全文获取类型
收费全文 | 1007篇 |
免费 | 75篇 |
国内免费 | 18篇 |
专业分类
1100篇 |
出版年
2023年 | 20篇 |
2022年 | 37篇 |
2021年 | 33篇 |
2020年 | 26篇 |
2019年 | 38篇 |
2018年 | 49篇 |
2017年 | 32篇 |
2016年 | 27篇 |
2015年 | 36篇 |
2014年 | 51篇 |
2013年 | 91篇 |
2012年 | 40篇 |
2011年 | 37篇 |
2010年 | 36篇 |
2009年 | 39篇 |
2008年 | 38篇 |
2007年 | 56篇 |
2006年 | 45篇 |
2005年 | 42篇 |
2004年 | 25篇 |
2003年 | 27篇 |
2002年 | 31篇 |
2001年 | 14篇 |
2000年 | 15篇 |
1999年 | 12篇 |
1998年 | 12篇 |
1997年 | 18篇 |
1996年 | 7篇 |
1995年 | 12篇 |
1994年 | 10篇 |
1993年 | 11篇 |
1992年 | 5篇 |
1991年 | 11篇 |
1990年 | 10篇 |
1989年 | 6篇 |
1988年 | 15篇 |
1987年 | 9篇 |
1986年 | 4篇 |
1985年 | 5篇 |
1984年 | 11篇 |
1983年 | 6篇 |
1982年 | 8篇 |
1981年 | 9篇 |
1980年 | 11篇 |
1979年 | 4篇 |
1978年 | 5篇 |
1975年 | 3篇 |
1973年 | 2篇 |
1972年 | 2篇 |
1971年 | 2篇 |
排序方式: 共有1100条查询结果,搜索用时 15 毫秒
91.
Anabel Brandoni Adriana M��nica Torres 《The journal of histochemistry and cytochemistry》2009,57(5):449-456
The kidneys and liver are the major routes for organic anion elimination. We have recently shown that acute obstructive jaundice is associated with increased systemic and renal elimination of two organic anions, p-aminohippurate and furosemide, principally excreted through urine. This study examined probable adaptive mechanisms involved in renal elimination of bromosulfophthalein (BSP), a prototypical organic anion principally excreted in bile, in rats with acute obstructive jaundice. Male Wistar rats underwent bile duct ligation (BDL rats). Pair-fed sham-operated rats served as controls. BSP renal clearance was performed by conventional techniques. Renal organic anion-transporting polypeptide 1 (Oatp1) expression was evaluated by immunoblotting and IHC. Excreted, filtered, and secreted loads of BSP were all higher in BDL rats compared with Sham rats. The higher BSP filtered load resulted from the increase in plasma BSP concentration in BDL rats, because glomerular filtration rate showed no difference with the Sham group. The increase in the secreted load might be explained by the higher expression of Oatp1 observed in apical membranes from kidneys of BDL animals. This likely adaptation to hepatic injury, specifically in biliary components elimination, might explain, at least in part, the huge increase in BSP renal excretion observed in this experimental model. (J Histochem Cytochem 57:449–456, 2009) 相似文献
92.
Michelle T. Burstein Pavlo Kyryakov Adam Beach Vincent R. Richard Olivia Koupaki Alejandra Gomez-Perez Anna Leonov Sean Levy Forough Noohi Vladimir I. Titorenko 《Cell cycle (Georgetown, Tex.)》2012,11(18):3443-3462
Our studies revealed that LCA (lithocholic bile acid) extends yeast chronological lifespan if added to growth medium at the time of cell inoculation. We also demonstrated that longevity in chronologically aging yeast is programmed by the level of metabolic capacity and organelle organization that they developed before entering a quiescent state and, thus, that chronological aging in yeast is likely to be the final step of a developmental program progressing through at least one checkpoint prior to entry into quiescence. Here, we investigate how LCA influences longevity and several longevity-defining cellular processes in chronologically aging yeast if added to growth medium at different periods of the lifespan. We found that LCA can extend longevity of yeast under CR (caloric restriction) conditions only if added at either of two lifespan periods. One of them includes logarithmic and diauxic growth phases, whereas the other period exists in early stationary phase. Our findings suggest a mechanism linking the ability of LCA to increase the lifespan of CR yeast only if added at either of the two periods to its differential effects on various longevity-defining processes. In this mechanism, LCA controls these processes at three checkpoints that exist in logarithmic/diauxic, post-diauxic and early stationary phases. We therefore hypothesize that a biomolecular longevity network progresses through a series of checkpoints, at each of which (1) genetic, dietary and pharmacological anti-aging interventions modulate a distinct set of longevity-defining processes comprising the network; and (2) checkpoint-specific master regulators monitor and govern the functional states of these processes. 相似文献
93.
目的:探讨改善妊娠期肝内胆汁淤积症患者围生结局及围生儿预后的方法。方法:对2006年3月-2011年3月在我院住院分娩的256例ICP患者及从我院住院无并发症正常分娩的10112个患者中随机抽取的256例患者的产检情况、分娩方式、围生儿结局进行回顾性分析。结果:ICP组与对照组在分娩方式、产后出血、早产、新生儿窒息、羊水粪染、围产儿死亡等方面比较差异均具有统计学意义(P<0.05);产检组与未检组在产后出血、早产、新生儿窒息、羊水粪染、围产儿死亡等方面比较差异有统计学意义(P<0.05)。结论:妊娠期肝内胆汁淤积症可增加早产、胎儿宫内窘迫、新生儿窒息、产后出血发生率,重视产前检查和孕期保健,对ICP患者做到早发现、早诊断、早治疗,选择适当分娩方式、适时终止妊娠,对改善围生结局及围生儿预后有积极的意义。 相似文献
94.
《Journal of molecular biology》2021,433(4):166764
Apical sodium-dependent bile acid transporter (ASBT) catalyses uphill transport of bile acids using the electrochemical gradient of Na+ as the driving force. The crystal structures of two bacterial homologues ASBTNM and ASBTYf have previously been determined, with the former showing an inward-facing conformation, and the latter adopting an outward-facing conformation accomplished by the substitution of the critical Na+-binding residue glutamate-254 with an alanine residue. While the two crystal structures suggested an elevator-like movement to afford alternating access to the substrate binding site, the mechanistic role of Na+ and substrate in the conformational isomerization remains unclear. In this study, we utilized site-directed alkylation monitored by in-gel fluorescence (SDAF) to probe the solvent accessibility of the residues lining the substrate permeation pathway of ASBTNM under different Na+ and substrate conditions, and interpreted the conformational states inferred from the crystal structures. Unexpectedly, the crosslinking experiments demonstrated that ASBTNM is a monomer protein, unlike the other elevator-type transporters, usually forming a homodimer or a homotrimer. The conformational dynamics observed by the biochemical experiments were further validated using DEER measuring the distance between the spin-labelled pairs. Our results revealed that Na+ ions shift the conformational equilibrium of ASBTNM toward the inward-facing state thereby facilitating cytoplasmic uptake of substrate. The current findings provide a novel perspective on the conformational equilibrium of secondary active transporters. 相似文献
95.
Aims
To clone, characterize and compare the bile salt hydrolase (BSH) genes of Lactobacillus johnsonii PF01.Methods and Results
The BSH genes were amplified by polymerase chain reaction (PCR) using specific oligonucleotide primers, and the products were inserted into the pET21b expression vector. Escherichia coli BLR (DE3) cells were transformed with pET21b vectors containing the BSH genes and induced using 0·1 mmol l?1 isopropylthiolgalactopyranoside. The overexpressed BSH enzymes were purified using a nickel–nitrilotriacetic acid (Ni2+‐NTA) agarose column and their activities characterized. BSH A hydrolysed tauro‐conjugated bile salts optimally at pH 5·0 and 55°C, whereas BSH C hydrolysed glyco‐conjugated bile salts optimally at pH 5·0 and 70°C. The enzymes had no preferential activities towards a specific cholyl moiety.Conclusions
BSH enzymes vary in their substrate specificities and characteristics to broaden its activity. Despite the lack of conservation in their putative substrate‐binding sites, these remain functional through motif conservation.Significance and Impact of the Study
This is to our knowledge the first report of isolation of BSH enzymes from a single strain, showing hydrolase activity towards either glyco‐conjugated or tauro‐conjugated bile salts. Future structural homology studies and site‐directed mutagenesis of sites associated with substrate specificity may elucidate specificities of BSH enzymes. 相似文献96.
PurposeTo determine the eye lens dose of the Interventional Cardiology (IC) personnel using optically stimulated luminescent dosimeter (OSLD) and the prevalence and risk of radiation – associated lens opacities in Thailand.Methods and results48 IC staff, with age- and sex- matches 37 unexposed controls obtained eye examines. Posterior lens change was graded using a modified Merriam-Focht technique by two independent ophthalmologists. Occupational exposure (mSv) was measured in 42 IC staff, using 2 OSLD badges place at inside lead apron and at collar. Annual eye lens doses (mSv) were also measured using 4 nanoDots OSL placed outside and inside lead glass eyewear. The prevalence of radiation-associated posterior lens opacities was 28.6% (2/7) for IC, 19.5% (8/41) for nurses, and 2.7% (1/37) for controls. The average and range of annual whole body effective dose, Hp(10), equivalent dose at skin of the neck, Hp(0.07) and equivalent dose at eye lens, Hp(3) were 0.80 (0.05–6.79), 5.88 (0.14–35.28), and 5.73 (0.14–33.20) mSv respectively. The annual average and range of eye lens dose using nano Dots OSL showed the outside lead glass eyewear on left and right sides as 8.06 (0.17–32.45), 3.55(0.06–8.04) mSv and inside left and right sides as 3.91(0.05–14.26) and 2.44(0.06–6.24) mSv respectively.ConclusionEye lens doses measured by OSLD badges and nano Dot dosimeter as Hp(10), Hp(0.07) and Hp(3). The eyes of the IC personnel were examined annually by two ophthalmologists for the prevalence of cataract induced by radiation. 相似文献
97.
Auditory function and cochlear morphology have previously been described in the postnatal German waltzing guinea pig, a strain with recessive deafness. In the present study, cochlear histopathology was further investigated in the inner ear of the developing German waltzing guinea pig (gw/gw). The lumen of the cochlear duct diminished progressively from embryonic day (E) 35 to E45 and was absent at E50 because of the complete collapse of Reissner's membrane onto the hearing organ. The embryonic stria vascularis, consisting of a simple epithelium, failed to transform into the complex trilaminar tissue seen in normal animals and displayed signs of degeneration. Subsequent degeneration of the sensory epithelium was observed from E50 and onwards. Defective and insufficient numbers of melanocytes were observed in the developing gw/gw stria vascularis. A gene involved in cochlear melanocyte development, Pax3, was markedly reduced in lateral wall tissue of the cochlea of both E40 and adult gw/gw individuals, whereas its expression was normal in the skin and diaphragm muscle of adult gw/gw animals. The Pax3 gene may thus be involved in the pathological process but is unlikely to be the primary mutated gene in the German waltzing guinea pig. TUNEL assay showed no signs of apoptotic cell death in the developing stria vascularis of this type of guinea pig. Thus, malformation of the stria vascularis appears to be the primary defect in the inner ear of the German waltzing guinea pig. Defective and insufficient numbers of melanocytes might migrate to the developing stria vascularis but fail to provide the proper support for the subsequent development of marginal and basal cells, thereby leading to stria vascularis malformation and dysfunction in the inner ear of the German waltzing guinea pig. 相似文献
98.
Ohmori Takaaki Iwakawa Kazuhide Matsumoto Yasushi Arita Norimasa Okada Kazuyo 《Mycopathologia》1997,139(3):123-128
We report a fatal case of fungal (candidal) endocarditis of the tricuspid valve with clinico-pathologically interesting findings
following and associated with candidal pneumonia during long-term central venous catheterization (CVC) for intravenous therapy
and long-term treatment with antibiotics for bacterial and fungal infection in a patient with a history of alcohol abuse.
We review the literature on fungal cardiac infection related to long-term catheterization and alcohol abuse, and discuss the
pathogenesis.
This revised version was published online in June 2006 with corrections to the Cover Date. 相似文献
99.
100.
Ricchiuto P Rocco AG Gianazza E Corrada D Beringhelli T Eberini I 《Journal of molecular recognition : JMR》2008,21(5):348-354
Chicken liver bile acid binding protein (cL-BABP) crystallizes with water molecules in its binding site. To obtain insights on the role of internal water, we performed two 100 ns molecular dynamics (MD) simulations in explicit solvent for cL-BABP, as apo form and as a complex with two molecules of cholic acid, and analyzed in detail the dynamics properties of all water molecules. The diffusion coefficients of the more persistent internal water molecules are significantly different from the bulk, but similar between the two protein forms. A different number of molecules and a different organization are observed for apo- and holo-cL-BABP. Most water molecules identified in the binding site of the apo-crystal diffuse to the bulk during the simulation. In contrast, almost all the internal waters of the holo-crystal maintain the same interactions with internal sidechains and ligands, which suggests they have a relevant role in protein-ligand molecular recognition. Only in the presence of these water molecules we were able to reproduce, by a classical molecular docking approach, the structure of the complex cL-BABP::cholic acid with a low ligand root mean square deviation (RMSD) with respect to its reference positioning. Literature data reported a conserved pattern of hydrogen bonds between a single water molecule and three amino acid residues of the binding site in a series of crystallized FABP. In cL-BABP, the interactions between this conserved water molecule and the three residues are present in the crystal of both apo- and holo-cL-BABP but are lost immediately after the start of molecular dynamics. Copyright (c) 2008 John Wiley & Sons, Ltd. 相似文献