全文获取类型
收费全文 | 1573篇 |
免费 | 108篇 |
国内免费 | 1篇 |
专业分类
1682篇 |
出版年
2023年 | 14篇 |
2022年 | 29篇 |
2021年 | 59篇 |
2020年 | 26篇 |
2019年 | 36篇 |
2018年 | 31篇 |
2017年 | 22篇 |
2016年 | 47篇 |
2015年 | 105篇 |
2014年 | 91篇 |
2013年 | 96篇 |
2012年 | 123篇 |
2011年 | 118篇 |
2010年 | 80篇 |
2009年 | 72篇 |
2008年 | 89篇 |
2007年 | 86篇 |
2006年 | 71篇 |
2005年 | 61篇 |
2004年 | 59篇 |
2003年 | 55篇 |
2002年 | 44篇 |
2001年 | 19篇 |
2000年 | 11篇 |
1999年 | 9篇 |
1998年 | 12篇 |
1997年 | 11篇 |
1996年 | 12篇 |
1995年 | 11篇 |
1994年 | 6篇 |
1993年 | 10篇 |
1992年 | 7篇 |
1991年 | 14篇 |
1990年 | 11篇 |
1989年 | 7篇 |
1988年 | 6篇 |
1987年 | 5篇 |
1986年 | 7篇 |
1985年 | 10篇 |
1984年 | 9篇 |
1983年 | 10篇 |
1982年 | 7篇 |
1981年 | 5篇 |
1980年 | 6篇 |
1979年 | 5篇 |
1978年 | 4篇 |
1977年 | 5篇 |
1975年 | 4篇 |
1958年 | 3篇 |
1952年 | 3篇 |
排序方式: 共有1682条查询结果,搜索用时 12 毫秒
111.
Matilda Chelimo Saina Xiuqiong Bi Raphael Lihana Raphael Lwembe Azumi Ishizaki Annie Panikulam Tresa Palakudy Rachel Musoke Mary Owens Elijah Maritim Songok Hiroshi Ichimura 《PloS one》2015,10(8)
Objectives
Disease progression varies among HIV-1-infected individuals. The present study aimed to explore possible viral and host factors affecting disease progression in HIV-1-infected children.Methods
Since 2000, 102 HIV-1 vertically-infected children have been followed-up in Kenya. Here we studied 29 children (15 male/14 female) who started antiretroviral treatment at <5 years of age (rapid progressors; RP), and 32 (17 male/15 female) who started at >10 years of age (slow progressors; SP). Sequence variations in the HIV-1 gag and nef genes and the HLA class I-related epitopes were compared between the two groups.Results
Based on nef sequences, HIV-1 subtypes A1/D were detected in 62.5%/12.5% of RP and 66.7%/20% of SP, with no significant difference in subtype distribution between groups (p = 0.8). In the ten Nef functional domains, only the PxxP3 region showed significantly greater variation in RP (33.3%) than SP (7.7%, p = 0.048). Gag sequences did not significantly differ between groups. The reportedly protective HLA-A alleles, A*74:01, A*32:01 and A*26, were more commonly observed in SP (50.0%) than RP (11.1%, p = 0.010), whereas the reportedly disease-susceptible HLA-B*45:01 was more common in RP (33.3%) than SP (7.4%, p = 0.045). Compared to RP, SP showed a significantly higher median number of predicted HLA-B-related 12-mer epitopes in Nef (3 vs. 2, p = 0.037), HLA-B-related 11-mer epitopes in Gag (2 vs. 1, p = 0.029), and HLA-A-related 9-mer epitopes in Gag (4 vs. 1, p = 0.051). SP also had fewer HLA-C-related epitopes in Nef (median 4 vs. 5, p = 0.046) and HLA-C-related 11-mer epitopes in Gag (median 1 vs. 1.5, p = 0.044) than RP.Conclusions
Compared to rapid progressors, slow progressors had more protective HLA-A alleles and more HLA-B-related epitopes in both the Nef and Gag proteins. These results suggest that the host factor HLA plays a stronger role in disease progression than the Nef and Gag sequence variations in HIV-1-infected Kenyan children. 相似文献112.
113.
Camila B. Piantino Juliana M. Sousa-Canavez Victor Srougi Fernanda Salvadori Raphael Kato Pedro Paulo R. Ayres Miguel Srougi Luiz Heraldo Camara-Lopes Gilka Jorge Figaro Gattás Cintia Fridman Fernanda de Toledo Isaque Santana Kátia Ramos Moreira Leite 《In vitro cellular & developmental biology. Animal》2010,46(2):131-139
Bladder cancer (BC) is the fourth most common cancer in the USA. In Brazil, BC represents 3% of the total existing carcinomas in the population and represents the second highest incidence among urological tumors. The majority of bladder cancer cell lines available were derived from Caucasians and established in the seventies or eighties. Thus, neoplasia development in these cells likely occurred in environment conditions vastly different than today. In the present study, we report the establishment and characterization of three Brazilian bladder cancer cell lines (BexBra1, BexBra2, and BexBra4). These cell lines may be helpful for dissecting the genetic and epigenetic aspects that trigger the progression of BC. Moreover, the development of a Brazilian representative of the disease will allow us to investigate the potential inter-racial differences of malignancy-associated phenotypes in bladder cancer. 相似文献
114.
Helena de Freitas Oliveira Paranhos Claudia Helena Lovato da Silva Raphael Freitas De Souza Karina Matthes de Freitas Pontes 《Gerodontology》2010,27(1):33-40
doi:10.1111/j.1741‐2358.2009.00285.x Evaluation of three indices for biofilm accumulation on complete dentures Objectives: The objective of this study was to evaluate the accuracy and reproducibility of three complete denture biofilm indices (Prosthesis Hygiene Index; Jeganathan et al. Index; Budtz‐Jørgensen Index) by means of a computerised comparison method. Background: Clinical studies into denture hygiene have employed a large number of biofilm indices among their outcome variables. However, the knowledge about the validity of these indices is still scarce. Materials and methods: Sixty‐two complete denture wearers were selected. The internal surfaces of the upper complete dentures were stained (5% erythrosine) and photographed. The slides were projected on paper, and the biofilm indices were applied over the photos by means of a scoring method. For the computerised method, the areas (total and biofilm‐covered) were measured by dedicated software (Image Tool). In addition, to compare the results of the computerised method and Prosthetic Hygiene Index, a new scoring scale (including four and five graded) was introduced. For the Jeganathan et al. and Budtz‐Jørgensen indices, the original scales were used. Values for each index were compared with the computerised method by the Friedman test. Their reproducibility was measured by means of weighed κ. Significance for both tests was set at 0.05. Results: The indices tested provided similar mean measures but they tended to overestimate biofilm coverage when compared with the computerised method (p < 0.001). Agreement between the Prosthesis Hygiene Index and the computerised method was not significant, regardless of the scale used. Jeghanathan et al. Index showed weak agreement, and consistent results were found for Budtz‐Jorgensen Index (κ = 0.19 and 0.39 respectively). Conclusion: Assessment of accuracy for the biofilm indices showed instrument bias that was similar among the tested methods. Weak inter‐instrument reproducibility was found for the indices, except for the Budtz‐Jørgensen Index. This should be the method of choice for clinical studies when more sophisticated approaches are not possible. 相似文献
115.
Gidon Ofek Enda P. Dowling Robert M. Raphael J. Patrick McGarry Kyriacos A. Athanasiou 《Biomechanics and modeling in mechanobiology》2010,9(2):153-162
Articular chondrocytes experience a variety of mechanical stimuli during daily activity. One such stimulus, direct shear,
is known to affect chondrocyte homeostasis and induce catabolic or anabolic pathways. Understanding how single chondrocytes
respond biomechanically and morphologically to various levels of applied shear is an important first step toward elucidating
tissue level responses and disease etiology. To this end, a novel videocapture method was developed in this study to examine
the effect of direct shear on single chondrocytes, applied via the controlled lateral displacement of a shearing probe. Through
this approach, precise force and deformation measurements could be obtained during the shear event, as well as clear pictures
of the initial cell-to-probe contact configuration. To further study the non-uniform shear characteristics of single chondrocytes,
the probe was positioned in three different placement ranges along the cell height. It was observed that the apparent shear
modulus of single chondrocytes decreased as the probe transitioned from being close to the cell base (4.1 ± 1.3 kPa), to the
middle of the cell (2.6 ± 1.1 kPa), and then near its top (1.7 ± 0.8 kPa). In addition, cells experienced the greatest peak
forward displacement (~30% of their initial diameter) when the probe was placed low, near the base. Forward cell movement
during shear, regardless of its magnitude, continued until it reached a plateau at ~35% shear strain for all probe positions,
suggesting that focal adhesions become activated at this shear level to firmly adhere the cell to its substrate. Based on
intracellular staining, the observed height-specific variation in cell shear stiffness and plateau in forward cell movement
appeared to be due to a rearrangement of focal adhesions and actin at higher shear strains. Understanding the fundamental
mechanisms at play during shear of single cells will help elucidate potential treatments for chondrocyte pathology and loading
regimens related to cartilage health and disease. 相似文献
116.
Thibaud Souter Raphael Cornette Julio Pedraza John Hutchinson Michel Baylac 《Comptes Rendus Palevol》2010,9(6-7):411-422
Geometric morphometrics involves defining landmark points to generate a discrete representation of an object. This crucial step is strongly influenced by the biological question guiding the analysis, and even more when using curve and surface semi-landmarks methods, because these require to generate a template of reference. We exemplify these constraints using two datasets from projects with very different backgrounds. The Theropod Dataset is a functional morphometric analysis of different extinct and extant theropod pelves. The Shrew Dataset is a populational morphometric analysis of the white-toothed shrew with very small variations in skull shape. We propose a novel procedure to generate a regular template configuration, using polygonal modelling tools. This method allows us to control the template geometry and adapt its complexity to the morphological variation in the sample. More studies are necessary to assess the morphometric and statistical importance of template design in curve and surface analyses. 相似文献
117.
Brian H. Raphael Mallory J. Choudoir Carolina Lúquez Rafael Fernández Susan E. Maslanka 《Applied and environmental microbiology》2010,76(14):4805-4812
Botulism due to type F botulinum neurotoxin (BoNT/F) is rare (<1% of cases), and only a limited number of clostridial strains producing this toxin type have been isolated. As a result, analysis of the diversity of genes encoding BoNT/F has been challenging. In this study, the entire bont/F nucleotide sequences were determined from 33 type F botulinum toxin-producing clostridial strains isolated from environmental sources and botulism outbreak investigations. We examined proteolytic and nonproteolytic Clostridium botulinum type F strains, bivalent strains, including Bf and Af, and Clostridium baratii type F strains. Phylogenetic analysis revealed that the bont/F genes examined formed 7 subtypes (F1 to F7) and that the nucleotide sequence identities of these subtypes differed by up to 25%. The genes from proteolytic (group I) C. botulinum strains formed subtypes F1 through F5, while the genes from nonproteolytic (group II) C. botulinum strains formed subtype F6. Subtype F7 was composed exclusively of bont/F genes from C. baratii strains. The region of the bont/F5 gene encoding the neurotoxin light chain was found to be highly divergent compared to the other subtypes. Although the bont/F5 nucleotide sequences were found to be identical in strains harboring this gene, the gene located directly upstream (ntnh/F) demonstrated sequence variation among representative strains of this subtype. These results demonstrate that extensive nucleotide diversity exists among genes encoding type F neurotoxins from strains with different phylogenetic backgrounds and from various geographical sources.Botulism is a potentially fatal disease caused solely by the action of serologically distinct neurotoxins (BoNT/A, -B, -C, -D, -E, -F, or -G) which prevent acetylcholine release at neuromuscular junctions, resulting in paralysis. Food-borne botulism may result from the ingestion of a preformed toxin that is produced in inadequately preserved food. Under certain conditions, botulinum neurotoxin-producing Clostridium sp. may colonize and produce toxin in wounds (wound botulism) or in the intestine (infant botulism or adult colonization). Globally, human botulism cases are associated with botulinum neurotoxin serotypes A, B, E, and rarely F. The Centers for Disease Control and Prevention (CDC) maintains active surveillance for botulism cases in the United States. Of 1,269 U.S. cases of botulism reported to the CDC between 1981 and 2002, approximately 1% were due to type F toxin (13). An additional 10 cases of type F botulism were reported to the CDC from 2003 to 2007 (http://www.cdc.gov/nationalsurveillance/botulism_surveillance.html).Type F botulism was first described in 1960 following an outbreak occurring in Denmark involving liver paste (30). The organism isolated in this outbreak metabolically resembled proteolytic Clostridium botulinum strains of types A and B. In a subsequent outbreak, type F toxin was found to be produced by a nonproteolytic C. botulinum strain isolated from venison jerky (29). Bivalent toxin-producing strains have been described, including Bf strains isolated from infants in the United States and England (1, 16, 17, 35) and an Af strain isolated from individuals in Argentina with food-borne botulism (11). Bivalent strains may produce higher titers of one toxin type, which are denoted with a capital letter. The only reported organism isolated from infants with botulism due to type F toxin alone (i.e., not associated with additional serotypes as in bivalent strains) is Clostridium baratii (2, 14, 24). In addition, C. baratii type F has been isolated from adults with botulism (28) as well as suspect foods associated with botulism cases (15; CDC, unpublished data).Botulinum neurotoxin genes (bont) are typically found within toxin gene clusters that include other genes encoding components of the toxin complex (ha70, ha17, ha33, ntnh), regulatory proteins (botR), or proteins with unknown functions (p47, orfX1, orfX2, orfX3). Two general toxin gene cluster arrangements have been described, including the orfX cluster (orfX3-orfX2-orfX1-botR-p47-ntnh-bont) and the ha cluster (ha70-ha17-ha33-botR-ntnh-bont) (21, 22). The bont/F genes of type F and type Bf strains examined by Hill et al. (21) were found in an orfX cluster.The amino acid sequence identities of the BoNT serotypes A to G range from approximately 35 to 70% (36). In addition, within nearly all toxin serotypes, various levels of amino acid sequence variation have been observed, resulting in the identification of toxin subtypes (20, 36, 37).Although a limited number of genes encoding type F botulinum neurotoxin have been sequenced, a comparison of sequences available in public databases indicates that significant diversity exists within this serotype. The nucleotide sequence identity of the type F neurotoxin gene from the proteolytic strain Langeland differs from that of the gene in the nonproteolytic strain 202F by 7%. The type F gene from C. baratii strain ATCC 43756 differs from those of Langeland and 202F by 18% and 20%, respectively. Although the bivalent (Bf) strain CDC3281 is phenotypically proteolytic, the toxin gene shows greater similarity to those from nonproteolytic strains (34). In addition to metabolic differences observed between proteolytic and nonproteolytic C. botulinum strains as well as C. baratii, these organisms are phylogenetically distinct based on differences among their 16S rRNA sequences (5, 20).In order to define the degree of genetic diversity among strains encoding botulinum neurotoxin type F, we sequenced the bont/F gene and partially characterized the toxin gene cluster by using a panel of 33 strains with diverse origins. These strains were selected from those available in the CDC culture collection as well as several isolated in Argentina. The only reported Af strains have been isolated in Argentina. Among 68 outbreaks of serotype-confirmed food-borne botulism in Argentina between 1922 and 2007, type F was isolated in two outbreaks, and type Af was isolated in one outbreak. In addition, Lúquez et al. (26) reported isolation of type F and Af strains from Argentine soils.Here, we report that analysis of the bont/F genes from the strains examined in this study revealed a high degree of nucleotide sequence heterogeneity and the identification of seven type F subtypes (F1 to F7). In addition, the nucleotide sequence of one subtype (F5) has not been previously reported and contains evidence of recombination compared to the other subtypes. 相似文献
118.
119.
120.
Antibodies raised against synaptosomal plasma membranes of rat hippocampus (anti-HPC IgG) caused inhibition of [3H]noradrenaline, [3H]5-hydroxytryptamine, [3H]GABA and [3H]aspartate uptake into S1 fractions and slices of hippocampus and cerebral cortex, but not those of caudate nucleus and hypothalamus. Similar inhibition was not observed on using antibodies against synaptosomal membranes of rat caudate nucleus. Anti-HPC IgG raised against synaptosomal membranes of hippocampus failed to alter both spontaneous and K+-evoked release of [3H]noradrenaline. They did not interfere with the binding of [3H]desipramine (the potent noradrenaline-uptake inhibitor) and with the binding of [3H]dihydroalprenolol, thus excluding any interaction of the antibodies with drug receptors which are located on either the pre- or postsynaptic membrane. The anti-HPC IgG inhibit the enzymatic activity of [Na+-K+-]ATPase by 30% upon incubation of the antibodies with crude membrane preparations. A comparison of their inhibitory effects with those of the neurotoxin 6-hydroxydopamine suggests that the corresponding hippocampal specific antigens are located at a presynaptic site. 相似文献