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51.
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 |
52.
53.
54.
Takeshi Aoki Masahiko Murakami Tomotake Koizumi Yuta Enami Reiko Koike Akira Fujimori Tomokazu Kusano Kazuhiro Matsuda Kosuke Yamada Koji Nogaki Makoto Watanabe Koji Otsuka Haytham Gareer Takashi Kato 《International surgery》2015,100(6):1048-1053
This study describes a novel technique for skeletonization and isolation of Glissonean and venous branches during liver surgery using a harmonic scalpel (HS). Hepatic resections with HS were performed with the skeletonization and isolation technique in 50 patients (HS group). Variables evaluated were blood loss, operative time, biliary leak, and morbidity. The results were compared with 50 hepatic resections that were performed using a previously established technique: Cavitron ultrasonic surgical aspirator with electric cautery, ligatures, and hemoclips (NHS group). The HS group had shorter total operative times (285 versus 358 minutes; P = 0.01), less blood loss (389 versus 871 mL; P = 0.034), and less crystalloid infusion (2744 versus 3299 mL; P = 0.027) compared with the NHS group. Postoperative liver function and complication rates were similar when comparing the two groups. These data demonstrate that HS is a simple, easy, and effective instrument for the skeletonization and isolation of vessels during liver transection.Key words: Liver resection, Ultrasonic scalpel, Skeletonization, Cavitation effectVarious devices are available for liver transection, but the availability of comparative data for transection techniques is limited by the diversity of operative procedures. Clamp crushing (CC) and a Cavitron ultrasonic surgical aspirator are widely used for splitting the liver parenchyma,1,2 and hemostasis is achieved by bipolar coagulation, ligatures, or hemoclips. Various coagulating devices, such as Ligasure,3 Tissuelink,4 and the Harmonic Scalpel (HS),5–7 have recently been developed to aid in liver splitting. The choice of instrument is often based on individual surgeon preference. Higami et al8,9 described a novel technique to skeletonize and harvest the internal thoracic artery with the HS, and the present study capitalizes on their experience to describe a unique method to skeletonize and isolate the Glissonean and venous branches using an HS. 相似文献
55.
56.
57.
58.
Kosuke Okuwaki Hironori Masutani Hiroshi Imaizumi Tsutomu Yoshida Mitsuhiro Kida Tomohisa Iwai Hiroshi Yamauchi Masayoshi Tadehara Kai Adachi Masafumi Watanabe Takahiro Kurosu Wasaburo Koizumi 《Pancreatology》2019,19(3):419-423
Background/Objectives
A breakthrough in chemotherapy for pancreatic ductal adenocarcinoma (PDAC) may be achieved using precision medicine, which involves identifying cases that are highly likely to respond to a certain treatment and then performing that treatment. BRCAness has been receiving attention as a novel predictor of anticancer drug sensitivity in PDAC, making the screening of BRCAness paramount.Methods
We conducted the first-ever examination of the feasibility of analyzing BRCAness using multiplex ligation-dependent probe amplification (MLPA). Formalin-fixed paraffin-embedded (FFPE) tissue samples obtained via endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) from 20 patients with the highest pancreatic carcinoma cell counts in tissue samples out of 40 consecutive PDAC patients who underwent EUS-FNAB at our hospital were analyzed by MLPA for BRCAness.Results
We were able to accurately analyze BRCAness in 75% of the 20 cases of PDAC using FFPE tissue obtained by EUS-FNAB. BRCAness was observed in one of the 20 cases.Conclusions
In PDAC, analyzing BRCAness by MLPA using FFPE tissue obtained by EUS-FNAB offers the remarkable benefit of yielding results in a short period of time and at a low cost. In addition, this method of BRCAness analysis may prove to be a feasible and effective approach for performing precision medicine. 相似文献59.
Mitani Genya Takagaki Tomonori Hamahashi Kosuke Serigano Kenji Nakamura Yutaka Sato Masato Mochida Joji 《Journal of orthopaedic surgery and research》2015,10(1):1-6
Growth factors such as nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1) have been shown to play a role in the healing process of nerve injury. Recent researches have also shown that oxytocin administration activates these growth factors of importance for the healing of nerve tissue. The objective of the present study was to evaluate the effects of oxytocin on peripheral nerve regeneration in rats. Twenty-four male Sprague-Dawley rats were underwent transection damage model on the right sciatic nerve and defective damage model on the left sciatic nerve. The animals were assigned to one of two groups: control group or treatment group (received 80 mg/kg oxytocin intraperitoneally for 12 weeks). The sciatic nerve was examined, both functionally (on the basis of climbing platform test) and histologically (on the basis of axon count), 3, 6, 9, and 12 weeks after the injury. Also, stereomicroscopic and electrophysiological evaluations were carried out. Significantly greater improvements in electrophysiological recordings and improved functional outcome measures were presented in the treatment group at 12-week follow-up. Stereomicroscopic examinations disclosed prominent increases in vascularization on proximal cut edges in the oxytocin group in comparison with the control group. Higher axon counts were also found in this group. Intraperitoneal oxytocin administration resulted in accelerated functional, histological, and electrophysiological recovery after different sciatic injury models in rats. 相似文献
60.
Dr. Yoshio Miura MD Yoshitaka Kato MD Rokuro Seiko MD Mari Nomura MD Kosuke Yamane MD Koichi Fujikawa MD Toshiyuki Iwamoto MD Kiyohiko Dohi MD 《Digestive diseases and sciences》1992,37(10):1619-1623
Summary A case of pancreatic arteriovenous malformation (AVM) with hepatocellular carcinoma is reported. The patient, a 56-year-old Japanese man, was asymptomatic. The pancreatic lesion was found incidentally during an evaluation for hepatocellular carcinoma. Celiac arteriogram demonstrated tortuous feeding arteries, a racemose intrapancreatic stain, which disappeared before the venous phase, and early portal filling. 相似文献