Thurstonolsson7016

ATR is a master regulator of cell response to replication stress. Adequate activation of ATR is essential for preventing genome aberrance induced by replication defect. However, the mechanism underlying ATR activation is not fully understood. Here, we identify that RBMX is an ssDNA binding protein that orchestrates a novel pathway to activate ATR. Using super-resolution STORM, we observe that RBMX and RPA bind to adjacent but nonoverlapping sites on ssDNA in response to replication stress. RBMX then binds to and facilitates positioning of TopBP1, which activates nearby ATR associated with RPA. In addition, ATR activation by ssDNA-RBMX-TopBP1 is independent of ssDNA-dsDNA junction and 9-1-1 complex. ChIP-seq analysis reveals that RBMX/RPA are highly enriched on repetitive DNAs, which are considered as fragile sites with high replication stress. RBMX depletion leads to defective localization of TopBP1 to replication stressed sites and inadequate activation of ATR. Furthermore, cells with deficient RBMX demonstrate replication defect, leading to formation of micronuclei and a high rate of sister-chromatin exchange, indicative of genome instability. Together, the results identify a new ssDNA-RBMX-TopBP1 pathway that is specifically required for activation of ATR on repetitive DNAs. Therefore, RBMX is a key factor to ensure genome stability during replication.Estrogen receptor α (ERα) is the crucial factor in ERα-positive breast cancer progression. Endocrine therapies targeting ERα signaling is one of the widely used therapeutic strategies for breast cancer. However, a large number of the patients become refractory to therapy. Abnormal expression of ERα co-regulator facilitates breast cancer development and tendency of endocrine resistance. Thus, it is necessary to discover the novel co-regulators modulating ERα action. Here, we demonstrate that histone deubiquitinase USP22 is highly expressed in breast cancer samples compared with that in the benign tissue, and high expression of USP22 was significantly associated with poorer overall survival in BCa samples. Moreover, USP22 associates with ERα to be involved in maintenance of ERα stability. USP22 enhances ERα-induced transactivation. We further provide the evidence that USP22 is recruited together with ERα to cis-regulatory elements of ERα target gene. USP22 promotes cell growth even under hypoxia condition and with the treatment of ERα antagonist in breast cancer cells. Importantly, the deubiquitination activity of USP22 is required for its functions on maintenance of ERα stability, thereby enhancing ERα action and conferring endocrine resistance in breast cancer.The niobium nitride (NbN) nanowires fabricated with the high-quality ultra-thin NbN film with a thickness of 3 nm-6 nm were widely used for single photon detectors. These nanowires had a low aspect ratio, less than 120. However, increasing the thickness and the aspect ratio of highly-uniformed NbN nanowires without reducing the superconductivity is crucial for the device in detecting high-energy photons. selleck kinase inhibitor In this paper, a high-quality superconducting nanowire with aspect ratio of 11 was fabricated with optimized process, which produced a superconducting critical current of 550 μA and a hysteresis of 36 μA at 2.2 K. With the optimization of the electron beam lithography process of AR-P6200.13 and the adjustion of the chamber pressure, the discharge power, as well as the auxiliary gas in the process of reactive ion etching (RIE), the meandered NbN nanowire structure with the minimum width of 80 nm, the duty cycle of 11 and the depth of 100 nm were finally obtained on the silicon nitride substrate. Simultaneously, the sidewall of nanowire was vertical and smooth, and the corresponding depth-width ratio was more than 11. The fabricated NbN nanowire will be applied to the detection of soft X-ray photon emitted from pulsars with a sub-10 ps time resolution.Metabotropic GABAB G protein-coupled receptor functions as a mandatory heterodimer of GB1 and GB2 subunits and mediates inhibitory neurotransmission in the central nervous system. Each subunit is composed of the extracellular Venus flytrap (VFT) domain and transmembrane (TM) domain. Here we present cryo-EM structures of full-length human heterodimeric GABAB receptor in the antagonist-bound inactive state and in the active state complexed with an agonist and a positive allosteric modulator in the presence of Gi1 protein at a resolution range of 2.8-3.0 Å. Our structures reveal that agonist binding stabilizes the closure of GB1 VFT, which in turn triggers a rearrangement of TM interfaces between the two subunits from TM3-TM5/TM3-TM5 in the inactive state to TM6/TM6 in the active state and finally induces the opening of intracellular loop 3 and synergistic shifting of TM3, 4 and 5 helices in GB2 TM domain to accommodate the α5-helix of Gi1. We also observed that the positive allosteric modulator anchors at the dimeric interface of TM domains. These results provide a structural framework for understanding class C GPCR activation and a rational template for allosteric modulator design targeting the dimeric interface of GABAB receptor.Resveratrol (RES) is a natural polyphenol with potential as an adjunctive therapeutic modality for periodontitis. However, its inferior pharmacokinetics and toxicity concerns about its commonly used solvent dimethyl sulfoxide (DMSO) hinder translation to clinical applicability. Our study aimed to investigate the comparative antimicrobial properties of RES and its analogues (pterostilbene [PTS], oxyresveratrol [OXY] and piceatannol [PIC]), utilizing 2-hydroxypropyl-β-cyclodextrin (HPβCD) as a solubiliser, which has a well-documented safety profile and FDA approval. These properties were investigated against Fusobacterium nucleatum, a key periodontal pathogen. PTS demonstrated the most potent antibacterial effects in HPβCD, with MIC > 60-fold lower than that of RES, OXY and PIC. In addition, PTS inhibited F. nucleatum biofilm formation. PTS exerted antimicrobial effects by eliciting leakage of cellular contents, leading to loss of bacterial cell viability. PTS also conferred immunomodulatory effects on F. nucleatum-challenged macrophages via upregulation of antioxidant pathways and inhibition of NF-κB activation.