Autophagy plays a central role in regulating important cellular functions such as cell survival during starvation and control of infectious pathogens. Recently, it has been shown that autophagy can induce cells to die; however, the mechanism of the autophagic cell death program is unclear. We now show that caspase inhibition leading to cell death by means of autophagy involves reactive oxygen species (ROS) accumulation, membrane lipid oxidation, and loss of plasma membrane integrity. Inhibition of autophagy by chemical compounds or knocking down the expression of key autophagy proteins such as ATG7, ATG8, and receptor interacting protein (RIP) blocks ROS accumulation and cell death. The cause of abnormal ROS accumulation is the selective autophagic degradation of the major enzymatic ROS scavenger, catalase. Caspase inhibition directly induces catalase degradation and ROS accumulation, which can be blocked by autophagy inhibitors. These findings unveil a molecular mechanism for the role of autophagy in cell death and provide insight into the complex relationship between ROS and nonapoptotic programmed cell death.apoptosis ͉ necrosis ͉ nonapoptotic ͉ reactive oxygen species P rogrammed cell death plays an important role in embryonic development, immune regulation, and general cellular homeostasis (1-3). Apoptosis, the most thoroughly studied form of programmed cell death is defined by dependence on a family of proteases known as caspases. Activation of caspases leads to distinct morphological features in the cell, such as nuclear condensation, membrane blebbing, and cell shrinkage (4). Several studies have identified cell death programs that are clearly distinct from apoptosis (5, 6). These nonapoptotic cell death programs are genetically regulated and often have morphological features resembling necrosis, yet their underlying molecular mechanisms are unclear. Molecular insights into alternative cell death programs could lead to a better understanding of their role in normal cellular homeostasis as well as disease processes.Autophagy is a cellular process that causes degradation of long-lived proteins and recycling of cellular components to ensure survival during starvation. During autophagy, cells exhibit extensive internal membrane remodeling, engulfing portions of the cytoplasm in large double-membrane vesicles. These autophagosomes dock and fuse with lysosomes, and the contents of the fusion vacuoles are eventually degraded (7). A group of genes known as ATG genes, which are conserved from yeast to humans, have been found to regulate autophagy (8). Genetic analyses in yeast, and recently in higher eukaryotes, have shown that autophagy plays a central role in the regulation of cell survival during nutritional deprivation (9, 10). In addition, autophagy has been shown to play a role in tumor suppression (11, 12), pathogen control (13), antigen presentation (14), and the regulation of organismal lifespan (15).The involvement of autophagy in programmed cell death has been controversial. Autophagy has long been obs...

Understanding the spatial patterns of fire occurrence and its response to climate change is vital to fire risk mitigation and vegetation management. Focusing on boreal forests in Northeast China, we used spatial point pattern analysis to model fire occurrence reported from 1965 to 2009. Our objectives were to quantitate the relative importance of biotic, abiotic, and human influences on patterns of fire occurrence and to map the spatial distribution of fire occurrence density (number of fires occurring over a given area and time period) under current and future climate conditions. Our results showed human-caused fires were strongly related to human activities (e.g. landscape accessibility), including proximity to settlements and roads. In contrast, fuel moisture and vegetation type were the most important controlling factors on the spatial pattern of lightning fires. Both current and future projected spatial distributions of the overall (human-+ lightning-caused) fire occurrence density were strongly clustered along linear components of human infrastructure. Our results demonstrated that the predicted change in overall fire occurrence density is positively related to the degree of temperature and precipitation change, although the spatial pattern of change is expected to vary spatially according to proximity to human ignition sources, and in a manner inconsistent with predicted climate change. Compared to the current overall fire occurrence density (median value: 0.36 fires per 1000 km 2 per year), the overall fire occurrence density is projected to increase by 30% under the CGCM3 B1 scenario and by 230% under HadCM3 A2 scenario in 2081-2100, respectively. Our results suggest that climate change effects may not outweigh the effects of human influence on overall fire occurrence over the next century in this cultural landscape. Accurate forecasts of future fire-climate relationships should account for anthropogenic influences on fire ignition density, such as roads and proximity to settlements.

The biophysical feedbacks of forest fire on Earth’s surface radiative budget remain uncertain at the global scale. Using satellite observations, we show that fire-induced forest loss accounts for about 15% of global forest loss, mostly in northern high latitudes. Forest fire increases surface temperature by 0.15 K (0.12 to 0.19 K) one year following fire in burned area globally. In high-latitudes, the initial positive climate-fire feedback was mainly attributed to reduced evapotranspiration and sustained for approximately 5 years. Over longer-term (> 5 years), increases in albedo dominated the surface radiative budget resulting in a net cooling effect. In tropical regions, fire had a long-term weaker warming effect mainly due to reduced evaporative cooling. Globally, biophysical feedbacks of fire-induced surface warming one year after fire are equivalent to 62% of warming due to annual fire-related CO2 emissions. Our results suggest that changes in the severity and/or frequency of fire disturbance may have strong impacts on Earth’s surface radiative budget and climate, especially at high latitudes.

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These authors equally contributed to this work. Keywords: FGFR3-TACC3, fusion gene, NPC, proliferation, tumorigenesisAbbreviations: FGFR3, fibroblast growth factor receptor 3; TACC3, transforming acidic coiled-coil-containing protein 3; NPC, nasopharyngeal carcinoma; LTBR, lymphotoxin b receptor; CCND1, cyclin D1; RT-PCR, reverse transcription-PCR; FBS, fetal bovine serum; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide; SDS, sodium dodecyl sulfate; DTT, DL-dithiothreitol; DMSO, dimethyl sulfoxide; PBS, phosphate-buffered saline; PI, propidium iodide.Nasopharyngeal carcinoma (NPC) is one of the most common head and neck malignancies and exhibits regional differences in incidence. Because many fusion genes have been discovered in different types of tumors over the past few years, we aimed to investigate the existence of a fusion gene in primary NPC patients using RNA-seq. In this study, for the first time, we found that fibroblast growth factor receptor 3-transforming acidic coiled-coil-containing protein 3 (FGFR3-TACC3) fusion transcripts are recurrently detected in NPC. The presence of this fusion gene was also detected in head and neck cancer, esophageal squamous cell carcinoma (ESCC), and lung cancer. Furthermore, we found certain new isoforms of the FGFR3-TACC3 fusion transcripts, such as a gene fusion between exon 18 of FGFR3 and exon 6 or exon 14 of TACC3 and agene fusion between exon 19 of FGFR3 and exon 11 of TACC3. In addition, we showed that the FGFR3-TACC3 fusion gene promotes cell proliferation, colony formation, and transforming ability in vitro, whereas the FGFR3-TACC3 K508M mutant or treatment with the FGFR inhibitor PD173074 abrogates these effects, suggesting that FGFR3-TACC3 most likely exerts its effects through activation of FGFR kinase activity. This activation likely leads to the development of NPC. Additionally, FGFR3-TACC3 could trigger activation of the ERK and Akt signaling pathways, whereas FGFR3-TACC3 K508M mutant could not, suggesting that these 2 signaling pathways might be involved in the function of FGFR3-TACC3. Taken together, our data demonstrated the oncogenic role of FGFR3-TACC3 in vitro, indicating that FGFR3-TACC3 may be useful as a diagnostic marker and therapeutic target in cancers.

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