Replication forks, chromatin loops and dormant replication origins

The plasticity of replication origin usage during mitosis is associated with longer-term changes to chromatin loop organization

Chk1 inhibits replication factory activation but allows dormant origin firing in existing factories

Replication origins are licensed by loading MCM2-7 hexamers before entry into S phase. However, only ∼10% of licensed origins are normally used in S phase, with the others remaining dormant. When fork progression is inhibited, dormant origins initiate nearby to ensure that all of the DNA is eventually replicated. In apparent contrast, replicative stress activates ataxia telangiectasia and rad-3–related (ATR) and Chk1 checkpoint kinases that inhibit origin firing. In this study, we show that at low levels of replication stress, ATR/Chk1 predominantly suppresses origin initiation by inhibiting the activation of new replication factories, thereby reducing the number of active factories. At the same time, inhibition of replication fork progression allows dormant origins to initiate within existing replication factories. The inhibition of new factory activation by ATR/Chk1 therefore redirects replication toward active factories where forks are inhibited and away from regions that have yet to start replication. This minimizes the deleterious consequences of fork stalling and prevents similar problems from arising in unreplicated regions of the genome

Artificial intelligence - based ultrasound elastography for disease evaluation - a narrative review

Ultrasound elastography (USE) provides complementary information of tissue stiffness and elasticity to conventional ultrasound imaging. It is noninvasive and free of radiation, and has become a valuable tool to improve diagnostic performance with conventional ultrasound imaging. However, the diagnostic accuracy will be reduced due to high operator-dependence and intra- and inter-observer variability in visual observations of radiologists. Artificial intelligence (AI) has great potential to perform automatic medical image analysis tasks to provide a more objective, accurate and intelligent diagnosis. More recently, the enhanced diagnostic performance of AI applied to USE have been demonstrated for various disease evaluations. This review provides an overview of the basic concepts of USE and AI techniques for clinical radiologists and then introduces the applications of AI in USE imaging that focus on the following anatomical sites: liver, breast, thyroid and other organs for lesion detection and segmentation, machine learning (ML) - assisted classification and prognosis prediction. In addition, the existing challenges and future trends of AI in USE are also discussed

Protective immunity against Trichinella spiralis infection induced by TsNd vaccine in mice

BACKGROUND: We have previously reported that Trichinella spiralis Nudix hydrolase (TsNd) bound to intestinal epithelial cells (IECs), and vaccination of mice with recombinant TsNd protein (rTsNd) produced a partial protective immunity. The aim of this study was to investigate the immune protection induced by TsNd DNA vaccine. METHODS: The full-length cDNA sequence of TsNd gene was cloned into pcDNA3.1 and used to immunize BALB/c mice by intramuscular injection. Transcription and expression of TsNd were detected by RT-PCR and IFT. The levels of specific IgA, IgG, IgG1 and IgG2a, and cytokines were assayed by ELISA at weeks 0, 6 and 8 post-immunization. The immune protection of TsNd DNA vaccine against challenge infection was investigated. RESULTS: Immunization of mice with TsNd DNA elicited a systemic Th1/Th2 immune response and a local mucosal IgA response. The in vitro transcription and expression of TsNd gene was observed at all developmental stages of T. spiralis (ML, IIL, AW and NBL). Anti-rTsNd IgG levels were increased after immunization and levels of IgG1 were obviously higher than that of IgG2a. Intestinal specific IgA levels of immunized mice were significantly higher than those of vector and PBS control mice. Cytokine profiling also showed a significant increase in Th1 (IFN-γ, IL-2) and Th2 (IL-4, 10) responses in splenocytes of immunized mice on stimulation with rTsNd. Vaccination of mice with pcDNA3.1-TsNd displayed a 40.44% reduction in adult worms and a 53.9% reduction in larval burden. CONCLUSIONS: TsNd DNA induced a mixed Th1/Th2 immune response and partial protection against T. spiralis infection in mice

Acetaldehyde dehydrogenase 2 (ALDH2) deficiency exacerbates pressure overload-induced cardiac dysfunction by inhibiting Beclin-1 dependent autophagy pathway

AbstractMitochondrial aldehyde dehydrogenase 2 (ALDH2) was demonstrated to play cardioprotective roles in cardiovascular diseases. Nonetheless, little is known about the roles and mechanisms of ALDH2 in pressure overload-induced cardiac damages. In this study, we revealed that ALDH2 deficiency overtly exacerbated transverse aortic constriction (TAC)-induced cardiac dysfunction. Cardiomyocyte enlargement was observed in both WT and ALDH2−/− mice in HE-stained myocardial tissue samples at 8weeks post TAC surgery. Mitochondrial morphology and structure were also significantly damaged post TAC surgery and the changes were aggravated in ALDH2−/− TAC hearts. ALDH2 deficiency also depressed myocardial autophagy in hearts at 8weeks post TAC surgery with a potential mechanism of repressing the expression of Beclin-1 and promoting the interaction between Bcl-2 and Beclin-1. These data indicate that ALDH2 deficiency exacerbates the pressure overload induced cardiac dysfunction partly by inhibiting Beclin-1 dependent autophagy pathway.This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases

Enabling Technologies for Petascale Electromagnetic Accelerator Simulation

The SciDAC2 accelerator project at SLAC aims to simulate an entire three-cryomodule radio frequency (RF) unit of the International Linear Collider (ILC) main Linac. Petascale computing resources supported by advances in Applied Mathematics (AM) and Computer Science (CS) and INCITE Program are essential to enable such very large-scale electromagnetic accelerator simulations required by the ILC Global Design Effort. This poster presents the recent advances and achievements in the areas of CS/AM through collaborations

Suppress HBV by therapeutic vaccine

乙肝预防性疫苗显著减少了乙肝新发感染，但目前全球仍有约2.5亿慢性乙肝感染者，若未得到有效治疗，可能发展为肝癌、肝硬化等终末期肝病并导致死亡。夏宁邵教授团队研究发展了一种新型的B细胞表位嵌合型类病毒颗粒乙肝治疗性疫苗（治疗性蛋白），在多种模型中证实了其对慢性乙肝感染的治疗潜力，为研发治疗慢性乙肝的原创药物提供了新思路。 我校博士后张天英、博士生郭雪染和博士生巫洋涛为该论文共同第一作者，夏宁邵教授、袁权副教授、张军教授为该论文的共同通讯作者。【Abstract】Objective: This study aimed to develop a novel therapeutic vaccine based on a unique B cell epitope and investigate its therapeutic potential against chronic hepatitis B (CHB) in animal models. Methods: A series of peptides and carrier proteins were evaluated in HBV-tolerant mice to obtain an optimized therapeutic molecule. The immunogenicity,therapeutic efficacy and mechanism of the candidate were investigated systematically. Results: Among the HBsAg-aa119-125-containing peptides evaluated in this study, HBsAg-aa113-135 (SEQ13) exhibited the most striking therapeutic effects. A novel immuno-enhanced virus-like particle carrier (CR-T3) derived from the roundleaf bat HBV core antigen (RBHBcAg) was created and used to display SEQ13, forming candidate molecule CR-T3-SEQ13. Multiple copies of SEQ13 displayed on the surface of this particulate antigen promote the induction of a potent anti-HBs antibody response in mice, rabbits and cynomolgus monkeys. Sera and purified polyclonal IgG from the immunized animals neutralized HBV infection in vitro and mediated efficient HBV/HBsAg clearance in the mice. CR-T3-SEQ13-based vaccination induced long-term suppression of HBsAg and HBV DNA in HBV transgenic mice and eradicated the virus completely in hydrodynamic-based HBV carrier mice. The suppressive effects on HBsAg were strongly correlated with the anti-HBs level after vaccination, suggesting that the main mechanism of CR-T3-SEQ13 vaccination therapy was the induction of a SEQ13-specific antibody response that mediated HBV/HBsAg clearance. Conclusions: The novel particulate protein CR-T3-SEQ13 suppressed HBsAg effectively through induction of a humoral immune response in HBV-tolerant mice. This B cell epitope-based therapeutic vaccine may provide a novel immunotherapeutic agent against chronic HBV infection in humans.This work was supported by the National Scientific and Technological Major project (2017ZX10202203-001), the National Natural Science Foundation of China (31730029, 81672023, 81871316 and 81702006) and the Xiamen University President Fund Project (20720160063). 该研究获得了“艾滋病和病毒性肝炎等重大传染病防治”科技重大专项、国家自然科学基金等资助