The anaphase promoting complex impacts repair choice by protecting ubiquitin signalling at DNA damage sites

Double-strand breaks (DSBs) are repaired through two major pathways, homology-directed recombination (HDR) and non-homologous end joining (NHEJ). While HDR can only occur in S/G2, NHEJ can happen in all cell cycle phases (except mitosis). How then is the repair choice made in S/G2 cells? Here we provide evidence demonstrating that APCCdh1 plays a critical role in choosing the repair pathways in S/G2 cells. Our results suggest that the default for all DSBs is to recruit 53BP1 and RIF1. BRCA1 is blocked from being recruited to broken ends because its recruitment signal, K63-linked poly-ubiquitin chains on histones, is actively destroyed by the deubiquitinating enzyme USP1. We show that the removal of USP1 depends on APCCdh1 and requires Chk1 activation known to be catalysed by ssDNA-RPA-ATR signalling at the ends designated for HDR, linking the status of end processing to RIF1 or BRCA1 recruitment.We thank S.-Y. Lin (MD Anderson Cancer Center) for cell lines; J. Rosen (Baylor College of Medicine) for reagents; H. Masai (Tokyo Metropolitan Institute of Medical Science) for U2OS-Fucci cell line; D. Durocher (University of Toronto) for HeLa-Fucci cell line; E. Citterio (Netherlands Cancer Institute) for GFP-USP3 construct; M.S.Y. Huen (The University of Hong Kong) for RNF168 antibody. This work was performed with facilities and instruments in the Imaging Core of National Center for Protein Science (Beijing), the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the NIH (P30 AI036211, P30 CA125123 and S10 RR024574), the Integrated Microscopy Core at Baylor College of Medicine with funding from the NIH (HD007495, DK56338 and CA125123), and the John S. Dunn Gulf Coast Consortium for Chemical Genomics. We also thank other members of the Zhang lab for helpful discussion and support. This work was supported in part by an international collaboration grant (# 2013DFB30210) and a 973 Project grant (# 2013CB910300) from Chinese Minister of Science and Technology, in part by a Chinese National Natural Science Foundation grant (# 81171920), in part by a grant from The Committee of Science and Technology of Beijing Municipality, China (# Z141100000214015), and in part by NIH grants CA116097 and CA122623 to P.Z. J.J. is supported by grants from National Institutes of Health (R01GM102529) and the Welch Foundation (AU-1711). S.H. is supported by grants (# 81272488 and 81472795) from Chinese National Natural Science Foundation. Y.Z. is supported by grants from the National Natural Scientific Foundation of China (No. 81430055), Programs for Changjiang Scholars and Innovative Research Team in University (No. IRT_15R13).S

Parallelism and non-parallelism in diabetic nephropathy and diabetic retinopathy

Diabetic nephropathy (DN) and diabetic retinopathy (DR), as microvascular complications of diabetes mellitus, are currently the leading causes of end-stage renal disease (ESRD) and blindness, respectively, in the adult working population, and they are major public health problems with social and economic burdens. The parallelism between the two in the process of occurrence and development manifests in the high overlap of disease-causing risk factors and pathogenesis, high rates of comorbidity, mutually predictive effects, and partial concordance in the clinical use of medications. However, since the two organs, the eye and the kidney, have their unique internal environment and physiological processes, each with specific influencing molecules, and the target organs have non-parallelism due to different pathological changes and responses to various influencing factors, this article provides an overview of the parallelism and non-parallelism between DN and DR to further recognize the commonalities and differences between the two diseases and provide references for early diagnosis, clinical guidance on the use of medication, and the development of new drugs

Diversity of House Dust Mite Species in Xishuangbanna Dai, a Tropical Rainforest Region in Southwest China

. Purpose. To survey the species diversity of home dust mites (HDM) in Xishuangbanna, a tropical rainforest region in Southwest China. Methods. From August 2010 to January 2011, mite-allergic patients and healthy controls were invited to participate. Dust samples from the patients' homes were collected, and mites in the samples were isolated. Permanent slides were prepared for morphologically based species determination. Results. In total, 6316 mite specimens of morphologically identifiable species were found in 233 dust samples taken from 41 homes. The result shows that the mite family of Pyroglyphidae occupied the highest percentage of the total amount of mites collected, followed by Cheyletidae family. The most common adult Pyroglyphidae mites were Dermatophagoides (D.) farinae, D. pteronyssinus, and D. siboney. The most common mites found from other families were Blomia tropicalis, Tyrophagus putrescentiae, and Aleuroglyphus ovatus. Four main allergenic dust mite species D. farinae, D. pteronyssinus, D. siboney, and Blomia tropicalis were found to be coinhabiting in 6/41 homes. Conclusion. The HDM population in homes in Xishuangbanna, a tropical rainforest region in Southwest China, has its own characteristics. It has rich dust mite species and the dust mite densities do not show significant variation across seasons

Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis in Multi-Ethnic Region, Xinjiang Uygur Autonomous Region, China

<div><h3>Background</h3><p>The multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) has emerged as a global threat. Xinjiang is a multi-ethnic region and suffered second highest incidence of TB in China. However, epidemiological information on MDR and XDR TB is scarcely investigated.</p> <h3>Methodology/Principal Findings</h3><p>A prospective study was conducted to analyze the prevalence of MDR and XDR TB and the differences of drug resistance TB between Chinese Han and other nationalities population at Chest Hospital of Xinjiang Uygur Autonomous Region, China. We performed in vitro drug susceptibility testing of <em>Mycobacterium tuberculosis</em> to first- and second-line anti-tuberculosis drugs for all 1893 culture confirmed positive TB cases that were diagnosed between June 2009 and June 2011. Totally 1117 (59.0%, 95% CI, 56.8%–61.2%) clinical isolates were resistant to ≥1 first-line drugs; the prevalence of MDR TB was 13.2% (95% CI, 11.7%–14.7%), of which, 77 (30.8%; 95% CI, 25.0%–36.6%) and 31 (12.8%; 95% CI, 8.6%–17.0%) isolates were pre-XDR and XDR TB respectively. Among the MDR/XDR TB, Chinese Han patients were significantly less likely to be younger with an odds ratio 0.42 for age 20–29 years and 0.52 for age 40–49 years; <em>P</em>_trend = 0.004), and Chinese Han patients has a lower prevalence of XDR TB (9.6%) than all the other nationality (14.9%).</p> <h3>Conclusions/Significance</h3><p>The burden of drug resistance TB cases is sizeable, which highlights an urgent need to reinforce the control, detection and treatment strategies for drug resistance TB. However, the difference of MDR and XDR TB between Chinese Han and other nationalities was not observed.</p> </div

In-orbit background simulation of a type-B CATCH satellite

The Chasing All Transients Constellation Hunters (CATCH) space mission plans to launch three types of micro-satellites (A, B, and C). The type-B CATCH satellites are dedicated to locating transients and detecting their time-dependent energy spectra. A type-B satellite is equipped with lightweight Wolter-I X-ray optics and an array of position-sensitive multi-pixel Silicon Drift Detectors. To optimize the scientific payloads for operating properly in orbit and performing the observations with high sensitivities, this work performs an in-orbit background simulation of a type-B CATCH satellite using the Geant4 toolkit. It shows that the persistent background is dominated by the cosmic X-ray diffuse background and the cosmic-ray protons. The dynamic background is also estimated considering trapped charged particles in the radiation belts and low-energy charged particles near the geomagnetic equator, which is dominated by the incident electrons outside the aperture. The simulated persistent background within the focal spot is used to estimate the observation sensitivity, i.e. 4.22$\times$10$^{-13}$ erg cm$^{-2}$ s$^{-1}$ with an exposure of 10$^{4}$ s and a Crab-like source spectrum, which can be utilized further to optimize the shielding design. The simulated in-orbit background also suggests that the magnetic diverter just underneath the optics may be unnecessary in this kind of micro-satellites, because the dynamic background induced by charged particles outside the aperture is around 3 orders of magnitude larger than that inside the aperture.Comment: 24 pages, 13 figures, 7 tables, accepted for publication in Experimental Astronom

A Comprehensive Study of Gamma-Ray Burst Optical Emission: I. Flares and Early Shallow Decay Component

Well-sampled optical lightcurves of 146 gamma-ray bursts (GRBs) are compiled from the literature. By empirical fitting we identify eight possible emission components and summarize the results in a "synthetic" lightcurve. Both optical flare and early shallow-decay components are likely related to long-term central engine activities. We focus on their statistical properties in this paper. Twenty-four optical flares are obtained from 19 GRBs. The isotropic R-band energy is smaller than 1% of $E_{\gamma, \rm iso}$. The relation between isotropic luminosities of the flares and gamma-rays follows $L^{\rm F}_{\rm R, iso}\propto L_{{\gamma}, \rm iso}^{1.11\pm 0.27}$. Later flares tend to be wider and dimmer, i.e., $w^{\rm F}\sim t^{\rm F}_{\rm p}/2$ and $L^{\rm F}_{\rm R, iso}\propto [t^{\rm F}_{\rm p}/(1+z)]^{-1.15\pm0.15}$. The detection probability of the optical flares is much smaller than that of X-ray flares. An optical shallow decay segment is observed in 39 GRBs. The relation between the break time and break luminosity is a power-law, with an index of $-0.78\pm 0.08$, similar to that derived from X-ray flares. The X-ray and optical breaks are usually chromatic, but a tentative correlation is found. We suggest that similar to the prompt optical emission that tracks $\gamma$-rays, the optical flares are also related to the erratic behavior of the central engine. The shallow decay component is likely related to a long-lasting spinning-down central engine or piling up of flare materials onto the blastwave. Mixing of different emission components may be the reason of the diverse chromatic afterglow behaviors.Comment: 43 pages, 13 figures, 3 tables, accepted for publication in Ap

Traffic4cast at NeurIPS 2022 -- Predict Dynamics along Graph Edges from Sparse Node Data: Whole City Traffic and ETA from Stationary Vehicle Detectors

The global trends of urbanization and increased personal mobility force us to rethink the way we live and use urban space. The Traffic4cast competition series tackles this problem in a data-driven way, advancing the latest methods in machine learning for modeling complex spatial systems over time. In this edition, our dynamic road graph data combine information from road maps, $10^{12}$ probe data points, and stationary vehicle detectors in three cities over the span of two years. While stationary vehicle detectors are the most accurate way to capture traffic volume, they are only available in few locations. Traffic4cast 2022 explores models that have the ability to generalize loosely related temporal vertex data on just a few nodes to predict dynamic future traffic states on the edges of the entire road graph. In the core challenge, participants are invited to predict the likelihoods of three congestion classes derived from the speed levels in the GPS data for the entire road graph in three cities 15 min into the future. We only provide vehicle count data from spatially sparse stationary vehicle detectors in these three cities as model input for this task. The data are aggregated in 15 min time bins for one hour prior to the prediction time. For the extended challenge, participants are tasked to predict the average travel times on super-segments 15 min into the future - super-segments are longer sequences of road segments in the graph. The competition results provide an important advance in the prediction of complex city-wide traffic states just from publicly available sparse vehicle data and without the need for large amounts of real-time floating vehicle data.Comment: Pre-print under review, submitted to Proceedings of Machine Learning Researc