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241.
242.
Proper expression of the replication licensing factor Cdt1 is primarily
regulated post-translationally by ubiquitylation and proteasome degradation.
In a screen to identify novel non-histone targets of histone deacetylases
(HDACs), we found Cdt1 as a binding partner for HDAC11. Cdt1 associates
specifically and directly with HDAC11. We show that Cdt1 undergoes acetylation
and is reversibly deacetylated by HDAC11. In vitro, Cdt1 can be
acetylated at its N terminus by the lysine acetyltransferases KAT2B and KAT3B.
Acetylation protects Cdt1 from ubiquitylation and subsequent proteasomal
degradation. These results extend the list of non-histone acetylated proteins
to include a critical DNA replication factor and provide an additional level
of complexity to the regulation of Cdt1.To maintain genomic integrity, DNA replication must be tightly controlled
to ensure that each portion of the genome replicates once and only once per
cell cycle (reviewed in Ref.
1). Replication licensing
begins by the formation of the prereplication complex at multiple potential
origins of replication. This is established sequentially, with the origin
recognition complex
(ORC)2 proteins
binding first, followed by the recruitment of Cdc6 and Cdt1, which in turn
recruit the MCM2–7 proteins. MCM proteins act as the replicative
helicase. The licensed replication origins are activated by cyclin-dependent
kinases at the start of S phase. Licensing occurs throughout the cell cycle
once S phase is complete.Cdt1 levels fluctuate throughout the cell cycle. It is destabilized at
G1/S transition, and then levels begin to climb again upon S phase
completion. To prevent licensing at inappropriate times, two separate
processes regulate the inactivation or destruction of Cdt1. First, geminin
negatively regulates Cdt1 function by prevention of the association of Cdt1
with MCM2–7 via steric hindrance
(2). Interestingly, geminin
also positively regulates Cdt1 by preventing its ubiquitylation, perhaps by
prevention of its interaction with an E3 ligase. This allows Cdt1 to
accumulate in G2 and M phases, to ensure adequate pools of Cdt1 to
license the next cycle of replication
(3). The ratio of geminin to
Cdt1 likely determines whether geminin positively or negatively regulates Cdt1
(4). Second, Cdt1 is targeted
for proteolysis by two distinct ubiquitin E3 ligases: the SCF-Skp2 complex and
the DDB1-Cul4 complex (5).
Phosphorylation by cyclin A/Cdk2 promotes interaction of Cdt1 with Skp2,
leading to Cdt1 degradation during S phase
(6–8).
In addition, DDB1-Cul4 utilizes proliferating cell nuclear antigen as a
binding platform to contact Cdt1, targeting the destruction of Cdt1 in S phase
or following DNA damage (9,
10). Ubiquitylation by either
of these E3 ligases promotes degradation of Cdt1 by the proteasome.Ubiquitylation occurs primarily (but not exclusively) on the ε-amino
group of lysine residues. Another prominent post-translational modification
that occurs on that residue is acetylation. Acetylation and, correspondingly,
deacetylation can modulate the function and activity of a variety of proteins
(see Ref. 11 for review).
Here, we report that Cdt1 physically interacts with HDAC11, a class IV histone
deacetylase (12,
13), as well as with several
lysine acetyltransferases (KATs). We show that Cdt1 is an acetylated protein
and further show that acetylation protects Cdt1 from ubiquitylation and
subsequent proteasomal degradation. This study uncovers yet another layer of
complexity to the regulation of the critical licensing factor Cdt1. 相似文献
243.
Joelle M. Brown Eugenie Poirot Kristen L. Hess Stephen Brown Michele Vertucci Marjan Hezareh 《PloS one》2016,11(3)
Objective
Intravaginal practices—including behaviors such as intravaginal cleansing and insertion of products—have been linked to a number of adverse reproductive health outcomes, including increased risk for bacterial vaginosis, sexually transmitted infections, and HIV. Currently, little is known about the motivations for intravaginal practices among women in the United States. The objective of this study was to identify and describe motivations for intravaginal washing and intravaginal insertion of products among women of differing ages and racial/ethnic groups.Methods
Between 2008 and 2010, we enrolled a convenience sample of sexually active women aged 18–65 years living in Los Angeles recruited through community education and outreach activities in HIV/AIDS service organizations, women’s health clinics, community-based organizations, and HIV testing sites. At the enrollment visit, women completed a self-administered, computer-assisted questionnaire covering demographics, sexual behaviors, intravaginal practices, and motivations for intravaginal practices over the past month and past year.Results
We enrolled 141 women; 34% of participants were Caucasian, 40% African American, and 26% Latina. Peri-sexual intravaginal washing was common in all groups, whether to clean up after sex (70%) or to prepare for sex (54%). African American women were more likely to report learning to wash intravaginally from their mothers compared to Latina or Caucasian women (70% vs. 49%, P = 0.04). Sixty-one percent of African American women reported using a douching device over the past year compared to 41% of Latina and 40% of Caucasian women (p = 0.02). Younger women were more likely to report that their male partners wanted them to wash intravaginally than older women (77% vs. 24%, P<0.01), and more likely to report the removal of odors as a motive than older women (65% vs. 40%, P = 0.04). The most commonly used intravaginal products included sexual lubricants, petroleum jelly, body lotions, oils, and wet wipes. Use of these products varied by race, and motives given included increasing lubrication, preparing for sex, smelling good, and preventing sexually transmitted infections.Conclusion
Women’s intravaginal practices and motivations for these practices differ across race and age. Motivations for use also vary by type of intravaginal product used. Given that some intravaginal practices have been shown to be harmful, interventions, programs and counseling messages to encourage less harmful practices are needed, and should consider underlying motivations that influence women’s vaginal practices. Practitioners may use these results to better support women in achieving vaginal health. 相似文献244.
Michael J. Renner Allyson J. Bennett Michele L. Ford Peter J. Pierre 《Primates; journal of primatology》1992,33(3):315-327
Investigatory behavior with novel, inanimate objects by two groups of four juvenile greater bushbabies (Otolemur garnettii) was examined in the laboratory. Substantial investigatory behavior was shown by all subjects. In the first study, subjects
showed interest in a wide variety of nonfood stimulus objects. In the second, subjects displayed sustained interest in and
investigation of non-food stimulus objects over three sessions. Bushbabies showed preferences for larger, more manipulable
objects and variations in total contact over days. Individual differences were observed in the duration and types of contact
with objects. These observations contradict earlier reports that prosimians show little interest in inanimate, non-food objects. 相似文献
245.
Pierpaolo Correale Antonio Procopio Luigi Celio Michele Caraglia Geppino Genua Vincenzo Coppola Stefano Pepe Nicola Normanno Immacolata Vecchio Giovannella Palmieri Stefania Montagnani Pierosandro Tagliaferri Angelo Raffaele Bianco 《Cancer immunology, immunotherapy : CII》1992,34(4):272-278
Summary Human melanoma cells are sensitive to the lytic activity of natural killer (NK) and lymphokine-activated killer (LAK) cells in vitro. The events resulting in tumour cell killing by lymphocytic effectors have not been completely clarified, and the same target cell determinants regulating responsiveness to immune cytolysis have not yet been identified. Indeed, changes in the differentiative status of leukemia cells as well as in the expression of major histocompatibility complex (MHC) antigens have been described to modulate sensitivity to cytotoxic effectors; moreover surface expression of adhesion factors or extracellular matrix proteins by the cancer cells can promote the activation of the cytolytic effectors and has been described to correlate with tumour cell sensitivity to cytolytic cells. We reasoned that treatment with differentiation inducers could modulate melanoma cell sensitivity to NK and LAK cells. The present study demonstrates that human melanoma GLL-19 cells, when treated with the phorbol diester phorbol 12-myristate 13-acetate (PMA) in vitro, undergo growth inhibition and neuron-like differentiation. Moreover PMA treatment induces an evident inhibition of GLL-19 cell sensitivity to NK- and LAK-mediated cytotoxicity. GLL-19 cells express constitutively MHC class I antigens. PMA treatment, however, does not modify the expression of MHC class I and class II DR antigens in human melanoma GLL-19 cells. We have finally evaluated the effects of PMA on the expression at the cell surface of adhesion factors such as ICAM-1, and extracellular matrix proteins such as collagen IV, laminin and fibronectin; we have also studied the expression of the integrin vitronectin receptor, a membrane receptor for adhesive proteins. While adhesion factors and extracellular matrix proteins appear to play an important role in the interaction between immune effector and tumour target, it can be supposed that the modulation of such membrane-associated proteins or glycoproteins induces NK and LAK resistance in cancer cells. We indeed found that PMA treatment induced in GLL-19 a marked reduction of membrane expression of collagen IV and ICAM-1; moreover PMA reduced the cell membrane expression of the integrin vitronectin receptor. On the other hand, membrane expression of fibronectin and laminin was not affected by PMA. These data indicate that the acquisition of a NK- and LAK-resistant phenotype by GLL-19 cells occurs together with cell differentiation, down-regulation of membrane expression of collagen IV, ICAM-1 and vitronectin receptor, but in the absence of changes in MHC antigens.This work has been supported by the Italian Association for Cancer Research (A. I. R. C.) and by Istituto Superiore di Sanità, Italy-USA joint program on New Therapies on Neoplasia. 相似文献
246.
Giuseppe Cassano Michele Maffia Sebastiano Vilella Carlo Storelli 《The Journal of membrane biology》1988,101(1):225-236
Summary The Na-dependent transport of a number of organic molecules (d-glucose,l-proline,l-alanine,l-phenylalanine) in brush-border membrane vesicles isolated from the intestine of the eel (Anguilla anguilla) was monitored by recording the fluorescence quenching of the voltage-sensitive cyanine dye 3,3-diethylthiacarbocyanine iodide (DiS-C2(5)). The experimental approach consisted of: a) generating an inside-negative membrane potential mimicking in vivo conditions: b) measuring the rate of membrane potential decay (i.e., the rate of fluorescence quenching decay) due to Na-neutral substrate cotransport. Rates of membrane potential decay showed saturation on substrate concentration andK
app values (the substrate concentration giving 50% of the maximal rate) were estimated for Na-dependent transport ofd-glucose (0,099mm),l-alanine (0.516mm),l-proline (0.118mm) andl-phenylalanine (2.04mm). The influence of an inside-negative membrane potential on the affinity of the transporter for glucose and for sodium is discussed. 相似文献
247.
Fiorella D'Anna Michele De Luca Ranieri Cancedda Antonio Zicca Adriano T. Franzi 《The Histochemical journal》1988,20(12):674-678
Summary Human epidermal keratinocytes grown in culture and at different stages of differentiation are shown to be viably separated by elutriation. A specific fraction enriched in melanocytes was obtained. Elutriation of cells obtained fromin vitro cultured epithlium could prove useful in studies concerning the biochemistry and molecular markers of cells isolated from normal epithelium and from different pathologies. 相似文献
248.
Bavro VN Pietras Z Furnham N Pérez-Cano L Fernández-Recio J Pei XY Misra R Luisi B 《Molecular cell》2008,30(1):114-121
Drugs and certain proteins are transported across the membranes of Gram-negative bacteria by energy-activated pumps. The outer membrane component of these pumps is a channel that opens from a sealed resting state during the transport process. We describe two crystal structures of the Escherichia coli outer membrane protein TolC in its partially open state. Opening is accompanied by the exposure of three shallow intraprotomer grooves in the TolC trimer, where our mutagenesis data identify a contact point with the periplasmic component of a drug efflux pump, AcrA. We suggest that the assembly of multidrug efflux pumps is accompanied by induced fit of TolC driven mainly by accommodation of the periplasmic component. 相似文献
249.
No Evidence for a Difference in Neuropsychological Profile among Carriers and Noncarriers of the FMR1 Premutation in Adults under the Age of 50 下载免费PDF全文
Jessica Ezzell Hunter Emily Graves Allen Ann Abramowitz Michele Rusin Mary Leslie Gloria Novak Debra Hamilton Lisa Shubeck Krista Charen Stephanie L. Sherman 《American journal of human genetics》2008,83(6):692-702
The 5′ untranslated region of the fragile X mental retardation gene, FMR1, contains a polymorphic CGG repeat. Expansions of this repeat are associated with a spectrum of disorders. Full mutation alleles, repeats ≥ 200, are associated with fragile X syndrome. Premutation alleles, repeats of ~55–199, are associated with a tremor-ataxia syndrome most commonly in older males and primary ovarian insufficiency in females. However, the neuropsychological impact of carrying a premutation allele is presently unclear in younger adults. In this study, we analyzed neuropsychological scores for 138 males and 506 females ascertained from the general population and from families with a history of fragile X syndrome. Subjects were age 18–50 years and had varying repeat lengths. Neuropsychological scores were obtained from measures of general intelligence, memory, and executive functioning, including attention. Principal component analysis followed by varimax rotation was used to create independent factors for analysis. These factors were modeled for males and females separately via a general linear model that accounted for correlation among related subjects. All models were adjusted for potential confounders, including age at testing, ethnicity, and household income. Among males, no repeat length associations were detected for any factor. Among females, only a significant association with repeat length and self-report attention (p < 0.01) was detected, with premutation carriers self-reporting significantly more attention-related problems compared to noncarriers. No significant interactions between repeat length and age were detected. Overall, these results indicate the lack of a global neuropsychological impact of carrying a premutation allele among adults under the age of 50. 相似文献
250.
[14C]OleoylCoA was incorporated into phosphatidylinositol 4 times more efficiently than into phosphatidylserine in rat brain and liver microsomes when incubated with various levels of 1-acyl-sn-glycero-3-phosphoserine. In contrast, 1-acyl-sn-glycero-3-phosphocholine dependent incorporation of oleoylCoA was only into phosphatidylcholine. When [l-3H]serine labeled 1-acyl-sn-glycero-3-phosphoserine was used as the labeled substrate, no phosphatidylserine synthesis could be detected in rat brain microsomes. OleoylCoA incorporation in phospholipids in the presence of lysophosphatidylserine was primarily at the 2-position while stearoylCoA was incorporated at the 1-position. These results are interpreted to suggest that there is no acylCoA:1-acyl-sn-glycero-3-phosphoserine acyltransferase in rat brain microsomes and the lysophosphatidylserine dependent position-specific incorporation of acylCoA into various phospholipids may be due to an exchange reaction. A simple highly reproducible one dimensional thin-layer chromatographic system is described for the separation of all the major phospholipids of brain and liver. 相似文献