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Nucleophosmin ( NPM1 ) is the most commonly mutated gene in acute myeloid leukemia (AML) resulting in aberrant cytoplasmic translocation of the encoded nucleolar protein (NPM1c + ). NPM1c + maintains a unique leukemic gene expression program, characterized by activation of HOXA / B clusters and MEIS1 oncogene to facilitate leukemogenesis. However, the mechanisms by which NPM1c + controls such gene expression patterns to promote leukemogenesis remain largely unknown. Here, we show that the activation of HOXBLINC , a HOXB locus-associated long non-coding RNA (lncRNA), is a critical downstream mediator of NPM1c + -associated leukemic transcription program and leukemogenesis. HOXBLINC loss attenuates NPM1c + -driven leukemogenesis by rectifying the signature of NPM1c + leukemic transcription programs. Furthermore, overexpression of HoxBlinc ( HoxBlinc Tg) in mice enhances HSC self-renewal and expands myelopoiesis, leading to the development of AML-like disease, reminiscent of the phenotypes seen in the Npm1 mutant knock-in ( Npm1 c/+ ) mice. HoxBlinc Tg and Npm1 c/+ HSPCs share significantly overlapped transcriptome and chromatin structure. Mechanistically, HoxBlinc binds to the promoter regions of NPM1c + signature genes to control their activation in HoxBlinc Tg HSPCs, via MLL1 recruitment and promoter H3K4me3 modification. Our study reveals that HOXBLINC lncRNA activation plays an essential oncogenic role in NPM1c + leukemia . HOXBLINC and its partner MLL1 are potential therapeutic targets for NPM1c + AML. Nucleophosmin (NPM1) gene mutation induces a specific gene expression program leading to acute myeloid leukaemia. Here, the authors show that mutant NPM1 activates a HOXB locus-associated long non-coding RNA which is essential for its associated oncogenic transcriptional program and leukaemia development.

Electrochemically converting nitrate, a widespread water pollutant, back to valuable ammonia is a green and delocalized route for ammonia synthesis, and can be an appealing and supplementary alternative to the Haber-Bosch process. However, as there are other nitrate reduction pathways present, selectively guiding the reaction pathway towards ammonia is currently challenged by the lack of efficient catalysts. Here we report a selective and active nitrate reduction to ammonia on Fe single atom catalyst, with a maximal ammonia Faradaic efficiency of ~ 75% and a yield rate of up to ~ 20,000 μg h −1 mg cat. −1 (0.46 mmol h −1 cm −2 ). Our Fe single atom catalyst can effectively prevent the N-N coupling step required for N 2 due to the lack of neighboring metal sites, promoting ammonia product selectivity. Density functional theory calculations reveal the reaction mechanisms and the potential limiting steps for nitrate reduction on atomically dispersed Fe sites. Developing green and delocalized routes for ammonia synthesis is highly important but still very challenging. Here the authors report an efficient ammonia synthesis process via nitrate reduction to ammonia on Fe single atom catalyst.

Pulmonary arterial hypertension (PAH) is clinically characterized by a progressive increase in pulmonary artery pressure, followed by right ventricular hypertrophy and subsequently right heart failure. The underlying mechanism of PAH includes endothelial dysfunction and intimal smooth muscle proliferation. Numerous studies have shown that oxidative stress is critical in the pathophysiology of PAH and involves changes in reactive oxygen species (ROS), reactive nitrogen (RNS), and nitric oxide (NO) signaling pathways. Disrupted ROS and NO signaling pathways cause the proliferation of pulmonary arterial endothelial cells (PAECs) and pulmonary vascular smooth muscle cells (PASMCs), resulting in DNA damage, metabolic abnormalities, and vascular remodeling. Antioxidant treatment has become a main area of research for the treatment of PAH. This review mainly introduces oxidative stress in the pathogenesis of PAH and antioxidative therapies and explains why targeting oxidative stress is a valid strategy for PAH treatment.

China has more patients with traumatic brain injury (TBI) than most other countries in the world, making this condition a major public health concern. Population-based mortality of TBI in China is estimated to be approximately 13 cases per 100 000 people, which is similar to the rates reported in other countries. The implementation of various measures, such as safety legislation for road traffic, establishment of specialised neurosurgical intensive care units, and the development of evidence-based guidelines, have contributed to advancing prevention and care of patients with TBI in China. However, many challenges remain, which are augmented further by regional differences in TBI care. High-level care, such as intracranial pressure monitoring, is not universally available yet. In the past 30 years, the quality of TBI research in China has substantially improved, as evidenced by an increasing number of clinical trials done. The large number of patients with TBI and specialised trauma centres offer unique opportunities for TBI research in China. Furthermore, the formation and development of research collaborations between China and international groups are considered essential to advancing the quality of TBI care and research in China, and to improve quality of life in patients with this condition.

In the Vaibhāṣika system, possession (prāpti), classified as a factor that is neither material nor mental, is posited as a real entity that links the various dharmas associated with a sentient being to its individual continuum. In this context, possession does not refer to legal ownership or supernatural possession; rather, it refers to the attainment or endowment of dharmas, that is, how particular qualities, actions, or mental states come to be present in a given individual. This paper examines the strategies by which Vaibhāṣikas defend the ontological status of possession, thereby shedding light on the motivations underlying this doctrinal commitment. Through close philological and historical analysis of a wide range of Sarvāstivāda Abhidharma sources, including passages from a newly available manuscript folio of the Abhidharmadīpa with Vibhāṣāprabhāvṛtti, this study reconstructs the diachronic development of Vaibhāṣika arguments for the real existence of possession. Vaibhāṣikas consistently employ two principal modes of justification: appeals to scriptural authority (āgama) and logical reasoning (yukti). As the tradition develops, their defenses of possession shift from reliance on scriptural sources toward increasingly sophisticated forms of doctrinal and functional integration. Possession thus evolves from a dharma serving to clarify specific doctrinal difficulties into a structurally embedded component of Vaibhāṣika doctrinal architecture, playing an important role in its accounts of soteriology, causality, and karma.

Immune-mediated inflammatory diseases(IMIDs) are referred to as highly disabling chronic diseases affecting different organs and systems. Inappropriate or excessive immune responses with chronic inflammation are typical manifestations. Usually in patients with chronic infection and cancer, due to long-term exposure to persistent antigens and inflammation microenvironment, T-cells are continuously stimulated and gradually differentiate into an exhausted state. Exhausted T-cells gradually lose effector function and characteristics of memory T-cells. However, existing studies have found that exhausted T-cells are not only present in the infection and tumor environment, but also in autoimmunity, and are associated with better prognosis of IMIDs. This suggests new prospects for the application of this reversible process of T-cell exhaustion in the treatment of IMID. This review will focus on the research progress of T-cell exhaustion in several IMIDs and its potential application for diagnosis and treatment in IMIDs.

This study aimed to determine the levels of health-related behaviours (physical activity, screen exposure and sleep status) among Chinese students from primary, secondary and high schools during the pandemic of COVID-19, as well as their changes compared with their status before the pandemic. A cross-sectional online survey of 10,933 students was conducted among 10 schools in Guangzhou, China, between 8th and 15th March, 2020. After getting the informed consent from student’s caregivers, an online questionnaire was designed and used to obtain time spending on health-related behaviours during the pandemic of COVID-19, as well as the changes compared with 3 months before the pandemic, which was completed by students themselves or their caregivers. Students were stratified by regions (urban, suburban, exurban), gender (boys and girls), and grades (lower grades of primary school, higher grades of primary schools, secondary schools and high schools). Data were expressed as number and percentages and Chi-square test was used to analyse difference between groups. Overall, the response rate of questionnaire was 95.3% (10,416/10,933). The median age of included students was 13.0 (10.0, 16.0) years and 50.1% (n = 5,219) were boys. 41.4%, 53.6% and 53.7% of total students reported less than 15 min per day in light, moderate and vigorous activities and 58.7% (n = 6,113) reported decreased participation in physical activity compared with the time before pandemic. Over 5 h of screen time spending on online study was reported by 44.6% (n = 4,649) of respondents, particular among high school students (81.0%). 76.9% of students reported increased screen time compared with the time before pandemic. Inadequate sleep was identified among 38.5% of students and the proportion was highest in high school students (56.9%). Our study indicated that, during the COVID-19 pandemic, the school closure exerted tremendous negative effects on school-aged children’s health habits, including less physical activity, longer screen exposure and irregular sleeping pattern.

Colorimetric sensors have attracted considerable attention in many sensing applications because of their specificity, high sensitivity, cost-effectiveness, ease of use, rapid analysis, simplicity of operation, and clear visibility to the naked eye [...]

Quadratic regression (QR) models naturally extend linear models by considering interaction effects between the covariates. To conduct model selection in QR, it is important to maintain the hierarchical model structure between main effects and interaction effects. Existing regularization methods generally achieve this goal by solving complex optimization problems, which usually demands high computational cost and hence are not feasible for high-dimensional data. This article focuses on scalable regularization methods for model selection in high-dimensional QR. We first consider two-stage regularization methods and establish theoretical properties of the two-stage LASSO. Then, a new regularization method, called regularization algorithm under marginality principle (RAMP), is proposed to compute a hierarchy-preserving regularization solution path efficiently. Both methods are further extended to solve generalized QR models. Numerical results are also shown to demonstrate performance of the methods. Supplementary materials for this article are available online.

Mitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Mutations in MFN2 cause the neurodegenerative disease Charcot-Marie-Tooth type 2A (CMT2A). The molecular basis underlying the physiological and pathological relevance of MFN2 is unclear. Here, we present crystal structures of truncated human MFN2 in different nucleotide-loading states. Unlike other dynamin superfamily members including MFN1, MFN2 forms sustained dimers even after GTP hydrolysis via the GTPase domain (G) interface, which accounts for its high membrane-tethering efficiency. The biochemical discrepancy between human MFN2 and MFN1 largely derives from a primate-only single amino acid variance. MFN2 and MFN1 can form heterodimers via the G interface in a nucleotide-dependent manner. CMT2A-related mutations, mapping to different functional zones of MFN2, lead to changes in GTP hydrolysis and homo/hetero-association ability. Our study provides fundamental insight into how mitofusins mediate mitochondrial fusion and the ways their disruptions cause disease. Mitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Here, authors report crystal structures of truncated human MFN2 in different nucleotide-loading states and show that MFN2 forms sustained dimers even after GTP hydrolysis.