Search

Purpose: The overall survival rate for metastatic osteosarcoma hovers around 20%. Responses to second-line chemotherapy, targeted therapies, and immunotherapies have demonstrated limited efficacy in metastatic osteosarcoma. Our objective is to validate differentially expressed genes and signaling pathways between non-metastatic and metastatic osteosarcoma, employing single-cell RNA sequencing (scRNA-seq) and additional functional investigations. We aim to enhance comprehension of metastatic mechanisms and potentially unveil a therapeutic target. Methods: scRNA-seq was performed on two primary osteosarcoma lesions (1 non-metastatic and 1 metastatic). Seurat package facilitated dimensionality reduction and cluster identification. Copy number variation (CNV) was predicted using InferCNV. CellChat characterized ligand-receptor-based intercellular communication networks. Differentially expressed genes underwent GO function enrichment analysis and GSEA. Validation was achieved through the GSE152048 dataset, which identified PDGFD-PDGFRB as a common ligand-receptor pair with significant contribution. Immunohistochemistry assessed PDGFD and PDGFRB expression, while multicolor immunofluorescence and flow cytometry provided insight into spatial relationships and the tumor immune microenvironment. Kaplan-Meier survival analysis compared metastasis-free survival and overall survival between high and low levels of PDGFD and PDGFRB. Manipulation of PDGFD expression in primary osteosarcoma cells examined invasion abilities and related markers. Results: Ten clusters encompassing osteoblasts, osteoclasts, osteocytes, fibroblasts, pericytes, endothelial cells, myeloid cells, T cells, B cells, and proliferating cells were identified. Osteoblasts, osteoclasts, and osteocytes exhibited heightened CNV levels. Ligand-receptor-based communication networks exposed significant fibroblast crosstalk with other cell types, and the PDGF signaling pathway was activated in non-metastatic osteosarcoma primary lesion. These results were corroborated by the GSE152048 dataset, confirming the prominence of PDGFD-PDGFRB as a common ligand-receptor pair. Immunohistochemistry demonstrated considerably greater PDGFD expression in non-metastatic osteosarcoma tissues and organoids, correlating with extended metastasis-free and overall survival. PDGFRB expression showed no significant variation between non-metastatic and metastatic osteosarcoma, nor strong correlations with survival times. Multicolor immunofluorescence suggested co-localization of PDGFD with PDGFRB. Flow cytometry unveiled a highly immunosuppressive microenvironment in metastatic osteosarcoma. Manipulating PDGFD expression demonstrated altered invasive abilities and marker expressions in primary osteosarcoma cells from both non-metastatic and metastatic lesions. Conclusions: scRNA-seq illuminated the activation of the PDGF signaling pathway in primary lesion of non-metastatic osteosarcoma. PDGFD displayed an inhibitory effect on osteosarcoma metastasis, likely through the suppression of the EMT signaling pathway. [ABSTRACT FROM AUTHOR]

Long noncoding RNA nuclear enriched abundant transcript 1 (NEAT1) has been reported to be involved in depression. This study aims to investigate the mechanism of NEAT1/microRNA (miR)-320-3p/Corticotropin-releasing hormone receptor 1 (CRHR1) axis in depressed rats. Rats with depression-like behaviors were prepared by exposing the rats to chronic unpredictable mild stress. Behavioral functions, pathological damage, neuronal apoptosis and monoamine neurotransmitter were examined in depressed rats. Primary hippocampal neurons were injured through simulation with corticosterone(CORT). Cell viability and apoptosis were measured in CORT-Induced hippocampal neurons. The binding relationship between NEAT1 and miR-320-3p and the targeting relationship between miR-320-3p and CRHR1 were detected. Elevated NEAT1, CRHR1 and reduced miR-320-3p exhibited in depressed rats and CORT-treated hippocampal neurons, NEAT1 bound to miR-320-3p to target CRHR1. Silencing NEAT1 or elevating miR-320-3p improved behavioral functions, attenuated pathological damage and apoptosis in the hippocampus, and increased monoamine neurotransmitter in depressed rats. Repression of NEAT1 or promotion of miR-320-3p enhanced viability and suppressed apoptosis of CORT-treated hippocampal neurons. The study highlights that NEAT1 competitively binds to miR-320-3p to up-regulate CRHR1 expression, thereby promoting hippocampal damage of depressed rats. [ABSTRACT FROM AUTHOR]

Acquired brain injury (ABI) is an injury that affects the brain structure and function. Traditional ABI treatment strategies, including medications and rehabilitation therapy, exhibit their ability to improve its impairments in cognition, emotion, and physical activity. Recently, near-infrared (NIR) photobiomodulation (PBM) has emerged as a promising physical intervention method for ABI, demonstrating that low-level light therapy can modulate cellular metabolic processes, reduce the inflammation and reactive oxygen species of ABI microenvironments, and promote neural repair and regeneration. Preclinical studies using ABI models have been carried out, revealing the potential of PBM in promoting brain injury recovery although its clinical application is still in its early stages. In this review, we first inspected the possible physical and biological mechanisms of NIR-PBM, and then reported the pathophysiology and physiology of ABI underlying NIR-PBM intervention. Therefore, the potential of NIR-PBM as a therapeutic intervention in ABI was demonstrated and it is also expected that further work can facilitate its clinical applications. [ABSTRACT FROM AUTHOR]

Three-dimensional porous NiO/CNT microspheres are constructed by the facile spray-drying method and subsequent annealing treatment under N2 atmosphere, which are subsequently wrapped by graphene oxide (GO) to form the porous NiO/CNT/GO microspheres. Benefiting from abundant pores distributed between NiO nanoparticles and CNT, porous NiO/CNT/GO microspheres exhibit a good cycling stability (333.6 mA h g−1 after 1000 cycles at 2000 mA g−1). Thanks to CNTs distributed inside the microspheres and GO that provides support for microspheres, porous NiO/CNT/GO microspheres show a high rate performance (445.1 mA h g−1 at 5000 mA g−1). This work provides an approach for the synthesis of high-performance lithium-ion battery anode materials, and the synthesis of porous NiO/CNT/GO microspheres plays a very important role in promoting applied physics, which has brought vitality to physics. [ABSTRACT FROM AUTHOR]

Fault diagnosis of rolling bearings under variable speed is a common issue in engineering practice, but it lacks an effective diagnosis algorithm, while approaches developed for steady speed cannot be directly applied. Therefore, for effectively identifying bearing faults under variable speed, this paper proposed a multiscale fractional dimensionless indicator (MSFDI) and put forward a fault diagnosis method with random forest (RF). It can overcome the feature space aliasing problem of traditional dimensionless indicators, which will lead to increased diagnosis uncertainty. The multiorder fractional Fourier transform is carried out on bearing signals to get a series of fractional Fourier domain components, which will be used to construct the original MSFDI feature set. Moreover, reliefF selects the sensitive MSFDIs as the input of the RF algorithm to determine the health condition. The effectiveness of the proposed method is verified by experiments and case studies. [ABSTRACT FROM AUTHOR]

Purpose: This retrospective study explored the clinical value of the plasma D-dimer level in osteosarcoma. Materials and Methods: We measured the plasma D-dimer level before neoadjuvant chemotherapy (D0) and the plasma D-dimer level after four courses of neoadjuvant chemotherapy (D1) in 103 patients with stage-IIB high-grade osteosarcoma of the limb. The change in the D-dimer level (ΔD) was defined as D1 minus D0. The chi-square test was used to compare categorical variables. Analyses of receiver operating characteristic (ROC) curves were undertaken to determine the optimal cutoff points for D0, D1, and ΔD. The area under the ROC (AUC) of D0, D1, and ΔD was calculated to evaluate their discriminatory abilities in monitoring the response to neoadjuvant chemotherapy (tumor necrosis). Survival curves were generated according to Kaplan–Meier analyses and compared using the Log rank test. Univariate analyses and multivariate analyses were carried out to determine independent prognostic factors. Results: Kaplan–Meier curves showed that a high D-dimer level at D0 and tumor diameter ≥ 8 cm were associated significantly with worse overall survival (OS) (P< 0.05). Multivariate Cox regression analyses revealed a high D-dimer level at D0 (hazard ratio, 3.92; 95% confidence interval, 1.756– 5.804; P=0.000) was an independent unfavorable prognostic factor. The chi-square test showed ΔD to be associated significantly with tumor necrosis. Analyses of ROC curves showed the D-dimer level at D0 and ΔD had better ability compared to that at D1 to discriminate the response to neoadjuvant chemotherapy. Conclusion: The D-dimer level was correlated with the prognosis and response to chemotherapy in patients with stage-IIB high-grade osteosarcoma of the limb. The D-dimer level may serve as a risk factor of the response to chemotherapy and prognosis of localized osteosarcoma. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (HCMV)–encoded microRNAs (miRNAs) are involved in posttranscriptional regulation of gene expression. Extracellular vesicles (EVs) can incorporate miRNAs. Relationship between HCMV infection and miRNAs in EVs remains unknown. EVs were isolated from supernatants of human embryonic lung fibroblasts (HELF) cells. Profiles of miRNAs in EVs were analyzed by deep sequencing. Dynamics of candidate viral miRNAs transportation via EVs was investigated using TaqMan PCR. Levels of candidate viral miRNAs in serum EVs from infants with HCMV active infection were detected and analyzed with their clinical index levels. A total of 16 HCMV miRNAs were found in EVs from infected HELF. Levels of miR-US25-1-5p and miR-UL112-3p in EVs increased at 6 h post-infection and were correlated with those in cells (for miR-US25-1-5p: r2 = 0.9375, p value < 0.05; for miR-UL112-3p: r2 = 0.7557, p value < 0.05). Viral miRNAs were transported into recipient cells at 2 h post-incubation. Moreover, levels of miR-US25-1-5p in serum EVs showed positive correlations with serum levels of γ-glutamyl transpeptidase, direct bilirubin, and total bile acid. Levels of miR-UL112-3p in serum EVs showed a positive correlation with serum levels of direct bilirubin. HCMV miRNAs could be transported to uninfected cells via EVs. Levels of miR-US25-1-5p and miR-UL112-3p in serum EVs from infants with HCMV active infection were significantly correlated with liver damage. [ABSTRACT FROM AUTHOR]

Background: Our previous study found that consumption of very low mineral drinking water may retard height development in schoolchildren; however, its association with bone modeling remained unknown.Objectives: The aim of this study was to investigate the influence of very low mineral water on biomarkers of bone modeling in children.Methods: A retrospective cohort study was conducted among 2 groups of 10-13-y-old children who had consumed drinking water with normal mineral contents (conductivity 345 μs/cm, the NW group including 119 boys and 110 girls) or very low mineral contents (conductivity 40.0 μs/cm, the VLW group including 223 boys and 208 girls) in school for 4 y. Differences in daily total mineral intakes, developmental parameters, serum biomarkers of osteoblast activity, and bone formation and resorption between the 2 groups were analyzed with independent t test and chi-square test. Associations of developmental parameters and serum biomarkers with Ca intake from drinking water were analyzed with multiple linear regression and binary logistic regression.Results: Compared with the NW group, the VLW group had lower daily Ca intake, height increase, bone mineral content (BMC), osteoblast activity [serum bone alkaline phosphatase (BALP)] (means ± SDs: 433 ± 131 mg, 16.6 ± 8.27 cm, 1.92 ± 0.431 kg, and 9.28 ± 1.42 μg/L compared with 497 ± 155 mg, 22.3 ± 8.45 cm, 2.14 ± 0.354 kg, and 11.0 ± 0.823 μg/L, respectively, P < 0.001), and higher bone resorption [serum crosslinked C-telopeptide of type I collagen (CTX), mean ± SD: 142 ± 46.9 nmol/L compared with 130 ± 40.6 nmol/L, P = 0.001). Ca intake from drinking water was positively associated with height increase, BMC, and BALP (β: 0.0667, 95% CI: 0.0540, 0.0793; β: 3.22, 95% CI: 2.37, 4.08; and β: 23.9, 95% CI: 20.6, 27.2), respectively, P < 0.001), and was negatively associated with CTX (β: -0.206, 95% CI:-0.321, -0.0904, P < 0.001).Conclusions: These changes suggested that consumption of very low mineral water may be associated with osteoblast inhibition, bone resorption activation, bone mineral reduction, and height development retardation. The health risk of consuming very low mineral water should be considered in children. [ABSTRACT FROM AUTHOR]

Abstract With the revolution of the traditional economic and social pattern based on centralized fossil energy consumption, the regional integrated energy system (RIES) has gained rapid development in recent years for achieving higher energy efficiency. This paper expands the Demand Response (DR) concept to the RIES and presents an optimal operation model of RIES considering the DR mechanism on the energy price. In this paper, a comprehensive DR strategy combining energy price and different loads is firstly developed to exploit the demand flexibility of RIES in the DR model established. Based on the DR modeling of the RIES, an operation optimization model with environmental, economic benefits and energy supply reliability as objective functions has been firstly established in detail. Secondly, a complete scheduling scheme is built based on the energy consumption characteristics and system operation characteristic of the integrated energy system. The model presented could reduce the cost of system without causing a significant amount of environmental pollution, and improve the energy efficiency of the RIES efficiently. Besides, the scheduling strategy proposed could also provide support for the operation strategy of integrated energy system under the energy development. Hopefully, this paper will provide reference for future research and engineering projects on DR programs in the RIES. Highlights • The typical structure of the RIES is introduced. • A DR model suitable for the RIES considering different loads is established. • An optimal operation model of the RIES based on DR is established. • The load in the RIES is affected not only by energy price but also by other loads. [ABSTRACT FROM AUTHOR]

Ischemic stroke is a major cerebrovascular disease resulting from a transient or permanent local reduction of cerebral blood flow. Angiogenesis plays an important role in cerebral microvascular repair after ischemic stroke. This study aimed at investigating the effect of NF-E2-related factor 2 (Nrf2) on the angiogenesis of mouse cerebral microvascular endothelial bEnd.3 cells in a hypoxic environment. We found that Nrf2 expression was temporarily increased in hypoxia-induced bEnd.3 cells. Knockdown of Nrf2 inhibited the proliferation, migration, as well as tube formation in hypoxia-induced bEnd.3 cells. Meanwhile, vascular endothelial growth factor and PI3K/Akt signaling pathways were identified to be regulated by Nrf2 in hypoxia-induced bEnd.3 cells. It was found that silencing of Nrf2 downregulated the expression levels of NAD(P)H:quinine oxidoreductase-1, vascular endothelial growth factor, p-Akt, and heme oxygenase-1 in hypoxia-induced bEnd.3 cells. Data suggested that hypoxia induced the transient increase of Nrf2, which plays a key role in the angiogenesis of cerebral microangiogenesis, and that Nrf2 regulates the proliferation, migration, as well as tube formation likely through PI3K/Akt signaling pathway in hypoxia-induced bEnd.3 cells. Our study provides proof of concept for the modulation of Nrf2, so as to tilt the balance toward angiogenesis, representing a therapeutic strategy for hypoxia or ischemia disorders such as stroke. [ABSTRACT FROM AUTHOR]

Although direct drinking water (DDW) systems that utilize a reverse-osmosis technique are thought to be harmful to children's development by reducing their daily mineral intake, few population data are available regarding this topic. We conducted an eco-epidemiological study to investigate the influence of low-mineral DDW on the development of schoolchildren. We collected developmental parameters of 13,723 girls and 16,161 boys before and after the introduction of DDW systems in 25 schools and measured the mineral levels in the DDW of each school. The DDW in 22 schools had lower-than-recommended levels of magnesium and calcium (magnesium, 10 mg/L and calcium, 20 mg/L, WHO). We found that children exposed to low-mineral DDW exhibited reduced height and diminished height increases as well as higher prevalences and incidences of hypoevolutism and dental caries ( p  < 0.01). This exposure was a risk factor for a greater incidence of both hypoevolutism and dental caries in children (RR = 7.110 (1.688, 29.953) and 1.813 (1.309, 2.509), respectively; p  < 0.01). Our results suggest that low-mineral DDW may retard height growth and promote the incidence of dental caries in schoolchildren; thus, schools should choose DDW treatment systems that retain the minerals in water. [ABSTRACT FROM AUTHOR]

Peroxisome-proliferator activated receptor gamma (PPARG) in placenta play an important role in pregnancy. Our previous study showed that it mediated the effects of phthalates on placental mRNA expression of estrogen synthetases in rats. To assess the effects of phthalate exposure on PPARG placental expression, and the contribution of PPARG to the effects of phthalates in human. 207 healthy pregnant women were recruited and their cord blood and placenta were collected upon delivery. Three phthalates, estrogens in cord blood and protein expression of PPARG in placenta were measured. Linear regression were used to analyze the relationship between phthalates exposure, PPARG expression and hormones. Phthalate levels in cord blood were positively associated with PPARG protein expression in placenta (p < 0.05), whereas estrogens in cord blood were negatively associated with phthalate levels and PPARG expression (p < 0.05). This study shows that PPARG in placenta may mediate the adverse effects of phthalates on pregnancy in human. [ABSTRACT FROM AUTHOR]

Humans experience more stress about uncertain situations than certain situations. However, the neural mechanism underlying the uncertainty of a negative stimulus has not been determined. In the present study, event-related potential was recorded to examine neural responses during the dread of unpredictable pain. We used a cueing paradigm in which predictable cues were always followed by electric shocks, unpredictable cues by electric shocks at a 50/50 ratio and safe cues by no electric shock. Visual analogue scales following electric shocks were presented to quantify subjective anxiety levels. The behavioral results showed that unpredictable cues evoked high-level anxiety compared with predictable cues in both painful and unpainful stimulation conditions. More importantly, the ERPs results revealed that unpredictable cues elicited a larger P200 at parietal sites than predictable cues. In addition, unpredictable cues evoked larger P200 compared with safe cues at frontal electrodes and compared with predictable cues at parietal electrodes. In addition, larger P3b and LPP were observed during perception of safe cues compared with predictable cues at frontal and central electrodes. The similar P3b effect was also revealed in the left sites. The present study underlined that the uncertain dread of pain was associated with threat appraisal process in pain system. These findings on early event-related potentials were significant for a neural marker and development of therapeutic interventions. [ABSTRACT FROM AUTHOR]

Perceptions of facial attractiveness are sensitive to emotional expression of the perceived face. However, little is known about whether the emotional expression on the face of another observer of the perceived face may have an effect on perceptions of facial attractiveness. The present study used event-related potential technique to examine social influence of the emotional expression on the face of another observer of the perceived face on perceptions of facial attractiveness. The experiment consisted of two phases. In the first phase, a neutral target face was paired with two images of individuals gazing at the target face with smiling, fearful or neutral expressions. In the second phase, participants were asked to judge the attractiveness of the target face. We found that a target face was more attractive when other observers positively gazing at the target face in contrast to the condition when other observers were negative. Additionally, the results of brain potentials showed that the visual positive component P3 with peak latency from 270 to 330 ms was larger after participants observed the target face paired with smiling individuals than the target face paired with neutral individuals. These findings suggested that facial attractiveness of an individual may be influenced by the emotional expression on the face of another observer of the perceived face. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (HCMV) encodes at least 26 microRNAs (miRNA). These miRNAs are utilized by HCMV to regulate its own genes as well as the genes of the host cell during infection. It has been reported that a cellular gene, solute carrier family 25, member 6 (SLC25A6), which is also designated adenine nucleotide translocator 3 (ANT3), was identified as a candidate target of hcmv-miR-UL36-5p by hybrid PCR. In this study, ANT3 was further demonstrated to be a direct target of hcmv-miR-UL36-5p by luciferase reporter assays. The expression level of ANT3 protein was confirmed, by western blotting, to be directly downregulated by overexpression of hcmv-miR-UL36-5p in HEK293 cells, U373 cells and HELF cells. Moreover, HCMV-infected cells showed a decrease in the ANT3 protein level. Using ANT3-specific small interfering RNA (siRNA) and an inhibitor for hcmv-miR-UL36-5p, it was shown that inhibition of apoptosis by hcmv-miR-UL36-5p in these cells specifically occurred via inhibition of ANT3 expression. These results imply that hcmv-miR-UL36-5 may play the same role during actual HCMV infection in order to establish a balance between the host cell and the virus. [ABSTRACT FROM AUTHOR]

Warning signal words are often used to convey valuable information about potential dangers in everyday life. In this study, we explored whether and how the hazard level of warning signal words modulated participants' attention to subsequent targets. Event-related potentials with high temporal resolution were employed in a cue-target paradigm. In this task, warning signal words with different hazard levels were used as cues. Participants were required to judge whether targets were presented on the screen horizontally or vertically. We found an inhibition of return (IOR) effect, i.e., participants had longer reaction times to validly cued targets than to invalidly cued targets. Accordingly, the IOR effect was reflected by a smaller P300 amplitude for invalidly cued targets compared to validly cued targets. Furthermore, the IOR effect was eliminated when the cues were high-hazard words. The dampening effect on the P300 was eliminated when the cues were high-hazard warning signal words. The lack of an IOR was attributed to participants' attentional bias to high-hazard stimuli, which are difficult for participants to disengage their attention from. The current study suggests that warning signal words are a particular type of stimulus that can override the IOR effect. Warning signal words with a high hazard level are more effective in successfully alerting people to risk in a hazardous environment. [ABSTRACT FROM AUTHOR]

Data concerning the effects of phthalate exposure on preterm delivery and fetal growth are limited in humans. In this paper, we assessed the relationship between 15 phthalate levels in cord blood and preterm delivery and fetal growth parameters in 207 Chinese women going into labor. Exposure to phthalates except DCHP was associated with gestational age reduction and preterm delivery (p<0.05). There were associations between phthalates and fetal growth parameters, many of which disappeared when analyses were adjusted for gestational age, especially in male infants (Only DEEP was associated with birth weight; DEP, DNHP, BBP, DNP with abdominal circumference; DEP, DBP, DCHP, DEHP with femur length in female infants. And DPP, DBEP was associated with birth length in male infants. p<0.05). This study indicates that prenatal exposure to phthalates is associated with younger gestational age and preterm delivery. Also, phthalate exposure may adversely affect fetal growth parameters via gestational age reduction and preterm delivery with a significant gender effect. [ABSTRACT FROM AUTHOR]

This paper mainly focuses on the low-carbon economic dispatch and energy sharing method of multiple Integrated Energy Systems (IES) from the perspective of System of Systems. First, a new model of carbon quota allocation and trading considering carbon balance and carbon sharing among multiple systems is established, and a low-carbon economic dispatch and energy sharing framework based on efficient utilization of regional carbon quota is proposed. Then, a Stackelberg game-based optimization model is proposed for energy service provider (ESP) and IES groups based on the collaborative optimization of IES and carbon transaction cost, where the ESP acts as a leader who chooses proper interactive price to promote energy sharing within the system while IES serves as a follower who minimizes its operation cost in response to the interactive price set by ESP. Moreover, the existence and uniqueness of the Stackelberg equilibrium are analyzed and a decentralized solution algorithm is suggested to reach the goal of optimal energy sharing and optimal operation. Finally, the case study of a joint energy sharing system containing three regional IESs are provided to show the effectiveness of the proposed method. The results demonstrate that the proposed method can not only increase profit of ESP and IES, but helpful to promote the optimal utilization of energy resources and the optimal distribution of carbon emission quota among energy systems. • A new model of carbon quota allocation and trading is established. • A low-carbon economic dispatch and energy sharing framework is proposed. • A cooperative optimization model of master-slave game is established. [ABSTRACT FROM AUTHOR]

Considering the flexibility and adjustability value of integrated energy system (IES) with flexible energy units and multivariate adjustable load in urban energy market, this paper proposes a two-stage energy management method of heat-electricity integrated energy system (HE-IES) considering dynamic pricing of Stackelberg game and operation strategy optimization. Firstly, a general comprehensive energy efficiency considering the exergy properties of electric and thermal energy is established, on this basis, this paper put forward a two-stage energy management framework considering interactive relationship between energy service provider (ESP) and users. Secondly, a two-stage energy management model is established to improve the energy efficiency and operation economy of the system, which includes the multi-objective optimization model of day-ahead scheduling and Stackelberg game dynamic pricing model of real-time energy management based on the source-load interaction optimization for hybrid energy. Finally, in order to illustrate the effectiveness of the proposed energy management method in improving system energy efficiency and operation strategy, a typical HE-IES consisting of 6 users and 1 ESP is chosen to simulation. The simulation results demonstrate that the proposed approach can not only enhance renewable energy utilization and reduce the cost of both ESP and users, but helpful to promote the benign interaction between energy equipment and load in IES, which could improve the energy efficiency of system operation. • The Hybrid energy conversion framework of integrated energy system is established. • A two-stage energy management model is constructed. • In the first stage, IES operation optimization based on economy and energy efficiency is implemented. • In the second stage, optimization strategy of users participating in game optimization guided by ESP is implemented. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small RNAs, 19-23 nucleotides in length, which regulate a variety of cellular processes. Human cytomegalovirus (HCMV) encodes only one intronic miRNA: human cytomegalovirus microRNA UL36 (hcmv-miR-UL36). In this study, we found that over-expression of hcmv-miR-UL36 resulted in a more than threefold increase in HCMV DNA synthesis at 24 h post infection. Fifteen putative targets of hcmv-miR-UL36 were identified using hybrid PCR, one being the HCMV UL138 gene that has previously been identified as a novel latency-associated determinant of HCMV infection. Down-regulation of UL138 expression by hcmv-miR-UL36 was validated using luciferase reporter assays and Western blot analysis in HEK293 cells. In the presence of hcmv-miR-UL36, we observed a 74.6% decrease in luciferase activity and a 46.2% decrease in HCMV UL138 protein expression. Our results indicate that hcmv-miR-UL36 may be a viral miRNA contributing to HCMV replication. [ABSTRACT FROM AUTHOR]

• Garden-path sentences can lead to lingering misinterpretations. • Reanalysis can result in a correct structural representation. • This correct structural representation is insufficient for a correct interpretation. A key question in research on sentence processing concerns how sentences that have been misanalyzed are reinterpreted, and to what extent the parser's attempts at revision are successful. Past work has shown that misinterpretations associated with a syntactic misparse linger even after the entire sentence has been processed (Christianson, Hollingworth, Halliwell, & Ferreira, 2001; Slattery, Sturt, Christianson, Yoshida and Ferreira, 2013). In two reading experiments, we sought to evaluate the level of representation that is responsible for misinterpretations of garden-path sentences. We combined reading measures with an offline comprehension task, which enabled us to conditionalize reading time analyses on correct versus incorrect question-answering performance. Our results suggest that reanalysis does not always result in a correct interpretation, either because the final interpretation does not always reflect the global structure or because reanalysis processes result in the creation of licit local trees but fail to generate a complete global parse for the entire sentence. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD), a common multifactorial neurodegenerative disease, is characterized by irreversible loss of dopaminergic neurons in the substantia nigra. In-depth study of the pathogenesis of PD is of great importance. High-mobility group AT-hook 2 (HMGA2) has been proposed to be implicated with neuronal differentiation and impairment of cognitive function. However, whether HMGA2 plays a role in PD is rarely explored. In the present study, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated PD mice models and N-methyl-4- phenylpyridinium (MPP+)-treated SH-SY5Y cell models were established. Reverse transcription-quantitative PCR showed that HMGA2 displayed low levels in brain tissues of MPTP-treated mice and MPP+-treated SH-SY5Y cells. Moreover, HMGA2 overexpression suppressed SH-SY5Y cell apoptosis. Additionally, let-7b-5p bound with HMGA2 3′ untranslated region (UTR), and its expression was negatively correlated with HMGA2 level. Moreover, let-7b-5p presented high levels in brain tissues of PD mice and MPP+-treated SH-SY5Y cells, and knockdown of let-7b-5p inhibited SH-SY5Y cell apoptosis. Rescue assays illustrated that HMGA2 neutralized the promotive effects of let-7b-5p mimics on SH-SY5Y cell apoptosis. In conclusion, the present study demonstrated that let-7b-5p contributes to cell apoptosis in PD by targeting HMGA2, which offers a potential theoretical basis for the study of effective therapy in PD. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most prevalent malignancy in women. With the improvement of medical treatment, breast cancer has become one of the solid tumors with the best curative effect. However, triple-negative breast cancer is not sensitive to conventional treatment due to its high invasiveness, resulting in a poorer prognosis than other types. The antibodies of programmed death receptor 1 and its ligands represent a new option as immunotherapy for patients with triple negative breast cancer. However, some recent clinical data suggest that a large proportion of patients exhibit primary or acquired resistance to treatment with programmed death receptor antibodies. In this review, we discuss the mechanisms that lead to resistance and also summarize potential strategies to overcome the resistance, improving the therapeutic efficacy of programmed death receptor 1 and its ligand-based antibodies in triple negative breast cancer. Triple-negative breast cancer (TNBC) is characterized by a high rate of systemic metastasis, insensitivity to conventional treatment and susceptibility to drug resistance, resulting in a poor patient prognosis. The immune checkpoint inhibitors (ICIs) represented by antibodies of programmed death receptor 1 (PD-1) and programmed death receptor ligand 1 (PD-L1) have provided new therapeutic options for TNBC. However, the efficacy of PD-1/PD-L1 blockade monotherapy is suboptimal immune response, which may be caused by reduced antigen presentation, immunosuppressive tumor microenvironment, interplay with other immune checkpoints and aberrant activation of oncological signaling in tumor cells. Therefore, to improve the sensitivity of TNBC to ICIs, suitable patients are selected based on reliable predictive markers and treated with a combination of ICIs with other therapies such as chemotherapy, radiotherapy, targeted therapy, oncologic virus and neoantigen-based therapies. This review discusses the current mechanisms underlying the resistance of TNBC to PD-1/PD-L1 inhibitors, the potential biomarkers for predicting the efficacy of anti-PD-1/PD-L1 immunotherapy and recent advances in the combination therapies to increase response rates, the depth of remission and the durability of the benefit of TNBC to ICIs. [ABSTRACT FROM AUTHOR]

Emodin has been reported to fulfill an important function in suppressing the vicious outcome of liver cancer. We aimed to elucidate the partial underlying molecular mechanism of emodin in inhibiting liver cancer, and we applied miRNA-sequence analysis and corresponding molecular functional experiments to find that the inhibitory effect of emodin on liver cancer was partly mediated by cellular autophagy through the miR-371a-5p/PTEN axis. The expression level of miR-371a-5p was down-regulated after emodin treatment in liver cancer cell lines (LCCLs). Restoring the expression level of miR-371a-5p attenuated the suppression of emodin on LCCLs. Additionally, we performed the prediction in relevant online databases and found that PTEN might functioned as a downstream target of miR-371a-5p to participate in the regulation on the above process. What's more, the detection of autophagy-related protein markers showed that LC3II was elevated accompanied by the decreased P62. The above results revealed that PTEN functioned as a key target to regulate the autophagy in the process where emodin inhibited the malignant outcome of LCCLs via miR-371a-5p, which further provided a theoretical basis for the application of traditional Chinese medicine (TCM) on clinical tumors. • We further enriched the role of emodin in suppressing liver cancer. • MiR-371a-5p was found to play an important role in the process of inhibiting liver cancer with emodin for the first time. • Emodin could modulate the miR-371a-5p/PTEN axis to suppress liver cancer via an autophagy-dependent pathway. [ABSTRACT FROM AUTHOR]

• FrFBE is proposed to construct multiple single-order FrFT filters. • Global/local minimum FrFBE criterion is proposed to determine FrFT filtering center. • The optimized FrFT filtering method can extract time-varying fault characteristics. • Simulated and experimental cases highlight the superiority of the proposed method. Fault diagnosis under varying speed conditions has become a research hotspot in rotating machinery monitoring. Due to the energy concentration property of linear frequency-modulated signals, fractional Fourier transform (FrFT) is helpful to bearing fault detection with varying speed. However, its performance depends on FrFT filter parameters, which are difficult to determine. So fractional frequency band entropy (FrFBE) is proposed to solve this problem, constructing optimized FrFT filter to extract time-varying fault characteristics. First, short-time fractional Fourier transform (STFrFT) is performed on the demodulated signal. Then, FrFBE is developed based on the obtained fractional time-frequency matrix to locate aggregation positions of fault harmonics. Next, a global/local minimum FrFBE criterion is proposed to determine FrFT filtering centers. Finally, the fault characteristics are extracted by computed order tracking (COT) from the filtered results. Simulation and experiment cases show good diagnosis result with different operating conditions, with recognition error kept within 1%. [ABSTRACT FROM AUTHOR]

Many syntactic theories posit a fundamental structural difference between intransitive verbs with agentive subjects (unergative verbs) and those with theme subjects (unaccusative verbs). This claim garners support from studies finding differences in the online comprehension of these verbs. The present experiments seek to replicate one such finding using the visual world paradigm (Koring, Mak, & Reuland, 2012). We control for several factors that were uncontrolled in previous studies. We find no differences in the processing of unergative and unaccusative sentences in logistic regressions and cluster analyses. However, in growth curve analyses, modeled closely on the original paper, we find differences between the verb conditions that appear to be statistically significant but are unstable across experiments. A resampling analysis reveals that the growth curve analyses are highly anticonservative, suggesting that the earlier finding was a false positive. We conclude that there is no strong evidence that unaccusatives are processed differently from unergatives. We suggest that growth curve analyses only be used with visual world paradigm data when the underlying assumptions of the analysis can be validated via resampling. [ABSTRACT FROM AUTHOR]

• Frontal cortex plays an important role in Stroop cognitive control. • Cingulate cortex is activated for the Stroop interference effect. • Left dorsolateral prefrontal cortex is activated for the interference effect. • Left and right inferior frontal gyrus may have different roles in the Stroop task. Age plays a significant role in executive control processes in the Stroop task. This study aims to draw together the Stroop tasks to determine the role of the frontal cortex in cognitive control among healthy young adults using activation likelihood estimation. Forty-six studies were selected according to the fMRI neuroimaging tools, Stroop experimental tasks, young participants' age. The results showed that the contrast of incongruent conditions and congruent conditions revealed 7 significant clusters, including the right cingulate cortex, left dorsolateral prefrontal cortex, bilateral inferior frontal gyrus, right superior frontal gyrus and temporal cortex. In addition, the contrast comparing incongruent conditions with neutral conditions activated a network including the right inferior frontal gyrus, left dorsolateral prefrontal cortex, bilateral medial frontal cortex, left insular cortex and bilateral inferior parietal lobule and precuneus. In this study, we found that the brain areas for executive performance had a higher concordance in the frontal cortex among healthy young adults than temporal-parietal network. [ABSTRACT FROM AUTHOR]

Background: Adult Ewing sarcoma (ES) is a rare disease, the optimal treatment model is unknown. This study aimed to retrospectively analyze treatment-related prognostic factors of nonspinal ES in Chinese adults.Methods: Eighty-one patients treated between January 2005 and December 2017 were included in the present study. Thirty-three (40.7%) presented with metastatic disease at diagnosis. Eight patients were submitted to primary surgery followed by chemotherapy, while 73 patients received chemotherapy before and after surgery and/or local radiotherapy. The chemotherapy regimen included 8-17 cycles of vincristine, doxorubicin, and cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE) every 3 weeks. Clinical outcomes and safety were analyzed.Results: VDC/IE chemotherapy was well tolerated in adult patients with ES. Multivariate Cox regression analyses revealed that chemotherapy of at least 12 cycles was a favorable independent prognostic factor of event-free survival (hazard ratio, 0.558; 95% confidence interval, 0.323-0.965; P = 0.037) and overall survival (hazard ratio, 0.424; 95% confidence interval, 0.240-0.748; P = 0.003). Similarly, a low frequency of chemotherapy delays was an independent prognostic factor of improved OS (hazard ratio, 0.438; 95% confidence interval, 0.217-0.887; P = 0.022).Conclusion: Our study suggests that adults with ES should be treated with an aggressive multidisciplinary approach, intensive chemotherapy with adequate cycles and appropriate intervals can be recommended in this group. [ABSTRACT FROM AUTHOR]

Congenital human cytomegalovirus (HCMV) infection is a major cause of abnormalities and disorders in the central nervous system (CNS) and/or the peripheral nervous system (PNS). However, the complete pathogenesis of neural differentiation disorders caused by HCMV infection remains to be fully elucidated. Stem cells from human exfoliated deciduous teeth (SHEDs) are mesenchymal stem cells (MSCs) with a high proliferation and neurogenic differentiation capacity. Since SHEDs originate from the neural crest of the early embryonic ectoderm, SHEDs were hypothesized to serve as a promising cell line for investigating the pathogenesis of neural differentiation disorders in the PNS caused by congenital HCMV infection. In this work, SHEDs were demonstrated to be fully permissive to HCMV infection and the virus was able to complete its life cycle in SHEDs. Under neurogenic inductive conditions, HCMV infection of SHEDs caused an abnormal neural morphology. The expression of stem/neural cell markers was also disturbed by HCMV infection. The impairment of neural differentiation was mainly due to a reduction of intracellular cholesterol levels caused by HCMV infection. Sterol regulatory element binding protein-2 (SREBP2) is a critical transcription regulator that guides cholesterol synthesis. HCMV infection was shown to hinder the migration of SREBP2 into nucleus and resulted in perinuclear aggregations of SREBP2 during neural differentiation. Our findings provide new insights into the prevention and treatment of nervous system diseases caused by congenital HCMV infection. [ABSTRACT FROM AUTHOR]

To expand the knowledge on the tempo-spatial patterns of zooplankton and the key modulated factors in urban aquatic ecosystem, we investigated zooplankton and water quality from April 2018 to January 2019 in the hinterland of the Three Gorges Reservoir area, Wanzhou City of China. The results indicated that water quality indicated by the trophic state index (TSI) reached a state of mesotrophication to light eutrophication in the Yangtze River, and a state of moderate- to hyper- eutrophication in its tributaries. Based on the biomass of zooplanktons, Asplanchna priodonta was the most common specie in April; Encentrum sp., Filinia cornuta and Epiphanes senta were the most noticeable species in summer; Cyclopoida Copepodid, Sinocalanus dorrii and Philodina erythrophthalma became the dominant species in winter. Generally, rotifers prevailed in April and August, and copepods became the most popular in January. According to canonical correspondence analysis, nitrate, temperature (T), ammonia, water level and permanganate index (CODMn) significantly influenced the community structure of zooplankton (p < 0.05). The dominant species shifts of zooplankton were partly associated with nutrient level (nitrate and ammonia) under periodic water level fluctuations. Rotifers and protozoans were characterized as high T adapted and CODMn-tolerant species comparing with cladocerans and copepods. The ratio of microzooplankton to mesozooplankton (Pmicro/meso) has presented a strongly positive relationship with T (p < 0.001), as well as Pmicro/meso and CODMn (p < 0.001). It implied that zooplankton tended to miniaturize individual size via species shift under high T and/or CODMn conditions induced by global warming and human activities. The information hints us that climate change and human activities are likely to produce fundamental changes in urban aquatic ecosystem by reorganizing biomass structure of the food web in future. [ABSTRACT FROM AUTHOR]

Several studies have emphasized the role of DNA methylation in vitiligo. However, its profile in human skin of individuals with vitiligo remains unknown. Here, we aimed to study the DNA methylation profile of vitiligo using pairwise comparisons of lesions, peri-lesions, and healthy skin. We investigated DNA methylation levels in six lesional skin, six peri-lesional skin, and eight healthy skin samples using an Illumina 850 K methylation chip. We then integrated DNA methylation data with transcriptome data to identify differentially methylated and expressed genes (DMEGs) and analyzed their functional enrichment. Subsequently, we compared the methylation and transcriptome characteristics of all skin samples, and the related genes were further studied using scRNA-seq data. Finally, validation was performed using an external dataset. We observed more DNA hypomethylated sites in patients with vitiligo. Further integrated analysis identified 264 DMEGs that were mainly functionally enriched in cell division, pigmentation, circadian rhythm, fatty acid metabolism, peroxidase activity, synapse regulation, and extracellular matrix. In addition, in the peri-lesional skin, we found that methylation levels of 102 DMEGs differed prior to changes in their transcription levels and identified 16 key pre-DMEGs (ANLN, CDCA3, CENPA, DEPDC1, ECT2, DEPDC1B, HMMR, KIF18A, KIF18B, TTK, KIF23, DCT, EDNRB, MITF, OCA2, and TYRP1). Single-cell RNA analysis showed that these genes were associated with cycling keratinocytes and melanocytes. Further analysis of cellular communication indicated the involvement of the extracellular matrix. The expression of related genes was verified using an external dataset. To the best of our knowledge, this is the first study to report a comprehensive DNA methylation profile of clinical vitiligo and peri-lesional skin. These findings would contribute to future research on the pathogenesis of vitiligo and potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Frontal fibrosis alopecia (FFA) is a primary cicatricial alopecia and has received increasing attention in recent years. However, the pathogenesis of FFA has not been fully elucidated. Methods and results: Herein, we collected the transcriptome data of scalp lesions of seven patients with FFA and seven healthy controls. The differential expression analysis and weighted gene co‐expression network analysis were conducted and we identified 458 differentially expressed genes (DEGs) in two key modules. Later, we performed functional enrichment analysis and functional modules identification, revealing the participation of immune response and fatty acid metabolism. Based on the results, we processed further studies. On the one hand, we analyzed the infiltrating immune cells of FFA through CIBERSORT algorithm, indicating the activation of M1 macrophage and CD8+ T cell. On the other hand, considering lipid metabolism of FFA and oxidative stress of hair follicle cells in alopecia, we explored the potential ferroptosis of FFA. By intersection of DEGs and ferroptosis‐related genes from FerrDb database, 19 genes were identified and their expression was validated in an external dataset containing 36 FFA cases and 12 controls. Then, we used LASSO algorithms to construct a four‐gene diagnostic model, which achieved an AUC of 0.924 in validation dataset. Additionally, the immune cells were found to be related to ferroptosis in FFA. Conclusion: Taken together, this study contributed to reveal the molecular mechanisms of FFA and is expected to inspire future research on treatment. [ABSTRACT FROM AUTHOR]

• AD is associated with significant regional increase of tau, microglia activation and GM atrophy. • Spatial distributions of different pathologies were highly overlapping. • GM atrophy mediated the effects of tau and neuroinflammation on cognitive impairments. • Multimodal imaging data fusion between multi-tracer PET and MRI. In addition to beta-amyloid accumulation, misfolded tau and activated microglia are also present in Alzheimer's disease (AD). It is important to study the relationship amongst these pathologies in vivo and their effects on the cognitive deficits for developing effective trails and future therapeutic or preventive strategies for AD. To investigate the relationships amongst different pathologies in AD, in particular how they interact resulting in cognitive impairments, we conducted a study of sixty-six subjects (15 AD, 24 Mild Cognitive Impairment (MCI) and 27 similarly aged healthy controls), who underwent standardised clinical and neuropsychological assessments followed by dynamic PET using [18F]AV1451 (tau) and [11C]PK11195 (activated microglia) and multimodal 3T MRI. MCI patients also underwent [11C]PIB (beta-amyloid) PET. We compared regional PET binding and grey matter atrophy amongst AD, amyloid positive MCI and controls, as well as their spatial distribution across different brain areas. We also applied a mediation analysis to infer the direct and indirect effects of tau, neuroinflammation and grey matter atrophy on cognitive functioning. We found increased [18F]AV1451 and [11C]PK11195 binding as well as grey matter atrophy in AD, with a strong spatial overlap amongst these AD related biomarkers suggesting them interacting with each other. We demonstrated that both tau ([18F]AV1451) and neuroinflammation ([11C]PK11195) have significant effects on cognition however their effects were fully mediated by grey matter atrophy. No mediation effect between tau and neuroinflammation were found with respect to cognition. In conclusion, grey matter atrophy not only spatially overlapped with tau and microglia activity in AD, but also mediate them in affecting cognitive impairments. The mediation analysis enabled data fusion across multiple imaging modalities (PET and MRI) and multiple PET tracers. Our results have significant implications for trials targeting tau and inflammation, and future therapeutic or preventive strategies for AD. [ABSTRACT FROM AUTHOR]

With the application and the rapid advancement of smart grid technology, the practical application and operation status of multi-energy complementary microgrids have been widely investigated. In the paper presented, the optimal operation of a solar unit, a storage battery and combined cooling, heating and power is studied via an economic optimization model implemented in General Algebraic Modeling Systems (GAMS). The model represents an optimization strategy for the economic operation of a microgrid considering demand response programs in different scenarios, and it is intended for the targets of minimizing the operating cost of the microgrid and maximizing the efficiency of renewable energy utilization. In addition, a multi-time electricity price response model based on user behavior and satisfaction is established, and the core value of the model is to describe the mechanism and effect of participation in electricity price demand response. In order to verify the accuracy of the model proposed, we design the dispatch strategy of a microgrid under different states considering demand response, and use genetic algorithm to solve the optimization problems. On the other hand, the application of methodology to a real case study in Suzhou demonstrates the effectiveness of this model to solve the economic dispatch of the microgrid’s renewable energy park. [ABSTRACT FROM AUTHOR]

Mechanical fault diagnosis under varying speed conditions has gradually become an important issue in rotating machinery monitoring, especially the research on compound fault diagnosis is still rare. Order analysis is one of the most effective and widely used methods to eliminate the effects of speed fluctuations; however, it is difficult to extract compound fault features directly. Moreover, there are often many restrictions on the number and locations of sensors to be installed in practice, which also brings great challenges to compound fault diagnosis under varying speed conditions. In this article, a novel compound fault detection method with virtual multichannel signals in the angle domain is proposed to solve these problems for rolling bearing monitoring under varying speed conditions. First, we aim to use only a vibration acceleration sensor and a noncontact rotational speed sensor to adapt to limitations on sensor installation in practical applications. However, this may result in an underdetermined problem when trying to detect a compound fault with only a single-channel vibration signal. Then we make it up through constructing virtual multichannel signals based on variational mode decomposition theory, before which the nonstationary vibration signal is converted from the time domain into a stationary signal in the angle domain with computed order tracking to eliminate speed fluctuations. Finally, these virtual signals can be easily taken as input to a normal independent component analysis, and different faults can be detected in the order spectrum of each independent component. Case studies on rolling bearing experiments verified the advantages of the proposed method in compound fault detection under varying speed conditions. [ABSTRACT FROM AUTHOR]

Background: Cell-based immunotherapy shows the therapeutic potential in sarcomas, in addition to angiogenesis-targeted tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI). Multi-antigen stimulated cell therapy-I (MASCT-I) technology is a sequential immune cell therapy for cancer, which composes of multiple antigen-loaded dendritic cell (DC) vaccines followed by the adoptive transfer of anti-tumor effector T-cells. Methods: In this phase 1 study, we assessed MASCT-I plus camrelizumab (an ICI against PD-1) and apatinib (a highly selective TKI targeting VEGFR2) in patients with unresectable recurrent or metastatic bone and soft-tissue sarcoma after at least one line of prior systemic therapy. One MASCT-I course consisted of 3 DC subcutaneous injections, followed by 3 active T cell infusions administered 18–27 days after each DC injection. In schedule-I group, 3 DC injections were administered with a 28-day interval in all courses; in schedule-II group, 3 DC injections were administered with a 7-day interval in the first course and with a 28-day interval thereafter. All patients received intravenous camrelizumab 200 mg every 3 weeks and oral apatinib 250 mg daily. Results: From October 30, 2019, to August 12, 2021, 19 patients were enrolled and randomly assigned to schedule-I group (n = 9) and schedule-II group (n = 10). Of the 19 patients, 11 (57.9%) experienced grade 3 or 4 treatment-related adverse events. No treatment-related deaths occurred. Patients in schedule-II group showed similar objective response rate (ORR) with those in schedule-I group (30.0% versus 33.3%) but had higher disease control rate (DCR; 90.0% versus 44.4%) and longer median progression-free survival (PFS; 7.7 versus 4.0 months). For the 13 patients with soft-tissue sarcomas, the ORR was 30.8%, DCR was 76.9%, and median PFS was 12.9 months; for the 6 patients with osteosarcomas, the ORR was 33.3%, the DCR was 50.0%, and median PFS was 5.7 months. Conclusions: Overall, MASCT-I plus camrelizumab and apatinib was safe and showed encouraging efficacy in advanced bone and soft-tissue sarcoma, and schedule-II administration method was recommended. Trial registration: ClinicalTrials.gov, NCT04074564. [ABSTRACT FROM AUTHOR]

Wnt signaling pathways are transmitted via 10 homologous frizzled receptors (FZD1-10) in humans. Reagents broadly inhibiting Wnt signaling pathways reduce growth and metastasis of many tumors, but their therapeutic development has been hampered by the side effect. Inhibitors targeting specific Wnt-FZD pair(s) enriched in cancer cells may reduce side effect, but the therapeutic effect of narrow-spectrum Wnt-FZD inhibitors remains to be established in vivo. Here, we developed a fragment of C. difficile toxin B (TcdBFBD), which recognizes and inhibits a subclass of FZDs, FZD1/2/7, and examined whether targeting this FZD subgroup may offer therapeutic benefits for treating breast cancer models in mice. Utilizing 2 basal-like and 1 luminal-like breast cancer models, we found that TcdBFBD reduces tumor-initiating cells and attenuates growth of basal-like mammary tumor organoids and xenografted tumors, without damaging Wnt-sensitive tissues such as bones in vivo. Furthermore, FZD1/2/7–positive cells are enriched in chemotherapy-resistant cells in both basal-like and luminal mammary tumors treated with cisplatin, and TcdBFBD synergizes strongly with cisplatin in inhibiting both tumor types. These data demonstrate the therapeutic value of narrow-spectrum Wnt signaling inhibitor in treating breast cancers. Wnt signaling is transmitted via ten homologous Frizzled receptors (FZD1-10) in humans, complicating the therapeutic use of inhibitors due to side-effects. This study shows that a bacterial toxin fragment can be used as a tool to specifically inhibit Wnt signaling mediated by a subset of Frizzed receptors (FZD1, 2, 7), with potential for cancer treatment. [ABSTRACT FROM AUTHOR]

Systemic inflammation responses have been associated with cancer development and progression. C-reactive protein (CRP), Glasgow prognostic score (GPS), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and neutrophil-platelet score (NPS) have been shown to be independent risk factors in various types of malignant tumors. This retrospective analysis of 162 osteosarcoma cases was performed to estimate their predictive value of survival in osteosarcoma. All statistical analyses were performed by SPSS statistical software. Receiver operating characteristic (ROC) analysis was generated to set optimal thresholds; area under the curve (AUC) was used to show the discriminatory abilities of inflammation-based scores; Kaplan-Meier analysis was performed to plot the survival curve; cox regression models were employed to determine the independent prognostic factors. The optimal cut-off points of NLR, PLR, and LMR were 2.57, 123.5 and 4.73, respectively. GPS and NLR had a markedly larger AUC than CRP, PLR and LMR. High levels of CRP, GPS, NLR, PLR, and low level of LMR were significantly associated with adverse prognosis (P < 0.05). Multivariate Cox regression analyses revealed that GPS, NLR, and occurrence of metastasis were top risk factors associated with death of osteosarcoma patients. [ABSTRACT FROM AUTHOR]

The digital preservation of intangible cultural heritage has become a major emphasis and challenge in China. This study investigated the state of the field by examining the activities of the local Intangible Cultural Heritage Protection Centers at Nanyang, Kaifeng, Xianning, Chibi, Sanming and Jingdezhen, using semi-structured interviews to document the status of digital preservation of intangible cultural heritage in China. This study found that the digital preservation system of Chinese cultural heritage has a clear structure and pluralistic components. The centers are rich in digital resources, but disordered in their storage, and are supported by policies, but weak in the area of management. It is necessary to further clarify these institutions' rights and responsibilities, formulate storage standards, build shared platforms, and strengthen digital preservation management. [ABSTRACT FROM AUTHOR]

Abstract This paper presents a two-stage optimization method for a coupled capacity planning and operation problem, cast within the economical operation of Regional Integrated Energy System. The first stage optimization of the proposed model represents a regional integrated energy system planner whose purpose is to minimize its energy and environmental cost, while the second stage is an operation problem whose primary role is to achieve the optimal operation scheme of the system. The regional integrated energy system planner pursues best interests by co-optimizing the capacity configuration and power output of individual energy supply module, while the regional integrated energy system maximizes the installed capacity of renewable energy sources and minimizes the environmental costs. To illustrate the advantage of the proposed method, the NSGA-II algorithm and the mixed integer linear programming method are implemented to solve the model based on simulation. Besides, application of the optimization method proposed to the energy infrastructure of a regional integrated energy system in China is discussed, and the results obtained through simulation are compared to the bi-level optimization objectives. The results show that the proposed method is economical and effective in practical application. Highlights • A bi-level optimization model for integrated energy system is presented. • A decentralized optimization method is proposed for solving capacity planning. • Accuracy and economy of capacity planning are improved. • The economic efficiency of the RIES is improved. [ABSTRACT FROM AUTHOR]

Endocrine disrupting chemicals may disrupt developing neuroendocrine systems, especially when the exposure occurs during a critical period. This study aimed to investigate whether prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a major component of plasticizers used worldwide, disrupted the development of a network of genes important for neuroendocrine function in male rats. Pregnant rats were treated with corn oil (vehicle control), 2, 10 or 50 mg/kg DEHP by gavage from gestational day 14 to 19. The neuroendocrine gene expressions were quantified using a 48-gene Taqman qPCR array in the whole hypothalamus of neonatal rats (postnatal day 1) and in the anteroventral periventricular nucleus (AVPV), medial preoptic nucleus (MPN) and arcuate nucleus (ARC) of adult rats (postnatal day 70). Immunofluorescent signals of ERα and CYP19 were detected using the confocal microscopy in adult AVPV, MPN and ARC. The results showed that prenatal DEHP exposure perturbed somatic and reproductive development of offspring. Eleven genes were down-regulated in neonatal hypothalamus and showed non-monotonic dose-response relationships, that the 10 mg/kg DEHP dosage was associated with the greatest number of gene expression changes. Different from this, 14 genes were altered in adult AVPV, MPN and ARC and most of alterations were found in the 50 mg/kg DEHP group. Also, 50 mg/kg DEHP reduced ERα expression in the ARC, but no alterations were observed in CYP19 expression. These results indicated that prenatal DEHP exposure may perturb hypothalamic gene programming and the influences are permanent. The effects showed dependence on developmental stages and nuclei region. [ABSTRACT FROM AUTHOR]

Background: Microbiome-gut-brain axis may be involved in the progression of age-related cognitive impairment and relevant brain structure changes, but evidence from large human cohorts is lacking. This study was aimed to investigate the associations of gut microbiome with cognitive impairment and brain structure based on multi-omics from three independent populations. Methods: We included 1430 participants from the Guangzhou Nutrition and Health Study (GNHS) with both gut microbiome and cognitive assessment data available as a discovery cohort, of whom 272 individuals provided fecal samples twice before cognitive assessment. We selected 208 individuals with baseline microbiome data for brain magnetic resonance imaging during the follow-up visit. Fecal 16S rRNA and shotgun metagenomic sequencing, targeted serum metabolomics, and cytokine measurements were performed in the GNHS. The validation analyses were conducted in an Alzheimer's disease case–control study (replication study 1, n = 90) and another community-based cohort (replication study 2, n = 1300) with cross-sectional dataset. Results: We found protective associations of specific gut microbial genera (Odoribacter, Butyricimonas, and Bacteroides) with cognitive impairment in both the discovery cohort and the replication study 1. Result of Bacteroides was further validated in the replication study 2. Odoribacter was positively associated with hippocampal volume (β, 0.16; 95% CI 0.06–0.26, P = 0.002), which might be mediated by acetic acids. Increased intra-individual alterations in gut microbial composition were found in participants with cognitive impairment. We also identified several serum metabolites and inflammation-associated metagenomic species and pathways linked to impaired cognition. Conclusions: Our findings reveal that specific gut microbial features are closely associated with cognitive impairment and decreased hippocampal volume, which may play an important role in dementia development. [ABSTRACT FROM AUTHOR]

During infection with human cytomegalovirus (HCMV), overexpression of hcmv-miR-US33 can inhibit the lytic viral replication and down-regulate US29 mRNA. However, it remains unknown whether inhibition of viral replication by miR-US33 is mediated by down-regulation of expression of US29 or another host gene. Here, we identified the host gene Syntaxin3 ( STX3 ) to be a direct target of hcmv-miR-US33-5p using Hybrid-PCR and luciferase-reporter assays. It was further demonstrated that the levels of STX3 protein were down-regulated in hcmv-miR-US33-5p-overexpressing cells. Experiments with STX3-specific siRNA, or with an inhibitor of hcmv-miR-US33-5p confirmed that hcmv-miR-US33-5p-mediated inhibition of HCMV DNA synthesis and of viral replication are specifically mediated by down-regulation of STX3 expression. [ABSTRACT FROM AUTHOR]

• The property of actual PVCS is investigated by characterizing the EV charging behaviors and PV power distribution to explore the net power data regularity. The external factors that most correlated with PVCS power variation are captured by interpretable algorithms to guide EV behaviors to maximally utilize renewable energy. • At the software algorithm design stage, the forecasting performance trade-off between algorithm complexity and forecasting accuracy is fully considered for edge computing use. The model complexity is maximumly reduced by covering the entire cycle of forecasting process, including input data pruning, lightweight model training, and hyperparameter optimization. • At the hardware configuration stage, forecasting programming is implemented on Raspberry pi-based edge platform for rapid online training. The forecasting model is tested on various scenarios to verify the algorithm feasibility on the edge device. The PV-assisted charging station (PVCS) aggregates the two key resources of electric vehicle (EV) charging load and photovoltaic (PV) system to maximize operation profit. In order to quantify the PVCS impact to grid and the renewable energy utilization by EV charging load, it is crucial to predict the PVCS net power and capture the most correlated factors for power variation. Given that the PVCS is located near the user side, the forecasting model complexity must be restricted to meet the online training demands on edge computing, apart from ensuring the prediction accuracy. A PVCS net power forecasting approach is proposed by simplifying model complexity from the entire cycle of training process, including the input data pruning, lightweight model training and hyperparameter optimization. Finally, a comprehensive analysis of the real data in PVCS shows that the most sensitivity factors affecting the net power of PVCS is time of use price, and the deep auto-encoded extreme learning machine (DA-ELM) can make a satisfactory compromise between prediction accuracy and model complexity for edge computing utilization. The forecasting model has outstanding prediction performance on Raspberry pi-based edge platform, which has enough significance for PVCS promotion. [ABSTRACT FROM AUTHOR]

[Display omitted] • Sequential degradation and efficient mineralization of TBBPA were achieved in SROS. • SROS produced more ROSs during the oxidation phase. • Degradation pathways of TBBPA in SROS were proposed. • SROS can effectively reduce the toxicity of degradation intermediates of TBBPA. Tetrabromobisphenol A (TBBPA), a brominated flame retardant with environmental hazards poses challenges for degradation into less dangerous small molecule compounds using conventional single reduction or oxidation methods. In this study, N-doped Fe/Fe 3 C@NC was prepared as an efficient catalyst for TBBPA degradation in a sequential reduction–oxidation system (SROS). Nitrogen-doped carbon as support decelerated the oxidation of Fe0 and simultaneously accelerated electron transfer within the composites. After the reduction reaction, the Fe species in Fe/Fe 3 C@NC were converted to Fe2+, which activated peroxymonosulfate more efficiently. Thus, the degradation rate constant (k obs) of TBBPA reached 0.132 min−1, significantly higher than that of a single oxidation system (0.0464 min−1). In addition, the SROS generated more reactive oxygen species, especially O 2 •- and 1O 2 , which facilitated electron transport and consequently led to the rapid degradation of TBBPA. Degradation pathways of TBBPA in a SROS were initially proposed, with TBBPA being debrominated gradually during reduction and then directly oxidized by cleaving the central carbon. TBBPA mineralization percentage in the SROS reached 86 %, which was the result of the reduction initially increased the oxidizability of the pollutant and ring-opening susceptibility. Predicting the toxicity of the intermediates revealed that the intermediate products generated by the SROS during the TBBPA degradation had lower toxicity. This study provides insights into the efficient mineralization of organic pollutants for the remediation of aquatic environments. [ABSTRACT FROM AUTHOR]

Background: The prognoses for patients with relapsed and refractory osteosarcoma are poor and the optimal treatment strategy is still to be defined. We conducted this retrospective study to compare the feasibility and efficacy of pirarubicin-based chemotherapy with gemcitabine-docetaxel combination regimens for the salvage of these patients. Methods: The clinical data of 75 patients who received pirarubicin-based ( n = 52) or gemcitabine-docetaxel ( n = 23) chemotherapy as a second-line treatment for relapsed and refractory osteosarcoma between January 2005 and September 2011were reviewed retrospectively. Tumor response was evaluated every two chemotherapy cycles by computed tomography/magnetic resonance imaging (CT/MRI) scans using the Response Evaluation Criteria in Solid Tumors. Progression-free survival and overall survival (OS) were evaluated by Kaplan-Meier analysis. Toxicity was examined according to the National Cancer Institute Toxicity Criteria grading system. Results: Patient characteristics were well balanced in the two groups. The response rate was 25.0 % in patients who received pirarubicin-based chemotherapy, while it was 13.0 % in the gemcitabine-docetaxel group. Moreover, the median OS was longer in the pirarubicin-based chemotherapy group (14.0 vs. 9.0 months, P < 0.05), especially in the pirarubicin-ifosfamide (14.0 months) and pirarubicin-cisplatin (15.0 months) subgroups. The incidence of grade 3-4 neutropenia was higher in the gemcitabine-docetaxel group (5.8 vs. 43.5 %, P < 0.05); other grade 3-4 toxicities were comparable in the two groups. Conclusions: In our experience, pirarubicin-based chemotherapy was comparable with gemcitabine-docetaxel as a second-line treatment for relapsed and refractory osteosarcoma, and it even seemed to show greater efficacy, with milder toxicity. Further studies, especially prospective clinical trials, focusing on pirarubicin-based treatments for relapsed and refractory osteosarcoma patients should be strongly considered. [ABSTRACT FROM AUTHOR]

• The collaborative optimization framework of distribution network and mobile network is proposed. • Optimal models of DNO and MNO with coupon incentive-based DR are established. • Stackelberg game model is employed to model the interaction between DNO and MNO. • Decentralized solution algorithm is designed to obtain SE with limited information exchange. Renewable energy sources are beneficial for both distribution network and mobile network in the context of Smart Grid, but brings greater challenges with high proportions of renewable energy penetration. In this regard, a Stackelberg game-based collaborative optimization approach is proposed for distribution network and 5G mobile network based on demand response, where the distribution network operator (DNO) works as a leader who chooses proper interactive price to reduce the peak-valley difference of net load while mobile network operator (MNO) serves as a follower who minimizes its total energy cost in response to the interactive price set by DNO. Besides, an exact convex relaxation method is proposed to omit the complementarity constraint in the optimal model of MNO, which makes the model strictly convex. Then, the existence and uniqueness of the Stackelberg equilibrium (SE) are analyzed and a distributed solution algorithm is suggested to reach the SE. The simulation results demonstrate that the proposed collaborative optimization approach can not only reduce the cost of DNO and MNO, but helpful to enhance renewable energy utilization, which realizes a win–win result. [ABSTRACT FROM AUTHOR]

• Combination therapy involving siRNA-HIF-1α and Lenvatinib inhibited tumor growth and prolonged mouse survival. • The strategy not only curtailed cell proliferation and angiogenesis within HCC tissues but also stimulated tumor cell apoptosis. • The treatment enhanced T lymphocyte and M1 macrophage presence in tumors, and increased immune cell ratios in the spleen, strengthening anti-tumor immunity. The treatment of hepatocellular carcinoma (HCC) remains a major challenge in the medical field. Lenvatinib, a multi-target tyrosine kinase inhibitor, has demonstrated anti-HCC effects by targeting and inhibiting pathways such as vascular endothelial growth factor receptor 1–3 (VEGFR1-3). However, the therapeutic efficacy of Lenvatinib is subject to various influences, with the hypoxic microenvironment of the tumor being a pivotal factor. Consequently, altering the hypoxic milieu of the tumor emerges as a viable strategy to augment the efficacy of Lenvatinib. Hypoxia-inducible factor-1α (HIF-1α), synthesized by tumor cells in response to oxygen-deprived conditions, regulates the expression of resistance genes, promotes tumor angiogenesis and cell proliferation, enhances tumor cell invasion, and confers resistance to radiotherapy and chemotherapy. Thus, we constructed a self-designed siRNA targeting HIF-1α to suppress its expression and improve the efficacy of Lenvatinib in treating HCC. The therapeutic efficacy of siRNA-HIF-1α in combination with Lenvatinib on HCC were evaluated through in vivo and in vitro experiments. The results showed that the recombinant Salmonella delivering siRNA-HIF-1α in combination with Lenvatinib effectively inhibited tumor growth and prolonged the survival of tumor-bearing mice. This treatment approach reduced cell proliferation and angiogenesis in HCC tissues while promoting tumor cell apoptosis. Additionally, this combined therapy significantly increased the infiltration of T lymphocytes and M1 macrophages within the tumor microenvironment, as well as elevated the proportion of immune cells in the spleen, thereby potentiating the host's immune response against the tumor. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a highly vascularized malignancy that relies on new vessel generation, and thus targeting angiogenesis has been a promising anti-GBM approach. ANGPTL1 is well-known for its anti-angiogenic property; nevertheless, its role in GBM is yet to be explored. Recently, the crucial role of exosomes (Exos) as intercellular communication mediators has gained prominence in GBM therapy. This work aimed to explore the role of exosomal ANGPTL1 in GBM angiogenesis and its mechanisms. Bioinformatic analysis was performed to evaluate ANGPTL expression in GBM. Human GBM cell lines (U87 and U251) and a xenograft mouse model were employed. Exos were isolated from oe-NC- and oe-ANGPTL-transfected bone mesenchymal stem cells and identified. Cell proliferation, migration, and apoptosis were detected. Immunofluorescence, qRT-PCR, western blotting, co-immunoprecipitation, and immunohistochemistry were used to determine the molecular mechanisms underlying exosomal ANGPTL1 against GBM angiogenesis. Besides, tube generation and transmission electron microscope assays were conducted to assess GBM angiogenesis. Low ANGPTL1 expression was observed in GBM tumor tissues and cells. Functionally, e-ANGPTL-Exos inhibited GBM malignant progression and angiogenesis in vitro and in vivo. Mechanically, e-ANGPTL-Exos reduced VEGFA expression and blocked the VEGFR2/Akt/eNOS pathway in GBM cells and tumor tissues. Co-immunoprecipitation revealed a link between ANGPTL1 and VEGFA in GBM cells. Notably, oe-VEGFA abolished the suppressive functions of e-ANGPTL-Exos in GBM progression and angiogenesis and the VEGFR2/Akt/eNOS axis. The VEGFR2 inhibitor, vandetanib, eliminated the promotive effects of oe-VEGFA on GBM angiogenesis with suppressed VEGFR2/Akt/eNOS pathway. Exosomal ANGPTL1 suppressed GBM angiogenesis by inhibiting the VEGFA/VEGFR2/Akt/eNOS axis. • ANGPTL1 expression was decreased in GBM tumor tissues and cells. • Exosomal ANGPTL1 inhibited GBM malignant progression and angiogenesis in vitro and in vivo. • Exosomal ANGPTL1 suppressed GBM cell angiogenesis by blocking the VEGFA/VEGFR2/Akt/eNOS axis. [ABSTRACT FROM AUTHOR]