全文获取类型
收费全文 | 429篇 |
免费 | 35篇 |
出版年
2022年 | 7篇 |
2021年 | 13篇 |
2020年 | 4篇 |
2019年 | 6篇 |
2018年 | 9篇 |
2017年 | 3篇 |
2016年 | 16篇 |
2015年 | 5篇 |
2014年 | 15篇 |
2013年 | 28篇 |
2012年 | 36篇 |
2011年 | 31篇 |
2010年 | 10篇 |
2009年 | 12篇 |
2008年 | 24篇 |
2007年 | 16篇 |
2006年 | 21篇 |
2005年 | 21篇 |
2004年 | 21篇 |
2003年 | 14篇 |
2002年 | 6篇 |
2001年 | 13篇 |
2000年 | 4篇 |
1999年 | 5篇 |
1998年 | 4篇 |
1997年 | 8篇 |
1996年 | 5篇 |
1995年 | 10篇 |
1994年 | 5篇 |
1993年 | 6篇 |
1992年 | 8篇 |
1991年 | 2篇 |
1990年 | 4篇 |
1989年 | 3篇 |
1988年 | 5篇 |
1987年 | 7篇 |
1984年 | 7篇 |
1983年 | 2篇 |
1981年 | 4篇 |
1980年 | 3篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1975年 | 4篇 |
1974年 | 7篇 |
1973年 | 3篇 |
1972年 | 3篇 |
1971年 | 3篇 |
1970年 | 3篇 |
1968年 | 2篇 |
1967年 | 5篇 |
排序方式: 共有464条查询结果,搜索用时 31 毫秒
71.
Tully DC Liu H Alper PB Chatterjee AK Epple R Roberts MJ Williams JA Nguyen KT Woodmansee DH Tumanut C Li J Spraggon G Chang J Tuntland T Harris JL Karanewsky DS 《Bioorganic & medicinal chemistry letters》2006,16(7):1975-1980
A series of N(alpha)-2-benzoxazolyl-alpha-amino acid-(arylaminoethyl)amides were identified as potent, selective, and noncovalent inhibitors of cathepsin S. Structure-activity relationships including strategies for modulating the selectivities among cathepsins S, K, and L, and in vivo pharmacokinetics are discussed. A X-ray structure of compound 3 bound to the active site of cathepsin S is also reported. 相似文献
72.
Tully DC Liu H Chatterjee AK Alper PB Williams JA Roberts MJ Mutnick D Woodmansee DH Hollenbeck T Gordon P Chang J Tuntland T Tumanut C Li J Harris JL Karanewsky DS 《Bioorganic & medicinal chemistry letters》2006,16(19):5107-5111
We report a novel series of noncovalent inhibitors of cathepsin S. The synthesis of the peptidomimetic scaffold is described and structure-activity relationships of P3, P1, and P1' subunits are discussed. Lead optimization to a non-peptidic scaffold has resulted in a new class of potent, highly selective, and orally bioavailable cathepsin S inhibitors. 相似文献
73.
Emir Alper Türkoğlu Deniz Ekinci 《Journal of enzyme inhibition and medicinal chemistry》2017,32(1):74-77
Inhibitors of carbonic anhydrase (CA) have been carried out in many therapeutic applications, especially antiglaucoma activity. In this study, we investigated some uracil derivatives (4–12) to inhibit human CA I (hCA I) and II (hCA II) isoenzymes. The KI values of the compounds 4–12 are in the range of 0.085–428?µM for hCA I and of 0.1715–645?µM against hCA II, respectively. It is concluded from the kinetic investigations, all compounds used in the study act as competitive inhibitors with substrate, 4-NPA. Uracil derivatives are emerging agents for the inhibiton of carbonic anhydrase which could be used in biomedicine. 相似文献
74.
Sephton CF Cenik C Kucukural A Dammer EB Cenik B Han Y Dewey CM Roth FP Herz J Peng J Moore MJ Yu G 《The Journal of biological chemistry》2011,286(2):1204-1215
TAR DNA-binding protein 43 (TDP-43) is associated with a spectrum of neurodegenerative diseases. Although TDP-43 resembles heterogeneous nuclear ribonucleoproteins, its RNA targets and physiological protein partners remain unknown. Here we identify RNA targets of TDP-43 from cortical neurons by RNA immunoprecipitation followed by deep sequencing (RIP-seq). The canonical TDP-43 binding site (TG)(n) is 55.1-fold enriched, and moreover, a variant with adenine in the middle, (TG)(n)TA(TG)(m), is highly abundant among reads in our TDP-43 RIP-seq library. TDP-43 RNA targets can be divided into three different groups: those primarily binding in introns, in exons, and across both introns and exons. TDP-43 RNA targets are particularly enriched for Gene Ontology terms related to synaptic function, RNA metabolism, and neuronal development. Furthermore, TDP-43 binds to a number of RNAs encoding for proteins implicated in neurodegeneration, including TDP-43 itself, FUS/TLS, progranulin, Tau, and ataxin 1 and -2. We also identify 25 proteins that co-purify with TDP-43 from rodent brain nuclear extracts. Prominent among them are nuclear proteins involved in pre-mRNA splicing and RNA stability and transport. Also notable are two neuron-enriched proteins, methyl CpG-binding protein 2 and polypyrimidine tract-binding protein 2 (PTBP2). A PTBP2 consensus RNA binding motif is enriched in the TDP-43 RIP-seq library, suggesting that PTBP2 may co-regulate TDP-43 RNA targets. This work thus reveals the protein and RNA components of the TDP-43-containing ribonucleoprotein complexes and provides a framework for understanding how dysregulation of TDP-43 in RNA metabolism contributes to neurodegeneration. 相似文献
75.
Stewart AK Shmukler BE Vandorpe DH Rivera A Heneghan JF Li X Hsu A Karpatkin M O'Neill AF Bauer DE Heeney MM John K Kuypers FA Gallagher PG Lux SE Brugnara C Westhoff CM Alper SL 《American journal of physiology. Cell physiology》2011,301(6):C1325-C1343
Four patients with overhydrated cation leak stomatocytosis (OHSt) exhibited the heterozygous RhAG missense mutation F65S. OHSt erythrocytes were osmotically fragile, with elevated Na and decreased K contents and increased cation channel-like activity. Xenopus oocytes expressing wild-type RhAG and RhAG F65S exhibited increased ouabain and bumetanide-resistant uptake of Li(+) and (86)Rb(+), with secondarily increased (86)Rb(+) influx sensitive to ouabain and to bumetanide. Increased RhAG-associated (14)C-methylammonium (MA) influx was severely reduced in RhAG F65S-expressing oocytes. RhAG-associated influxes of Li(+), (86)Rb(+), and (14)C-MA were pharmacologically distinct, and Li(+) uptakes associated with RhAG and RhAG F65S were differentially inhibited by NH(4)(+) and Gd(3+). RhAG-expressing oocytes were acidified and depolarized by 5 mM bath NH(3)/NH(4)(+), but alkalinized and depolarized by subsequent bath exposure to 5 mM methylammonium chloride (MA/MA(+)). RhAG F65S-expressing oocytes exhibited near-wild-type responses to NH(4)Cl, but MA/MA(+) elicited attenuated alkalinization and strong hyperpolarization. Expression of RhAG or RhAG F65S increased steady-state cation currents unaltered by bath Li(+) substitution or bath addition of 5 mM NH(4)Cl or MA/MA(+). These oocyte studies suggest that 1) RhAG expression increases oocyte transport of NH(3)/NH(4)(+) and MA/MA(+); 2) RhAG F65S exhibits gain-of-function phenotypes of increased cation conductance/permeability, and loss-of-function phenotypes of decreased and modified MA/MA(+) transport, and decreased NH(3)/NH(4)(+)-associated depolarization; and 3) RhAG transports NH(3)/NH(4)(+) and MA/MA(+) by distinct mechanisms, and/or the substrates elicit distinct cellular responses. Thus, RhAG F65S is a loss-of-function mutation for amine transport. The altered oocyte intracellular pH, membrane potential, and currents associated with RhAG or RhAG F65S expression may reflect distinct transport mechanisms. 相似文献
76.
Seely KA Holthoff JH Burns ST Wang Z Thakali KM Gokden N Rhee SW Mayeux PR 《American journal of physiology. Renal physiology》2011,301(1):F209-F217
Sepsis is a leading cause of acute kidney injury (AKI) and mortality in children. Understanding the development of pediatric sepsis and its effects on the kidney are critical in uncovering new therapies. The goal of this study was to characterize the development of sepsis-induced AKI in the clinically relevant cecal ligation and puncture (CLP) model of peritonitis in rat pups 17-18 days old. CLP produced severe sepsis demonstrated by time-dependent increase in serum cytokines, NO, markers of multiorgan injury, and renal microcirculatory hypoperfusion. Although blood pressure and heart rate remained unchanged after CLP, renal blood flow (RBF) was decreased 61% by 6 h. Renal microcirculatory analysis showed the number of continuously flowing cortical capillaries decreased significantly from 69 to 48% by 6 h with a 66% decrease in red blood cell velocity and a 57% decline in volumetric flow. The progression of renal microcirculatory hypoperfusion was associated with peritubular capillary leakage and reactive nitrogen species generation. Sham adults had higher mean arterial pressure (118 vs. 69 mmHg), RBF (4.2 vs. 1.1 ml·min(-1)·g(-1)), and peritubular capillary velocity (78% continuous flowing capillaries vs. 69%) compared with pups. CLP produced a greater decrease in renal microcirculation in pups, supporting the notion that adult models may not be the most appropriate for studying pediatric sepsis-induced AKI. Lower RBF and reduced peritubular capillary perfusion in the pup suggest the pediatric kidney may be more susceptible to AKI than would be predicted using adults models. 相似文献
77.
İbrahim Demirkale Argun A. Özak Alper Yanar Geoffrey Allan Boxshall 《Systematic parasitology》2014,89(1):23-32
A new species of caligid copepod, Caligus solea n. sp., is described from the common sole Solea solea (Linnaeus) caught off the north-eastern Mediterranean coast of Turkey. Both sexes of the parasite were collected from all over the upper body surface of its host. The new species belongs to the macarovi-group of species as established by Boxshall & Gurney (Bull Br Mus (Nat Hist) (Zool), 39:161–178, 1980), with which it shares the following four characters: (i) leg 4 with two-segmented exopod, distal segment carrying three apical spines but no lateral spine; (ii) distal exopodal segment of leg 1 with three plumose setae posteriorly plus four distal margin elements, spine 1 naked, spines 2 and 3 with accessory process and spine 4 about twice length of the others; (iii) females with one-segmented abdomen while males with two-segmented abdomen; (iv) male maxilliped with myxal process opposing the tip of the subchela. However, the new species differs from its congeners within the macarovi-group in the number of sensillae on each papilla on and around the postantennal process, and also in the absence of serrations along the distal margin of the maxilla. This is the twenty-eighth species of Caligus to be reported from the Mediterranean Sea. 相似文献
78.
During free-viewing of natural scenes, eye movements are guided by bottom-up factors inherent to the stimulus, as well as top-down factors inherent to the observer. The question of how these two different sources of information interact and contribute to fixation behavior has recently received a lot of attention. Here, a battery of 15 visual stimulus features was used to quantify the contribution of stimulus properties during free-viewing of 4 different categories of images (Natural, Urban, Fractal and Pink Noise). Behaviorally relevant information was estimated in the form of topographical interestingness maps by asking an independent set of subjects to click at image regions that they subjectively found most interesting. Using a Bayesian scheme, we computed saliency functions that described the probability of a given feature to be fixated. In the case of stimulus features, the precise shape of the saliency functions was strongly dependent upon image category and overall the saliency associated with these features was generally weak. When testing multiple features jointly, a linear additive integration model of individual saliencies performed satisfactorily. We found that the saliency associated with interesting locations was much higher than any low-level image feature and any pair-wise combination thereof. Furthermore, the low-level image features were found to be maximally salient at those locations that had already high interestingness ratings. Temporal analysis showed that regions with high interestingness ratings were fixated as early as the third fixation following stimulus onset. Paralleling these findings, fixation durations were found to be dependent mainly on interestingness ratings and to a lesser extent on the low-level image features. Our results suggest that both low- and high-level sources of information play a significant role during exploration of complex scenes with behaviorally relevant information being more effective compared to stimulus features. 相似文献
79.
Functional and molecular characterization of an anion exchanger in airway serous epithelial cells 总被引:5,自引:0,他引:5
Loffing J Moyer BD Reynolds D Shmukler BE Alper SL Stanton BA 《American journal of physiology. Cell physiology》2000,279(4):C1016-C1023
Serous cells secreteCl and HCO3 and play an importantrole in airway function. Recent studies suggest that aCl/HCO3 anion exchanger (AE) maycontribute to Cl secretion by airway epithelial cells.However, the molecular identity, the cellular location, and thecontribution of AEs to Cl secretion in serous epithelialcells in tracheal submucosal glands are unknown. The goal of thepresent study was to determine the molecular identity, the cellularlocation, and the role of AEs in the function of serous epithelialcells. To this end, Calu-3 cells, a human airway cell line with aserous-cell phenotype, were studied by RT-PCR, immunoblot, andelectrophysiological analysis to examine the role of AEs inCl secretion. In addition, the subcellular location of AEproteins was examined by immunofluorescence microscopy. Calu-3 cellsexpressed mRNA and protein for AE2 as determined by RT-PCR and Westernblot analysis, respectively. Immunofluorescence microscopy identified AE2 in the basolateral membrane of Calu-3 cells in culture and rattracheal serous cells in situ. InCl/HCO3/Na+-containingmedia, the 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate(CPT-cAMP)-stimulated short-circuit anion current (Isc) was reduced by basolateral but not byapical application of 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid(50 µM) and 4,4'-dinitrostilbene-2,2'-disulfonic acid [DNDS (500 µM)], inhibitors of AEs. In the absence of Na+ in thebath solutions, to eliminate the contributions of the Na+/HCO3 andNa+/K+/2Cl cotransporters toIsc, CPT-cAMP stimulated a small DNDS-sensitive Isc. Taken together with previous studies, theseobservations suggest that a small component of cAMP-stimulatedIsc across serous cells may be referable toCl secretion and that uptake of Cl acrossthe basolateral membrane may be mediated by AE2. 相似文献
80.
Alper Karakas 《Chronobiology international》2013,30(1-2):225-236
The suprachiasmatic nuclei (SCN) generate the circadian rhythm of many hormones. The hormone leptin is a metabolic signal that informs the brain about fat and energy stores of the body. We investigated whether the rhythm of leptin hormone release in Syrian hamsters is directly controlled by the SCN. Three experiments were performed: in the first, hamsters were SCN‐lesioned; in the second, hamsters were exposed to different feeding regimes; and in the third, hamsters were adrenalectomized and implanted with cortisol capsules to maintain constant glucocorticoid release. Blood samples were collected before and after the experiments at different clock times and examined for leptin levels by enzyme‐linked immunosorbant assay (ELISA). Different feeding regimes and constant glucocorticoid release did not alter the rhythm of leptin release; whereas, SCN lesions abolished the rhythm. The results of the present study suggest the rhythm in leptin release in Syrian hamsters may be controlled by the SCN. 相似文献