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Repair of DNA double-strand breaks (DSBs) is essential for genome integrity, and is accompanied by transcriptional repression at the DSB regions. However, the mechanisms how DNA repair induces transcriptional inhibition remain elusive. Here, it is identified that BRD7 participates in DNA damage response (DDR) and is recruited to the damaged chromatin via ATM signaling. Mechanistically, BRD7 joins the polycomb repressive complex 2 (PRC2), the nucleosome remodeling and histone deacetylation (NuRD) complex at the damaged DNA and recruits E3 ubiquitin ligase RNF168 to the DSBs. Furthermore, ATM-mediated BRD7 phosphorylation is required for recruitment of the PRC2 complex, NuRD complex, DSB sensor complex MRE11-RAD50-NBS1 (MRN), and RNF168 to the active transcription sites at DSBs, resulting in transcriptional repression and DNA repair. Moreover, BRD7 deficiency sensitizes cancer cells to PARP inhibition. Collectively, BRD7 is crucial for DNA repair and DDR-mediated transcription repression, which may serve as a therapeutic target. The findings identify the missing link between DNA repair and transcription regulation that maintains genome integrity.

Objective Thyroid-stimulating hormone (TSH) levels are associated with serum lipid concentrations in the general nonpregnant population. Here, we aimed to establish trimester-specific reference intervals and to explore the associations of their variations within the specific reference intervals during pregnancy. Methods Trimester-specific reference intervals were established according to the Clinical and Laboratory Standard Institute EP28-A3c guidelines using a direct sampling method based on a large prospective cohort. After making one-to-one matches, correlation analyses between TSH and lipid index levels, especially within the reference intervals, were conducted. Result A total of 1648 pregnant women for TSH and 2045 subjects for lipids were recruited to establish the trimester-specific reference intervals. The upper reference limit (90% confidence interval) of TSH for pregnant women in the first trimester is 3.95 (3.66–4.29) mIU/L, which is very close to the default value (4.0 mIU/L) recommended by the American Thyroid Association in 2017. Apart from triglyceride and high-density lipoprotein cholesterol, TSH levels were positively associated with the serum concentrations of total cholesterol, low-density lipoprotein cholesterol, non–high-density lipoprotein cholesterol (non–HDL-C), and remnant cholesterol (RC) either in the entire range or within the specific reference intervals. Of note, the positive correlations between TSH and non–HDL-C and RC were, albeit similarly weak (r  < 0.25), relatively more robust (P  < .001). Conclusion In this study, we showed positive correlations between TSH and lipid components within trimester-specific reference intervals, highlighting the need for the integrated management of pregnant women over age 35 and with nonoptimal lipid status in China. [ABSTRACT FROM AUTHOR]

Immunogenic cell death (ICD) approaches by encumbering mitochondrial functions provide great promise for the treatment of malignant tumors, but these kinds of ICD strategies are still in their infancy. Here, one multifunctional drug‐loaded, cascade‐targeted, and enzyme‐instructed self‐assembling peptide nanomedicine (Comp. 4) for ICD‐based cancer therapy is constructed. Comp. 4 consists of 1) lonidamine (LND) that specifically interferes with mitochondrial functions; 2) a programmed death ligand 1 (PD‐L1) binding peptide sequence (NTYYEDQG) and a mitochondria‐specific motif (triphenylphosphonium, TPP) that can sequentially control the cell membrane and mitochondria targeting capacities, respectively; and 3) a ‐GDFDFpDY‐ assembly core to in situ organize peptide assemblies responsive to alkaline phosphatase (ALP). Comp. 4 demonstrates noticeable structural and morphological transformations in the presence of ALP and produces peptide assemblies in mouse colon cancer cells (CT26) with high expressions of both ALP and PD‐L1. Moreover, the presence of PD‐L1‐ and mitochondria‐specific motifs can assist Comp. 4 for effective endocytosis and endosomal escape, forming peptide assemblies and delivering LND into mitochondria. Consequently, Comp. 4 shows superior capacities to in vivo induce abundant mitochondrial oxidative stress, provoke robust ICD responses, and produce an immunogenic tumor microenvironment, successfully inhibiting CT26 tumor growth by eliciting a systemic ICD‐based antitumor immunity. [ABSTRACT FROM AUTHOR]

Totally 789 students from 18 schools (9 primary schools and 9 junior high schools) at a medium managed level from Shanghai, Wenzhou, and Aojiang, which are located in the Eastern coastal developed areas of China were investigated with the questionnaire of Hong Kong Classroom Environment Scale in this study. The result indicates that the actual classroom environment in the Eastern coastal developed areas at the present stage of curriculum reform is as follows. (1) The satisfaction of the students is above the average. Teachers' involvement and support are higher than collaboration, classroom order and the student involvement. (2) There are significant differences between urban and rural areas. The big cities are better than the middle-sized cities, while the latter are better than the counties in the aspects of collaboration, teacher involvement and support. The big cities are better than counties, but the counties are better than the middle-sized cities in the aspects of classroom order and student involvement. (3) The three main types of the actual classroom environment are high, middle and low ones, which distribute in a descending way in big cities, middle-sized cities and counties. (4) Per capita GDP of a region is a main factor affecting classroom environment.

The flexibility of the free-floating flexible space manipulator system's link and joint may affect the control accuracy and cause vibrations. We studied the dynamics modeling, joint trajectory tracking control, and vibration suppressing problem of free-floating flexible-link and flexible-joints space manipulator system with external interference and uncertain parameter. The system's dynamic equations are established using linear momentum conservation, angular momentum conservation, assumed mode method, and Lagrange equation. Then, the system's singular perturbation model is established, and a hybrid control is presented. For the slow subsystem, a robust fuzzy sliding mode control is proposed to realize the joint desired trajectory tracking. For the fast subsystem, a speed difference feedback control and a linear-quadratic optimal control are designed to suppress the vibration caused by the flexible joints and the flexible link separately. The simulation comparison experiments under different conditions are taken. The simulate results demonstrate the proposed hybrid control's validity. [ABSTRACT FROM AUTHOR]

Background: MRI is the most effective diagnostic tool of osteonecrosis of the femoral head (ONFH), especially for early diagnosis, but its detection of subchondral or cortical fractures is less accurate than CT. Therefore, it is difficult to accurately stage ONFH in the peri‐collapse period by MRI. Purpose To improve the accuracy of MR for distinguishing between Association Research Circulation Osseous (ARCO) stages 2 and 3A in ONFH. Study Type: Retrospective. Subjects: One hundred and fifty five cases of ARCO stage 2/3A of ONFH underwent MR examinations, M/F = 72/83. CT was used as reference standard for collapse, which was decided by an orthopedist and a radiologist in consultation. Field Strength/Sequence: 3 T/axial and coronal T1‐weighted Turbo Spin Echo (T1W TSE) sequence, axial T2‐weighted fat‐saturated (T2W FS) TSE sequence, and coronal proton density‐weighted imaging (PDWI)‐FS‐Dixon fat/water image. Assessment Five potential MR signs (the maximum width of the necrotic‐viable interface, bone marrow edema (BME), irregular articular surface of the femoral head, T2 heterogeneous high signal, and the absence of a necrotic‐viable interface with the morphology of closed loop) were evaluated blindly by five radiologists independently and the total scores of different combinations of MR signs were calculated. Statistical Tests: Mann–Whitney U test and Chi‐square test were used to evaluate age, gender, and MR signs differences between the two groups. ROC curve was used to access the distinguishing value of MR signs. The consistency of the five radiologists was analyzed by intraclass correlation coefficient. Results: The area under the curve of the combined MR signs 2 for distinguishing between ARCO stages 2 and 3A was the greatest (0.967), sensitivity and specificity were 100.00% and 88.71% respectively, and greater than 1 was the threshold. Data Conclusion: Combined MR signs 2 has great values in distinguishing between ARCO stages 2 and 3A in ONFH, thus helping clinical therapy. Level of Evidence: 4 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]