The Circadian Clock Component RORA Increases Immunosurveillance in Melanoma by Inhibiting PD-L1 Expression.

Circadian clock perturbation frequently occurs in cancer and facilitates tumor progression by regulating malignant growth and shaping the immune microenvironment. Emerging evidence has indicated that clock genes are disrupted in melanoma and linked to immune escape. Here, we found that the expression of retinoic acid receptor-related orphan receptor-α (RORA) is downregulated in melanoma patients and that patients with higher RORA expression have a better prognosis after immunotherapy. Additionally, RORA was significantly positively correlated with T-cell infiltration and recruitment. Overexpression or activation of RORA stimulated cytotoxic T-cell-mediated antitumor responses. RORA bound to the CD274 promoter and formed an inhibitory complex with HDAC3 to suppress PD-L1 expression. In contrast, the DEAD-box helicase family member DDX3X competed with HDAC3 for binding to RORA, and DDX3X overexpression promoted RORA release from the suppressive complex and thereby increased PD-L1 expression to generate an inhibitory immune environment. The combination of a RORA agonist with an anti-CTLA4 antibody synergistically increased T-cell antitumor immunity in vivo. A score based on the combined expression of HDAC3, DDX3X and RORA correlated with immunotherapy response in melanoma patients. Together, this study elucidates a mechanism of clock component-regulated antitumor immunity, which will help inform the use of immunotherapy and lead to improved outcomes for melanoma patients receiving combined therapeutic treatments.

Aging and comprehensive molecular profiling in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion-negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF- AML cohort, namely, CH-AML, CH-MDS-AML, and other GF- AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA/B, platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML.

Contributions of climate change and urbanization to urban flood hazard changes in China's 293 major cities since 1980.

The growing incidence of urban flood disasters poses a major challenge to urban sustainability in China. Previous studies have reported that climate change and urbanization exacerbate urban flood risk in some major cities of China. However, few assessments have quantified the contributions of these two factors to urban flood changes in recent decades at the nationwide scale. Here, surface runoff caused by precipitation extremes was used as the urban flood hazard to evaluate the impacts of climate change and urbanization in China's 293 major cities. This study assessed the contributions of these drivers to urban flood hazard changes and identified the hotspot cities with increased trends under both factors during the past four decades (1980-2019). The results showed that approximately 70% of the cities analyzed have seen an increase of urban flood hazard in the latest decade. Urbanization made a positive contribution to increased urban flood hazards in more than 90% of the cities. The contribution direction of climate change showed significant variations across China. Overall, the absolute contribution rate of climate change far outweighed that of urbanization. In half of the cities (mainly distributed in eastern China), both climate change and urbanization led to increased urban flood hazard over the past decade. Among them, 33 cities have suffered a consecutive increase in urban flood hazard driven by both factors.

miR-30e-5p regulates leukemia stem cell self-renewal through the Cyb561/ROS signaling pathway.

Leukemia stem cells (LSC) represent a crucial and rare subset of cells present in acute myeloid leukemia (AML); they play a pivotal role in the initiation, maintenance, and relapse of this disease. Targeting LSC holds great promise for preventing AML relapse and improving long-term outcomes. However the precise molecular mechanisms governing LSC self-renewal are still poorly understood. Here, we present compelling evidence that the expression of miR-30e-5p, a potential tumor-suppressive microRNA, is significantly lower in AML samples than in healthy bone marrow samples. Forced expression of miR- 30e effectively inhibits leukemogenesis, impairs LSC self-renewal, and delays leukemia progression. Mechanistically, Cyb561 acts as a direct target of miR-30e-5p in LSC, and its deficiency restricts the self-renewal of LSC by activating reactive oxygen series signaling and markedly prolongs recipients' survival. Moreover, genetic or pharmacological overexpression of miR-30e-5p or knockdown of Cyb561 suppresses the growth of human AML cells. In conclusion, our findings establish the crucial role of the miR-30e-5p/Cyb561/ROS axis in finely regulating LSC self-renewal, highlighting Cyb561 as a potential therapeutic target for LSC-directed therapies.

Pyrolysis of municipal plastic waste: Chlorine distribution and formation of organic chlorinated compounds.

The release of chlorine during the pyrolysis of actual municipal plastic waste (MPW) was studied. Firstly, thermogravimetry-Fourier transform infrared (TG-FTIR) was analyzed to investigate the chlorine release behavior. Then, the effect of temperature on chlorine migrations was investigated by fast pyrolysis experiments in a fixed bed reactor. Results showed that chlorine released mainly between 241 and 353 °C in the form of HCl or chloroesters during MPW pyrolysis. After pyrolysis, chlorine was mainly distributed in the pyrolytic gas (74.34-82.89 %) and char (10.17-21.29 %). However, the release of chlorine was inhibited due to the melting behavior of MPW at <350 °C. Besides, the relative contents and types of organic chlorinated compounds in liquid products were both decreased with temperature. It was observed that polyethylene terephthalate (PET) was the greatest contributor to the formation of organic chlorinated compounds during MPW pyrolysis. Meanwhile, the pyrolysis of PET was significantly promoted by the HCl released from polyvinyl chloride (PVC). Subsequently, the pathways for the formation of organic chlorinated compounds through the co-pyrolysis of PVC and PET were proposed, including the initial degradation and subsequent chlorination of PET. These findings provided new insights into the release and regulation of chlorine-containing pollutants during actual MPW pyrolysis.

MSCT-UNET: multi-scale contrastive transformer within U-shaped network for medical image segmentation.

Objective.Automatic mutli-organ segmentation from anotomical images is essential in disease diagnosis and treatment planning. The U-shaped neural network with encoder-decoder has achieved great success in various segmentation tasks. However, a pure convolutional neural network (CNN) is not suitable for modeling long-range relations due to limited receptive fields, and a pure transformer is not good at capturing pixel-level features.Approach.We propose a new hybrid network named MSCT-UNET which fuses CNN features with transformer features at multi-scale and introduces multi-task contrastive learning to improve the segmentation performance. Specifically, the multi-scale low-level features extracted from CNN are further encoded through several transformers to build hierarchical global contexts. Then the cross fusion block fuses the low-level and high-level features in different directions. The deep-fused features are flowed back to the CNN and transformer branch for the next scale fusion. We introduce multi-task contrastive learning including a self-supervised global contrast learning and a supervised local contrast learning into MSCT-UNET. We also make the decoder stronger by using a transformer to better restore the segmentation map.Results.Evaluation results on ACDC, Synapase and BraTS datasets demonstrate the improved performance over other methods compared. Ablation study results prove the effectiveness of our major innovations.Significance.The hybrid encoder of MSCT-UNET can capture multi-scale long-range dependencies and fine-grained detail features at the same time. The cross fusion block can fuse these features deeply. The multi-task contrastive learning of MSCT-UNET can strengthen the representation ability of the encoder and jointly optimize the networks. The source code is publicly available at:https://github.com/msctunet/MSCT_UNET.git.

Acupuncture for lumbar myofascial pain syndrome: systematic review and Meta-analysis. / é’ˆåˆºæ²»ç–—è °èƒŒè‚Œç­‹è†œç‚Žï¼šç³»ç»Ÿè¯„ä»·ä¸ŽMeta分析.

This study systematically reviewed the clinical efficacy of acupuncture for lumbar myofascial pain syndrome. The randomized controlled trials (RCTs) regarding acupuncture for lumbar myofascial pain syndrome were searched in PubMed, Cochrane Library, Web of Science, EMbase, Scopus, China national knowledge infrastructure (CNKI), Wanfang database, VIP database, and China biomedical literature service system (SinoMed) from database inception until August 1st, 2022. The Cochrane's risk of bias assessment tool was used to assess the risk of bias in all included studies, and Review Manager 5.3 software was used for statistical analysis of the extracted data. As a result, 12 RCTs, involving 1 087 patients with lumbar myofascial pain syndrome, were ultimately included. The Meta-analysis results showed that the visual analog scale (VAS) score of pain in the observation group was lower than those in the oral non-steroidal anti-inflammatory medication control [SMD=-1.67, 95%CI (-2.44, -0.90), Z=4.26, P<0.000 1] and other treatment control [low-frequency electrical stimulation, tuina, electromagnetic wave irradiation combined with piroxicam gel, SMD=-1.98, 95%CI (-2.48, -1.48), Z=7.74, P<0.000 01]. The pain rating index (PRI) score in the observation group was lower than those in the lidocaine injection control [MD=-2.17, 95%CI (-3.41, -0.93), Z=3.44, P=0.000 6] and other treatment control [low-frequency electrical stimulation, tuina, MD=-5.75, 95%CI (-9.97, -1.53), Z=2.67, P=0.008]. The present pain intensity (PPI) score in the observation group was lower than that in other treatment control [low-frequency electrical stimulation, tuina, MD=-1.04, 95%CI (-1.55, -0.53), Z=4.01, P<0.000 1]. In conclusion, compared with oral non-steroidal anti-inflammatory medication, low-frequency electrical stimulation, tuina, and electromagnetic wave irradiation combined with piroxicam gel, acupuncture is more effective in reducing pain in patients with lumbar myofascial pain syndrome; acupuncture also exhibites advantage over lidocaine injection in improving PRI score and showed better outcomes over tuina and low-frequency electrical stimulation in improving PRI and PPI scores.

A novel mutation of CTC1 leads to telomere shortening in a chinese family with interstitial lung disease.

Interstitial lung diseases (ILDs), or diffuse pulmonary lung disease, are a subset of lung diseases that primarily affect lung alveoli and the space around interstitial tissue and bronchioles. It clinically manifests as progressive dyspnea, and patients often exhibit a varied decrease in pulmonary diffusion function. Recently, variants in telomere biology-related genes have been identified as genetic lesions of ILDs. Here, we enrolled 82 patients with interstitial pneumonia from 2017 to 2021 in our hospital to explore the candidate gene mutations of these patients via whole-exome sequencing. After data filtering, a novel heterozygous mutation (NM_025099: p.Gly131Arg) of CTC1 was identified in two affected family members. As a component of CST (CTC1-STN1-TEN1) complex, CTC1 is responsible for maintaining telomeric structure integrity and has also been identified as a candidate gene for IPF, a special kind of chronic ILD with insidious onset. Simultaneously, real-time PCR revealed that two affected family members presented with short telomere lengths, which further confirmed the effect of the mutation in the CTC1 gene. Our study not only expanded the mutation spectrum of CTC1 and provided epidemiological data on ILDs caused by CTC1 mutations but also further confirmed the relationship between heterozygous mutations in CTC1 and ILDs, which may further contribute to understanding the mechanisms underlying ILDs.

Migration characteristics of chlorine during pyrolysis of municipal solid waste pellets.

The migration process of chlorine during municipal solid waste (MSW) pellets pyrolysis was studied in a fixed bed reactor. Distribution and speciation changes of chlorine at different pyrolysis temperatures were determined by ion chromatography (IC) and X-ray photoelectron spectroscopy (XPS) analyses. Results showed that chlorine was mainly distributed in pyrolysis char (42.36-65.29 %) and gas (26.66-35.03 %) after MSW pellets pyrolysis. With the temperature increasing, chlorine in char and tar was enriched due to the increase of chlorine release and the decrease of product yields, with chlorine concentration increasing to 3498 ppm and 1415 ppm at 800 °C, respectively. Results of chlorine forms analysis indicated that most of the organic-Cl in MSW was released into the volatiles during pyrolysis due to the dissociation of CCl. Inorganic-Cl became the dominant form of chlorine in char after pyrolysis, with the proportion increasing from 46.69 % (raw) to 61.22 % (500 °C), which also suggested that part of organic-Cl was converted into the inorganic-Cl. Notably, the proportions of inorganic-Cl decreased at >600 °C due to the migration of inorganic. In addition, the pyrolysis release behavior of chlorine was affected by the pore structure of char, which could be inhibited by the unprosperous pores in char, especially at low temperatures (<600 °C). These findings provided a reference for the chlorine regulation of MSW pyrolytic products.

Case report: Identification of a recurrent pathogenic DHDDS mutation in Chinese family with epilepsy, intellectual disability and myoclonus.

Background: Heterozygous mutations in the dehydrodolichol diphosphate synthase (DHDDS) gene are one of the causes generating developmental and epileptic encephalopathies. So far, only eleven mutations in the DHDDS gene have been identified. The mutation spectrum of the DHDDS gene in the Chinese population remains unclear. Methods: In this study, we enrolled a Chinese family with myoclonus and/or epilepsy and intellectual disability. The epilepsy and myoclonic tremor were improved after deep brain stimulation (DBS) of the subthalamic nucleus (STN) treatment. Whole exome sequencing and Sanger sequencing were employed to explore the genetic variations of the family. Results: Subsequent to data filtering, we identified a recurrent pathogenic mutation (NM_001243564.1, c.113G>A/p.R38H) in the DHDDS gene in the proband. Sanger sequencing further validated that the presence of the mutation in his affected mother but absent in the health family members. Further bioinformatics analysis revealed that this mutation (p.R38H), located in an evolutionarily conserved region of DHDDS, was predicted to be deleterious. Discussion: In this report, we present the first case of intractable epilepsy and/or myoclonus caused by p.R38H mutation of the DHDDS gene in the Chinese population. Furthermore, this study represents the third report of autosomal dominant familial inheritance of DHDDS mutation worldwide.

GPCR signaling contributes to immune characteristics of microenvironment and process of EBV-induced lymphomagenesis.

Epstein-Barr virus (EBV) is the oncogenic driver of multiple cancers. However, the underlying mechanism of virus-cancer immunological interaction during disease pathogenesis remains largely elusive. Here we reported the first comprehensive proteogenomic characterization of natural killer/T-cell lymphoma (NKTCL), a representative disease model to study EBV-induced lymphomagenesis, incorporating genomic, transcriptomic, and in-depth proteomic data. Our multi-omics analysis of NKTCL revealed that EBV gene pattern correlated with immune-related oncogenic signaling. Single-cell transcriptome further delineated the tumor microenvironment as immune-inflamed, -deficient, and -desert phenotypes, in association with different setpoints of cancer-immunity cycle. EBV interacted with transcriptional factors to provoke GPCR interactome (GPCRome) reprogramming. Enhanced expression of chemokine receptor-1 (CCR1) on malignant and immunosuppressive cells modulated virus-cancer interaction on microenvironment. Therapeutic targeting CCR1 showed promising efficacy with EBV eradication, T-cell activation, and lymphoma cell killing in NKTCL organoid. Collectively, our study identified a previously unknown GPCR-mediated malignant progression and translated sensors of viral molecules into EBV-specific anti-cancer therapeutics.

A cross-sectional study: family communication, anxiety, and depression in adolescents: the mediating role of family violence and problematic internet use.

OBJECTIVE: The objective of this study is to explore the relationship between family communication, family violence, problematic internet use, anxiety, and depression and validate their potential mediating role. METHODS: The study population consisted of Chinese adolescents aged 12 to 18 years, and a cross-sectional survey was conducted in 2022. Structural equation models were constructed using AMOS 25.0 software to examine the factors that influence adolescent anxiety and depression and the mediating effects of problematic internet use and family violence. RESULTS: The results indicate that family communication was significantly and negatively related to family violence (ß = -.494, p < 0.001), problematic internet use (ß = -.056, p < .05), depression (ß = -.076, p < .01), and anxiety (ß = -.071, p < .05). And the finds also indicate that family violence mediated the relationships between family communication and depression (ß = -.143, CI: -.198 -.080), and between family communication and anxiety (ß = -.141; CI: -.198 -.074). Chain indirect effects between family communication and depression (ß = -.051; CI: -.081 -.030) or anxiety (ß = -.046; CI: -.080 -.043) via family violence and then through problematic internet use were also found in the present study. CONCLUSIONS: In conclusion, positive family communication is crucial in reducing anxiety and depression in adolescents. Moreover, problematic internet use and family violence mediate the effects of positive family communication on anxiety and depression. Therefore, improving family communication and promoting interventions aimed at reducing family violence and problematic internet use can help reduce anxiety and depression in adolescents, thus promoting their healthy development.

Foxm1 haploinsufficiency drives clonal hematopoiesis and promotes a stress-related transition to hematologic malignancy in mice.

Clonal hematopoiesis plays a critical role in the initiation and development of hematologic malignancies. In patients with del(5q) myelodysplastic syndrome (MDS), the transcription factor FOXM1 is frequently downregulated in CD34+ cells. In this study, we demonstrated that Foxm1 haploinsufficiency disturbed normal hematopoiesis and conferred a competitive repopulation advantage for a short period. However, it impaired the long-term self-renewal capacity of hematopoietic stem cells, recapitulating the phenotypes of abnormal hematopoietic stem cells observed in patients with MDS. Moreover, heterozygous inactivation of Foxm1 led to an increase in DNA damage in hematopoietic stem/progenitor cells (HSPCs). Foxm1 haploinsufficiency induced hematopoietic dysplasia in a mouse model with LPS-induced chronic inflammation and accelerated AML-ETO9a-mediated leukemogenesis. We have also identified Parp1, an important enzyme that responds to various types of DNA damage, as a target of Foxm1. Foxm1 haploinsufficiency decreased the ability of HSPCs to efficiently repair DNA damage by downregulating Parp1 expression. Our findings suggest that the downregulation of the Foxm1-Parp1 molecular axis may promote clonal hematopoiesis and reduce genome stability, contributing to del(5q) MDS pathogenesis.

Sulforaphene suppresses RANKL-induced osteoclastogenesis and LPS-induced bone erosion by activating Nrf2 signaling pathway.

BACKGROUND AND PURPOSE: Inflammatory disorders have been found to induce bone loss through sustained and persistent activation of osteoclast differentiation, leading to heightened bone resorption. The current pharmacological interventions for combating bone loss to harbor adverse effects or contraindications. There is a pressing need to identify drugs with fewer side effects. EXPERIMENTAL APPROACH: The effect and underlying mechanism of sulforaphene (LFS) on osteoclast differentiation were illustrated in vitro and in vivo with RANKL-induced Raw264.7 cell line osteoclastogenesis and lipopolysaccharide (LPS)-induced bone erosion model. KEY RESULTS: In this study, LFS has been shown to effectively impede the formation of mature osteoclasts induced from both Raw264.7 cell line and bone marrow macrophages (BMMs), mainly at the early stage. Further mechanistic investigations uncovered that LFS suppressed AKT phosphorylation. SC-79, a potent AKT activator, was found to reverse the inhibitory impact of LFS on osteoclast differentiation. Moreover, transcriptome sequencing analysis revealed that treatment with LFS led to a significant upregulation in the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant-related genes. Then it's validated that LFS could promote NRF2 expression and nuclear translocation, as well as effectively resist oxidative stress. NRF2 knockdown reversed the suppression effect of LFS on osteoclast differentiation. In vivo experiments provide convincing evidence that LFS is protective against LPS-induced inflammatory osteolysis. CONCLUSION AND IMPLICATIONS: These well-grounded and promising findings suggest LFS as a promising agent to addressing oxidative-stress related diseases and bone loss disorders.

[Assessing the Environmental and Health Co-benefits of Accelerated Energy Transition and Industrial Restructuring: A Case Study of the BTHS Region].

The Beijing-Tianjin-Hebei-Shandong Region (BTHS Region) is a crucial area for China to achieve synergy between pollution reduction and carbon emissions reduction. The demand for coordinated emissions reduction through source control measures such as energy transition and industrial restructuring are becoming increasingly necessary owing to the limited emissions reductions potential of end-of-pipe control measures. An assessment of the emissions reductions potential through strengthening the end-of-pipe control in the BTHS Region, as well as the environmental and health co-benefits from accelerated energy transition and industrial restructuring, was conducted using scenario simulation analysis based on the REACH model. The results showed that the rapid implementation of the best available end-of-pipe control technologies in the BTHS Region would result in 3.3 µg·m-3 reduction in PM2.5 concentration in 2035, but this would not be sufficient to achieve the PM2.5 concentration control targets. Accelerating the energy transition and the industrial restructuring are necessary for the BTHS Region to achieve air quality standards, which would reduce the PM2.5 concentrations by 6.3 µg·m-3 in 2035. The environmental and health co-benefits brought by the accelerated transition could partially or entirely offset the additional socio-economic cost (compared to that of the current policy efforts) of approximately 0.9%-2.5% of the total regional GDP in achieving the PM2.5 concentration control target paid by the four provinces.

Phosphorylation stabilized TET1 acts as an oncoprotein and therapeutic target in B cell acute lymphoblastic leukemia.

Although the overall survival rate of B cell acute lymphoblastic leukemia (B-ALL) in childhood is more than 80%, it is merely 30% in refractory/relapsed and adult patients with B-ALL. This demonstrates a need for improved therapy targeting this subgroup of B-ALL. Here, we show that the ten-eleven translocation 1 (TET1) protein, a dioxygenase involved in DNA demethylation, is overexpressed and plays a crucial oncogenic role independent of its catalytic activity in B-ALL. Consistent with its oncogenic role in B-ALL, overexpression of TET1 alone in normal precursor B cells is sufficient to transform the cells and cause B-ALL in mice within 3 to 4 months. We found that TET1 protein is stabilized and overexpressed because of its phosphorylation mediated by protein kinase C epsilon (PRKCE) and ATM serine/threonine kinase (ATM), which are also overexpressed in B-ALL. Mechanistically, TET1 recruits STAT5B to the promoters of CD72 and JCHAIN and promotes their transcription, which in turn promotes B-ALL development. Destabilization of TET1 protein by treatment with PKC or ATM inhibitors (staurosporine or AZD0156; both tested in clinical trials), or by pharmacological targeting of STAT5B, greatly decreases B-ALL cell viability and inhibits B-ALL progression in vitro and in vivo. The combination of AZD0156 with staurosporine or vincristine exhibits a synergistic effect on inhibition of refractory/relapsed B-ALL cell survival and leukemia progression in PDX models. Collectively, our study reveals an oncogenic role of the phosphorylated TET1 protein in B-ALL independent of its catalytic activity and highlights the therapeutic potential of targeting TET1 signaling for the treatment of refractory/relapsed B-ALL.