High affinity binding of H3K14ac through collaboration of bromodomains 2, 4 and 5 is critical for the molecular and tumor suppressor functions of PBRM1.

Polybromo-1 (PBRM1) is an important tumor suppressor in kidney cancer. It contains six tandem bromodomains (BDs), which are specialized structures that recognize acetyl-lysine residues. While BD2 has been found to bind acetylated histone H3 lysine 14 (H3K14ac), it is not known whether other BDs collaborate with BD2 to generate strong binding to H3K14ac, and the importance of H3K14ac recognition for the molecular and tumor suppressor function of PBRM1 is also unknown. We discovered that full-length PBRM1, but not its individual BDs, strongly binds H3K14ac. BDs 2, 4, and 5 were found to collaborate to facilitate strong binding to H3K14ac. Quantitative measurement of the interactions between purified BD proteins and H3K14ac or nonacetylated peptides confirmed the tight and specific association of the former. Interestingly, while the structural integrity of BD4 was found to be required for H3K14ac recognition, the conserved acetyl-lysine binding site of BD4 was not. Furthermore, simultaneous point mutations in BDs 2, 4, and 5 prevented recognition of H3K14ac, altered promoter binding and gene expression, and caused PBRM1 to relocalize to the cytoplasm. In contrast, tumor-derived point mutations in BD2 alone lowered PBRM1\u27s affinity to H3K14ac and also disrupted promoter binding and gene expression without altering cellular localization. Finally, overexpression of PBRM1 variants containing point mutations in BDs 2, 4, and 5 or BD2 alone failed to suppress tumor growth in a xenograft model. Taken together, our study demonstrates that BDs 2, 4, and 5 of PBRM1 collaborate to generate high affinity to H3K14ac and tether PBRM1 to chromatin. Mutations in BD2 alone weaken these interactions, and this is sufficient to abolish its molecular and tumor suppressor functions

PBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth.

p53 acetylation is indispensable for its transcriptional activity and tumor suppressive function. However, the identity of reader protein(s) for p53 acetylation remains elusive. PBRM1, the second most highly mutated tumor suppressor gene in kidney cancer, encodes PBRM1. Here, we identify PBRM1 as a reader for p53 acetylation on lysine 382 (K382Ac) through its bromodomain 4 (BD4). Notably, mutations on key residues of BD4 disrupt recognition of p53 K382Ac. The mutation in BD4 also reduces p53 binding to promoters of target genes such as CDKN1A (p21). Consequently, the PBRM1 BD4 mutant fails to fully support p53 transcriptional activity and is defective as a tumor suppressor. We also find that expressions of PBRM1 and p21 correlate with each other in human kidney cancer samples. Our findings uncover a tumor suppressive mechanism of PBRM1 in kidney cancer and provide a mechanistic insight into the crosstalk between p53 and SWI/SNF complexes

Experimental Application of Intelligent Robot Technology in Antarctic Scientific Expedition

Intelligent robot technology has great potential for application in polar scientific expedition. During the 24th Chinese Antarctic Expedition in the summer of 2007/08, our ice-snow surface mobile and low-flying robots were successfully employed for the first time in the Antarctic. This paper firstly gives a brief introduction to the intelligent robot technology developed abroad and used in the Antarctic, then focuses on the ice-snow surface mobile and low-flying robots developed by China as well as their field trials in the Antarctic. Moreover, the authors have considered the potential demand for the intelligent robot technology in China's Antarctic scientific expedition, in the hope of providing some reference for the future development of robot technologies

Climate change drives rapid warming and increasing heatwaves of lakes

Climate change could seriously threaten global lake ecosystems by warming lake surface water and increasing the occurrence of lake heatwaves. Yet, there are great uncertainties in quantifying lake temperature changes globally due to a lack of accurate large-scale model simulations. Here, we integrated satellite observations and a numerical model to improve lake temperature modeling and explore the multifaceted characteristics of trends in surface temperatures and lake heatwave occurrence in Chinese lakes from 1980 to 2100. Our model-data integration approach revealed that the lake surface waters have warmed at a rate of 0.11 °C 10a-1 during the period 1980-2021, being only half of the pure model-based estimate. Moreover, our analysis suggested that an asymmetric seasonal warming rate has led to a reduced temperature seasonality in eastern plain lakes but an amplified one in alpine lakes. The durations of lake heatwaves have also increased at a rate of 7.7 d 10a-1. Under the high-greenhouse-gas-emission scenario, lake surface temperature and lake heatwave duration were projected to increase by 2.2 °C and 197 d at the end of the 21st century, respectively. Such drastic changes would worsen the environmental conditions of lakes subjected to high and increasing anthropogenic pressures, posing great threats to aquatic biodiversity and human health.</p

Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer.

Whereas VHL inactivation is a primary event in clear cell renal cell carcinoma (ccRCC), the precise mechanism(s) of how this interacts with the secondary mutations in tumor suppressor genes, including PBRM1, KDM5C/JARID1C, SETD2, and/or BAP1, remains unclear. Gene expression analyses reveal that VHL, PBRM1, or KDM5C share a common regulation of interferon response expression signature. Loss of HIF2α, PBRM1, or KDM5C in VHL-/-cells reduces the expression of interferon stimulated gene factor 3 (ISGF3), a transcription factor that regulates the interferon signature. Moreover, loss of SETD2 or BAP1 also reduces the ISGF3 level. Finally, ISGF3 is strongly tumor-suppressive in a xenograft model as its loss significantly enhances tumor growth. Conversely, reactivation of ISGF3 retards tumor growth by PBRM1-deficient ccRCC cells. Thus after VHL inactivation, HIF induces ISGF3, which is reversed by the loss of secondary tumor suppressors, suggesting that this is a key negative feedback loop in ccRCC. © 2018, Liao et al

The role of tidal interactions in the formation of slowly rotating early-type stars in young star clusters

The split main sequences found in the colour-magnitude diagrams of star clusters younger than ~600 Myr are suggested to be caused by the dichotomy of stellar rotation rates of upper main-sequence stars. Tidal interactions have been suggested as a possible explanation of the dichotomy of the stellar rotation rates. This hypothesis proposes that the slow rotation rates of stars along the split main sequences are caused by tidal interactions in binaries. To test this scenario, we measured the variations in the radial velocities of slowly rotating stars along the split main sequence of the young Galactic cluster NGC 2422 (~90 Myr) using spectra obtained at multiple epochs with the Canada-France-Hawai'i Telescope. Our results show that most slowly rotating stars are not radial-velocity variables. Using the theory of dynamical tides, we find that the binary separations necessary to fully or partially synchronise our spectroscopic targets, on time-scales shorter than the cluster age, predict much larger radial velocity variations across multiple-epoch observations, or a much larger radial velocity dispersion at a single epoch, than the observed values. This indicates that tidal interactions are not the dominant mechanism to form slowly rotating stars along the split main sequences. As the observations of the rotation velocity distribution among B- and A-type stars in binaries of larger separations hint at a much stronger effect of braking with age, we discuss the consequences of relaxing the constraints of the dynamical tides theory.Comment: 14 pages, 10 figures, 2 tables, accepted for publication in MNRA

Genetic Background of Patients from a University Medical Center in Manhattan: Implications for Personalized Medicine

Background: The rapid progress currently being made in genomic science has created interest in potential clinical applications; however, formal translational research has been limited thus far. Studies of population genetics have demonstrated substantial variation in allele frequencies and haplotype structure at loci of medical relevance and the genetic background of patient cohorts may often be complex. Methods and Findings: To describe the heterogeneity in an unselected clinical sample we used the Affymetrix 6.0 gene array chip to genotype self-identified European Americans (N = 326), African Americans (N = 324) and Hispanics (N = 327) from the medical practice of Mount Sinai Medical Center in Manhattan, NY. Additional data from US minority groups and Brazil were used for external comparison. Substantial variation in ancestral origin was observed for both African Americans and Hispanics; data from the latter group overlapped with both Mexican Americans and Brazilians in the external data sets. A pooled analysis of the African Americans and Hispanics from NY demonstrated a broad continuum of ancestral origin making classification by race/ethnicity uninformative. Selected loci harboring variants associated with medical traits and drug response confirmed substantial within-and between-group heterogeneity. Conclusion: As a consequence of these complementary levels of heterogeneity group labels offered no guidance at the individual level. These findings demonstrate the complexity involved in clinical translation of the results from genome-wide association studies and suggest that in the genomic era conventional racial/ethnic labels are of little value.National Heart Lung and Blood Institute (NHLBI/NIH)[RO1 HL53353]Andrea and Charles Bronfman Philantropie

Prognostic Value of Gamma-Glutamyl Transpeptidase to Lymphocyte Count Ratio in Patients With Single Tumor Size ≤ 5 cm Hepatocellular Carcinoma After Radical Resection

Prediction of prognosis of hepatocellular carcinoma (HCC) has shown an important role in improving treatment outcomes and preventing disease progression, however, the prognostic indicator of HCC is still lacking. The purpose of this study is to investigate the predictive value of GLR (gamma-glutamyl transpeptidase to lymphocyte count ratio) in single HCC with a tumor size (TS) ≤ 5 cm. A retrospective analysis was performed on 272 patients with TS ≤ 5 cm who underwent radical resection. The Pearson χ2 test was applied to discuss the relationship between HCC and GLR, alpha-fetoprotein (AFP). Then univariate and multivariate analysis was utilized to predict the risk factors for survival prognosis in patients. In this study, GLR showed a positive relation with tumor size, tumor-node-metastasis (TNM) stage, microvascular invasion, early recurrence, and serum aspartate aminotransferase (AST) level, while the AFP value only correlated with drinking. Elevated GLR value had poor overall survival (OS) and progression-free survival (PFS) of TS ≤ 5 cm HCC patients, GLR level and tumor size were closely related to the prognosis of small HCC patients compared with AFP. GLR may serve as a prognostic marker for dynamic monitoring of HCC patients with single TS ≤ 5 cm after radical resection

The First Release of the CSTAR Point Source Catalog from Dome A, Antarctica

In 2008 January the 24th Chinese expedition team successfully deployed the Chinese Small Telescope ARray (CSTAR) to DomeA, the highest point on the Antarctic plateau. CSTAR consists of four 14.5cm optical telescopes, each with a different filter (g, r, i and open) and has a 4.5degree x 4.5degree field of view (FOV). It operates robotically as part of the Plateau Observatory, PLATO, with each telescope taking an image every 30 seconds throughout the year whenever it is dark. During 2008, CSTAR #1 performed almost flawlessly, acquiring more than 0.3 million i-band images for a total integration time of 1728 hours during 158 days of observations. For each image taken under good sky conditions, more than 10,000 sources down to 16 mag could be detected. We performed aperture photometry on all the sources in the field to create the catalog described herein. Since CSTAR has a fixed pointing centered on the South Celestial Pole (Dec =-90 degree), all the sources within the FOV of CSTAR were monitored continuously for several months. The photometric catalog can be used for studying any variability in these sources, and for the discovery of transient sources such as supernovae, gamma-ray bursts and minor planets.Comment: 1 latex file and 9 figures The paper is accepted by PAS

The sky brightness and transparency in i-band at Dome A, Antarctica

The i-band observing conditions at Dome A on the Antarctic plateau have been investigated using data acquired during 2008 with the Chinese Small Telescope ARray. The sky brightness, variations in atmospheric transparency, cloud cover, and the presence of aurorae are obtained from these images. The median sky brightness of moonless clear nights is 20.5 mag arcsec^{-2} in the SDSS $i$ band at the South Celestial Pole (which includes a contribution of about 0.06 mag from diffuse Galactic light). The median over all Moon phases in the Antarctic winter is about 19.8 mag arcsec^{-2}. There were no thick clouds in 2008. We model contributions of the Sun and the Moon to the sky background to obtain the relationship between the sky brightness and transparency. Aurorae are identified by comparing the observed sky brightness to the sky brightness expected from this model. About 2% of the images are affected by relatively strong aurorae.Comment: There are 1 Latex file and 14 figures accepted by A