全文获取类型
收费全文 | 182篇 |
免费 | 20篇 |
专业分类
202篇 |
出版年
2022年 | 3篇 |
2021年 | 2篇 |
2020年 | 2篇 |
2019年 | 3篇 |
2018年 | 5篇 |
2017年 | 5篇 |
2016年 | 2篇 |
2015年 | 6篇 |
2014年 | 12篇 |
2013年 | 5篇 |
2012年 | 10篇 |
2011年 | 14篇 |
2010年 | 8篇 |
2009年 | 4篇 |
2008年 | 12篇 |
2007年 | 5篇 |
2006年 | 7篇 |
2005年 | 5篇 |
2004年 | 5篇 |
2003年 | 9篇 |
2002年 | 4篇 |
2001年 | 5篇 |
2000年 | 3篇 |
1999年 | 4篇 |
1998年 | 9篇 |
1997年 | 4篇 |
1996年 | 1篇 |
1995年 | 3篇 |
1992年 | 4篇 |
1991年 | 2篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1988年 | 1篇 |
1987年 | 5篇 |
1986年 | 1篇 |
1985年 | 3篇 |
1983年 | 1篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1978年 | 1篇 |
1977年 | 4篇 |
1975年 | 3篇 |
1974年 | 2篇 |
1973年 | 4篇 |
1971年 | 2篇 |
1970年 | 1篇 |
1969年 | 2篇 |
1954年 | 1篇 |
1941年 | 1篇 |
排序方式: 共有202条查询结果,搜索用时 15 毫秒
121.
122.
123.
Paul C. Guest Sebastian Urday Dan Ma Viktoria Stelzhammer Laura W. Harris Bob Amess Sandra Pietsch Christin Oheim Susan E. Ozanne Sabine Bahn 《Proteomics》2012,12(23-24):3580-3589
Previous studies have found that some first onset schizophrenia patients show signs of impaired insulin signaling. Also, epidemiological studies have shown that periods of suboptimal nutrition including protein deficiencies during pregnancy can lead to increased incidence of metabolic conditions and psychiatric disorders in the offspring. For these reasons, we have carried out a molecular profiling analysis of blood serum and brain tissues from adult offspring produced by the maternal low protein (LP) rat model. The results showed similar changes to those seen in schizophrenia. Multiplex immunoassay profiling identified changes in the levels of insulin, adiponectin, and leptin along with alterations in inflammatory and vascular system‐related proteins such as osteopontin, macrophage colony‐stimulating factor 1, and vascular cell adhesion molecule 1. LC‐MSE proteomic profiling showed that glutamatergic pathways were altered in frontal cortex, while signaling pathways and cytoskeletal proteins involved in hormonal secretion and synaptic remodeling were altered in the hypothalamus. Taken together, these studies indicate that the LP rat model recapitulates several pathophysiological attributes seen in schizophrenia patients. We propose that the LP model may have utility for drug discovery efforts, especially to identify compounds that modulate the metabolic and glutamatergic systems. 相似文献
124.
Pietsch J Sickmann A Weber G Bauer J Egli M Wildgruber R Infanger M Grimm D 《Proteomics》2012,12(15-16):2539-2546
Many cancer cells show unique protein expression patterns. We used proteome technology including MS, free flow isoelectric focusing and Western blotting to determine current concentrations of metabolic enzymes in healthy and malignant human thyroid cells. Three different types of human thyroid cells were investigated after they had been cultured under equal conditions. MS revealed high quantities of glycolytic enzymes and moderate quantities of citric acid cycle enzymes in malignant FTC-133 cells with abnormal LDH B-chains, high quantities of glycolytic enzymes and marginal quantities of citric acid cycle enzymes in normal HTU-5 cells, and low quantities of glycolytic enzymes and marginal quantities of citrate cycle enzymes in malignant CGTH-W1 cells with abnormal LDH A-chains. When an alteration of gene expression activity was challenged physically by removing gravity forces, the concentrations of various glycolytic enzymes were changed in normal and malignant thyroid cells. However, the changes varied among the different cell types. Different cellular alignment of the enzymes could be one reason for the cell type-specific behavior as demonstrated by histological analysis of alpha-enolase. 相似文献
125.
Judith A. M. Marx Ansgar J. Röhrborn Bernd U. Koelsch Christine Fischer Thomas Herrmann Torsten Pietsch Manfred F. Rajewsky Andrea Kindler-Röhrborn 《Cancer immunology, immunotherapy : CII》2009,58(8):1287-1295
Inbred rat strains BDIX and BDIV are constitutionally susceptible and resistant, respectively, to the development of malignant
peripheral nerve sheath tumors (MPNST) induced by neonatal exposure to N-ethyl-N-nitrosourea (EtNU). They represent a model system for analysis of molecular and cellular processes underlying differential
cancer susceptibility. A point mutation in the Neu/ErbB-2 gene is an early marker of Schwann precursor cells at high risk of malignant conversion and is diagnostic of the resulting
MPNST predominantly developing in the trigeminal nerves. Initially considerable amounts of Neu/ErbB-2-mutant cells arise in nerve tissue of both rat strains subsequently disappearing in resistant BDIV rats, but persisting and
giving rise to MPNST in susceptible BDIX animals. An almost identical cellular immune response—sequentially involving macrophages,
T helper- and cytotoxic T lymphocytes—is mounted in the trigeminal nerves of EtNU-treated rats of both strains. In this study, T cell maturation was prevented by neonatal thymectomy following EtNU-exposure. While resistance against MPNST
development significantly decreased in BDIV rats MPNST incidence and survival time remained unaltered in thymectomized BDIX
rats. Contrary to euthymic animals a number of both thymectomized BDIV and BDIX rats developed MPNST lacking the Neu/ErbB-2-mutation. This suggests that Schwann cells initiated by other genetic alterations can progress to full malignancy in immune-compromised
rats only. T cell-dependent resistance against tumorigenesis originating from non-Neu/ErbB-2-mutant Schwann precursors might thus be shared by both strains while BDIV T lymphocytes additionally prevent the development
of Neu/ErbB-2-mutant MPNST. Rat strain-specific differences in the interaction of T lymphocytes with (pre)malignant Neu-mutant cells may thus critically contribute to susceptibility and resistance towards EtNU-induced MPNST development. 相似文献
126.
Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features 总被引:1,自引:0,他引:1
Kool M Koster J Bunt J Hasselt NE Lakeman A van Sluis P Troost D Meeteren NS Caron HN Cloos J Mrsić A Ylstra B Grajkowska W Hartmann W Pietsch T Ellison D Clifford SC Versteeg R 《PloS one》2008,3(8):e3088
Background
Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms.Methods and Findings
To get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH) arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases), SHH signaling (B; 15 cases), expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively) or photoreceptor genes (D and E; both 11 cases). Mutations in β-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E. Patients below 3 yrs of age had type B, D, or E tumors. Type B included most desmoplastic cases. We validated and confirmed the molecular subtypes and their associated clinicopathological features with expression data from a second independent series of 46 medulloblastomas.Conclusions
The new medulloblastoma classification presented in this study will greatly enhance the understanding of this heterogeneous disease. It will enable a better selection and evaluation of patients in clinical trials, and it will support the development of new molecular targeted therapies. Ultimately, our results may lead to more individualized therapies with improved cure rates and a better quality of life. 相似文献127.
Daniel Luxen Gerrit H. Gielen Anke Waha Lukas Isselstein Tim Müller Philipp Koch Jennifer Hammes Albert Becker Matthias Simon Peter Wurst Elmar Endl Torsten Pietsch Marco Gessi Andreas Waha 《Translational oncology》2017,10(1):70-79
Epigenetic silencing by DNA methylation in brain tumors has been reported for many genes, however, their function on pathogenesis needs to be evaluated. We investigated the MTSS1 gene, identified as hypermethylated by differential methylation hybridization (DMH). Fifty-nine glioma tissue samples and seven glioma cell lines were examined for hypermethylation of the MTSS1 promotor, MTSS1 expression levels and gene dosage. GBM cell lines were treated with demethylating agents and interrogated for functional consequences of MTSS1 expression after transient transfection. Hypermethylation was significantly associated with IDH1/2 mutation. Comparative SNP analysis indicates higher incidence of loss of heterozygosity of MTSS1 in anaplastic astrocytomas and secondary glioblastomas as well as hypermethylation of the remaining allele. Reversal of promoter hypermethylation results in an increased MTSS1 expression. Cell motility was significantly inhibited by MTSS1 overexpression without influencing cell growth or apoptosis. Immunofluorescence analysis of MTSS1 in human astrocytes indicates co-localization with actin filaments. MTSS1 is down-regulated by DNA methylation in glioblastoma cell lines and is part of the G-CIMP phenotype in primary glioma tissues. Our data on normal astrocytes suggest a function of MTSS1 at focal contact structures with an impact on migratory capacity but no influence on apoptosis or cellular proliferation. 相似文献
128.
The harbor seal (Phoca vitulina) has the most extensive distribution of any
phocid seal species. An analysis of population structure in this species
across its European range was made using 7 phocid derived microsatellites
in a sample of 1,029 individuals from 12 separate geographic areas. Despite
the species potential for long-distance movement, significant genetic
differentiation between areas was observed using an unbiased estimator of
RST. Six distinct population units were identified: Ireland-Scotland,
English east coast, Waddensea, western Scandinavia
(Norway-Kattegat-Skagerrak-west Baltic), east Baltic, and Iceland. Little
local substructuring is present along coastlines with a continuous
distribution of breeding animals, but differentiation does increase with
geographic distance. The degree of differentiation is greater over
equivalent distances where the distribution is discontinuous, such as along
coasts where breeding colonies are separated by large distances or by
stretches of open sea. Patterns of population differentiation derived from
microsatellites are very similar to those obtained from previous
mitochondrial DNA analysis and suggest that philopatry in harbor seals
operates over 300-500 km. In Europe, harbor seals have experienced a
complex demographic history and patterns of population structure are likely
to have been affected by natural environmental influences such as
Pleistocene glaciations and epizootics. Comparison of Nm values from an
unbiased estimator of RST, GST, and theta are consistent and, in some
cases, may indicate populations where conditions deviate from the
expectations of the RST model.
相似文献
129.
We introduce a new kinematic model describing the motion of the human forearm bones, ulna and radius, during forearm rotation. During this motion between the two forearm extrem-positions, referred to as supination (palm up) and pronation (palm down), effects occur, that cannot be explained by the the established kinematic model of R. Fick from 1904. Especially, the motion of the ulna is not properly reproduced by Fick's model. During forearm rotation an evasive motion of the ulna is observed by various authors, using magnetic resonance imaging MRI) technology. Our new kinematic model also simulates this evasive motion. Furthermore, the model is enlarged to include angulations of the forearm bones. Using these results the influence of forearm fractures on the range of forearm motion can be predicted. This knowledge can be used by surgeons to choose the optimal therapy in re-establishing free forearm mobility. 相似文献
130.
King RA Willaert RK Schmidt RM Pietsch J Savage S Brott MJ Fryer JP Summers CG Oetting WS 《American journal of human genetics》2003,73(3):638-645
The heterogeneous group of disorders known as oculocutaneous albinism (OCA) shares cutaneous and ocular hypopigmentation associated with common developmental abnormalities of the eye. Mutations of at least 11 loci produce this phenotype. The majority of affected individuals develop some cutaneous melanin; this is predominantly seen as yellow/blond hair, whereas fewer have brown hair. The OCA phenotype is dependent on the constitutional pigmentation background of the family, with more OCA pigmentation found in families with darker constitutional pigmentation, which indicates that other genes may modify the OCA phenotype. Sequence variation in the melanocortin-1 receptor (MC1R) gene is associated with red hair in the normal population, but red hair is unusual in OCA. We identified eight probands with OCA who had red hair at birth. Mutations in the P gene were responsible for classic phenotype of oculocutaneous albinism type 2 (OCA2) in all eight, and mutations in the MC1R gene were responsible for the red (rather than yellow/blond) hair in the six of eight who continued to have red hair after birth. This is the first demonstration of a gene modifying the OCA phenotype in humans. 相似文献