CHFR is important for the first wave of ubiquitination at DNA damage sites

Protein ubiquitination plays an important role in activating the DNA damage response and maintain-ing genomic stability. In response to DNA double-strand breaks (DSBs), a ubiquitination cascade occurs at DNA lesions. Here, we show that checkpoint with Forkhead-associated (FHA) and RING finger domain protein (CHFR), an E3 ubi-quitin ligase, is recruited to DSBs by poly(ADP-ribose) (PAR). At DSBs, CHFR regulates the first wave of protein ubiquitination. Moreover, CHFR ubiquitinates PAR polymerase 1 (PARP1) and regulates chromatin-associated PARP1 in vivo. Thus, these results demonstrate that CHFR is an important E3 ligase in the early stage of the DNA damage response, which mediates the crosstalk between ubiquitination and poly-ADP-ribosylation

Mulberry biomass-derived nanomedicines mitigate colitis through improved inflamed mucosa accumulation and intestinal microenvironment modulation

The therapeutic outcomes of conventional oral medications against ulcerative colitis (UC) are restricted by inefficient drug delivery to the colitis mucosa and weak capacity to modulate the inflammatory microenvironment. Herein, a fluorinated pluronic (FP127) was synthesized and employed to functionalize the surface of mulberry leaf-derived nanoparticles (MLNs) loading with resveratrol nanocrystals (RNs). The obtained FP127@RN-MLNs possessed exosome-like morphologies, desirable particle sizes (around 171.4 nm), and negatively charged surfaces (â 14.8 mV). The introduction of FP127 to RN-MLNs greatly improved their stability in the colon and promoted their mucus infiltration and mucosal penetration capacities due to the unique fluorine effect. These MLNs could efficiently be internalized by colon epithelial cells and macrophages, reconstruct disrupted epithelial barriers, alleviate oxidative stress, provoke macrophage polarization to M2 phenotype, and down-regulate inflammatory responses. Importantly, in vivo studies based on chronic and acute UC mouse models demonstrated that oral administration of chitosan/alginate hydrogel-embedding FP127@RN-MLNs achieved substantially improved therapeutic efficacies compared with nonfluorinated MLNs and a first-line UC drug (dexamethasone), as evidenced by decreased colonic and systemic inflammation, integrated colonic tight junctions, and intestinal microbiota balance. This study brings new insights into the facile construction of a natural, versatile nanoplatform for oral treatment of UC without adverse effects.We are grateful to Dr. J. Sun from University of Oxford for his corrections and improvement of this manuscript. Funding: This study was supported by the National Natural Science Foundation of China (82072060 and 22008201), the Fundamental Research Funds for the Central Universities (SWU-XDPY22006), the Venture & Innovation Support Program for Chongqing Overseas Returnees (2205012980212766), the Natural Science Foundation Project of Chongqing (cstc2020jcyj-msxmX0292), and the Natural Science Foundation Project of Chongqing for Distinguished Young Scholar. Author contributions: W.Y., M.W., X.S., and B.X. designed experiments, supervised the project, and wrote the manuscript draft. W.Y., Y.M., H.X., Z.Z., J.W., C.X., W.S., and E.Z. performed the experiments. R.L.R., S.C.K., M.W., X.S., and B.X. edited and revised the manuscript. All authors have approved the final version of the manuscript. Competing interests: The authors declare that there is no con flict of interest regarding the publication of this article

Nicotine Enhances Staphylococcus epidermidis Biofilm Formation by Altering the Bacterial Autolysis, Extracellular DNA Releasing, and Polysaccharide Intercellular Adhesin Production

Staphylococcus epidermidis is a common bacterial colonizer of human skin and mucous membranes, yet it has emerged as an important nosocomial pathogen largely due to its ability to form biofilms. Tobacco smoke has been demonstrated as a contributor to various infection diseases by improving the biofilm formation of multiple bacterial species; however, the association between tobacco smoke and S. epidermidis biofilm is still unclear. In this study, we tested the effect of nicotine, one of the most active components of tobacco, on S. epidermidis biofilm formation, and we studied the underlying mechanisms. Our results showed that nicotine promoted the biofilm formation of S. epidermidis 1457 strain (SE1457) and enhanced its initial attachment to a polyethylene surface as well as polysaccharide intercellular adhesin (PIA) production. In addition, an increased extracellular DNA release and a higher autolysis rate of SE1457 was detected after nicotine treatment, which was consistent with the increased ratio of dead cells in nicotine-treated SE1457 biofilm observed with confocal laser-scanning microscopy. Furthermore, the effect of nicotine on several autolysis-related and biofilm-related gene knockout mutants of SE1457 was tested. It showed that in ΔsaeRS, ΔlytSR, and ΔsceD, nicotine induced increase in biofilm formation was similar to that in SE1457; but in ΔarlRS, ΔatlE, and ΔicaC, the effect was obviously impaired. Consistently, the increase of the bacterial autolysis rate in ΔarlRS and ΔatlE induced by nicotine was not as significant as that in SE1457. Meanwhile, the growth inhibition of nicotine on SE1457 was observed, and it was much less on ΔarlRS and restored by the arlRS complementation. The arlRS transcription in SE1457 was inhibited by nicotine during cultivation as indicated by a promoter reporter assay using green fluoresent protein. Taken together, our study indicates that nicotine improves S. epidermidis biofilm formation by promoting its initial attachment and intercellular accumulation; the arlRS, atlE, and ica genes mediating bacterial autolysis and PIA production play an important role in this process

Physical dynamics structures and oxygen budget of summer hypoxia in the Pearl River Estuary

A summertime hypoxia sporadically occurred in the lower Pearl River Estuary (PRE) for more than three decades. Although its mechanism has already been extensively studied, the topic on why seasonal hypoxia is persistent in patchy waters is still an open question. Here, we presented the investigation of physical dynamics structures and dissolved oxygen (DO) processes for controlling the spatial distribution and maintenance of coastal hypoxia. Field observations were conducted in the 2015 summer in the PRE and adjacent shelf sea. High river discharge forms intense haloclines in the river plume, while salinity intrusion of shelf benthic waters results in a notable pycnocline at the top of salt wedge. A mid-depth transitional layer with the weakest mixing over water column functions as a barrier for DO vertical exchange between river plume and shelf salt wedge. A benthic hypoxia in the 2015 summer appears at the overlapping zone between river plume and shelf salt wedge. Based on physical and biological processes, a DO budget for the hypoxic system was established. The DO advection by gravitational circulation from shelf benthic waters is roughly balanced by bacterial respiration in water column. The DO diffusion from river plume to benthic hypoxia is completely inhibited by the barrier layer. The patchy distribution of benthic hypoxia for the 30-yr period in the PRE can be satisfactorily predicted by the numerical simulations of the overlapping zones between river plume and shelf salt wedge. These findings will have an important implication for predicting and mitigating coastal hypoxia. Physical structures and processes of DO dynamics were investigated to understand the spatial distribution and maintenance of coastal hypoxia. Summertime hypoxia appear near the head of shelf salinity intrusion, where a mid-depth barrier layer inhibits the vertical exchange between river plume and shelf salt wedge. DO advection by gravitational circulation from DO-rich shelf benthic waters is roughly balanced by bacterial respiration in water column. The spatial distribution of coastal hypoxia can be well predicted by the overlapping zone between river plume and shelf salt wedge

Progress in the research of Ground Bounce Removal for Landmine Detection with Ground Penetrating radar

Abstract Downward looking ground penetrating radar (GPR) has been considered a viable technology for landmine detection. For such a GPR with the antennas positioned very close to the ground surface, the reflections from the ground surface, i.e., the ground bounce, are very strong and can completely dominate the weak returns from shallowly buried plastic mines. Hence, one of the key challenges of using GPRs for landmine detection is to remove the ground bounce as completely as possible without altering the landmine return. In this paper, we first review existing ground bounce removal algorithms. Then two newly devised adaptive ground bounce removal algorithms, ASaS (Adaptive Shifted and Scaled algorithm) and RLP (Robust Linear Prediction) will be presented. Both ASaS and RLP are based on a flexible data model applicable to rough ground surface and an effective generalized likelihood ratio (GLR) based non-homogeneous detector is devised to further improve their performance. Experimental results show that the proposed algorithms are more robust than conventional ground bounce removal algorithms

Development of Flow Cytometric Assay for Detecting Papillary Thyroid Carcinoma Related hsa-miR-146b-5p through Toehold-Mediated Strand Displacement Reaction on Magnetic Beads

In this work, a simple enzyme-free flow cytometric assay (termed as TSDR-based flow cytometric assay) has been developed for the detection of papillary thyroid carcinoma (PTC)-related microRNA (miRNA), hsa-miR-146b-5p with high performance through the toehold-mediated strand displacement reaction (TSDR) on magnetic beads (MBs). The complementary single-stranded DNA (ssDNA) probe of hsa-miR-146b-5p was first immobilized on the surface of MB, which can partly hybridize with the carboxy-fluorescein (FAM)-modified ssDNA, resulting in strong fluorescence emission. In the presence of hsa-miR-146b-5p, the TSDR is trigged, and the FAM-modified ssDNA is released form the MB surface due to the formation of DNA/RNA heteroduplexes on the MB surface. The fluorescence emission change of MBs can be easily read by flow cytometry and is strongly dependent on the concentration of hsa-miR-146b-5p. Under optimal conditions, the TSDR-based flow cytometric assay exhibits good specificity, a wide linear range from 5 to 5000 pM and a relatively low detection limit (LOD, 3σ) of 4.21 pM. Moreover, the practicability of the assay was demonstrated by the analysis of hsa-miR-146b-5p amounts in different PTC cells and clinical PTC tissues

PALB2 Links BRCA1 and BRCA2 in the DNA-Damage Response

SummaryBRCA1 and BRCA2 are often mutated in familial breast and ovarian cancer. Both tumor suppressors play key roles in the DNA-damage response [1, 2]. However, it remains unclear whether these two tumor suppressor function together in the same DNA-damage response pathway. Here, we show that BRCA1 associates with BRCA2 through PALB2/FANCN, a major binding partner of BRCA2 [3]. The interaction between BRCA1 and BRCA2 is abrogated in PALB2-deficient Fanconi anemia cells and in the cells depleted of PALB2 by small interfering RNA. Moreover, we show that BRCA1 promotes the concentration of PALB2 and BRCA2 at DNA-damage sites and the interaction between BRCA1 and PALB2 is important for the homologous recombination repair. Taken together, our results indicate that BRCA1 is an upstream regulator of BRCA2 in the DNA-damage response, and PALB2 is the linker between BRCA1 and BRCA2