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Weekly Reports ㄗ99ㄘon International Trends of Cutting 每edge Life Science Development
Add Timeㄩ2013/8/26 14:18:31
1. Optical control of mammalian endogenous transcription and epigenetic states
▽Text abstracts▼Nature 500, 472每476 (22 August 2013) doi:10.1038/nature12466
Optical control of mammalian endogenous transcription and epigenetic states
Silvana Konermann, Mark D. Brigham, Alexandro E. Trevino, et al.
The dynamic nature of gene expression enables cellular programming, homeostasis and environmental adaptation in living systems. Dissection of causal gene functions in cellular and organismal processes therefore necessitates approaches that enable spatially and temporally precise modulation of gene expression. Recently, a variety of microbial and plant-derived light-sensitive proteins have been engineered as optogenetic actuators, enabling high-precision spatiotemporal control of many cellular functions1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. However, versatile and robust technologies that enable optical modulation of transcription in the mammalian endogenous genome remain elusive. Here we describe the development of light-inducible transcriptional effectors (LITEs), an optogenetic two-hybrid system integrating the customizable TALE DNA-binding domain12, 13, 14 with the light-sensitive cryptochrome 2 protein and its interacting partner CIB1 from Arabidopsis thaliana. LITEs do not require additional exogenous chemical cofactors, are easily customized to target many endogenous genomic loci, and can be activated within minutes with reversibility6, 15. LITEs can be packaged into viral vectors and genetically targeted to probe specific cell populations. We have applied this system in primary mouse neurons, as well as in the brain of freely behaving mice in vivo to mediate reversible modulation of mammalian endogenous gene expression as well as targeted epigenetic chromatin modifications. The LITE system establishes a novel mode of optogenetic control of endogenous cellular processes and enables direct testing of the causal roles of genetic and epigenetic regulation in normal biological processes and disease states.
2 . Signatures of mutational processes in human cancer
▽Text abstracts▼Nature 500, 415每421 (22 August 2013) doi:10.1038/nature12477
Signatures of mutational processes in human cancer
All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, &kataegis*, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
3. Epithelial junctions maintain tissue architecture by directing planar spindle orientation
▽Text abstracts▼Nature 500, 359每362 (15 August 2013) doi:10.1038/nature1233
Epithelial junctions maintain tissue architecture by directing planar spindle orientation
During epithelial cell proliferation, planar alignment of the mitotic spindle coordinates the local process of symmetric cell cleavage with the global maintenance of polarized tissue architecture1, 2. Although the disruption of planar spindle alignment is proposed to cause epithelial to mesenchymal transition and cancer3, 4, 5, 6, the in vivo mechanisms regulating mitotic spindle orientation remain elusive. Here we demonstrate that the actomyosin cortex and the junction-localized neoplastic tumour suppressors Scribbled and Discs large 1 have essential roles in planar spindle alignment and thus the control of epithelial integrity in the Drosophila imaginal disc. We show that defective alignment of the mitotic spindle correlates with cell delamination and apoptotic death, and that blocking the death of misaligned cells is sufficient to drive the formation of basally localized tumour-like masses. These findings indicate a key role for junction-mediated spindle alignment in the maintenance of epithelial integrity, and also reveal a previously unknown cell-death-mediated tumour-suppressor function inherent in the polarized architecture of epithelia.
4. Bacteria activate sensory neurons that modulate pain and inflammation
▽Text abstracts▼Nature (2013) doi:10.1038/nature12479
Bacteria activate sensory neurons that modulate pain and inflammation
Nociceptor sensory neurons are specialized to detect potentially damaging stimuli, protecting the organism by initiating the sensation of pain and eliciting defensive behaviours. Bacterial infections produce pain by unknown molecular mechanisms, although they are presumed to be secondary to immune activation. Here we demonstrate that bacteria directly activate nociceptors, and that the immune response mediated through TLR2, MyD88, T cells, B cells, and neutrophils and monocytes is not necessary for Staphylococcus aureus-induced pain in mice. Mechanical and thermal hyperalgesia in mice is correlated with live bacterial load rather than tissue swelling or immune activation. Bacteria induce calcium flux and action potentials in nociceptor neurons, in part via bacterial N-formylated peptides and the pore-forming toxin 汐-haemolysin, through distinct mechanisms. Specific ablation of Nav1.8-lineage neurons, which include nociceptors, abrogated pain during bacterial infection, but concurrently increased local immune infiltration and lymphadenopathy of the draining lymph node. Thus, bacterial pathogens produce pain by directly activating sensory neurons that modulate inflammation, an unsuspected role for the nervous system in host每pathogen interactions.
5. Groundwater Arsenic Contamination Throughout China
▽Text abstracts▼Science 23 August 2013: Vol. 341 no. 6148 pp. 866-868 DOI: 10.1126/science.1237484
Groundwater Arsenic Contamination Throughout China
Arsenic-contaminated groundwater used for drinking in China is a health threat that was first recognized in the 1960s. However, because of the sheer size of the country, millions of groundwater wells remain to be tested in order to determine the magnitude of the problem. We developed a statistical risk model that classifies safe and unsafe areas with respect to geogenic arsenic contamination in China, using the threshold of 10 micrograms per liter, the World Health Organization guideline and current Chinese standard for drinking water. We estimate that 19.6 million people are at risk of being affected by the consumption of arsenic-contaminated groundwater. Although the results must be confirmed with additional field measurements, our risk model identifies numerous arsenic-affected areas and highlights the potential magnitude of this health threat in China.
An Arsenic Forecast for China
▽Text abstracts▼Science 23 August 2013: Vol. 341 no. 6148 pp. 852-853
About 140 million people worldwide drink groundwater containing unsafe levels of arsenic (1). Chronic exposure to this tasteless, odorless poison leads to health effects such as skin lesions and cancer. In China, pollution is pervasive and anthropogenic groundwater contamination has attracted attention (2). Naturally-occurring arsenic is perhaps less widespread, yet equally dangerous to those exposed. Though the problem has been known for decades (3) and mitigation is ongoing (4), estimates of the exposed population differ widely (5, 6). On page 866 of this issue, Rodr赤guez-Lado et al. (7) assess the probability of the occurrence of unsafe arsenic levels in China's groundwater and identify at-risk areas where data are sparse. They suggest that more than 19 million Chinese may be drinking water above the World Health Organization guideline of 10 µg/liter. Such predictive models could guide action toward minimizing the impact of this widespread threat to human health.

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