全文获取类型
收费全文 | 946篇 |
免费 | 63篇 |
国内免费 | 54篇 |
专业分类
耳鼻咽喉 | 5篇 |
儿科学 | 34篇 |
妇产科学 | 35篇 |
基础医学 | 203篇 |
口腔科学 | 10篇 |
临床医学 | 29篇 |
内科学 | 186篇 |
皮肤病学 | 9篇 |
神经病学 | 134篇 |
特种医学 | 7篇 |
外科学 | 70篇 |
综合类 | 47篇 |
预防医学 | 43篇 |
眼科学 | 12篇 |
药学 | 85篇 |
中国医学 | 6篇 |
肿瘤学 | 148篇 |
出版年
2024年 | 1篇 |
2023年 | 20篇 |
2022年 | 60篇 |
2021年 | 74篇 |
2020年 | 51篇 |
2019年 | 47篇 |
2018年 | 76篇 |
2017年 | 57篇 |
2016年 | 63篇 |
2015年 | 74篇 |
2014年 | 102篇 |
2013年 | 90篇 |
2012年 | 58篇 |
2011年 | 98篇 |
2010年 | 44篇 |
2009年 | 42篇 |
2008年 | 31篇 |
2007年 | 25篇 |
2006年 | 31篇 |
2005年 | 5篇 |
2004年 | 10篇 |
2003年 | 3篇 |
2000年 | 1篇 |
排序方式: 共有1063条查询结果,搜索用时 546 毫秒
71.
The acquisition of reproductive competence is organized and activated by steroid hormones acting upon the hypothalamus during critical windows of development. This review describes the potential role of epigenetic processes, particularly DNA methylation, in the regulation of sexual differentiation of the hypothalamus by hormones. We examine disruption of these processes by endocrine-disrupting chemicals (EDCs) in an age-, sex-, and region-specific manner, focusing on how perinatal EDCs act through epigenetic mechanisms to reprogram DNA methylation and sex steroid hormone receptor expression throughout life. These receptors are necessary for brain sexual differentiation and their altered expression may underlie disrupted reproductive physiology and behavior. Finally, we review the literature on histone modifications and non-coding RNA involvement in brain sexual differentiation and their perturbation by EDCs. By putting these data into a sex and developmental context we conclude that perinatal EDC exposure alters the developmental trajectory of reproductive neuroendocrine systems in a sex-specific manner. 相似文献
72.
Epigenetics and Epigenetic Alterations in Pancreatic Cancer 总被引:1,自引:0,他引:1
Noriyuki Omura Michael Goggins 《International journal of clinical and experimental pathology》2009,2(4):310-326
Pancreatic cancer remains a major therapeutic challenge. In 2008, there will be approximately 37,680 new cases and 34,290 deaths attributable to pancreatic cancer in the United States (U.S.), making it the fourth leading cause of cancer-related death. Recent comprehensive pancreatic cancer genome project found that pancreatic adenocarcinomas harbored 63 intragenic mutations or amplifications/homozygous deletions and these alterations clustered in 12 signaling pathways. In addition to widespread genetic alterations, it is now apparent that epigenetic mechanisms are also central to the evolution and progression of human cancers. Since epigenetic silencing processes are mitotically heritable, they can drive neoplastic progression and undergo the same selective pressure as genetic alterations. This review will describe recent developments in cancer epigenetics and their importance in our understanding of pancreatic adenocarcinomas. 相似文献
73.
A balance between rapid, short lived, neuronal responses and prolonged ones fulfill the biochemical and cellular requirements for creating a molecular memory. I provide an overview of epigenetic mechanisms in the brain and discuss their impact on synaptic plasticity, cognitive functions, and discuss a recent example of how they can contribute to neurodegeneration and the cognitive decline associated with Alzheimer's disease. 相似文献
74.
75.
76.
77.
Molecular studies of many types of cancer have revealed that clinically evident tumours carry multiple genetic and epigenetic abnormalities, including DNA sequence alterations, chromosome copy number changes and aberrant promoter hypermethylation. Together, these aberrant changes result in the activation of oncogenes and inactivation of tumour-suppressor genes (TSG). In many cases these abnormalities can be found in premalignant lesions and even in histological normal adjacent cells. Many tumour types are difficult to detect early and are frequently resistant to available chemotherapy and radiotherapy. Therefore, the early detection, chemoprevention and the design of new therapeutic strategies based on the increased understanding of cancer molecular changes are one of the great challenges nowadays. Insertions of a methyl group at the fifth carbon of cytosines within the dinucleotide 5'- CpG-3' is the best studied epigenetic mechanism. DNA methylation acts together with others mechanisms like histone modification, chromatin remodelling and microRNAs to mould the DNA structure according to the functional state required. The aberrant methylation of the CpG islands located at the promoter region of specific genes is a common and early event involved in cancer development. Thus, hypermethylated DNA sequences from tumours are one of the most promising markers for early detection screenings as well as tumour classification and chemotherapy response in many types of cancer. 相似文献
78.
Differential allele-specific expression has been observed in several genes involved in immunity. SP-A and OPN play a role in innate host defense. To determine whether SP-A and OPN are subject to differential allele-specific regulation, we investigated their gene or allele-specific expression in various tissues. The results showed: (1) Tissue-specific expression with high levels in lung (SP-A) and kidney (OPN). (2) Differences in allele-specific expression among individuals and tissues. SP-A showed an exclusively balanced biallelic expression (BB) in lung, but both BB and imbalanced biallelic (IB) expression in colon. Allele expression of OPN was more heterogeneous, e.g. in colon BB (22%), IB (64%), and monoallelic expression (MO) (14%). (3) Differential allele-specific expression was observed in all tissues studied (OPN) or in all extrapulmonary tissues (SP-A). (4) Family studies indicated that inheritable factor(s) may be involved in the regulation of allele-specific expression. (5) Analysis of co-expression of gene-specific alleles from double heterozygous rats revealed lack of coordinate allele expression among SP-A, SP-D, and OPN. We conclude that allele-specific expression occurs among genes of innate host defense. This may yet provide another level of regulatory complexity for molecules involved in the first line of defense. 相似文献
79.
80.
William Jaime Jo Xuefeng Ren Feixia Chu Luoping Zhang 《Toxicology and applied pharmacology》2009,241(3):294-302
Arsenic, a human carcinogen that is associated with an increased risk of bladder cancer, is commonly found in drinking water. An important mechanism by which arsenic is thought to be carcinogenic is through the induction of epigenetic changes that lead to aberrant gene expression. Previously, we reported that the SAS2 gene is required for optimal growth of yeast in the presence of arsenite (AsIII). Yeast Sas2p is orthologous to human MYST1, a histone 4 lysine 16 (H4K16) acetyltransferase. Here, we show that H4K16 acetylation is necessary for the resistance of yeast to AsIII through the modulation of chromatin state. We further explored the role of MYST1 and H4K16 acetylation in arsenic toxicity and carcinogenesis in human bladder epithelial cells. The expression of MYST1 was knocked down in UROtsa cells, a model of bladder epithelium that has been used to study arsenic-induced carcinogenesis. Silencing of MYST1 reduced acetylation of H4K16 and induced sensitivity to AsIII and to its more toxic metabolite monomethylarsonous acid (MMAIII) at doses relevant to high environmental human exposures. In addition, both AsIII and MMAIII treatments decreased global H4K16 acetylation levels in a dose- and time-dependent manner. This indicates that acetylated H4K16 is required for resistance to arsenic and that a reduction in its levels as a consequence of arsenic exposure may contribute to toxicity in UROtsa cells. Based on these findings, we propose a novel role for the MYST1 gene in human sensitivity to arsenic. 相似文献