GPAT1 Deficiency in Mice Modulates NASH Progression in a Model-Dependent Manner.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD), and its more severe form, nonalcoholic steatohepatitis (NASH), is the leading cause for liver failure and liver cancer. Although the etiology is likely multifactorial, genes involved in regulating lipid metabolism are enriched in human NAFLD genome-wide association studies (GWAS), pointing to dysregulated lipid metabolism as a major pathogenic factor. Glycerol-3-phosphate acyltransferase 1 (GPAT1), encoded by GPAM, converts acyl-CoAs and glycerol-3-phosphate into lysophosphatidic acid and has been shown to regulate lipid accumulation in the liver. However, its role in mediating the progression from NAFLD to NASH has not been explored. METHODS: GPAT1-deficient mice were generated and challenged with diets inducing hepatic steatosis and NASH. Effects of GPAT1 deficiency on lipid and systemic metabolic end points were evaluated. RESULTS: Ablating GPAT1 globally or specifically in mouse hepatocytes reduced hepatic steatosis in the context of diet-induced or genetic obesity. Interestingly, blunting of progression from NAFLD to NASH in global GPAT1 knockout (KO) mice was model dependent. GPAT1 KO mice were protected from choline deficient, amino acid defined high-fat diet-induced NASH development, but not from the high fat, high carbohydrate, and high cholesterol diet-induced NASH. CONCLUSIONS: Our preclinical data support the notion that lipid metabolism pathways regulated by GPAT1 in hepatocytes play an essential role in NASH progression, albeit in a model-dependent manner.

Visible-Light-Promoted Intermolecular ß-Acyl Difunctionalization of Alkenes via Oxidative Radical-Polar Crossover.

A visible-light-induced ß-acyl difunctionalization of alkenes with acyl oxime esters and various nucleophiles was developed to achieve molecular complexity from readily available raw materials via oxidative radical-polar crossover. A variety of nucleophiles, including NH-sulfoximines, indoles, indazole, and trimethoxybenzene, were all effectively applicable to the sustainable reaction system. The novel synthetic strategy features mild reaction conditions, a broad substrate scope (39 examples), easy scale-up, and excellent regioselectivity.

Accurate real-time obstacle detection of coal mine driverless electric locomotive based on ODEL-YOLOv5s.

The accurate identification and real-time detection of obstacles have been considered the premise to ensure the safe operation of coal mine driverless electric locomotives. The harsh coal mine roadway environment leads to low detection accuracy of obstacles based on traditional detection methods such as LiDAR and machine learning, and these traditional obstacle detection methods lead to slower detection speeds due to excessive computational reasoning. To address the above-mentioned problems, we propose a deep learning-based ODEL-YOLOv5s detection model based on the conventional YOLOv5s. In this work, several data augmentation methods are introduced to increase the diversity of obstacle features in the dataset images. An attention mechanism is introduced to the neck of the model to improve the focus of the model on obstacle features. The three-scale prediction of the model is increased to a four-scale prediction to improve the detection ability of the model for small obstacles. We also optimize the localization loss function and non-maximum suppression method of the model to improve the regression accuracy and reduce the redundancy of the prediction boxes. The experimental results show that the mean average precision (mAP) of the proposed ODEL-YOLOv5s model is increased from 95.2 to 98.9% compared to the conventional YOLOv5s, the average precision of small obstacle rock is increased from 89.2 to 97.9%, the detection speed of the model is 60.2 FPS, and it has better detection performance compared with other detection models, which can provide technical support for obstacle identification and real-time detection of coal mine driverless electric locomotives.

Metabolic switch from glycogen to lipid in the liver maintains glucose homeostasis in neonatal mice.

Neonates strive to acquire energy when the continuous transplacental nutrient supply ceases at birth, whereas milk consumption takes hours to start. Using murine models, we report the metabolic switches in the first days of life, with an unexpected discovery of glucose as the universal fuel essential for neonatal life. Blood glucose quickly drops as soon as birth, but immediately rebounds even before suckling and maintains stable afterward. Meanwhile, neonatal liver undergoes drastic metabolic changes, from extensive glycogenolysis before suckling to dramatically induced fatty acid oxidation (FAO) and gluconeogenesis after milk suckling. Unexpectedly, blocking hepatic glycogenolysis only caused a transient hypoglycemia before milk suckling without causing lethality. Limiting lipid supply in milk (low-fat milk, [LFM]) using Cidea-/- mice, however, led to a chronic and severe hypoglycemia and consequently claimed neonatal lives. While fat replenishment rescued LFM-caused neonatal lethality, the rescue effects were abolished by blocking FAO or gluconeogenesis, pointing to a funneling of lipids and downstream metabolites into glucose as the essential fuel. Finally, glucose administration also rescued LFM-caused neonatal lethality, independent on FAO or gluconeogenesis. Therefore, our results show that the liver works as an energy conversion center to maintain blood glucose homeostasis in neonates, providing theoretical basis for managing infant hypoglycemia.

Adversarial Defense Method Based on Latent Representation Guidance for Remote Sensing Image Scene Classification.

Deep neural networks have made great achievements in remote sensing image analyses; however, previous studies have shown that deep neural networks exhibit incredible vulnerability to adversarial examples, which raises concerns about regional safety and production safety. In this paper, we propose an adversarial denoising method based on latent representation guidance for remote sensing image scene classification. In the training phase, we train a variational autoencoder to reconstruct the data using only the clean dataset. At test time, we first calculate the normalized mutual information between the reconstructed image using the variational autoencoder and the reference image as denoised by a discrete cosine transform. The reconstructed image is selectively utilized according to the result of the image quality assessment. Then, the latent representation of the current image is iteratively updated according to the reconstruction loss so as to gradually eliminate the influence of adversarial noise. Because the training of the denoiser only involves clean data, the proposed method is more robust against unknown adversarial noise. Experimental results on the scene classification dataset show the effectiveness of the proposed method. Furthermore, the method achieves better robust accuracy compared with state-of-the-art adversarial defense methods in image classification tasks.

Application of low molecular weight heparins in umbilical artery thrombosis: A case series and review of the literature.

RATIONALE: Low molecular weight heparins are widely used in various thrombotic diseases and exert a preventive effect on thrombosis in high-risk patients. Umbilical artery thrombosis (UAT) is a rare occurrence that is difficult to detect during routine prenatal visits but can lead to adverse perinatal outcomes. PATIENT CONCERNS: The aim of this study was to elucidate the therapeutic effect of low molecular weight heparins on UAT and to provide a new treatment option for the timing of delivery timing. DIAGNOSES AND INTERVENTIONS: A retrospective study was conducted on cases involving thrombosis of the umbilical cord enrolled from July 2017 to July 2022. Data were acquired and analyzed from medical records and the final diagnosis was confirmed by histopathology. All included patients received LWMHs therapy after initial diagnosis of UAT. OUTCOMES: The mean age of the 10 pregnant women recruited into this study was 27.9 ± 4.0 year-of-age; 1 (10%) was elderly. The gestational age at diagnosis was 29.9 ± 3.7 weeks, the gestational age at termination was 36.3 ± 2.5 weeks and the mean gestational age of extension was 6.4 ± 4.2 weeks. Low molecular weight heparin sodium was administered after umbilical artery embolism was detected on ultrasound. The LWMHs treatment received by the included patients in this study was subcutaneous injection. The specific usage varies due to the types of LWMHs. Of the 10 cases, 5 (50%) had fetal distress but all fetuses were born alive without neonatal asphyxia. With regards to delivery mode, 9 pregnancies were terminated by cesarean section. LESSON: Early anticoagulant treatment with LWMHs may improve pregnancy outcomes. The timing and mode of termination of pregnancy should be determined according to the condition of the mother and the fetus along with the gestational age.

Hyaluronic Acid-Guided Cerasome Nano-Agents for Simultaneous Imaging and Treatment of Advanced Atherosclerosis.

Early noninvasive screening and regression therapy for vulnerable atherosclerotic plaques remain challenging. In this study, it is aimed to develop a new approach for the active targeting of atherosclerotic plaques with nano-agents to aid imaging and treatment. Biocompatible hyaluronic acid (HA)-guided cerasomes are generated to selectively target CD44-positive cells within the plaque in in vitro studies and in vivo testing in Apoe-/- mice. Rosuvastatin (RST) is encapsulated in the HA-guided cerasome nano-formulation to produce HA-CC-RST, which results in significant plaque regression as compared to treatment with the free drug. Moreover, gadodiamide-loaded HA-CC enhances magnetic resonance images of vulnerable plaques, thereby attaining the goal of improved simultaneous treatment and imaging. Transcriptomic analysis confirms plaque regression with HA-CC-RST treatment, which potentially benefits from the anti-inflammatory effect of RST. In summary, a safe and efficient nano-formulation for the targeted delivery of active agents to atherosclerotic plaques is developed and may be applicable to other diagnostic and therapeutic agents for atherosclerosis treatment.

Inhibition of myeloid-derived suppressive cell function with all-trans retinoic acid enhanced anti-PD-L1 efficacy in cervical cancer.

PD-1/PD-L1 inhibitor treatments are relatively inefficacious in advanced cervical cancer patients. The presence of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment may be one significant barrier to efficacy. It has been shown that all-trans retinoic acid (ATRA) can differentiate MDSCs into mature myeloid cells. However, whether ATRA suppression of MDSCs function could enhance PD-L1 blockade-mediated tumor immunotherapy remains unknown. Here, the frequency of tumor-infiltrating MDSCs in cervical cancer patients was measured. ATRA was used to target MDSCs both in vitro and in tumor-bearing mice. The impact of ATRA on the human cell line HeLa was also investigated. The frequency of MDSCs and T cells was determined by flow cytometry. The expression of immunosuppressive genes was measured with quantitative real time-PCR and infiltration of immune cells was assessed by immunohistochemical examination. We found that tumor-infiltrating PD-L1+ MDSCs were more prevalent in cervical cancer patients. Blockade of PD-L1 expression in MDSCs with anti-PD-L1 antibody cannot relieve the suppressive activity of MDSCs induced by HeLa cells, while ATRA efficiently abrogated the suppressive activity of MDSCs. Furthermore, ATRA had no effect on PD-L1 expression in HeLa cells in vitro. In in vivo treatment, ATRA decreased MDSCs accumulation and increased the frequency of CD8+ T cells in BALB/C mice with U14 cervical tumors. Importantly, a combination treatment of ATRA and anti-PD-L1 antibody further delayed U14 tumor growth and increased the proportion of CD62L-CD8+ T cells, CD62L-CD4+ T cells, CD107a+CD8+ T cells as well as IFN-γ and TNF-α levels in tumors. Our results provide a rationale for the use of ATRA to suppress MDSCs and enhance anti-PD-L1 cancer immunotherapy in cervical cancer.

Development of a single capacitor-voltage-divider flux-loop for field-reversed theta-pinch plasmas.

As one of the most important diagnostics of field reversed plasma, the single-flux loop around the vacuum chamber is usually used to measure the magnetic flux to deduce the plasma size. In the theta-pinch process, the power supply will drive a large current through the coil in a short time to generate a high magnetic field, which will cause the magnetic flux in the vacuum chamber to rise sharply. Therefore, the induced voltage on the single-flux loop may be very strong and have high-frequency components. A voltage divider must be used to reduce the induced voltage to the range that the transmission line can withstand. According to the high-frequency characteristics of the measured signal, this paper designs a capacitor voltage divider single-flux loop with reference to the capacitive voltage divider in the industry. After theoretical derivation of parameter selection and then in the preliminary experimental test with and without plasma, the effectiveness of the distributed capacitor flux loop is verified.

A PRDM16-Driven Metabolic Signal from Adipocytes Regulates Precursor Cell Fate.

The precursor cells for metabolically beneficial beige adipocytes can alternatively become fibrogenic and contribute to adipose fibrosis. We found that cold exposure or ß3-adrenergic agonist treatment of mice decreased the fibrogenic profile of precursor cells and stimulated beige adipocyte differentiation. This fibrogenic-to-adipogenic transition was impaired in aged animals, correlating with reduced adipocyte expression of the transcription factor PRDM16. Genetic loss of Prdm16 mimicked the effect of aging in promoting fibrosis, whereas increasing PRDM16 in aged mice decreased fibrosis and restored beige adipose development. PRDM16-expressing adipose cells secreted the metabolite ß-hydroxybutyrate (BHB), which blocked precursor fibrogenesis and facilitated beige adipogenesis. BHB catabolism in precursor cells, mediated by BDH1, was required for beige fat differentiation in vivo. Finally, dietary BHB supplementation in aged animals reduced adipose fibrosis and promoted beige fat formation. Together, our results demonstrate that adipocytes secrete a metabolite signal that controls beige fat remodeling.

miR-20a inhibits hypoxia-induced autophagy by targeting ATG5/FIP200 in colorectal cancer.

Autophagy is a highly conserved lysosome-mediated protective cellular process in which cytosolic components, including damaged organelles and long-lived proteins, are cleared. Many studies have shown that autophagy was upregulated in hypoxic regions. However, the precise molecular mechanism of hypoxia-induced autophagy in colorectal cancer (CRC) is still elusive. In this study, we found that miR-20a was significantly downregulated under hypoxia in colon cancer cells, and overexpression of miR-20a alleviated hypoxia-induced autophagy. Moreover, miR-20a inhibits the hypoxia-induced autophagic flux by targeting multiple key regulators of autophagy, including ATG5 and FIP200. Furthermore, by dual-luciferase assay we demonstrated that miR-20a directly targeted the 3'-untranslated region of ATG5 and FIP200, regulating their messenger RNA and protein levels. In addition, reintroduction of exogenous ATG5 or FIP200 partially reversed miR-20a-mediated autophagy inhibition under hypoxia. A negative correlation between miR-20a and its target genes is observed in the hypoxic region of colon cancer tissues. Taken together, our findings suggest that hypoxia-mediated autophagy was regulated by miR-20a/ATG5/FI200 signaling pathway in CRC. miR-20a-mediated autophagy defect that might play an important role in hypoxia-induced autophagy during colorectal tumorigenesis.

Climatic Responses to Future Trans-Arctic Shipping.

As global temperatures increase, sea ice loss will increasingly enable commercial shipping traffic to cross the Arctic Ocean, where the ships' gas and particulate emissions may have strong regional effects. Here we investigate impacts of shipping emissions on Arctic climate using a fully coupled Earth system model (CESM 1.2.2) and a suite of newly developed projections of 21st-century trans-Arctic shipping emissions. We find that trans-Arctic shipping will reduce Arctic warming by nearly 1 °C by 2099, due to sulfate-driven liquid water cloud formation. Cloud fraction and liquid water path exhibit significant positive trends, cooling the lower atmosphere and surface. Positive feedbacks from sea ice growth-induced albedo increases and decreased downwelling longwave radiation due to reduced water vapor content amplify the cooling relative to the shipping-free Arctic. Our findings thus point to the complexity in Arctic climate responses to increased shipping traffic, justifying further study and policy considerations as trade routes open.

[Changes of Leukemia Stem Cells in Acute Myeloid Leukemia before and after Treatment].

OBJECTIVE: To investigate the presence of leukemia stem cells (LSC) in acute myeloid leukemia (AML) and find out the relative position of leukemia cells in the figures of flow cytometry, and to analyze the relationship between minimal residual diseases (MRD) and the level of LSC, so as to explore the correlation of LSC changes with the curative effect and the prognosis during chemical therapy. METHODS: A total of 85 samples were collected from 50 AML (except M3) patients, including 50 samples from the newly diagnosed patients, 7 samples of AML patients with non-remission and 28 samples of AML patients with complete remission. All samples were used for detection of LSC from immune phenotype of CD34+/CD38-/CD123+ by flow cytometry. The detection of immune phenotypic of leukemia cells was performed in the newly diagnosed patients. The detection of leukemia- associated immune phenotypes (LAIP) was implemented in the non-newly diagnosed patients. RESULTS: The LSC was identified in the CD34+/ CD38-/ CD123+ in AML and consistent with the relative position of the leukemia cell in flow cytometry figures. Statistical analysis showed significant difference in LSC content between the newly diagnosed AML group and the post-chemotherapy complete remission group(P<0.01),but did not between the newly diagnosed AML group and the post-chemotherapy non-remission group(P>0.05).There was significant positive correlation between the LSC content and MRD level in 28 AML patients with complete remission (r=0.680,P<0.01). CONCLUSION: LSC exist in AML and the relative position are consistent with the leukemia cells in flow cytometry figures, the size characteristics and weak expression of CD45 are also similar to leukemia cells. The proportion of LSC decreases after chemotherapy. Detecting and tracking the LSC changes in bone marrow and combination with detecting minimal resident disease(MRD) may contribute to evaluate the theraputic efficacy and prognosis of leukemia patients.

New applications of Schrödinger type inequalities in the Schrödingerean Hardy space.

As new applications of Schrödinger type inequalities obtained by Jiang (J. Inequal. Appl. 2016: Article ID 247, 2016) in the Schrödingerean Hardy space, we not only obtain the representation of Schrödingerean harmonic functions but also give a sufficient and necessary condition between the Schrödingerean distributional function and its derivative in the Schrödingerean Hardy space.

Control of brown and beige fat development.

Brown and beige adipocytes expend chemical energy to produce heat and are therefore important in regulating body temperature and body weight. Brown adipocytes develop in discrete and relatively homogenous depots of brown adipose tissue, whereas beige adipocytes are induced to develop in white adipose tissue in response to certain stimuli - notably, exposure to cold. Fate-mapping analyses have identified progenitor populations that give rise to brown and beige fat cells, and have revealed unanticipated cell-lineage relationships between vascular smooth muscle cells and beige adipocytes, and between skeletal muscle cells and brown fat. In addition, non-adipocyte cells in adipose tissue, including neurons, blood vessel-associated cells and immune cells, have crucial roles in regulating the differentiation and function of brown and beige fat.

Ubiquitous Robotic Technology for Smart Manufacturing System.

As the manufacturing tasks become more individualized and more flexible, the machines in smart factory are required to do variable tasks collaboratively without reprogramming. This paper for the first time discusses the similarity between smart manufacturing systems and the ubiquitous robotic systems and makes an effort on deploying ubiquitous robotic technology to the smart factory. Specifically, a component based framework is proposed in order to enable the communication and cooperation of the heterogeneous robotic devices. Further, compared to the service robotic domain, the smart manufacturing systems are often in larger size. So a hierarchical planning method was implemented to improve the planning efficiency. A test bed of smart factory is developed. It demonstrates that the proposed framework is suitable for industrial domain, and the hierarchical planning method is able to solve large problems intractable with flat methods.

Single-cell transcriptomics and functional target validation of brown adipocytes show their complex roles in metabolic homeostasis.

Brown adipocytes (BAs) are specialized for adaptive thermogenesis and, upon sympathetic stimulation, activate mitochondrial uncoupling protein (UCP)-1 and oxidize fatty acids to generate heat. The capacity for brown adipose tissue (BAT) to protect against obesity and metabolic disease is recognized, yet information about which signals activate BA, besides ß3-adrenergic receptor stimulation, is limited. Using single-cell transcriptomics, we confirmed the presence of mRNAs encoding traditional BAT markers (i.e., UCP1, expressed in 100% of BAs Adrb3, expressed in <50% of BAs) in mouse and have shown single-cell variability (>1000-fold) in their expression at both the mRNA and protein levels. We further identified mRNAs encoding novel markers, orphan GPCRs, and many receptors that bind the classic neurotransmitters, neuropeptides, chemokines, cytokines, and hormones. The transcriptome variability between BAs suggests a much larger range of responsiveness of BAT than previously recognized and that not all BAs function identically. We examined the in vivo functional expression of 12 selected receptors by microinjecting agonists into live mouse BAT and analyzing the metabolic response. In this manner, we expanded the number of known receptors on BAs at least 25-fold, while showing that the expression of classic BA markers is more complex and variable than previously thought.

Ebf2 is a selective marker of brown and beige adipogenic precursor cells.

Brown adipocytes and muscle and dorsal dermis descend from precursor cells in the dermomyotome, but the factors that regulate commitment to the brown adipose lineage are unknown. Here, we prospectively isolated and determined the molecular profile of embryonic brown preadipose cells. Brown adipogenic precursor activity in embryos was confined to platelet-derived growth factor α(+), myogenic factor 5(Cre)-lineage-marked cells. RNA-sequence analysis identified early B-cell factor 2 (Ebf2) as one of the most selectively expressed genes in this cell fraction. Importantly, Ebf2-expressing cells purified from Ebf2(GFP) embryos or brown fat tissue did not express myoblast or dermal cell markers and uniformly differentiated into brown adipocytes. Interestingly, Ebf2-expressing cells from white fat tissue in adult animals differentiated into brown-like (or beige) adipocytes. Loss of Ebf2 in brown preadipose cells reduced the expression levels of brown preadipose-signature genes, whereas ectopic Ebf2 expression in myoblasts activated brown preadipose-specific genes. Altogether, these results indicate that Ebf2 specifically marks and regulates the molecular profile of brown preadipose cells.

Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice.

Prdm16 is a transcription factor that regulates the thermogenic gene program in brown and beige adipocytes. However, whether Prdm16 is required for the development or physiological function of brown adipose tissue (BAT) in vivo has been unclear. By analyzing mice that selectively lacked Prdm16 in the brown adipose lineage, we found that Prdm16 was dispensable for embryonic BAT development. However, Prdm16 was required in young mice to suppress the expression of white-fat-selective genes in BAT through recruitment of the histone methyltransferase Ehmt1. Additionally, Prdm16 deficiency caused a severe adult-onset decline in the thermogenic character of interscapular BAT. This resulted in BAT dysfunction and cold sensitivity but did not predispose the animals to obesity. Interestingly, the loss of brown fat identity due to ablation of Prdm16 was accelerated by concurrent deletion of the closely related Prdm3 gene. Together, these results show that Prdm16 and Prdm3 control postnatal BAT identity and function.

Cidea promotes hepatic steatosis by sensing dietary fatty acids.

UNLABELLED: High levels of dietary saturated fat have been closely associated with the development of hepatic steatosis, but the factors that mediate this process remain elusive. Here, we observed that the level of cell death-inducing DNA fragmentation factor-alpha-like effector a (Cidea) expression was highly correlated with the severity of hepatic steatosis in humans. Overexpression of Cidea in mouse liver resulted in increased hepatic lipid accumulation and the formation of large lipid droplets (LDs). In contrast, mice with a Cidea deficiency had decreased lipid accumulation and alleviated hepatic steatosis when they received a high-fat-diet feeding or in ob/ob mice. Furthermore, the knockdown of Cidea in livers of ob/ob mice resulted in significantly reduced hepatic lipid accumulation and smaller LDs. Importantly, we observed that Cidea expression in hepatocytes was specifically induced by saturated fatty acids (FAs), and such induction was reduced when sterol response element-binding protein (SREBP)1c was knocked down. In contrast, the overexpression of SREBP1c restored the saturated FA-induced expression of Cidea. In addition, we observed that the stability of Cidea protein in hepatocytes increased significantly in response to treatment with FAs. CONCLUSION: Cidea plays critical roles in promoting hepatic lipid accumulation and in the development of hepatic steatosis by acting as a sensor that responds to diets that contain FAs.