The regulation of chromatin configuration at AGAMOUS locus by LFR-SYD-containing complex is critical for reproductive organ development in Arabidopsis.

Switch defective/sucrose non-fermentable (SWI/SNF) chromatin remodeling complexes are evolutionarily conserved, multi-subunit machinery that play vital roles in the regulation of gene expression by controlling nucleosome positioning and occupancy. However, little is known about the subunit composition of SPLAYED (SYD)-containing SWI/SNF complexes in plants. Here, we show that the Arabidopsis thaliana Leaf and Flower Related (LFR) is a subunit of SYD-containing SWI/SNF complexes. LFR interacts directly with multiple SWI/SNF subunits, including the catalytic ATPase subunit SYD, in vitro and in vivo. Phenotypic analyses of lfr-2 mutant flowers revealed that LFR is important for proper filament and pistil development, resembling the function of SYD. Transcriptome profiling revealed that LFR and SYD shared a subset of co-regulated genes. We further demonstrate that the LFR and SYD interdependently activate the transcription of AGAMOUS (AG), a C-class floral organ identity gene, by regulating the occupation of nucleosome, chromatin loop, histone modification, and Pol II enrichment on the AG locus. Furthermore, the chromosome conformation capture (3C) assay revealed that the gene loop at AG locus is negatively correlated with the AG expression level, and LFR-SYD was functional to demolish the AG chromatin loop to promote its transcription. Collectively, these results provide insight into the molecular mechanism of the Arabidopsis SYD-SWI/SNF complex in the control of higher chromatin conformation of the floral identity gene essential to plant reproductive organ development.

Mitophagy associated self-degradation of phosphorylated MAP4 guarantees the migration and proliferation responses of keratinocytes to hypoxia.

Our previous study has announced that phosphorylated microtubule-associated protein 4 (p-MAP4) accelerated keratinocytes migration and proliferation under hypoxia through depolymerizing microtubules. However, p-MAP4 should exhibit inhibitory effects on wound healing, for it also impaired mitochondria. Thus, figuring out the outcome of p-MAP4 after it impaired mitochondria and how the outcome influenced wound healing were far-reaching significance. Herein, the results revealed that p-MAP4 might undergo self-degradation through autophagy in hypoxic keratinocytes. Next, p-MAP4 activated mitophagy which was unobstructed and was also the principal pathway of its self-degradation triggered by hypoxia. Moreover, both Bcl-2 homology 3 (BH3) and LC3 interacting region (LIR) domains had been verified in MAP4, and they endowed MAP4 with the capability to synchronously function as a mitophagy initiator and a mitophagy substrate receptor. And, mutating any one of them ruined hypoxia-induced self-degradation of p-MAP4, resulting in destroyed proliferation and migration responses of keratinocytes to hypoxia. Our findings unviewed that p-MAP4 experienced mitophagy-associated self-degradation through utilizing its BH3 and LIR domains under hypoxia. As a result, the mitophagy-associated self-degradation of p-MAP4 guaranteed the migration and proliferation responses of keratinocytes to hypoxia. Together, this research provided a bran-new pattern of proteins in regulating wound healing, and offered a new direction for intervening wound healing.

Dealloying Synthesis of Bimetallic (Au-Pd)/CeO2 Catalysts for CO Oxidation.

The nanorod-structured (Au-Pd)/CeO2 catalysts with different Au/Pd ratios were prepared from Al-Ce-Au-Pd precursor alloys through combined dealloying and calcination treatment. XRD, SEM, TEM, XPS, Raman spectroscopy, and N2 adsorption-desorption measurements were applied to test the structure and physicochemical properties of samples. Catalytic evaluation results imply that the (Pd0.15-Au0.15)/CeO2 catalyst calcined at 500 °C possesses optimal catalytic activity for CO oxidation when compared with other catalysts with different Au/Pd ratios or (Pd0.15-Au0.15)/CeO2 calcined at other temperatures, whose 50% and 99% reaction temperature can be reached as low as 50 and 85 °C, respectively. This superior catalytic property is attributed to their robust nanorod structure and the introduction of noble bimetal Pd and Au, which can construct a nanoscale interface to access fast electron motion, thus enhancing catalytic efficiency.

Atrial fibrillation classification based on the 2D representation of minimal subset ECG and a non-deep neural network.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its early detection is critical for preventing complications and optimizing treatment. In this study, a novel AF prediction method is proposed, which is based on investigating a subset of the 12-lead ECG data using a recurrent plot and ParNet-adv model. The minimal subset of ECG leads (II &V1) is determined via a forward stepwise selection procedure, and the selected 1D ECG data is transformed into 2D recurrence plot (RP) images as an input to train a shallow ParNet-adv Network for AF prediction. In this study, the proposed method achieved F1 score of 0.9763, Precision of 0.9654, Recall of 0.9875, Specificity of 0.9646, and Accuracy of 0.9760, which significantly outperformed solutions based on single leads and complete 12 leads. When studying several ECG datasets, including the CPSC and Georgia ECG databases of the PhysioNet/Computing in Cardiology Challenge 2020, the new method achieved F1 score of 0.9693 and 0.8660, respectively. The results suggested a good generalization of the proposed method. Compared with several state-of-art frameworks, the proposed model with a shallow network of only 12 depths and asymmetric convolutions achieved the highest average F1 score. Extensive experimental studies proved that the proposed method has a high potential for AF prediction in clinical and particularly wearable applications.

Optimizing heterotrophic nitrification process: The significance of demand-driven aeration and organic matter concentration.

Heterotrophic nitrification and aerobic denitrification (HNAD) sludge were successfully acclimated. The effects of organics and dissolved oxygen (DO) on nitrogen and phosphorus removal by the HNAD sludge were investigated. The nitrogen can be heterotrophically nitrified and denitrified in the sludge at a DO of 6 mg/L. The TOC/N (total organic carbon to nitrogen) ratio of 3 was found to result in removal efficiencies of over 88% for nitrogen and 99% for phosphorus. The use of demand-driven aeration with a TOC/N ratio of 1.7 improved nitrogen and phosphorus removal from 35.68% and 48.17% to 68% and 93%, respectively. The kinetics analysis generated an empirical formula, Ammonia oxidation rate = 0.08917·(TOC·Ammonia)0.329·Biomass0.342. The nitrogen, carbon, glycogen, and poly-ß-hydroxybutyric acid (PHB) metabolism pathways of HNAD sludge were constructed using the Kyoto Encyclopedia of Genes and Genomes (KEGG). The findings suggest that heterotrophic nitrification precedes aerobic denitrification, glycogen synthesis, and PHB synthesis.

Assessment of radiation exposure and public health before and after the operation of Sanmen nuclear power plant.

Introduction: Sanmen nuclear power plant (SNPP) operates the first advanced passive (AP1000) nuclear power unit in China. Methods: To assess the radiological impacts of SNPP operation on the surrounding environment and the public health, annual effective dose (AED) and excess risk (ER) were estimated based on continuous radioactivity monitoring in drinking water and ambient dose before and after its operation during 2014-2021. In addition, the residents' cancer incidence was further analyzed through authorized health data collection. Results: The results showed that the gross α and gross ß radioactivity in all types of drinking water were ranged from 0.008 to 0.017 Bq/L and 0.032 to 0.112 Bq/L, respectively. The cumulative ambient dose in Sanmen county ranged from 0.254 to 0.460 mSv/y, with an average of 0.354 ± 0.075 mSv/y. There is no statistical difference in drinking water radioactivity and ambient dose before and after the operation of SNPP according to Mann-Whitney U test. The Mann-Kendall test also indicates there is neither increasing nor decreasing trend during the period from 2014 to 2021. The age-dependent annual effective doses due to the ingestion of drinking water or exposure to the outdoor ambient environment are lower than the recommended threshold of 0.1 mSv/y. The incidence of cancer (include leukemia and thyroid cancer) in the population around SNPP is slightly higher than that in other areas, while it is still in a stable state characterized by annual percentage changes. Discussion: The current comprehensive results show that the operation of SNPP has so far no evident radiological impact on the surrounding environment and public health, but continued monitoring is still needed in the future.

Polymer-Dispersed Liquid Crystal Films on Flexible Substrates with Excellent Bending Resistance and Spacing Stability.

Polymer-dispersed liquid crystals (PDLCs) are very attractive due to their electrically switchable properties. However, current PDLC films still have problems such as high driving voltages, low contrast ratio (CR), and poor bending resistance and spacing stability. To solve these problems, a PDLC film with a system of coexisting polymer spacer columns and polymer network was proposed. First, based on the adhesive systems of IBMA and UV6301, the effects of IBMA concentration and LC content on the morphology of the polymer network and the electro-optical properties of PDLC were investigated, respectively. Then, the effects of the process conditions of mask polymerization such as temperature, time, and UV light intensity on the morphology and electro-optical properties of the polymer spacer columns were systematically investigated. It was found that PDLC films with the coexistence system exhibit both excellent electro-optical properties and outstanding bending resistance and spacing stability. Thus, it provides new practical possibilities for the preparation of high-performance PDLC films used in flexible devices.

Cardiac Arrhythmia classification based on 3D recurrence plot analysis and deep learning.

Artificial intelligence (AI) aided cardiac arrhythmia (CA) classification has been an emerging research topic. Existing AI-based classification methods commonly analyze electrocardiogram (ECG) signals in lower dimensions, using one-dimensional (1D) temporal signals or two-dimensional (2D) images, which, however, may have limited capability in characterizing lead-wise spatiotemporal correlations, which are critical to the classification accuracy. In addition, existing methods mostly assume that the ECG data are linear temporal signals. This assumption may not accurately represent the nonlinear, nonstationary nature of the cardiac electrophysiological process. In this work, we have developed a three-dimensional (3D) recurrence plot (RP)-based deep learning algorithm to explore the nonlinear recurrent features of ECG and Vectorcardiography (VCG) signals, aiming to improve the arrhythmia classification performance. The 3D ECG/VCG images are generated from standard 12 lead ECG and 3 lead VCG signals for neural network training, validation, and testing. The superiority and effectiveness of the proposed method are validated by various experiments. Based on the PTB-XL dataset, the proposed method achieved an average F1 score of 0.9254 for the 3D ECG-based case and 0.9350 for the 3D VCG-based case. In contrast, recently published 1D and 2D ECG-based CA classification methods yielded lower average F1 scores of 0.843 and 0.9015, respectively. Thus, the improved performance and visual interpretability make the proposed 3D RP-based method appealing for practical CA classification.

Long-term investigation of environmental radioactivity levels and public health around the Qinshan Nuclear Power Plant, China.

To evaluate the impact of the Qinshan Nuclear Power Plant (Qinshan NPP) in normal operation on the surrounding environment and population, the radioactivity levels of drinking water and the ambient environment, as well as the residents' cancer incidence, were continuously monitored for a period of 9 years (2012-2020). All of the gross α and ß radioactivity concentrations in drinking water were less than the WHO recommended values (0.5 Bq/L for gross α and 1 Bq/L for gross ß). The results of ambient environment accumulated dose monitored by thermoluminescent dosimeters (TLDs) indicated that the ambient environment radioactive level around the Qinshan NPP is consistently at natural background radiation levels. The age-dependent annual effective doses due to the ingestion of tap water or exposure to the outdoor ambient environment are lower than the reference dose of 0.1 mSv/year. The corresponding excess risks are at relatively low levels. Thus, the consumption of drinking water and outdoor activities are not expected to give rise to any detectable adverse effects on the health of the public around the Qinshan NPP. For all cancers combined, the age-standardized incidence rate by the Chinese 2000 standard population of the inhabitants living around Qinshan NPP is consistent with that of Zhejiang Province as a whole. Based on current radiation risk estimates, radiation exposure is not a plausible explanation for any excess cancers observed in the vicinity of the Qinshan NPP.

Therapeutic Effects of Shikonin on Skin Diseases: A Review.

Shikonin is one of the primary active components extracted from the dried root ofZicao (Lithospermum erythrorhizon, Onosma paniculata, or Arnebia euchroma), a traditional Chinese herbal medicine. Shikonin is known to not only exert anti-proliferative, anti-inflammatory, and anti-angiogenic activities, but also play a crucial role in triggering the production of reactive oxygen species, suppressing the release of exosomes, and inducing apoptosis. Increasing evidence suggests that shikonin has a protective effect against skin diseases, including psoriasis, melanoma, and hypertrophic scars. In order to evaluate the application potential of shikonin in the treatment of skin diseases, this review is the first of its kind to provide comprehensive and up-to-date information regarding the uses of shikonin and its derivatives on skin diseases and its underlying mechanisms. In this review, we have focused on the signaling pathways and cellular targets involved in the anti-dermatosis effects of shikonin to bridge the gaps in the literature, thereby providing scientific support for the research and development of new drugs from a traditional medicinal plant.

Long-term variation of 90Sr and 137Cs in environmental and food samples around Qinshan nuclear power plant, China.

Environmental radioactivity monitoring in the surroundings of nuclear facilities is important to provide baseline data for effective detection in case of any radioactive release in the region. In this work, we report for the first time the long-term monitoring data of 137Cs and 90Sr in environmental and food samples around Qinshan nuclear power plant in 2012-2019. The distribution levels, temporal variations and source terms of 137Cs and 90Sr in the investigated samples were discussed. The annual effective dose (AED) for the local population from the ingestion of foods was also evaluated. Peak values of 90Sr and 137Cs concentrations and 137Cs/90Sr activity ratio were observed in total atmospheric deposition in 2016 and some water and food samples in the following years. This seems to be associated to an additional radioactive input, mostly likely from the operational release of a local facility. This demonstrates that 90Sr and 137Cs, especially the 137Cs/90Sr activity ratio, are sensitive indicators for detecting potential radioactive releases. Nevertheless, overall 90Sr and 137Cs activity concentrations measured during 2012-2019 in this work were at the background levels with average AED far below the internationally permissible limit and recommendation.

Autophagy-Related LC3 Accumulation Interacted Directly With LIR Containing RIPK1 and RIPK3, Stimulating Necroptosis in Hypoxic Cardiomyocytes.

The exact relationships and detailed mechanisms between autophagy and necroptosis remain obscure. Here, we demonstrated the link between accumulated autophagosome and necroptosis by intervening with autophagic flux. We first confirmed that the LC3 interacting region (LIR) domain is present in the protein sequences of RIPK1 and RIPK3. Mutual effects among LC3, RIPK1, and RIPK3 have been identified in myocardium and cardiomyocytes. Direct LC3-RIPK1 and LC3-RIPK3 interactions were confirmed by pull-down assays, and their interactions were deleted after LIR domain mutation. Moreover, after disrupting autophagic flux under normoxia with bafilomycin A1 treatment, or with LC3 or ATG5 overexpression adenovirus, RIPK1, RIPK3, p-RIPK3, and p-MLKL levels increased, suggesting necroptosis activation. Severe disruptions in autophagic flux were observed under hypoxia and bafilomycin A1 co-treated cardiomyocytes and myocardium and led to more significant activation of necroptosis. Conversely, after alleviating hypoxia-induced autophagic flux impairment with LC3 or ATG5 knockdown adenovirus, the effects of hypoxia on RIPK1 and RIPK3 levels were reduced, which resulted in decreased p-RIPK3 and p-MLKL. Furthermore, necroptosis was inhibited by siRNAs against RIPK1 and RIPK3 under hypoxia or normoxia. Based on our results, LIR domain mediated LC3-RIPK1 and LC3-RIPK3 interaction. Besides, autophagosome accumulation under hypoxia lead to necrosome formation and, in turn, necroptosis, while when autophagic flux was uninterrupted, RIPK1 and RIPK3 were cleared through an autophagy-related pathway which inhibited necroptosis. These findings provide novel insights for the role of LC3 in regulating cardiomyocyte necroptosis, indicating its therapeutic potential in the prevention and treatment of hypoxic myocardial injury and other hypoxia-related diseases.

Microtubule associated protein 4 (MAP4) phosphorylation reduces cardiac microvascular density through NLRP3-related pyroptosis.

Phosphorylation of MAP4 (p-MAP4) causes cardiac remodeling, with the cardiac microvascular endothelium being considered a vital mediator of this process. In the current study, we investigated the mechanism underlying p-MAP4 influences on cardiac microvascular density. We firstly confirmed elevated MAP4 phosphorylation in the myocardium of MAP4 knock-in (KI) mice. When compared with the corresponding control group, we detected the decreased expression of CD31, CD34, VEGFA, VEGFR2, ANG2, and TIE2 in the myocardium of MAP4 KI mice, accompanied by a reduced plasma concentration of VEGF. Moreover, we observed apoptosis and mitochondrial disruption in the cardiac microvascular endothelium of MAP4 KI animals. Consistently, we noted a decreased cardiac microvascular density, measured by CD31 and lectin staining, in MAP4 KI mice. To explore the underlying mechanism, we targeted the NLRP3-related pyroptosis and found increased expression of the corresponding proteins, including NLRP3, ASC, mature IL-1ß, IL-18, and GSDMD-N in the myocardium of MAP4 KI mice. Furthermore, we utilized a MAP4 (Glu) adenovirus to mimic cellular p-MAP4. After incubating HUVECs with MAP4 (Glu) adenovirus, the angiogenic ability was inhibited, and NLRP3-related pyroptosis were significantly activated. Moreover, both cytotoxicity and PI signal were upregulated by the MAP4 (Glu) adenovirus. Finally, NLRP3 inflammasome blockage alleviated the inhibited angiogenic ability induced by MAP4 (Glu) adenovirus. These results demonstrated that p-MAP4 reduced cardiac microvascular density by activating NLRP3-related pyroptosis in both young and aged mice. We thus managed to provide clues explaining MAP4 phosphorylation-induced cardiac remodeling and enriched current knowledge regarding the role of MAP4.

Clinical significance of hypertension in patients with different types of cancer treated with antiangiogenic drugs.

Hypertension is a common comorbidity in patients receiving antiangiogenic therapy. Prior studies have reported worsening or new-onset hypertension as an adverse event of antiangiogenetic therapy, which can be managed by dose reduction or discontinuation of the culprit medication. By contrast, other studies have found that the occurrence of hypertension is a potential biomarker associated with greater efficacy of antiangiogenic therapy and predicts improved survival. At present, there is no consensus on the effects of hypertension in patients treated with antiangiogenic drugs. The present study reviewed the relationship between antiangiogenic drugs and hypertension in different types of cancer. It was demonstrated that the use of antiangiogenic drugs was associated with an increased risk of hypertension in most types of solid cancers. There was no significant difference in the incidence of hypertension between monoclonal antibody and small-molecule tyrosine kinase inhibitor treatments. Hypertension was more likely to occur in patients younger than 75 years old, female, and those with no history of bevacizumab use. Discontinuation or death caused by hypertension was rare, although previous studies have reported that hypertension was a risk factor for acute and chronic cardiovascular diseases and ischemic stroke. Of note, the early development of hypertension may serve as a potential biomarker associated with greater efficacy of antiangiogenic therapy.

H(+)/Cl(­) exchange transporter 7 promotes lysosomal acidification­mediated autophagy in mouse cardiomyocytes.

Autophagy protects cardiomyocytes in various pathological and physiological conditions; however, the molecular mechanisms underlying its influence and the promotion of autophagic clearance are not completely understood. The present study aimed to explore the role of H(+)/Cl(­) exchange transporter 7 (CLC­7) in cardiomyocyte autophagy. In this study, rapamycin was used to induce autophagy in mouse cardiomyocytes, and the changes in CLC­7 were investigated. The expression levels of CLC­7 and autophagy­related proteins, such as microtubule associated protein 1 light chain 3, autophagy related 5 and Beclin 1, were detected using western blotting or immunofluorescence. Autolysosomes were observed and analyzed using transmission electron microscopy and immunofluorescence following CLC­7 silencing with small interfering RNAs. Cellular viability was assessed using Cell Counting Kit­8 and lactate dehydrogenase assays. Lysosomal acidification was measured using an acidification indicator. Increased CLC­7 co­localization with lysosomes was identified during autophagy. CLC­7 knockdown weakened the acidification of lysosomes, which are the terminal compartments of autophagy flux, and consequently impaired autophagy flux, ultimately resulting in cell injury. Collectively, the present study demonstrated that in cardiomyocytes, CLC­7 may contribute to autophagy via regulation of lysosomal acidification. These findings provide novel insights into the role of CLC­7 in autophagy and cytoprotection.

Impaired Retrograde Transport Due to Lack of TBC1D5 Contributes to the Trafficking Defect of Lysosomal Cathepsins in Ischemic/Hypoxic Cardiomyocytes.

Lysosomal dysfunction has been found in many pathological conditions, and methods to improve lysosomal function have been reported to be protective against infarcted hearts. However, the mechanisms underlying lysosomal dysfunction caused by ischemic injury are far less well-established. The retromer complex is implicated in the trafficking of cation-independent mannose 6-phosphate receptor (CI-MPR), which is an important protein tag for the proper transport of lysosomal contents and therefore is important for the maintenance of lysosomal function. In this study, we found that the function of retrograde transport in cardiomyocytes was impaired with ischemia/hypoxia (I/H) treatment, which resulted in a decrease in CI-MPR and an abnormal distribution of lysosomal cathepsins. I/H treatment caused a reduction in TBC1D5 and a blockade of the Rab7 membrane cycle, which impeded retromer binding to microtubules and motor proteins, resulting in an impairment of retrograde transport and a decrease in CI-MPR. We also established that TBC1D5 was an important regulator of the distribution of lysosomal cathepsins. Our findings shed light on the regulatory role of retromer in ischemic injury and uncover the regulatory mechanism of TBC1D5 over retromer.

CELSR1 Acts as an Oncogene Regulated by miR-199a-5p in Glioma.

PURPOSE: This study aimed to elucidate the biological function and upstream regulatory mechanism of CELSR1 in glioma. MATERIALS AND METHODS: We evaluated the expression of CELSR1 in glioma by TCGA_GEPIA tool, RT-qPCR, and Western blot assays. CCK-8, wound healing, and transwell invasion assays were, respectively, performed to detect the effect of CELSR1 on cell proliferation, migration, and invasion. The upstream regulatory miRNAs of CELSR1 were predicted by TargetScan and validated by luciferase activity reporter assay. RESULTS: CELSR1 is overexpressed in glioma (P<0.05). CELSR1 promoted glioma cell proliferation, migration and invasion (P<0.01). CELSR1 was a direct target of miR-199a-5p. miR199a-5p mimics significantly inhibited CELSR1 mRNA and protein expression (P<0.01). miR199a-5p mimics reversed the effects of CELSR1 on glioma cell behaviors (P<0.01). CONCLUSION: CELSR1 acts as an oncogene promoting glioma cell proliferation, migration, and invasion, which is regulated by miR199a-5p.

CD38 Causes Autophagic Flux Inhibition and Cardiac Dysfunction Through a Transcriptional Inhibition Pathway Under Hypoxia/Ischemia Conditions.

Induced autophagy is protective against myocardial hypoxia/ischemia (H/I) injury, but evidence regarding the extent of autophagic clearance under H/I and the molecular mechanisms that influence autophagic flux has scarcely been presented. Here, we report that CD38 knockout improved cardiac function and autophagic flux in CD38-/- mice and CD38-/- neonatal cardiomyocytes (CMs) under H/I conditions. Mechanistic studies demonstrated that overexpression of CD38 specifically downregulated the expression of Rab7 and its adaptor protein pleckstrin homology domain-containing protein family member 1 (PLEKHM1) through nicotinamide adenine dinucleotide (NAD)-dependent and non-NAD-dependent pathways, respectively. Loss of Rab7/PLEKHM1 impaired the fusion of autophagosomes and lysosomes, resulting in autophagosome accumulation in the myocardium and consequent cardiac dysfunction under H/I conditions. Thus, CD38 mediated autophagic flux blockade and cardiac dysfunction in a Rab7/PLEKHM1-dependent manner. These findings suggest a potential therapeutic strategy involving targeted suppression of CD38 expression.