全文获取类型
收费全文 | 990篇 |
免费 | 63篇 |
国内免费 | 1篇 |
专业分类
1054篇 |
出版年
2023年 | 4篇 |
2022年 | 8篇 |
2021年 | 19篇 |
2020年 | 11篇 |
2019年 | 13篇 |
2018年 | 11篇 |
2017年 | 15篇 |
2016年 | 21篇 |
2015年 | 34篇 |
2014年 | 34篇 |
2013年 | 54篇 |
2012年 | 61篇 |
2011年 | 77篇 |
2010年 | 45篇 |
2009年 | 52篇 |
2008年 | 65篇 |
2007年 | 77篇 |
2006年 | 91篇 |
2005年 | 55篇 |
2004年 | 73篇 |
2003年 | 48篇 |
2002年 | 45篇 |
2001年 | 6篇 |
2000年 | 2篇 |
1999年 | 8篇 |
1998年 | 9篇 |
1997年 | 9篇 |
1996年 | 14篇 |
1995年 | 12篇 |
1994年 | 4篇 |
1993年 | 5篇 |
1992年 | 3篇 |
1991年 | 7篇 |
1990年 | 5篇 |
1988年 | 7篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 5篇 |
1984年 | 5篇 |
1983年 | 2篇 |
1982年 | 5篇 |
1981年 | 3篇 |
1980年 | 7篇 |
1979年 | 3篇 |
1978年 | 2篇 |
1977年 | 4篇 |
1976年 | 1篇 |
1975年 | 3篇 |
1974年 | 1篇 |
1973年 | 3篇 |
排序方式: 共有1054条查询结果,搜索用时 0 毫秒
71.
Introduction
In adults, microalbuminuria indicates generalized endothelial dysfunction, and is an independent risk factor for cardiovascular and all cause mortality. Slovak adults present one of the highest cardiovascular mortality rates in Europe. Thus Slovak adolescents are on a high-risk to develop cardiovascular afflictions early, and screening for microalbuminuria might be useful in early assessment of their cardiovascular risk. We aimed to study the prevalence of microalbuminuria in Slovak adolescents, and the association of urinary albumin-to-creatinine ratio (ACR) to cardiovascular risk factors.Subjects and methods
Anthropometric data, blood pressure, blood count, glucose homeostasis, lipid profile, renal function, inflammatory status, concentrations of homocysteine and uric acid were determined and associated with ACR in 2 666 adolescents (49.4% boys, 51.6% girls) aged 14-to-20 years. Microalbuminuria was classified as ACR 2.5–25.0 mg/mmol in boys and 3.5–35.0 mg/mmol in girls.Results
Prevalence of microalbuminuria in both genders reached 3.3%, and did not differ significantly between lean and centrally obese subjects. Girls presented higher ACR than boys (normoalbuminuric: 0.6±0.5 mg/mmol vs. 0.5±0.4 mg/mmol, p>0.001; microalbuminuric: 9.3±7.3 mg/mmol vs. 5.0±3.8 mg/mmol; p>0.001). Microalbuminuric adolescents and those presenting normoalbuminuria within the upper ACR quartile were slimmer than their normoalbuminuric counterparts or adolescents with normoalbuminuria within the lower quartile, respectively. No association between microalbuminuria and cardiovascular risk markers was revealed.Conclusion
Results obtained in this study do not support our assumption that ACR associates with cardiometabolic risk factors in apparently healthy adolescents. Follow-up studies until adulthood are needed to estimate the potential cardiometabolic risk of apparently healthy microalbuminuric adolescents. 相似文献72.
Amimul M. Ehsan Thomas Geurden Stijn Casaert Sonia M. Parvin Taohidul M. Islam Uddin M. Ahmed Bruno Levecke Jozef Vercruysse Edwin Claerebout 《PloS one》2015,10(2)
Giardia and Cryptosporidium are important causes of diarrhoea in Bangladesh. The high prevalence of both parasites in humans and cattle in rural Bangladesh and the common use of water ponds by village inhabitants and their animals suggest a potential for zoonotic transmission. Direct transmission of Giardia and Cryptosporidium between cattle and their handlers and indirect transmission through water ponds was investigated. Faecal/stool samples were collected from 623 calves and 125 calf handlers in a cross-sectional survey. In two villages, water samples were collected monthly from water ponds and faecal/stool samples were collected monthly from inhabitants and their cattle. Giardia cysts and Cryptosporidium oocysts were detected in water samples and in faecal/stool samples and positive samples were genotyped, to determine their human or animal origin. The prevalence of Giardia and Cryptosporidium in calves was 22% and 5% respectively. In calf handlers, the prevalence of Giardia and Cryptosporidium was 11.2% and 3.2% respectively. Both in the cross-sectional survey and in the longitudinal study in the villages, G. duodenalis assemblage E was most prevalent in calves, while in humans assemblage AII, BIII and BIV were found. In cattle, Cryptosporidium parvum, C. bovis and C. andersoni were identified, but no Cryptosporidium sequences were obtained from humans. Giardia and Cryptosporidium were detected in 14/24 and 12/24 water samples respectively. G. duodenalis assemblage E and BIV (-like), as well as C. andersoni and C. hominis were identified. Although the presence of Giardia and Cryptosporidium in both water ponds suggests that water-borne transmission of Giardia and Cryptosporidium is possible, the genotyping results indicate that there is no significant direct or indirect (water-borne) transmission of Giardia between cattle and people in this area of rural Bangladesh. No conclusions could be drawn for Cryptosporidium, because of the low number of sequences that were obtained from human and water samples. 相似文献
73.
Jozef Hritz Tilman Läppchen Chris Oostenbrink 《European biophysics journal : EBJ》2010,39(12):1573-1580
The FtsZ protein is a self-polymerizing GTPase that plays a central role in bacterial cell division. Several C8-substituted
GTP analogs are known to inhibit the polymerization of FtsZ by competing for the same binding site as its endogenous activating
ligand GTP. Free energy calculations of the relative binding affinities to FtsZ for a set of five C8-substituted GTP analogs
were performed. The calculated values agree well with the available experimental data, and the main contribution to the free
energy differences is determined to be the conformational restriction of the ligands. The dihedral angle distributions around
the glycosidic bond of these compounds in water are known to vary considerably depending on the physicochemical properties
of the substituent at C8. However, within the FtsZ protein, this substitution has a negligible influence on the dihedral angle
distributions, which fall within the narrow range of −140° to −90° for all investigated compounds. The corresponding ensemble
average of the coupling constants 3
J(C4,H1′) is calculated to be 2.95 ± 0.1 Hz. The contribution of the conformational selection of the GTP analogs upon binding
was quantified from the corresponding populations. The obtained restraining free energy values follow the same trend as the
relative binding affinities to FtsZ, indicating their dominant contribution. 相似文献
74.
Twitching motility, a flagella-independent type of translocation of bacteria over moist surfaces, requires an array of proteins,
including FimV. To investigate the role of this protein in twitching motility in Legionella pneumophila, we have generated a knockout mutant of fimV and characterized its phenotypic effects. In addition to a major reduction in twitching motility, deletion of the fimV gene caused a number of other phenotypic effects including decreased protective pigment formation, and it also affected cell
morphology. Since fimV contains a variable number of tandem repeats, which can vary according to the origin of a given strain, we have examined
the importance of this variability found within the coding region of this gene. By complementing the knockout strain with
constructs containing a different number of this tandem repeat, we have been able to also show that repeat copy number is
important in the functioning of this gene. 相似文献
75.
76.
Jens Müller Martina Beck Ursula Mettbach George Komis Gerd Hause Diedrik Menzel Jozef Šamaj 《The Plant journal : for cell and molecular biology》2010,61(2):234-248
The proper spatial and temporal expression and localization of mitogen‐activated protein kinases (MAPKs) is essential for developmental and cellular signalling in all eukaryotes. Here, we analysed expression, subcellular localization and function of MPK6 in roots of Arabidopsis thaliana using wild‐type plants and three mpk6 knock‐out mutant lines. The MPK6 promoter showed two expression maxima in the most apical part of the root meristem and in the root transition zone. This expression pattern was highly consistent with ‘no root’ and ‘short root’ phenotypes, as well as with ectopic cell divisions and aberrant cell division planes, resulting in disordered cell files in the roots of these mpk6 knock‐out mutants. In dividing root cells, MPK6 was localized on the subcellular level to distinct fine spots in the pre‐prophase band and phragmoplast, representing the two most important cytoskeletal structures controlling the cell division plane. By combining subcellular fractionation and microscopic in situ and in vivo co‐localization methods, MPK6 was localized to the plasma membrane (PM) and the trans‐Golgi network (TGN). In summary, these data suggest that MPK6 localizing to mitotic microtubules, secretory TGN vesicles and the PM is involved in cell division plane control and root development in Arabidopsis. 相似文献
77.
Jozef Langfort Slawomir Jagsz Zofia Brzezinska Henrik Galbo 《Biochemical and biophysical research communications》2010,399(4):670-676
Fatty acids, which are the major cardiac fuel, are derived from lipid droplets stored in cardiomyocytes, among other sources. The heart expresses hormone-sensitive lipase (HSL), which regulates triglycerides (TG) breakdown, and the enzyme is under hormonal control. Evidence obtained from adipose tissue suggests that testosterone regulates HSL activity. To test whether this is also true in the heart, we measured HSL activity in the left ventricle of sedentary male rats that had been treated with testosterone supplementation or orchidectomy with or without testosterone substitution. Left ventricle HSL activity against TG was significantly elevated in intact rats supplemented with testosterone. HSL activity against both TG and diacylglyceride was reduced by orchidectomy, whereas testosterone replacement fully reversed this effect. Moreover, testosterone increased left ventricle free fatty acid levels, caused an inhibitory effect on carbohydrate metabolism in the heart, and elevated left ventricular phosphocreatine and ATP levels as compared to control rats. These data indicate that testosterone is involved in cardiac HSL activity regulation which, in turn, may affect cardiac lipid and carbohydrate metabolism. 相似文献
78.
Maila Giannandrea Maria Lidia Mignogna Salvatore Carrabino Matteo Vecellio Silvia Russo Lidia Larizza Hans-Hilger Ropers Vera Kalscheuer Cindy Skinner Jozef Gecz Hilde Van Esch Jamel Chelly Daniela Toniolo Patrizia D'Adamo 《American journal of human genetics》2010,86(2):185-195
Human Mental Retardation (MR) is a common and highly heterogeneous pediatric disorder affecting around 3% of the general population; at least 215 X-linked MR (XLMR) conditions have been described, and mutations have been identified in 83 different genes, encoding proteins with a variety of function, such as chromatin remodeling, synaptic function, and intracellular trafficking. The small GTPases of the RAB family, which play an essential role in intracellular vesicular trafficking, have been shown to be involved in MR. We report here the identification of mutations in the small GTPase RAB39B gene in two male patients. One mutation in family X (D-23) introduced a stop codon seven amino acids after the start codon (c.21C > A; p.Y7X). A second mutation, in the MRX72 family, altered the 5′ splice site (c.215+1G > A) and normal splicing. Neither instance produced a protein. Mutations segregate with the disease in the families, and in some family members intellectual disabilities were associated with autism spectrum disorder, epileptic seizures, and macrocephaly. We show that RAB39B, a novel RAB GTPase of unknown function, is a neuronal-specific protein that is localized to the Golgi compartment. Its downregulation leads to an alteration in the number and morphology of neurite growth cones and a significant reduction in presynaptic buttons, suggesting that RAB39B is required for synapse formation and maintenance. Our results demonstrate developmental and functional neuronal alteration as a consequence of downregulation of RAB39B and emphasize the critical role of vesicular trafficking in the development of neurons and human intellectual abilities. 相似文献
79.
Agnieszka Jazwa Paulina Kucharzewska Justyna Leja Anna Zagorska Aleksandra Sierpniowska Jacek Stepniewski Magdalena Kozakowska Hevidar Taha Takahiro Ochiya Rafal Derlacz Elisa Vahakangas Seppo Yla-Herttuala Alicja Jozkowicz Jozef Dulak 《Genetic vaccines and therapy》2010,8(1):1-16
Background
Impaired wound healing in diabetes is related to decreased production of growth factors. Hence, gene therapy is considered as promising treatment modality. So far, efforts concentrated on single gene therapy with particular emphasis on vascular endothelial growth factor-A (VEGF-A). However, as multiple proteins are involved in this process it is rational to test new approaches. Therefore, the aim of this study was to investigate whether single AAV vector-mediated simultaneous transfer of VEGF-A and fibroblast growth factor 4 (FGF4) coding sequences will improve the wound healing over the effect of VEGF-A in diabetic (db/db) mice.Methods
Leptin receptor-deficient db/db mice were randomized to receive intradermal injections of PBS or AAVs carrying β-galactosidase gene (AAV-LacZ), VEGF-A (AAV-VEGF-A), FGF-4 (AAV-FGF4-IRES-GFP) or both therapeutic genes (AAV-FGF4-IRES-VEGF-A). Wound healing kinetics was analyzed until day 21 when all animals were sacrificed for biochemical and histological examination.Results
Complete wound closure in animals treated with AAV-VEGF-A was achieved earlier (day 19) than in control mice or animals injected with AAV harboring FGF4 (both on day 21). However, the fastest healing was observed in mice injected with bicistronic AAV-FGF4-IRES-VEGF-A vector (day 17). This was paralleled by significantly increased granulation tissue formation, vascularity and dermal matrix deposition. Mechanistically, as shown in vitro, FGF4 stimulated matrix metalloproteinase-9 (MMP-9) and VEGF receptor-1 expression in mouse dermal fibroblasts and when delivered in combination with VEGF-A, enhanced their migration.Conclusion
Combined gene transfer of VEGF-A and FGF4 can improve reparative processes in the wounded skin of diabetic mice better than single agent treatment. 相似文献80.
Jochen Schulze Sebastian Seitz Hiroaki Saito Michael Schneebauer Robert P. Marshall Anke Baranowsky Bjoern Busse Arndt F. Schilling Felix W. Friedrich Joachim Albers Alexander S. Spiro Jozef Zustin Thomas Streichert Kristina Ellwanger Christof Niehrs Michael Amling Roland Baron Thorsten Schinke 《PloS one》2010,5(4)
Wnt signalling is a key pathway controlling bone formation in mice and humans. One of the regulators of this pathway is Dkk1, which antagonizes Wnt signalling through the formation of a ternary complex with the transmembrane receptors Krm1/2 and Lrp5/6, thereby blocking the induction of Wnt signalling by the latter ones. Here we show that Kremen-2 (Krm2) is predominantly expressed in bone, and that its osteoblast-specific over-expression in transgenic mice (Col1a1-Krm2) results in severe osteoporosis. Histomorphometric analysis revealed that osteoblast maturation and bone formation are disturbed in Col1a1-Krm2 mice, whereas bone resorption is increased. In line with these findings, primary osteoblasts derived from Col1a1-Krm2 mice display a cell-autonomous differentiation defect, impaired canonical Wnt signalling and decreased production of the osteoclast inhibitory factor Opg. To determine whether the observed effects of Krm2 on bone remodeling are physiologically relevant, we analyzed the skeletal phenotype of 24 weeks old Krm2-deficient mice and observed high bone mass caused by a more than three-fold increase in bone formation. Taken together, these data identify Krm2 as a regulator of bone remodeling and raise the possibility that antagonizing KRM2 might prove beneficial in patients with bone loss disorders. 相似文献