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91.
Kate E. Smith Martin M. Shafer Debora Weiss Henry A. Anderson Patrick R. Gorski 《Biological trace element research》2017,175(1):33-41
This study aimed at evaluation of a relationship between blood selenium concentration (Se-B) and blood cystatin C concentration (CST) in a randomly selected population of healthy children, environmentally exposed to lead and cadmium. The studies were conducted on 172 randomly selected children (7.98 ± 0.97 years). Among participants, the subgroups were distinguished, manifesting marginally low blood selenium concentration (Se-B 40–59 μg/l), suboptimal blood selenium concentration (Se-B: 60–79 μg/l) or optimal blood selenium concentration (Se-B ≥ 80 μg/l). At the subsequent stage, analogous subgroups of participants were selected separately in groups of children with BMI below median value (BMI <16.48 kg/m2) and in children with BMI ≥ median value (BMI ≥16.48 kg/m2). In all participants, values of Se-B and CST were estimated. In the entire group of examined children no significant differences in mean CST values were detected between groups distinguished on the base of normative Se-B values. Among children with BMI below 16.48 kg/m2, children with marginally low Se-B manifested significantly higher mean CST values, as compared to children with optimum Se-B (0.95 ± 0.07 vs. 0.82 ± 0.15 mg/l, p < 0.05). In summary, in a randomly selected population of healthy children no relationships could be detected between blood selenium concentration and blood cystatin C concentration. On the other hand, in children with low body mass index, a negative non-linear relationship was present between blood selenium concentration and blood cystatin C concentration. 相似文献
92.
93.
Lamellipodia/ruffles and filopodia are protruding organelles containing short and highly branched or long and unbranched actin filaments, respectively. The microscopic morphology, dynamic development and protein signature of both lamellipodia/ruffles and filopodia have been investigated; however, little is known about the mechanisms by which cells coordinate the formation of these actin-based extensions. Here, we show that WAVE holds mDia2 and the Arp2/3 complex in a multimolecular complex. WAVE- and Arp2/3-dependent ruffling induced by EGF does not require mDia2. Conversely, the emission of mDia2-dependent filopodia correlates with its disengagement from WAVE. Consistently, the ability of EGF, Cdc42 and serum to induce mDia2-dependent formation of filopodia is increased in the absence of either the WAVE/Abi1/Nap1/PIR121 (WANP) or the Arp2/3 complex. Reintroduction of WAVE2 into WANP-complex knockdown cells markedly reduces filopodia formation independently of actin polymerization. Thus, WAVE and the Arp2/3 complex jointly orchestrate different types of actin-based plasma membrane protrusions by promoting ruffling and inhibiting mDia2-induced filopodia. 相似文献
94.
Debora Williams-Herman Elizabeth Round Arlene S Swern Bret Musser Michael J Davies Peter P Stein Keith D Kaufman John M Amatruda 《BMC endocrine disorders》2008,8(1):1-16
Background
Sitagliptin, a highly selective dipeptidyl peptidase-4 inhibitor, is the first in a new class of oral antihyperglycemic agents (AHAs) for the treatment of patients with type 2 diabetes. Type 2 diabetes is a life-long disease requiring chronic treatment and management. Therefore, robust assessment of the long-term safety and tolerability of newer therapeutic agents is of importance. The purpose of this analysis was to assess the safety and tolerability of sitagliptin by pooling 12 large, double-blind, Phase IIb and III studies up to 2 years in duration. Methods: This analysis included 6139 patients with type 2 diabetes receiving either sitagliptin 100 mg/day (N = 3415) or a comparator agent (placebo or an active comparator) (N = 2724; non-exposed group). The 12 studies from which this pooled population was drawn represent the double-blind, randomized, Phase IIB and III studies that included patients treated with the clinical dose of sitagliptin (100 mg/day) for at least 18 weeks up to 2 years and that were available in a single safety database as of November 2007. These 12 studies assessed sitagliptin as monotherapy, initial combination therapy with metformin, or add-on combination therapy with other oral AHAs (metformin, pioglitazone, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone). Patients in the non-exposed group were taking placebo, pioglitazone, metformin, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone. This safety analysis used patient-level data from each study to evaluate clinical and laboratory adverse experiences.Results
For clinical adverse experiences, the incidence rates of adverse experiences overall, serious adverse experiences, and discontinuations due to adverse experiences were similar in the sitagliptin and non-exposed groups. The incidence rates of specific adverse experiences were also generally similar in the two groups, with the exception of an increased incidence rate of hypoglycemia observed in the non-exposed group. The incidence rates of drug-related adverse experiences overall and discontinuations due to drug-related adverse experiences were higher in the non-exposed group, primarily due to the increased incidence rate of hypoglycemia in this group. For cardiac- and ischemia-related adverse experiences (including serious events), there were no meaningful between-group differences. No meaningful differences between groups in laboratory adverse experiences, either summary measures or specific adverse experiences, were observed.Conclusion
In patients with type 2 diabetes, sitagliptin 100 mg/day was well tolerated in clinical trials up to 2 years in duration. 相似文献95.
A. Brent Richards Sarah Ward Debora A. Rothmond Pam L. Noble James T. Winslow 《Hormones and behavior》2009,56(1):140-148
Social behavior changes dramatically during primate adolescence. However, the extent to which testosterone and other gonadal hormones are necessary for adolescent social behavioral development is unknown. In this study, we determined that gonadectomy significantly impairs social dominance in naturalistic settings and changes reactions to social stimuli in experimental settings. Rhesus macaques were castrated (n = 6) or sham operated (n = 6) at age 2.4 years, group-housed for 2 years, and ethograms were collected weekly. During adolescence the gonadally intact monkeys displayed a decrease in subordinate behaviors and an increase in dominant behaviors, which ultimately related to a rise in social status and rank in the dominance hierarchy. We measured monkey's reactions to emotional faces (fear, threat, neutral) of conspecifics of three ages (adult, peer, infant). Intact monkeys were faster to retrieve a treat in front of a threatening or infant face, while castrated monkeys did not show a differential response to different emotional faces or ages. No group difference in reaction to an innate fear-eliciting object (snake) was found. Approach and proximity responses to familiar vs unfamiliar conspecifics were tested, and intact monkeys spent more time proximal to a novel conspecific as compared to castrates who tended to spend more time with a familiar conspecific. No group differences in time spent with novel or familiar objects were found. Thus, gonadectomy resulted in the emergence of significantly different responses to social stimuli, but not non-social stimuli. Our work suggests that intact gonads, which are needed to produce adolescent increases in circulating testosterone, impact social behavior during adolescences in primates. 相似文献
96.
Debora Barros Barbosa Douglas Roberto Monteiro Valentim Adelino Ricardo Barão Ana Carolina Pero Marco Antonio Compagnoni 《Gerodontology》2009,26(3):225-231
Background: The fracture between acrylic denture base material and artificial teeth is a common clinical occurrence in dental prosthodontic practice. Objective: To evaluate the bond strength between acrylic resins and resin denture teeth when submitted by two protocols of monomer liquid application on the tooth surface and using different polymerisation methods. Material and methods: Microwave‐polymerised (Onda‐Cryl), heat‐polymerised (Clássico) and autopolymerising (Jet) acrylic resins and a brand of resin denture teeth (Biotone) were used. The acrylic resins were polymerised according to the cycles: (A) microwave – fast cycle, Onda‐Cryl; (B) microwave – long cycle, Onda‐Cryl; (C) microwave – manufacturer’s cycle, Onda‐Cryl; (T) water bath – long cycle, Clássico and (Q) bench polymerisation cycle, Jet. Thirty specimens were prepared for each polymerisation method; 10 were packed with acrylic resin after 60 s of monomer liquid application on the tooth surface, 10 after 180 s and 10 without any monomer liquid application. For the purpose of the study, a shear test was used. anova and Tukey tests were performed to identify significant differences (α = 0.05). Results: The highest bond strength values were found for monomer surface treatments, regardless of the polymerisation cycles. The highest significant values were found for cycles B (15.4 ± 1.8 MPa), C (11.9 ± 4.9 MPa) and T (15.4 ± 2.6 MPa) for non‐treated and 60 s methylmethacrylate treated groups. Comparing the monomer liquid treatment, they did not differ significantly (p > 0.05), except for cycle A (p < 0.05). Conclusion: Chemical treatment using monomer on the tooth surface prior to the acrylic resin packing improved the bond strength between resin denture tooth and acrylic resin, regardless of monomer liquid treatment protocols. The microwavable resin, polymerised by fast cycle and autopolymerising resin should be avoided for processing denture and denture repairs, respectively. 相似文献
97.
Caccamo D Di Mauro D Condello S Currò M Cutroneo G Anastasi GP Ientile R Trimarchi F 《Amino acids》2009,36(1):49-56
Several studies demonstrated that transglutaminases play a key role in extracellular matrix stabilization needed for cell
differentiation. We evaluated transglutaminase expression and activity in the pre-secretory stage of differentiation of the
continuously erupting rat incisor. We observed that transglutaminase-mediated incorporation of monodansylcadaverine into protein
substrates was specifically located in the apical loop, and along the basement membrane joining mesenchyme and inner dental
epithelium in the odontogenic organ. Enzyme activity was associated with mRNAs for transglutaminase 1 and 2. Notably, labelling
cells for these isoenzymes were observed in both mesenchymal and epithelial compartments, but not in the basement membrane,
in the ameloblast facing pulp anterior region, where ameloblast and odontoblast differentiation begins. These findings demonstrate
that transglutaminase 1 and transglutaminase 2 are expressed at a major extent in the pre-secretory stage of regenerating
rat incisor, where they probably play complementary roles in cell signalling between mesenchyme and epithelium and extracellular
matrix. 相似文献
98.
Valentino Di Donato Paola Esposito Debora Naimo Mauro Caffau Antonino Greco 《Geobios》2009,42(5):561-82
The palaeontological, geochemical and mineralogical records of core GNS84-C106 were analysed in order to reconstruct palaeohydrological changes and palaeoproductivity patterns in the Gulf of Salerno for the last 34 kyr. This approach, including compositional analysis of planktonic and benthic assemblages, gave an insight into the relationships between continental, sea surface and bottom environmental changes. The main source of variability of planktonic and benthic assemblages is related respectively to sea surface temperature and palaeobathymetry. Interrelated changes in surface salinity, nutrients, density gradient in the water column and organic fluxes at the bottom act as a secondary factor controlling the composition of both planktonic and benthic assemblages. The highest palaeoproductivity rates were reached during an interval spanning from late glacial to Middle Holocene, in conditions of enhanced continental run-off. During the Early and Middle Holocene, reduced surface salinity and density stratification were also coupled with the development of a deep chlorophyll maximum and enhanced flux or organic matter at the bottom. From about 6.5 kyr B.P. onward, a sharp reduction in palaeoproductivity took place, coupled with an increase in surface salinities. 相似文献
99.
Vincent Chaptal Michela Ottolia Gabriel Mercado-Besserer Debora A. Nicoll Kenneth D. Philipson Jeff Abramson 《The Journal of biological chemistry》2009,284(22):14688-14692
The mammalian Na+/Ca2+ exchanger, NCX1.1, serves as
the main mechanism for Ca2+ efflux across the sarcolemma following
cardiac contraction. In addition to transporting Ca2+, NCX1.1
activity is also strongly regulated by Ca2+ binding to two
intracellular regulatory domains, CBD1 and CBD2. The structures of both of
these domains have been solved by NMR spectroscopy and x-ray crystallography,
greatly enhancing our understanding of Ca2+ regulation.
Nevertheless, the mechanisms by which Ca2+ regulates the exchanger
remain incompletely understood. The initial NMR study showed that the first
regulatory domain, CBD1, unfolds in the absence of regulatory Ca2+.
It was further demonstrated that a mutation of an acidic residue involved in
Ca2+ binding, E454K, prevents this structural unfolding. A
contradictory result was recently obtained in a second NMR study in which
Ca2+ removal merely triggered local rearrangements of CBD1. To
address this issue, we solved the crystal structure of the E454K-CBD1 mutant
and performed electrophysiological analyses of the full-length exchanger with
mutations at position 454. We show that the lysine substitution replaces the
Ca2+ ion at position 1 of the CBD1 Ca2+ binding site and
participates in a charge compensation mechanism. Electrophysiological analyses
show that mutations of residue Glu-454 have no impact on Ca2+
regulation of NCX1.1. Together, structural and mutational analyses indicate
that only two of the four Ca2+ ions that bind to CBD1 are important
for regulating exchanger activity.Cardiac contraction/relaxation relies upon Ca2+ fluxes across
the plasma membrane (sarcolemma) of cardiomyocytes. Rapid Ca2+
influx (primarily through L-type Ca2+ channels) triggers the
release of additional Ca2+ from the sarcoplasmic reticulum
(SR),4 resulting in
cardiomyocyte contraction. Removal of cytosolic Ca2+ by reuptake
into the SR (through the SR Ca2+-ATPase) and expulsion from the
cell (primarily through the Na+/Ca2+ exchanger, NCX1.1)
results in relaxation (1).
Altered Ca2+ cycling is observed in a number of pathophysiological
situations including ischemia, hypertrophy, and heart failure
(2). Understanding the function
and regulation of NCX1.1 is thus of fundamental importance to understand
cardiac physiology.NCX1.1 utilizes the electrochemical potential of the Na+
gradient to extrude Ca2+ in a ratio of three Na+ ions to
one Ca2+ ion (3). In
addition to transporting both Na+ and Ca2+, NCX1.1 is
also strongly regulated by these two ions. Intracellular Na+ can
induce NCX1.1 to enter an inactivated state, whereas Ca2+ bound to
regulatory sites removes Na+-dependent inactivation and also
activates Na+/Ca2+ exchange
(3). These regulatory sites are
located on a large cytoplasmic loop (∼500 residues located between
transmembrane helices V and VI) containing two calcium binding domains (CBD1
and CBD2), which sense cytosolic Ca2+ levels. We have previously
shown that Ca2+ binding to the primary site in CBD2 is required for
full exchange regulation (4);
CBD1, however, is a site of higher affinity and appears to dominate the
activation of exchange activity by Ca2+.Both CBDs have an immunoglobulin fold formed from two antiparallel β
sheets generating a β sandwich with a differing number of Ca2+
ions coordinated at the tip of the domain
(4,
5). CBD1 binds four
Ca2+ ions, whereas CBD2 binds only two Ca2+ ions. An
initial NMR study revealed a local unfolding of the upper portion of CBD1 upon
release of Ca2+ (6).
In contrast, CBD2 did not display an unfolding response upon Ca2+
removal. A comparative analysis between CBDs revealed a difference in charge
at residues in equivalent positions near the Ca2+ coordination
site; Glu-454 in CBD1 is replaced by Lys-585 in CBD2. The unstructuring of
CBD1 upon Ca2+ removal was alleviated by reversing the charge of
the acidic residue (E454K) involved in Ca2+ coordination
(6). Previously, we solved the
structures of the Ca2+-bound and -free conformations of CBD2 and
revealed a charge compensation mechanism involving Lys-585
(4). The positively charged
lysine residue assumes the position of one of the Ca2+ ions upon
Ca2+ depletion, permitting CBD2 to retain its overall fold
(4). A similar phenomenon is
predicted to take place in E454K-CBD1 mutant. In addition, Hilge et
al. (6) showed that the
E454K mutation of CBD1 decreases Ca2+ affinity to a level similar
to that of CBD2 and suggested that the E454K mutation would cause the loss of
primary regulation of NCX1.1 by CBD1.The significance of some of these observations is unclear as a recent NMR
study (7) of CBD1 under more
physiologically relevant conditions revealed no significant alteration in
tertiary structure in the absence of Ca2+. It was hypothesized that
Ca2+ binding induces localized conformational and dynamic changes
involving several of the binding site residues. To clarify this issue, we
solved the crystal structure of the E454K-CBD1 mutant and examined the
functional effects of different CBD1 mutations in the full-length NCX1.1. The
results indicate that charge compensation is indeed provided by the residue
Lys-454 to replace one Ca2+, whereas the overall E454K-CBD1
structure is only slightly perturbed. The charge compensation, however, has no
impact on Ca2+ regulation of NCX1.1. 相似文献
100.
Santina Bruzzone Floriana Fruscione Sara Morando Tiziana Ferrando Alessandro Poggi Anna Garuti Agustina D'Urso Martina Selmo Federica Benvenuto Michele Cea Gabriele Zoppoli Eva Moran Debora Soncini Alberto Ballestrero Bernard Sordat Franco Patrone Raul Mostoslavsky Antonio Uccelli Alessio Nencioni 《PloS one》2009,4(11)
Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD+ synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD+ depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-γ and TNF-α production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD+-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD+ depletion. In addition, we relate defective IFN-γ and TNF-α production in response to FK866 to impaired Sirt6 activity. Finally, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly Sirt6 inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders. 相似文献