Electrophysiological analyses revealed that repeated D2 receptor stimulation facilitated excitatory inputs in the CS indirect pathway medium spiny neurons (iMSNs), and this effect was suppressed by the genetic deletion or pharmacological inhibition of NOX1. Nox1 deficiency potentiated protein tyrosine phosphatase activity and attenuated the accumulation of activated Src kinase, which is required for the synaptic potentiation in CS iMSNs. Inhibition of NOX1 or β-arrestin in the CS was sufficient to ameliorate repetitive behavior. Striatal-specific Nox1 knockdown also ameliorated repetitive and perseverative behavior. Collectively, these results indicate that NOX1 acts as an enhancer of synaptic facilitation in CS iMSNs and plays a key role in the molecular link between abnormal dopamine signaling and behavioral repetition and perseveration.SIGNIFICANCE STATEMENT Behavioral repetition is a form of compulsivity, which is one of the core symptoms of psychiatric disorders, such as obsessive-compulsive disorder. Perseveration is also a hallmark of such disorders. Both clinical and animal studies suggest important roles of abnormal dopaminergic signaling and striatal hyperactivity in compulsivity; however, the precise molecular link between them remains unclear. Here, we demonstrated the contribution of NOX1 to behavioral repetition induced by repeated stimulation of D2 receptors. Repeated stimulation of D2 receptors upregulated Nox1 mRNA in a striatal subregion-specific manner. The upregulated NOX1 promoted striatal synaptic facilitation in iMSNs by enhancing phosphorylation signaling. These results provide a novel mechanism for D2 receptor-mediated excitatory synaptic facilitation and indicate the therapeutic potential of NOX1 inhibition in compulsivity. 相似文献
7.
Hikari Okita Yuna Kato Tatsuki Masuzawa Kosuke Arai Sayuri Takeo Kohei Sato Nobuyuki Mase Takanori Oyoshi Tetsuo Narumi 《RSC advances》2020,10(49):29373
Stereoselective and efficient synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres is realized by organocuprate-mediated single electron transfer reduction. The synthetic isosteres can be used in Fmoc-based solid phase peptide synthesis, resulting in the preparation of the 14-mer RGG peptidomimetics containing an (E)-methylalkene or a (Z)-chloroalkene unit.An efficient synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres is realized by organocuprate-mediated single electron transfer reduction.Glycylglycine (Gly-Gly) is the smallest dipeptide and has been synthesized by many approaches in the last 100 years.1 Due to its versatile nature and ready availability, glycylglycine has been used as a chemical probe2 and buffer3 in biochemical studies and also as a reagent which can enhance the solubility of overexpressed proteins.4 In addition to the utility of Gly-Gly itself, oligoglycine (oligo-Gly) motifs are notable for being more flexible and less-functionalized than any combination of other amino acids. These features are useful in bioconjugation strategies which link multiple biomolecules without interfering with the function of each biomolecule, allowing synthesis of bioconjugated artificial molecules including dimeric, multi-domain, and fusion proteins.5 The flexibility of oligo-Gly enables the formation of unusual secondary structures of peptides and proteins.6 Thus, the oligo-Gly motif can be found in the biologically important peptides and proteins such as Met/Leu-enkephalin ( and ), the C-terminus of ubiquitin , ctenidin,7 shepherin I,8 and DNA/RNA-binding proteins with repeated sequences related to the various physiological processes via protein–protein and protein–nucleic acids interactions.9 These proteins relate with gene expression, DNA damage signal and apoptosis, however, the detail effects of Gly-Gly with steric and electronic factors to these functions are unknown. Given the importance of oligo-Gly in various fields, non-hydrolyzable peptidomimetics of oligo-Gly could be attractive building blocks for the synthesis of novel bioconjugated molecules and complex peptidomimetics with improved chemical stability and functionality. For example, even the Gly-Gly dipeptide mimic with the tetra-substituted alkene unit replacing the Gly-Gly peptide bond has been shown to promote the β-hairpin formation, and is thus the smallest peptidomimetic that is known to control a peptide structure.10 There are two reports of the synthesis of Gly-Gly-type fluoroalkene dipeptide isosteres.11 However, the poor synthetic access to such molecules has hindered their application to the peptidomimetics. Our long-standing interest in the drug discovery with amide-to-alkene isosteric switching prompted this investigation into the stereoselective synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres.In this report, we describe the beginning of our oligo-Gly-based peptidomimetic study with the stereoselective synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres and their use in Fmoc-based solid phase peptide synthesis (SPPS). In the first application of isosteres of this type to access complex peptidomimetics, we synthesize 14-mer RGG peptidomimetics containing (E)-methylalkene or (Z)-chloroalkene unit as surrogates for a Gly-Gly peptide bond. These two isosteres were selected because the potentials of both isosteres have not been fully uncovered, though there are several promising examples.12,13 Since the carbonyl oxygen equivalents of those isosteres are similar in their size14 but differ in their electronic properties,15 comparative studies of these isosteres would have the advantage of exploring the role of peptide bonds in terms of their steric and electronic natures. This work also uncovered the unique ability of the Gly-Gly-type (Z)-chloroalkene isostere to induce β-turn structures in the almost unfoled peptides (Fig. 1).Open in a separate windowFig. 1Gly-Gly peptide and its alkene-type peptidomimetics.The main challenges in this study include the stereoselective formation of the (E)-methylalkene and (Z)-chloroalkene moieties as the surrogates of the Gly-Gly trans-peptide bond, together with the control of the olefine isomerization under the condition of the isostere synthesis and Fmoc-based SPPS. There are several synthetic approaches toward tri-substituted alkene-type isosteres, including the Overman rearrangement,13 the SN2′-type opening of alkenylaziridines,12a Cu-mediated CF3-coupling of vinyl iodide,16 and cross-couplings of vinyl stannane.17 Organocuprate-mediated reactions of α,β-unsaturated carbonyl compounds with γ-leaving group(s) are also powerful methods to produce tri-substituted alkene-type isosteres, and are particularly suitable for the stereoselective synthesis of (Z)-fluoroalkene18 and (Z)-chloroalkene isosteres.19The preparation of Gly-Gly-type alkene dipeptide isosteres was facilitated by the organocuprate-mediated SET reduction that was used in the stereoselective formation of the (E)-methylalkene and (Z)-chloroalkene moieties. Scheme 1 shows the synthesis of (E)-methylalkene isosteres (5). A Witting reaction of methacrolein (1) with ethyl (triphenylphosphoranylidene)acetate followed by epoxidation with m-CPBA afforded the alkenyl oxirane (2) which, treated with Gillman reagent (n-Bu2CuLi), produced the allylic alcohol (3) with high E-selectivity. A Mitsunobu reaction of 3 with Ns(Boc)NH and deprotection provided the Gly-Gly-type (E)-methylalkene dipeptide isostere 5 that can be applied to the Fmoc-based SPPS. All reactions leading to the synthesis of 5 were performed on a gram scale.Open in a separate windowScheme 1Synthesis of Gly-Gly-type (E)-methylalkene dipeptide isosteres (5).Synthesis of chloroalkene isostere (14) is shown in Scheme 2. Based on previous results for the successful, efficient synthesis of Val-Xaa-type chloroalkene isosteres,19c we assumed that a similar protocol would allow for the synthesis of 14. However, our attempts revealed that the Gly substrate used has different reactivity and selectivity compared to the other substrates, particularly in the SET reduction step. Consequently, Gly-specific reaction conditions are necessary. The nucleophilic addition of the lithium enolate of methyl dichloroacetate to the N-sulfinylaldimine (7), prepared from (±)-tert-butylsulfinamide (6) and paraformaldehyde and m-CPBA oxidation of 6 gave the N-tert-butylsulfonyl (Bus)-protected α,α-dichloro-β-amino ester (8). Precise control of the amount of DIBAL-H at low temperatures enables the partial reduction of 8, and this is followed by a Horner–Wadsworth–Emmons reaction to produce the corresponding (E)-enoate (9). Initial efforts to apply our established conditions for SET reduction with Me2CuLi identified the poor Z-selectivity of the reaction and also its propensity to form the α-methylated side products 11 and 12 (Open in a separate windowScheme 2Synthesis of Gly-Gly-type (Z)-chloroalkene dipeptide isosteres (14).Reactivity of (E)-enoate (9) with organocupratesa
Open in a separate windowaAll reactions were carried out at −78 °C for 30 min on a 0.25 mmol scale with 4 equiv. of organocuprates in the presence of metal salts.bYield is determined by 1H NMR analysis of the crude mixture utilizing mesitylene as an internal standard.cR = Me.dR = n-Bu.eR = sec-Bu.fR = tert-Bu.With these isosteres in hand, we explored their use in Fmoc-based SPPS for the preparation of peptidomimetics of the 14-mer RGG peptide derived from translocation in lipo-sarcoma/fused in sarcoma (TLS/FUS) related to the RNA processing (Schemes 3 and and44).20 Starting from the Rink Amide ChemMatrix resin, standard Fmoc-based SPPS with DIC/Oxyma for peptide couplings and 20% (v/v) piperidine/DMF for Fmoc removals were performed for the construction of the peptide resin (15). The synthesized isosteres were incorporated into the peptide-chain by HATU/DIPEA in DMF affording the peptide resins 16 and 18. For the synthesis of (E)-methylalkene-type peptidomimetic, deprotection of Ns group with thiophenol/K2CO3 in DMF and chain elongation followed by global deprotection with TFA/m-cresol/thioanisole/H2O (87.5/5/5/2.5, v/v/v/v) provided the desired (E)-methylalkene-type peptidomimetic (17). Synthesis of the (Z)-chloroalkene-type peptidomimetic (19) was achieved using standard conditions. NMR analysis of the purified peptidomimetics revealed that although (Z)-chloroalkene-type peptidomimetic (19) can be purified solely, a trace amount of olefin isomerized compounds of 17, possibly generated under the coupling, is observed as a side product and was difficult to remove from the desired product.21 Since we used a single coupling protocol with HATU for this study, optimization for the coupling without olefin isomerization is likely to be possible.Open in a separate windowScheme 3Synthesis of Gly-Gly-type (E)-methylalkene-type peptidomimetic (17).Open in a separate windowScheme 4Synthesis of (Z)-chloroalkene-type peptidomimetic (19).It has been demonstrated that d-Ala-l-Ala-type (E)-methylalkene isostere sequence shows a higher preference for a type-II′ β-turn than the corresponding (E)-alkene isostere.12a To determine whether amide-to-alkene isosteric switching in Gly-Gly peptide bonds affects the ability of a peptide to form a β-turn structure, CD spectra were obtained for peptidomimetics (17 and 19) in 50 mM Tris–HCl (pH 7.5) with 100 mM KCl (Fig. 2). The native peptide (20) was included as the control. The CD spectra analysis of turn structures has been discussed in the literature, albeit with lower accuracies.22 Although (E)-methylalkene-type peptidomimetic (17) appears to be random coil, the spectra of 19 exhibited a minimal absorbance peak at 202 nm, which is a typical characteristic of a β-turn conformation.20 On the other hand, the peptide 20 appears to form a β-turn conformation slightly. These results indicated that isosteric switching of Gly-Gly peptide bond with a (Z)-chloroalkene unit can induce a β-turn conformation in the secondary structure of peptides and also that the β-turn inducing ability of (Z)-chloroalkene isosteres is superior to that of (E)-methylalkene isosteres. To the best of our knowledge, this is the first example of such drastic structural control effects of (Z)-chloroalkene isosteres on peptides. We speculated that the electronic effects of the chlorine substituent are responsible for the superior β-turn inducing ability. Efforts to determine their biological activity, including DNA/RNA-binding affinity, are currently in progress.Open in a separate windowFig. 2CD spectra of peptidomimetics (17 and 19) and the corresponding native peptide (20). 相似文献
Entry | Conditions | Yieldb (%) | |||
---|---|---|---|---|---|
10-Z | 10-E | 11 | 12 | ||
1 | Me2CuLi | 48 | 19 | 15c | 1c |
2 | n-Bu2CuLi | 55 | 0 | 25d | 20d |
3 | n-Bu2CuLi, HMPA | 0 | 0 | 46d | 13d |
4 | n-Bu2CuLi, NMP | 44 | 0 | 29d | 6d |
5 | n-Bu2CuLi, DMSO | 46 | 7 | 19d | 2d |
6 | sec-Bu2CuLi | 67 | 6 | 27e | 0 |
7 | tert-Bu2CuLi | 74 | 4 | 2f | 0 |
8 | tert-Bu2CuMgCl | 63 | 0 | 0 | 0 |
8.
Kinoshita H Matsuda N Kaba H Hatakeyama N Azma T Nakahata K Kuroda Y Tange K Iranami H Hatano Y 《Hypertension》2008,52(3):507-513
The present study was designed to examine roles of the phosphatidylinositol 3-kinase-Akt pathway and reduced nicotinamide-adenine dinucleotide phosphate oxidases in the reduced ATP-sensitive K(+) channel function via superoxide produced by high glucose in the human artery. We evaluated the activity of the phosphatidylinositol 3-kinase-Akt pathway, as well as reduced nicotinamide-adenine dinucleotide phosphate oxidases, the intracellular levels of superoxide and ATP-sensitive K(+) channel function in the human omental artery without endothelium. Levels of the p85-alpha subunit and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits, including p47phox, p22phox, and Rac-1, increased in the membrane fraction from arteries treated with D-glucose (20 mmol/L) accompanied by increased intracellular superoxide production. High glucose simultaneously augmented Akt phosphorylation at Ser 473, as well as Thr 308 in the human vascular smooth muscle cells. A phosphatidylinositol 3-kinase inhibitor LY294002, as well as tiron and apocynin, restored vasorelaxation and hyperpolarization in response to an ATP-sensitive K(+) channel opener levcromakalim. Therefore, it can be concluded that the activation of the phosphatidylinositol 3-kinase-Akt pathway, in combination with the translocation of p47phox, p22phox, and Rac-1, contributes to the superoxide production induced by high glucose, resulting in the impairment of ATP-sensitive K(+) channel function in the human visceral artery. 相似文献
9.
Yuko Kozasa Hikari Takaseya Yukari Koga Teruyuki Hiraki Yasunori Mishima Shuhei Niiyama Kazuo Ushijima 《Journal of anesthesia》2013,27(5):764-767
Cerebral venous sinus thrombosis (CVST) is rare but displays various and often dramatic clinical symptoms. Few cases of CVST have been reported in the field of anesthesiology. We encountered an unexpected case of CVST that presented with delayed emergence from anesthesia after resection of a brain tumor. A 55-year-old man was scheduled for resection of an oligoastrocytoma in his right frontal lobe. After smooth induction of general anesthesia, anesthesia was maintained uneventfully for about 7 h with target-controlled infusion (TCI) of propofol and remifentanil, except for a seizure generated when the right anterior central gyrus was stimulated to allow motor evoked potential monitoring. Immediately after the cessation of TCI, spontaneous respiration was restored. However, the patient was unexpectedly comatose, and no response to painful stimuli or coughing during tracheal suctioning was observed. A computed tomogram taken 2 h after surgery showed diffuse brain edema, even though the neurosurgeons did not notice any cerebral swelling during closing of the dura mater. A magnetic resonance venogram revealed thromboses in the superior sagittal and straight sinuses. On the 9th postoperative day, the patient died without recovering consciousness or his brainstem reflexes. Anesthesiologists should be aware of CVST as a cause of delayed emergence from anesthesia after craniotomy. 相似文献
10.
Keijiro Nakamura Takahito Takagi Norihiro Kogame Hikari Hashimoto Masako Asami Yasutake Toyoda Yoshinari Enomoto Hidehiko Hara Mahito Noro Kaoru Sugi Masao Moroi Masato Nakamura 《Journal of atherosclerosis and thrombosis》2021,28(6):590
Aim: Arterial stiffness results in elevated left ventricular filling pressure and can promote atrial remodeling due to chronic pressure overload. However, the impact of arterial stiffness on the process of atrial remodeling in association with atrial fibrillation (AF) has not been fully evaluated. Methods: We enrolled 237 consecutive patients diagnosed with AF who had undergone ablation; data from 213 patients were analyzed. Cardio-ankle vascular index (CAVI) was used as a marker of arterial stiffness. The left atrial (LA) and right atrial (RA) volumes were determined by computed tomography imaging; atrial conduction and voltage amplitude were evaluated using a three-dimensional electromapping system used to guide the ablation procedure. Result: In univariate analysis, CAVI significantly correlated with atrial structural and electrical remodeling (LA volume index, r =0.297, P =0.001; RA volume index, r =0.252, P =0.004; LA conduction velocity, r =0.254, P = 0.003; LA mean voltage, r =−0.343, P =0.001, RA mean voltage; r =−0.245, P =0.015). Multivariate regression analysis revealed that CAVI and plasma levels of N-terminal B-type natriuretic peptide were independent determinants of LA and RA remodeling, respectively. On the other hand, age and LA conduction velocity were independent variables with respect to CAVI. Age-adjusted CAVI was highest in long-standing persistent AF when compared with measures of persistent or paroxysmal AF. Conclusion: CAVI was closely associated with biatrial remodeling in patients diagnosed with AF. These results suggest that arterial stiffness may play a significant role with respect to disease progression. 相似文献