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111.
Enzymatic characterization of the pancreatic islet-specific glucose-6-phosphatase-related protein (IGRP) 总被引:5,自引:0,他引:5
Petrolonis AJ Yang Q Tummino PJ Fish SM Prack AE Jain S Parsons TF Li P Dales NA Ge L Langston SP Schuller AG An WF Tartaglia LA Chen H Hong SB 《The Journal of biological chemistry》2004,279(14):13976-13983
Glucose is the main physiological stimulus for insulin biosynthesis and secretion by pancreatic beta-cells. Glucose-6-phosphatase (G-6-Pase) catalyzes the dephosphorylation of glucose-6-phosphate to glucose, an opposite process to glucose utilization. G-6-Pase activity in pancreatic islets could therefore be an important factor in the control of glucose metabolism and, consequently, of glucose-dependent insulin secretion. While G-6-Pase activity has been shown to be present in pancreatic islets, the gene responsible for this activity has not been conclusively identified. A homolog of liver glucose-6-phosphatase (LG-6-Pase) specifically expressed in islets was described earlier; however, the authors could not demonstrate enzymatic activity for this protein. Here we present evidence that the previously identified islet-specific glucose-6-phosphatase-related protein (IGRP) is indeed the major islet glucose-6-phosphatase. IGRP overexpressed in insect cells possesses enzymatic activity comparable to the previously described G-6-Pase activity in islets. The K(m) and V(max) values determined using glucose-6-phosphate as the substrate were 0.45 mm and 32 nmol/mg/min by malachite green assay, and 0.29 mm and 77 nmol/mg/min by glucose oxidase/peroxidase coupling assay, respectively. High-throughput screening of a small molecule library led to the identification of an active compound that specifically inhibits IGRP enzymatic activity. Interestingly, this inhibitor did not affect LG-6-Pase activity, while conversely LG-6-Pase inhibitors did not affect IGRP activity. These data demonstrate that IGRP is likely the authentic islet-specific glucose-6-phosphatase catalytic subunit, and selective inhibitors to this molecule can be obtained. IGRP inhibitors may be an attractive new approach for the treatment of insulin secretion defects in type 2 diabetes. 相似文献
112.
Marco Tartaglia Sonia Valeri Francesco Velardi Concezio Di Rocco P. A. Battaglia 《Human genetics》1997,99(5):602-606
Pfeiffer syndrome is a skeletal disorder characterized by craniosynostosis associated with foot and hand anomalies. Mutations
in the genes encoding fibroblast growth factor receptors 1 and 2 (FGFR1 and FGFR2) have recently been implicated in the aetiology
of such a syndrome, as well as of other craniosynostotic conditions. We now report a novel missense mutation, a G to C transversion
at position 1049 (exon IIIa) of FGFR2, detected in a patient with severe Pfeiffer clinical features. The mutation results
in the substitution of a cysteine for tryptophan-290 in the third immunoglobulin-like domain and affects both spliceoforms
of FGFR2. Mutations causing replacement of tryptophan-290 have also been reported previously in Crouzon syndrome, a similar
but clinically distinct craniosynostotic disorder. This finding confirms the involvement of mutations of FGFR2 exon IIIa in
Pfeiffer syndrome, and emphasizes both the extensive heterogeneity of the FGFR2 mutations that result in the Pfeiffer phenotype
and the perturbations caused by unpaired cysteine residues in receptor dimerization and transduction of the FGFs signal.
Received: 15 August 1996 / Revised: 19 October 1996 相似文献
113.
Canine distemper virus (CDV) infection of ferrets as a model for testing Morbillivirus vaccine strategies: NYVAC- and ALVAC-based CDV recombinants protect against symptomatic infection. 总被引:3,自引:0,他引:3 下载免费PDF全文
C B Stephensen J Welter S R Thaker J Taylor J Tartaglia E Paoletti 《Journal of virology》1997,71(2):1506-1513
114.
The respiratory sensation and some routine cardiorespiratory parameters were studied on native Highlanders from the Argentine
Andes and on Lowlanders from Europe, already tested during previous high altitude expeditions. The tests were performed at
various altitude levels from 2688m e.i., the village altitude for Highlanders, to 5600m during an expedition to Mt. Aconcagua
(6990m). At rest, the perception of 4 external inspiratory resistive loads (ranged between 2.5 and 13 cm.H2O.L-1.s) can allow
us to fix by discrimination the sensitivity index P(A) independently of response bias (B) according to Sensory Decision Theory
(SDT). The Andean highlanders did not experience the respiratory sensation at the same limits as the European lowlanders well
adaptated to high altitude. At higher altitudes than their village altitude, their respiratory sensation presented a lower
threshold of perception and a weaker discrimination which might be partly explained by the evolution of some parameters of
their cardio-respiratory function when altitude increased. Indeed, in response to high altitude hypoxia (5600m), they increased
their respiratory frequency and not their minuteventilation or mouth pressure. This chosen ventilatory pattern was opposite
to the one chosen by the Lowlanders and did not allow for sufficient adaptation to a more important altitude hypoxia than
that of their village altitude. In conclusion, the Andean highlanders wellbeing adapted to their village altitude, exhibited
a difficult acclimatization to higher altitudes which might be due to the characteristics of their respiratory sensation.
These results might explain their weak physical performances during ascent to the Mt. Aconcagua summit in spite of special
training. 相似文献
115.
Variant forms of a group I intron in nuclear small-subunit rRNA genes of the marine red alga Porphyra spiralis var. amplifolia 总被引:3,自引:0,他引:3
A group IC1 intron occurs in nuclear small-subunit (18S) ribosomal RNA (SSU
rRNA) genes of the marine red alga Porphyra spiralis var. amplifolia. This
intron occurs at the same position as the self- splicing group IC1 introns
in nuclear SSU rDNAs of the fungus Pneumocystis carinii and in the green
alga Chlorella ellipsoidea and shares sequence identity with the
Pneumocystis carinii intron in domains L1, P1, P2, and L2, outside the
conserved core. Three size variants, differing in amount of sequence in L1,
exist and are differentially distributed in geographically distinct
populations. Preliminary data suggest that the largest variant can
self-splice in vitro. Short open reading frames are present but do not
correspond to known genes. Repeated nucleotide motifs, reminiscent of
duplicated target sites of transposons or Alu elements, are associated with
the intron and with one of the variant forms of L1. Insertions are present
in nuclear SSU rDNAs of several other Porphyra species and of the red alga
Bangia atropurpurea; insertionless rDNA variants also occur in several
Porphyra species. Our observations are most readily explained by intron
mobility, although it remains unclear how transfer could have been mediated
between genomes of organisms as ecologically diverse as marine red algae,
freshwater green algae, and a mammalian-pathogenic fungus.
相似文献
116.
Preclinical gastrointestinal prokinetic efficacy and endocrine effects of the ghrelin mimetic RM-131
Lex Van der Ploeg Haley Laken Shubh Sharma Rakesh Datta Heather Halem Jesse Dong Caroline Touvay Marc Teillot Patrick Noonan Lou Tartaglia Liz Stoner Bart Henderson Keith Gottesdiener Michael Culler 《Life sciences》2014
Aims
The 28 amino acid hormone ghrelin, the natural ligand for the growth hormone secretagogue, or ghrelin receptor (GHR), has diverse physiological functions, including a possible role as a gastrointestinal prokinetic. The synthetic ghrelin mimetic RM-131 is in Phase II clinical trials for treatment of diabetic gastroparesis and other gastrointestinal (GI) disorders. We aimed to determine the relative potency of RM-131, when compared to other GI ghrelin mimetics, to predict efficacy and determine the role of RM-131 in models of inflammatory bowel disease.Main methods
We evaluated and compared ghrelin, RM-131 and other synthetic ghrelin mimetics for their prokinetic potency in models of gastrointestinal disorders in the rat and we evaluated the endocrine (rats and dogs) and anti-inflammatory effects (mice) of the ghrelin mimetic RM-131.Key findings
The pentapeptide RM-131 increased gastric emptying in rodent models of ileus. RM-131 is about 100-fold more potent than human ghrelin and is 600 to 1800-fold more potent, when compared to several investigational ghrelin mimetics tested in clinical trials. RM-131 has anti-inflammatory effects and significantly increases survival and reduces macroscopic markers of tissue damage in a TNBS model of inflammatory bowel disease. RM-131 treatment shows a transient increase in growth hormone levels in Beagle dogs and rats, returning to baseline upon chronic treatment. Significant effects on glucose and insulin are not observed in chronic studies.Significance
RM-131's potency, efficacy and endocrine profile, are promising attributes for the treatment of diverse functional gastrointestinal disorders in humans. 相似文献117.
118.
Davide Cirillo Domenica Marchese Federico Agostini Carmen Maria Livi Teresa Botta-Orfila Gian Gaetano Tartaglia 《Genome biology》2014,15(1):R13
Background
RNA-binding proteins regulate a number of cellular processes, including synthesis, folding, translocation, assembly and clearance of RNAs. Recent studies have reported that an unexpectedly large number of proteins are able to interact with RNA, but the partners of many RNA-binding proteins are still uncharacterized.Results
We combined prediction of ribonucleoprotein interactions, based on catRAPID calculations, with analysis of protein and RNA expression profiles from human tissues. We found strong interaction propensities for both positively and negatively correlated expression patterns. Our integration of in silico and ex vivo data unraveled two major types of protein–RNA interactions, with positively correlated patterns related to cell cycle control and negatively correlated patterns related to survival, growth and differentiation. To facilitate the investigation of protein–RNA interactions and expression networks, we developed the catRAPID express web server.Conclusions
Our analysis sheds light on the role of RNA-binding proteins in regulating proliferation and differentiation processes, and we provide a data exploration tool to aid future experimental studies. 相似文献119.
120.