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Formation of metastases is the major cause of death in patients diagnosed with cancer. It is a complex multistep process, including tumor cell migration, intravasation, survival in the circulation, and extravasation. Previously it was shown that tumor cell-induced endothelial necroptosis promotes tumor cell extravasation and metastasis. Here, we identified endothelial TGF-β-activated kinase 1 (TAK1) as a critical regulator of endothelial necroptosis and metastasis. Human and murine endothelial cells lacking TAK1 exhibit higher levels of necroptosis both in vitro and in vivo, and mice with endothelial cell-specific loss of TAK1 are more prone to form metastases. Endothelial RIPK3, a key component of the necroptotic machinery, was upregulated in mice with endothelial TAK1-deficiency, and endothelial knockout of RIPK3 reverted the effects of TAK1-deficiency. Moreover, altered expression levels of TAK1 and RIPK3 in pulmonary endothelial cells of mice bearing primary tumors correlated with increased endothelial necroptosis and metastasis. Together, our data suggest an important protective role for endothelial TAK1 in tumor progression by keeping endothelial necroptosis in check.

The Hippo/YAP pathway controls cell proliferation through sensing physical and spatial organization of cells. How cell-cell contact is sensed by Hippo signaling is poorly understood. Here, we identified the cell adhesion molecule KIRREL1 as an upstream positive regulator of the mammalian Hippo pathway. KIRREL1 physically interacts with SAV1 and recruits SAV1 to cell-cell contact sites. Consistent with the hypothesis that KIRREL1-mediated cell adhesion suppresses YAP activity, knockout of KIRREL1 increases YAP activity in neighboring cells. Analyzing pan-cancer CRISPR proliferation screen data reveals KIRREL1 as the top plasma membrane protein showing strong correlation with known Hippo regulators, highlighting a critical role of KIRREL1 in regulating Hippo signaling and cell proliferation. During liver regeneration in mice, KIRREL1 is upregulated, and its genetic ablation enhances hepatic YAP activity, hepatocyte reprogramming and biliary epithelial cell proliferation. Our data suggest that KIRREL1 functions as a feedback regulator of the mammalian Hippo pathway through sensing cell-cell interaction and recruiting SAV1 to cell-cell contact sites. How cell-cell contact is sensed by Hippo pathway is poorly understood. Here, the authors show that KIRREL1 functions as a feedback regulator of the mammalian Hippo pathway by sensing cell-cell interaction and recruiting SAV1 to cell-cell contacts.

Dimethylation of histone H3 lysine 9 （H3K9me2） is an important epigenetic mark associated with transcription repression. Here, we identified PHF8, a JmjC-domain-containing protein, as a histone demethylase specific for this repressing mark. Recombinant full-length wild type protein could remove methylation from H3K9me2, but mutation of a conserved histidine to alanine H247A abolished the demethylase activity. Overexpressed exogenous PHF8 was colocalized with B23 staining. Endogenous PHF8 was also colocalized with B23 and fibrillarin, two well-established nucleolus proteins, suggesting that PHF8 is localized in the nucleolus and may regulate rRNA transcription. Indeed, PHF8 bound to the promoter region of the rDNA gene. Knockdown of PHF8 reduced the expression of rRNA, and overexpression of the gene resulted in upregulation of rRNA transcript. Concomitantly, H3K9me2 level was elevated in the promoter region of the rDNA gene in PHF8 knockdown cells and reduced significantly when the wild type but not the catalytically inactive H247A mutant PHF8 was overexpressed. Thus, our study identified a histone demethylase for H3K9me2 that regulates rRNA transcription.

The inhibitor of the nuclear factor-κB (IκB) kinase (IKK) complex is a key regulator of the canonical NF-κB signalling cascade and is crucial for fundamental cellular functions, including stress and immune responses. The majority of IKK complex functions are attributed to NF-κB activation; however, there is increasing evidence for NF-κB pathway-independent signalling. Here we combine quantitative mass spectrometry with random forest bioinformatics to dissect the TNF-α-IKKβ-induced phosphoproteome in MCF-7 breast cancer cells. In total, we identify over 20,000 phosphorylation sites, of which ∼1% are regulated up on TNF-α stimulation. We identify various potential novel IKKβ substrates including kinases and regulators of cellular trafficking. Moreover, we show that one of the candidates, AEG-1/MTDH/LYRIC, is directly phosphorylated by IKKβ on serine 298. We provide evidence that IKKβ-mediated AEG-1 phosphorylation is essential for IκBα degradation as well as NF-κB-dependent gene expression and cell proliferation, which correlate with cancer patient survival in vivo . Inflammatory cytokines such as TNF-α influence inflammation, apoptosis and tumour development through regulation of the kinase IKKβ. Krishnan and Nolte et al. apply quantitative proteomics to identify potential IKKβ targets, and reveal phosphorylation of AEG-1 by IKKβ as a mechanism controlling NF-κB signalling.

Based on a comprehensive analysis on Sonic Anemometer and gradient data, wind profile radar（WPR） and GPS sounding data of March-August 2008 from the boundary layer（BL） tower observation system at Dali on the southeastern edge of Tibetan Plateau（TP）, it is found that the strengths of turbulent kinetic energy（TKE）, buoyancy term and shear term depend on vegetation cover in association with local stability and thermodynamic condition. Strong kinetic turbulence appears when near surface layer in neutral condition with the large contribution from shear term. In an unstable condition within near surface layer, the atmospheric turbulent motion is mainly thermal turbulence, as buoyancy term is obviously larger than shear term. Under a stable condition the intermittent turbulence is accompanied by weak shear and buoyancy term, and TKE is significantly less than neutral or instable condition. The study also presents that the buoyancy term contribution at Nyingchi station in the southern slopes of the TP large topography in spring is significantly larger than that at Dali over the southeastern TP edge, reflecting that the thermal turbulence makes an important contribution to convection activity in the southern slopes of TP. Dali station is located in complex terrain with mountain and valley leading to larger kinetic turbulence. From the perspective of interaction of turbulence-convection in different scales, the study revealed that the height of convective boundary layer（CBL） could reach up to 1500-2000 m. TKE, shear term, and buoyancy term in near surface layer have the notable correlations with BL height and local vertical motion. The daytime thermodynamic turbulence effect of heat flux and buoyancy term has an obvious impact on the height of CBL, whereas mechanical turbulence only exerts a less impact. Mechanical turbulence in near surface layer has a significant impact on vertical motion especially in the forenoon with impacting height of 2500-3000 m. The peaks in diurnal variations of shear term and buoyancy term correspond to the high instable periods, especially in summer forenoon. Our observation analysis characterized the convection activity triggered by TKE source and their interaction in the southeastern TP edge.

The inhibitor of the nuclear factor-κB (IκB) kinase (IKK) complex is a key regulator of the canonical NF-κB signalling cascade and is crucial for fundamental cellular functions, including stress and immune responses. The majority of IKK complex functions are attributed to NF-κB activation; however, there is increasing evidence for NF-κB pathway-independent signalling. Here we combine quantitative mass spectrometry with random forest bioinformatics to dissect the TNF-α-IKKβ-induced phosphoproteome in MCF-7 breast cancer cells. In total, we identify over 20,000 phosphorylation sites, of which ∼1% are regulated up on TNF-α stimulation. We identify various potential novel IKKβ substrates including kinases and regulators of cellular trafficking. Moreover, we show that one of the candidates, AEG-1/MTDH/LYRIC, is directly phosphorylated by IKKβ on serine 298. We provide evidence that IKKβ-mediated AEG-1 phosphorylation is essential for IκBα degradation as well as NF-κB-dependent gene expression and cell proliferation, which correlate with cancer patient survival in vivo.

Correction to: (2010) 20:794–801. doi: 10.1038/cr.2010.75; published online 8 June 2010 The authors report that the name of the third author from the last was incorrect in the article. The correct name is Jinsong Li, not Jingsong Li. The authors apologize for the error.

Interannual variation of summer precipitation in East China, and frequency of rainstorms during the monsoon season from 1961 to 2010, are analyzed in this study. It is found that the two variables show opposite trends on a decadal time scale： frequency of rainstorms increases significantly after the 1990s, while summer precipitation in East China decreases during the same period. Analysis of the spatial distribution of summer rainstorm frequency from 1961 to 2010 indicates that it decreases from the southeast to the northwest at the east edge of the large-scale topography associated with the plateaus. Spatial distribution of rainstorms with daily rainfall greater than 50 mm is characterized by a ＂high in the southeast and low in the northwest＂ pattern, similar to the staircase distribution of the topography. However, the spatial distribution of variation in both summer precipitation and frequency of extreme rainstorms under global warming differs significantly from the three-step staircase topography. It is shown that moisture characteristics of summer precipitation and extreme rainstorms during the monsoon season in East China, including moisture transport pathways, moist flow pattern, and spatial structure of the merging area of moist flows, differ significantly. Areas of frequent rainstorms include the Yangtze River Valley and South China. Col- umn-integrated moisture transport and its spatial structure could be summarized as a ＂merging＂ of three branches of intense moist flows from low and middle latitude oceans, and ＂convergence＂ of column-integrated moisture fluxes, The merging area for moist flow associated with rainstorms in the high frequency region is located slightly to the south of the monsoonal precipitation or non-rainstorm precipitation, with significantly strong moisture convergence. In addition, the summer moist flow pattern in East China has a great influence on the frequency of extreme rainstorms. Moisture flux vectors in the region of frequent rainstorms correspond to vortical flow pattern. A comparison of moisture flux vectors associated with non-rainstorms and rainstorms indicates that the moist vortex associated with rainstorms is smaller in size and located to the south of the precipitation maximum, while the moist vortex associated with non-rainstorms is larger and located to the north. It is shown that col- umn-integrated moist transport vortices and the structure of moist flux convergence have significant impacts on the north-south oscillation of frequent rainstorm areas in East China, which is synchronized with the maximum vorticity of moisture transport and the minimum of convergence on the decadal time scale. Synthesis of moisture transport pathways and related circulation impacts leads to a conceptual model of moisture flow associated with rainstorms.

The concentration of fine particulate matter (PM 2.5 ) across China has decreased by 30–50% over the period 2013–2018 due to stringent emission controls. However, the nitrate component of PM 2.5 has not responded effectively to decreasing emissions of nitrogen oxides and has actually increased during winter haze pollution events in the North China Plain. Here, we show that the GEOS-Chem atmospheric chemistry model successfully simulates the nitrate concentrations and trends. We find that winter mean nitrate would have increased over 2013–2018 were it not for favourable meteorology. The principal cause of this nitrate increase is weaker deposition. The fraction of total inorganic nitrate as particulate nitrate instead of gaseous nitric acid over the North China Plain in winter increased from 90% in 2013 to 98% in 2017, as emissions of nitrogen oxides and sulfur dioxide decreased while ammonia emissions remained high. This small increase in the particulate fraction greatly slows down deposition of total inorganic nitrate and hence drives the particulate nitrate increase. Our results suggest that decreasing ammonia emissions would decrease particulate nitrate by driving faster deposition of total inorganic nitrate. Decreasing nitrogen oxide emissions is less effective because it drives faster oxidation of nitrogen oxides and slower deposition of total inorganic nitrate. Reduction of ammonia emissions may be effective in reducing the nitrate component of fine particulate matter air pollution across the North China Plain, according to the simulation of nitrate trends using the GEOS-Chem atmospheric chemistry model.