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Abstract Background It has been proposed that anti-angiogenesis therapy could induce tumor "vascular normalization" and further enhance the efficacy of chemotherapy, radiotherapy, target therapy, and immunotherapy for nearly twenty years. However, the detailed molecular mechanism of this phenomenon is still obscure. Method Overexpression and knockout of CCL28 in human lung adenocarcinoma cell line A549 and murine lung adenocarcinoma cell line LLC, respectively, were utilized to establish mouse models. Single-cell sequencing was performed to analyze the proportion of different cell clusters and metabolic changes in the tumor microenvironment (TME). Immunofluorescence and multiplex immunohistochemistry were conducted in murine tumor tissues and clinical biopsy samples to assess the percentage of pericytes coverage. Primary pericytes were isolated from lung adenocarcinoma tumor tissues using magnetic-activated cell sorting (MACS). These pericytes were then treated with recombinant human CCL28 protein, followed by transwell migration assays and RNA sequencing analysis. Changes in the secretome and metabolome were examined, and verification of retinoic acid metabolism alterations in pericytes was conducted using quantitative real-time PCR, western blotting, and LC–MS technology. Chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) was employed to validate the transcriptional regulatory ability and affinity of RXRα to specific sites at the ANGPT1 promoter. Results Our study showed that after undergoing anti-angiogenesis treatment, the tumor exhibited a state of ischemia and hypoxia, leading to an upregulation in the expression of CCL28 in hypoxic lung adenocarcinoma cells by the hypoxia-sensitive transcription factor CEBPB. Increased CCL28 could promote tumor vascular normalization through recruiting and metabolic reprogramming pericytes in the tumor microenvironment. Mechanistically, CCL28 modified the retinoic acid (RA) metabolism and increased ANGPT1 expression via RXRα in pericytes, thereby enhancing the stability of endothelial cells. Conclusion We reported the details of the molecular mechanisms of "vascular normalization" after anti-angiogenesis therapy for the first time. Our work might provide a prospective molecular marker for guiding the clinical arrangement of combination therapy between anti-angiogenesis treatment and other therapies.

Abstract Wnt/β-catenin signaling is critical for various cellular processes in multiple cell types, including osteoblast (OB) differentiation and function. Exactly how Wnt/β-catenin signaling is regulated in OBs remain elusive. ATP6AP2, an accessory subunit of V-ATPase, plays important roles in multiple cell types/organs and multiple signaling pathways. However, little is known whether and how ATP6AP2 in OBs regulates Wnt/β-catenin signaling and bone formation. Here we provide evidence for ATP6AP2 in the OB-lineage cells to promote OB-mediated bone formation and bone homeostasis selectively in the trabecular bone regions. Conditionally knocking out (CKO) ATP6AP2 in the OB-lineage cells (Atp6ap2 Ocn-Cre ) reduced trabecular, but not cortical, bone formation and bone mass. Proteomic and cellular biochemical studies revealed that LRP6 and N-cadherin were reduced in ATP6AP2-KO BMSCs and OBs, but not osteocytes. Additional in vitro and in vivo studies revealed impaired β-catenin signaling in ATP6AP2-KO BMSCs and OBs, but not osteocytes, under both basal and Wnt stimulated conditions, although LRP5 was decreased in ATP6AP2-KO osteocytes, but not BMSCs. Further cell biological studies uncovered that osteoblastic ATP6AP2 is not required for Wnt3a suppression of β-catenin phosphorylation, but necessary for LRP6/β-catenin and N-cadherin/β-catenin protein complex distribution at the cell membrane, thus preventing their degradation. Expression of active β-catenin diminished the OB differentiation deficit in ATP6AP2-KO BMSCs. Taken together, these results support the view for ATP6AP2 as a critical regulator of both LRP6 and N-cadherin protein trafficking and stability, and thus regulating β-catenin levels, demonstrating an un-recognized function of osteoblastic ATP6AP2 in promoting Wnt/LRP6/β-catenin signaling and trabecular bone formation.

In response to public health emergencies, many regions have requisitioned daily travel hotels as temporary quarantine places. However, few previous studies examine this policy and reflect on the rationality of urban spatial resource allocation and utilization in terms of comfort during quarantine. This study uses a hybrid multi-attribute decision-making model, based on the collection of 438 pieces of evaluation data about the comfort of isolation hotels in Guangzhou, to build an evaluation framework for the comfort of the quarantine environment. Then, this study uses the ANP-V technique to complete the performance evaluation of selected cases and combines the epidemic spread data in Guangzhou to explore the rationality and improvement strategies of local government epidemic prevention resource allocation and utilization. Based on the results of this study, local decision-makers can optimize the allocation of future epidemic prevention resources and minimize the negative impact on personal health during the emergency period.

The yield stability of the neutron generator directly affects the accuracy of elemental analysis. This paper presents an industrial fully automatic neutron generator with a 48 mm neutron tube based on PLC to improve the stability and reliability of the neutron generator in industrial applications. By integrating a Kalman Filter with the PID algorithm in a PLC, the neutron yield of the generator is remarkably stabilized, achieving 1 × 108n/s. The neutron generator has been employed for industrial online elemental analysis. The results demonstrate that only a slight fluctuation of ±0.82 % exists in the neutron yield, and the reproducibility of the generator holds at a significant level of 0.05. This improved neutron generator can be applied to the online bulk analysis of carbon in coal-fired power stations and absolute measurement of neutron source emission rate.

Introductionmyo7aa, the homolog of the human Usher 1B syndrome pathogenic gene, myo7A, plays an important role in stereociliary development and maintenance, therefore, is critical for hearing and balance. However, the molecular mechanisms that myo7aa regulate hearing and balance still need to be studied.MethodsIn this study, we generated two independent zebrafish myo7aa knockout lines using CRISPR/Cas9 technology. To investigate the effects of myo7aa on hearing, YO-PRO-1 staining and startle response assay were used. To gain insight into the specific molecular mechanisms by which myo7aa affects hearing, transcriptome sequencing and bioinformatics analysis were employed.ResultsOur study showed that hair cells of myo7aa-/- zebrafish can not take up YO-PRO-1 fluorescent dye and are insensitive to acoustic stimulation in myo7aa-/- zebrafish compared to wild type. Genes related to the Rho GTPase signaling pathway, such as arhgap33, dab2ip, and arghef40, are significantly down-regulated in myo7aa-/- zebrafish embryos at 3 dpf. GTP and ATP compensation can partially rescue the hair cell defects in myo7aa knockout zebrafish.DiscussionOur findings suggest that zebrafish myo7aa affects congenital hearing by regulating Rho GTPase signaling, and loss of myo7aa leads to abnormal Rho GTPase signaling and impairs hair cell function. myo7aa, myo7A, arhgap33, dab2ip, arghef40 and myo7aa-/- fonts in the abstract are italicized. -/- is a superscript format.

With the intensification of global climate change, extreme rainfall events are occurring more frequently. Continuous rainfall causes the debris flow gully to collect a large amount of rainwater. Under the continuous increase in the water level, the water flow has enough power to carry plenty of loose solids, thus causing debris flow disasters. The intensity of the soil is reduced with the infiltration of rainwater, which is one of the key causes of the disaster. The rise in the water level affects the infiltration behavior. There have been few previous studies on infiltration under variable head. In order to understand the infiltration behavior of soils under the action of water level rises, this paper conducted an indoor permeability test on non-cohesive soil under the condition of an increasing water level. A numerical model was established using the finite element analysis software, Abaqus 6.14, and the pore pressure was increased intermittently to simulate the intermittent increase in the water level. Thereafter, the permeability coefficient and seepage length were changed to interpret the changes in the flow velocity and rate in the permeability test of the non-cohesive soil. The results showed that the finite element numerical simulation method could not reflect the particle movement process in the soil. The test could better reflect the through passage and void plugging phenomenon in soil; when the permeability coefficient alone changed, the velocity of the measuring point with higher velocity changed more violently with the permeability coefficient; when the length of soil seepage diameter was uniformly shortened, the velocity of water flow increased faster and faster.

We previously revealed that Cang-ai volatile oil (CAVO) regulates T-cell activity, enhancing the immune response in people with chronic respiratory diseases. However, the effects of CAVO on allergic rhinitis (AR) have not been investigated. Herein, we established an ovalbumin (OVA)-induced AR rat model to determine these effects. Sprague–Dawley (SD) rats were exposed to OVA for 3 weeks. CAVO or loratadine (positive control) was given orally once daily for 2 weeks to OVA-exposed rats. Behavior modeling nasal allergies was observed. Nasal mucosa, serum, and spleen samples of AR rats were analyzed. CAVO treatment significantly reduced the number of nose rubs and sneezes, and ameliorated several hallmarks of nasal mucosa tissue remodeling: inflammation, eosinophilic infiltration, goblet cell metaplasia, and mast cell hyperplasia. CAVO administration markedly upregulated expressions of interferon-γ, interleukin (IL)-2, and IL-12, and downregulated expressions of serum tumor necrosis factor-α, IL-4, IL-5, IL-6, IL-13, immunoglobulin-E, and histamine. CAVO therapy also increased production of IFN-γ and T-helper type 1 (Th1)-specific T-box transcription factor (T-bet) of the cluster of differentiation-4+ T-cells in splenic lymphocytes, and protein and mRNA expressions of T-bet in nasal mucosa. In contrast, levels of the Th2 cytokine IL-4 and Th2-specific transcription factor GATA binding protein-3 were suppressed by CAVO. These cumulative findings demonstrate that CAVO therapy can alleviate AR by regulating the balance between Th1 and Th2 cells.

Polyphenols are the most prevalent naturally occurring phytochemicals in the human diet and range in complexity from simple molecules to high-molecular-weight polymers. They have a broad range of chemical structures and are generally categorized as “neuroprotective”, “anti-inflammatory”, and “antioxidant” given their main function of halting disease onset and promoting health. Research has shown that some polyphenols and their metabolites can penetrate the blood–brain barrier and hence increase neuroprotective signaling and neurohormonal effects to provide anti-inflammatory and antioxidant effects. Therefore, multi-targeted modulation of polyphenols may prevent the progression of neuropsychiatric disorders and provide a new practical therapeutic strategy for difficult-to-treat neuropsychiatric disorders. Therefore, multi-target modulation of polyphenols has the potential to prevent the progression of neuropsychiatric disorders and provide a new practical therapeutic strategy for such nervous system diseases. Herein, we review the therapeutic benefits of polyphenols on autism-spectrum disorders, anxiety disorders, depression, and sleep disorders, along with in vitro and ex vivo experimental and clinical trials. Although their methods of action are still under investigation, polyphenols are still seldom employed directly as therapeutic agents for nervous system disorders. Comprehensive mechanistic investigations and large-scale multicenter randomized controlled trials are required to properly evaluate the safety, effectiveness, and side effects of polyphenols.

Lung cancer is the leading cause of cancer death, and non-small cell lung cancer (NSCLC) accounts for 85%. Immunotherapy has significantly improved the clinical prognosis of patients with NSCLC. However, because of the complexity and heterogeneousness of the tumor microenvironment, only a subset of individuals can benefit from immunotherapy. Therefore, it is necessary to explore effective predictive biomarkers for immunotherapy of NSCLC. Tertiary lymphoid structure (TLS) is an ectopic lymphoid organ that is highly similar to secondary lymphoid organs (SLO), and the presence of TLS has been found to be closely associated with a good prognosis in immunotherapy for a variety of solid tumors, including NSCLC. This article provides a review of the prognostic role of tertiary lymphoid structures in immunotherapy of NSCLC, in order to offer references for screening suitable candidates for immunotherapy of NSCLC and develop personalized and precise treatment plans.

In this paper, ray tracing (RT) is used to analyze the characteristics of train-to-train (T2T) wireless channel in 2.1 GHz frequency band, including path loss, multipath clustering, delay spread, Rice factor, angular spread, and channel nonstationarity. It is found that the change of environment has a great influence on the characteristics of the wireless channel, which not only causes the birth and death of multipath clusters but also makes the channel appear nonstationary characteristics. In order to characterize the nonstationarity of the T2T wireless channel, we introduce the time correlation coefficient (TPCC) of the power delay profile (PDP), analyze the nonstationarity of the T2T wireless channel, and give the quasi-stationarity distance. The results are basically consistent with the measured data.

Advances in producing tailored ultrashort laser pulses have enabled the generation and control of molecular dissociative Rydberg excitation along the polarization axis of the laser field. Here, we exploit the orthogonally polarized two-color femtosecond laser fields and achieve an unprecedented two-dimensional control of Rydberg fragment emission in the dissociative frustrated single ionization of oxygen. The Rydberg fragments are collected over the 4π solid angle, whose momentum distribution is manifested in a characteristic four-lobe pattern. Through precise scanning of the relative phase of the orthogonal two-color laser fields, we demonstrate control over asymmetric directional emission of the Rydberg fragments. Our experimental findings are well supported by classical trajectory Monte Carlo simulations, which suggest an efficient emission control achieved through the manipulation of charge localization upon ionization.

ABSTRACTThis study aimed to investigate the relationship between complete pathological remission (PCR), tertiary lymphoid structure (TLS) maturation and expression and clinical outcomes of patients with resectable non-small cell lung cancer (NSCLC) receiving neoadjuvant chemoimmunotherapy. Totally 80 patients with resectable NSCLC (stage IB-IIIB) receiving neoadjuvant chemoimmunotherapy were analyzed. We used the Kaplan-Meier method to plot survival curves and the log-rank test to compare differences. Among all patients included, 45 patients (56.25%) achieved major pathological response (MPR), including 30 patients (37.50%) with PCR. The proportion of patients diagnosed with stage IB, II, IIIA and IIIB was 1.25%, 10.00%, 52.50% and 36.25%, respectively. We divided patients into PCR group and non-PCR group respectively according to whether they achieved PCR. We found that patients achieving PCR had significantly improved disease-free survival (DFS) (mDFS: NR vs. 20.24 months, P = .020). TLS expression was low in 43 cases (53.75%) and high in 37 cases (46.25%). TLS maturation was low in 55 cases (68.75%) and high in 25 cases (31.25%). The DFS of patients with TLS high-maturation (34.07 vs. 22.30 months, P = .024) and TLS high-expression (34.07 vs. 22.30 months, P = .041) was significantly longer. In most subgroups, the PCR, TLS high-maturation and TLS high-expression group respectively achieved a better clinical outcome relative to the non-PCR, TLS low-maturation and TLS low-expression group. In patients with resectable NSCLC receiving neoadjuvant chemoimmunotherapy, the acquirement of PCR may predict better DFS. In addition, high expression and maturation of TLS may be prognostic factors.

Abstract The accuracy of the monocular 3D detection tasks based on the Pseudo‐LiDAR method is improved greatly. However, the depth map obtained by depth estimation contains a lot of noise, which limits the detection accuracy. To address this problem, an efficient monocular 3D target detection method combined with a Mask‐Revised Network and Quality Perception Loss is proposed. The method adaptively encodes the image into the mask and adjusts the feature weight from the region of interest by the visual attention mechanism. Then, the 2D bounding box confidence and 3D bounding box quality are used to calculate each confidence of the 3D bounding box to realize the quality perception of prediction results. The proposed algorithm is evaluated on the KITTI test datasets, and the results show that the proposed method achieves state‐of‐the‐art performance on the task of monocular 3D target detection and outperforms the existing methods by about 2.75% on AP40 for Car categories.

With the intensification of population aging and the increasing awareness of public health protection in the post-epidemic era, the renewal of the old urban community neighborhood space is facing many new challenges and problems. Neighborhood Public Open Space (POS) is the main place for people to carry out various social activities in community life. The quality of the social interaction environment that a neighborhood POS can provide can have a vital impact on people’s well-being, as well as their physical and mental health. Therefore, the purpose of this research is to identify and clarify the key physical environmental design attributes/features of the old urban community neighborhood POS, and to explore the relationship between them from the perspective of creating a high-quality social environment. Through the investigation of relevant cases in Shenzhen and Guangzhou, China, the classification performance of each case on the key physical and environmental elements is used as the conditional attribute, and the quality of the social interaction environment in the current situation of each case is used as the decision making attribute to conduct a data mining analysis. Using rough set theory, this study screened out four important elements: greenbelt form planning (C1); ped and bike system (C2); space organization and zoning planning (C6); Public facilities (C8). Moreover, this study also presents a set of hierarchical decision rules to describe the classification status of the matching physical environmental design elements when the social interaction environment reaches a high quality in the neighborhood POS. This study provides local policy makers with key current situation assessment and diagnostic tools in urban-built environmental renewal projects. The results of this study can help designers draw up the renovation design plans of neighborhood POS on the basis of efficiently obtaining the practical experience of relevant cases, and then create a high-quality social interaction environment.

Abstract Background Alzheimer’s disease (AD) and osteoporosis are two distinct diseases but often occur in the same patient. Their relationship remains poorly understood. Studies using Tg2576 AD animal model demonstrate bone deficits, which precede the brain phenotypes by several months, arguing for the independence of bone deficits on brain degeneration and raising a question if the bone deficits contribute to the AD development. To address this question, we investigated the effects of PTH1-34, a peptide of parathyroid hormone analog and a well-recognized effective anabolic therapy drug for patients with osteoporosis, on 5XFAD animal model. Methods 5XFAD mice, an early onset β-amyloid (Aβ)-based AD mouse model, were treated with PTH1-34 intermittently [once daily injection of hPTH1–34 (50 μg/Kg), 5 days/week, starting at 2-month old (MO) for 2–3 month]. Wild type mice (C57BL/6) were used as control. The bone phenotypes were examined by microCT and evaluated by measuring serum bone formation and resorption markers. The AD relevant brain pathology (e.g., Aβ and glial activation) and behaviors were assessed by a combination of immunohistochemical staining analysis, western blots, and behavior tests. Additionally, systemic and brain inflammation were evaluated by serum cytokine array, real-time PCR (qPCR), and RNAscope. Results A reduced trabecular, but not cortical, bone mass, accompanied with a decrease in bone formation and an increase in bone resorption, was detected in 5XFAD mice at age of 5/6-month old (MO). Upon PTH1-34 treatments, not only these bone deficits but also Aβ-associated brain pathologies, including Aβ and Aβ deposition levels, dystrophic neurites, glial cell activation, and brain inflammatory cytokines, were all diminished; and the cognitive function was improved. Further studies suggest that PTH1-34 acts on not only osteoblasts in the bone but also astrocytes in the brain, suppressing astrocyte senescence and expression of inflammatory cytokines in 5XFAD mice. Conclusions These results suggest that PTH1-34 may act as a senolytic-like drug, reducing systemic and brain inflammation and improving cognitive function, and implicate PTH1-34’s therapeutic potential for patients with not only osteoporosis but also AD.

Cells defend against oxidative stress by enhancing antioxidant capacity, including stress-activated metabolic alterations, but the underlying intracellular signaling mechanisms remain unclear. This paper reports that immunoglobulin superfamily containing leucine-rich repeat (ISLR) functions as a redox sensor that responds to reactive oxygen species (ROS) stimulation and modulates the antioxidant capacity by suppressing pyruvate kinase isozyme M2 (PKM2) activity. Following oxidative stress, ISLR perceives ROS stimulation through its cysteine residue 19, and rapidly degrades in the autophagy–lysosome pathway. The downregulated ISLR enhances the antioxidant capacity by promoting the tetramerization of PKM2, and then enhancing the pyruvate kinase activity, PKM2-mediated glycolysis is crucial to the ISLR-mediated antioxidant capacity. In addition, our results demonstrated that, in triple-negative breast cancer, cisplatin treatment reduced the level of ISLR, and PKM2 inhibition sensitizes tumors to cisplatin by enhancing ROS production; and argued that PKM2 inhibition can synergize with cisplatin to limit tumor growth. Our results demonstrate a molecular mechanism by which cells respond to oxidative stress and modulate the redox balance.

The Internet of Vehicles (IoV) has a significant impact on improving traffic efficiency and driving safety. In this paper, we propose an intelligent transportation credit system based on blockchain, and design a crossroad passing smart contract that allows time-sensitive convoys to pass a crossroad earlier by paying traffic tokens for right-of-way trade. Second, this paper formulates the time–cost optimization problem under the premise of protecting the privacy of preceding convoys. Based on game theory with incomplete information, two right-of-way optimal bid strategies are given. Both theoretical analysis and simulation prove that the strategy proposed in this paper effectively reduces the waiting time of time-sensitive vehicles at a crossroad and increases the trade success probability, which, in turn, improves the expected total profit of convoys and achieves Pareto improvement.

Backgrounds and aims: Carcinogenesis is characterized by an unlimited growth of cells exacerbated by Cox-2 overexpression. Cox-2 inhibitors have been proven effective in preventing and treating tumors. In our previous studies, we found that 4-Amino-2-Trifluoromethylphenyl Retinate (ATPR) induces cell apoptosis and inhibits cell proliferation to exhibit anti-cancer properties. The use of ATRA as well as Cox-2 inhibitors in clinical settings can cause adverse reactions. It is unknown what the effects and mechanisms of co-administration of ATPR and Cox-2 inhibitors are. Results: A combination of ATPR and Cox-2 inhibitors, Celecoxib, inhibited pharyngeal cancer cell proliferation in vitro and induced apoptosis. The cell cycle was arrested at G0/G1 by activating P53 and CDNA1. By activating MAPK/JNK pathways, ATPR and Celecoxib led to intrinsic and extrinsic apoptosis in pharyngeal cancer cells. ATPR/Celecoxib combined treatment suppressed tumor growth in the pharyngeal cancer cell-derived xenograft mouse model by increasing the number of apoptotic cells. The expression of the RARA and PTGS2 genes was significantly increased in tumor tissue compared to non-tumor tissue in the clinical analysis of the head and neck squamous cell carcinoma dataset. An association was found between this and the level of intrinsic apoptotic signals. Furthermore, a survival analysis conducted over a period of five years indicated that higher levels of RARA expression were associated with a better clinical outcome. Conclusion: ATPR and celecoxib inhibit the proliferation of cancer cells as well as induce apoptosis. Co-administration of ATPR and Cox-2 inhibitors has the potential to be a novel treatment plan for cancer.

Tripterygium hypoglaucum (Levl.) Hutch (THH) has long been used as a remedy for rheumatoid arthritis (RA) in China. However, it is unclear whether the anti-RA mechanism of THH is associated with inflammasome or gut-joint axis. In this study, we aimed to explore the critical role of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and bile acid (BA) in the anti-RA mechanism. Complete Freund’s adjuvant (CFA)-injected mice were treated with THH extract (250 mg/kg/d) for 35 days, and joint swelling and disease scores were measured. After THH treatment, the joint swelling and RA disease score in CFA-treated mice significantly subsided. The increased ratios of lymphocytes, monocytes, and white blood cells were attenuated by THH treatment. Notably, THH treatment blocked the inflammation in both joints and colons by suppressing the NLRP3-mediated inflammasome, as indicated by NLRP3, interleukin 1beta (IL-1β), and Caspase-1. Meanwhile, THH significantly remodeled the bile acid (BA) profiles in RA mice. Spearman’s analysis shed light on the close link between BAs, NLRP3 inflammasome, and RA indicators. However, THH treatment failed to improve inflammasome activation, snoptivis, and joint swelling in RA mice with gut microbiota depletion. In summary, we revealed the pivotal role of BA-mediated gut-joint axis and inflammasome in THH’s RA amelioration. In the future, more work should be done to explain the in-depth mechanism between altered BAs and inflammasome.

Ulcerative colitis (UC) has been confirmed as a disease with a high incidence and low cure rate worldwide. In severe cases, UC can develop into colon cancer. Modern research has confirmed that berberine (BBR) can treat UC by inhibiting the expressions of inflammatory factors. However, the contribution of gut microbiota and flora metabolites in treating UC with BBR remains unclear. In this study, the ameliorative effects of BBR on gut microbiota dysbiosis and flora metabolites were investigated in a dextran sodium sulfate (DSS)-induced UC rodent model. We found that BBR significantly improved the pathological phenotype, attenuated intestinal barrier disruption, and mitigated colonic inflammation in DSS mice. By 16 S rDNA sequencing, BBR alleviated gut microbiota dysbiosis in UC mice. Moreover, the gut microbiota depletion experiment confirmed that the therapeutic effect of BBR was inextricably correlated with the gut microbiota. Besides, the flora metabolites (e.g., short-chain fatty acids, bile acids, and 5-hydroxytryptamine) were studied using HPLC-MS. The results suggested that BBR ameliorated the bile acid imbalance induced by DSS in the liver and gut. Furthermore, BBR treatment repaired gut barrier damage. The above results revealed that BBR alleviated DSS-induced UC in mice by restoring the disturbed gut microbiota, elevating unconjugated and secondary bile acids in the gastrointestinal tract, and activating the FXR and TGR5 signal pathway. This study provides novel insights into the mechanism of BBR in treating UC.

Abstract Alzheimer’s disease (AD) is the most common form of dementia. Notably, patients with AD often suffer from severe sarcopenia. However, their direct link and relationship remain poorly understood. Here, we generated a mouse line, TgAPP swe HSA , by crossing LSL (LoxP-STOP-LoxP)-APP swe with HSA-Cre mice, which express APPswe (Swedish mutant APP) selectively in skeletal muscles. Examining phenotypes in TgAPP swe HSA mice showed not only sarcopenia-like deficit, but also AD-relevant hippocampal inflammation, impairments in adult hippocampal neurogenesis and blood brain barrier (BBB), and depression-like behaviors. Further studies suggest that APPswe expression in skeletal muscles induces senescence and expressions of senescence-associated secretory phenotypes (SASPs), which include inflammatory cytokines and chemokines; but decreases growth factors, such as PDGF-BB and BDNF. These changes likely contribute to the systemic and hippocampal inflammation, deficits in neurogenesis and BBB, and depression-like behaviors, revealing a link of sarcopenia with AD, and uncovering an axis of muscular APPswe to brain in AD development.

Integrative analyses of single-cell datasets are facing new challenges as data size and complexity grow. Here the authors present SCALEX, which projects cells from different datasets into a common latent space, allowing accurate online integration as well as cross-referencing with atlas-scale data.

Depression is a complex and biologically heterogeneous disorder. Recent studies have shown that central nervous system (CNS) inflammation plays a key role in the development of depression. Lipopolysaccharide (LPS)-induced depression-like model in mice is commonly used to studying the mechanisms of inflammation-associated depression and the therapeutic effects of drugs. Numerous LPS-induced depression-like models in mice exist and differ widely in animal characteristics and methodological parameters. Here, we systematically reviewed studies on PubMed from January 2017 to July 2022 and performed cardinal of 170 studies and meta-analyses of 61 studies to support finding suitable animal models for future experimental studies on inflammation-associated depression. Mouse strains, LPS administration, and behavioral outcomes of these models have been assessed. In the meta-analysis, forced swimming test (FST) was used to evaluate the effect size of different mouse strains and LPS doses. The results revealed large effect sizes in ICR and Swiss mice, but less heterogeneity in C57BL/6 mice. For LPS intraperitoneal dose, the difference did not affect behavioral outcomes in C57BL/6 mice. However, in ICR mice, the most significant effect on behavioral outcomes was observed after the injection of 0.5 mg/kg LPS. Our results suggests that mice strains and LPS administration play a key role in the evaluation of behavioral outcomes in such models.

Inflammatory bowel disease (IBD) is caused by a variety of pathogenic factors, including chronic recurrent inflammation of the ileum, rectum, and colon. Immune cells and adhesion molecules play an important role in the course of the disease, which is actually an autoimmune disease. During IBD, CD34 is involved in mediating the migration of a variety of immune cells (neutrophils, eosinophils, and mast cells) to the inflammatory site, and its interaction with various adhesion molecules is involved in the occurrence and development of IBD. Although the function of CD34 as a partial cell marker is well known, little is known on its role in IBD. Therefore, this article describes the structure and biological function of CD34, as well as on its potential mechanism in the development of IBD.

The interplay between platelets and tumors has long been studied. It has been widely accepted that platelets could promote tumor metastasis. However, the precise interactions between platelets and tumor cells have not been thoroughly investigated. Although platelets may play complex roles in multiple steps of tumor development, most studies focus on the platelets in the circulation of tumor patients. Platelets in the primary tumor microenvironment, in addition to platelets in the circulation during tumor cell dissemination, have recently been studied. Their effects on tumor biology are gradually figured out. According to updated cancer hallmarks, we reviewed the biological effects of platelets on tumors, including regulating tumor proliferation and growth, promoting cancer invasion and metastasis, inducing vasculature, avoiding immune destruction, and mediating tumor metabolism and inflammation.

Background: Cang-Ai Volatile Oil (CAVO) is a traditional Chinese medicine prescription that can be used for improving depressive symptoms through the regulation of dopamine (DA) and 5-hydroxytryptamine (5-HT) and inhibition of the inflammation. The purpose of this study is to verify whether CAVO has effects on depressed mood and cortical excitability in human. Methods: Forty-six healthy individuals were enrolled and instructed to inhale the CAVO for a month (five times per day). Each inhalation lasted for at least one minute. Depressed mood was assessed using Hamilton Rating Scale for Depression (24-items) (HAM-D24), and cortical excitability was tested using functional near-infrared spectroscopy (fNIRS). During fNIRS assessment, two types of verbal fluency tests (VFT) were adopted. Results: One month of CAVO inhalation led to significant decreases in HAM-D24 score, and the mean concentration of oxygenated hemoglobin (HbO2) was significantly increased in the right frontal pole. Conclusion: Inhaling the CAVO can significantly improve depressed mood and cortical excitability in human. The improvement of cortical excitability is mainly focused on the right frontal pole, which is closely associated with emotional processing and executive functioning.

Abstract Background The identification of indeterminate pulmonary nodules (IPNs) following a low-dose computed tomography (LDCT) is a major challenge for early diagnosis of lung cancer. The inadequate assessment of IPNs’ malignancy risk results in a large number of unnecessary surgeries or an increased risk of cancer metastases. However, limited studies on non-invasive diagnosis of IPNs have been reported. Methods In this study, we identified and evaluated the diagnostic value of circulating small extracellular vesicle (sEV) microRNAs (miRNAs) in patients with IPNs that had been newly detected using LDCT scanning and were scheduled for surgery. Out of 459 recruited patients, 109 eligible patients with IPNs were enrolled in the training cohort (n = 47) and the test cohort (n = 62). An external cohort (n = 99) was used for validation. MiRNAs were extracted from plasma sEVs, and assessed using Small RNA sequencing. 490 lung adenocarcinoma samples and follow-up data were used to investigate the role of miRNAs in overall survival. Results A circulating sEV miRNA (CirsEV-miR) model was constructed from five differentially expressed miRNAs (DEMs), showing 0.920 AUC in the training cohort (n = 47), and further identified in the test cohort (n = 62) and in an external validation cohort (n = 99). Among five DEMs of the CirsEV-miR model, miR-101-3p and miR-150-5p were significantly associated with better overall survival (p = 0.0001 and p = 0.0069). The CirsEV-miR scores were calculated, which significantly correlated with IPNs diameters (p

The arrangement of the induction coil influences the electromagnetic damping force and output characteristics of electromagnetic energy harvesters. Based on the aforementioned information, this paper presents a proposal for a multiple off-center coil electromagnetic galloping energy harvester (MEGEH). This study establishes both a theoretical model and a physical model to research the influence of the position and quantity of the induction coils on the output characteristics of an energy harvester. Additionally, it conducts wind tunnel tests and analyzes the obtained results. With the increase in the number of induction coils, there is a significant improvement in the duty cycle and output power of the MEGEH, resulting in an amplified energy conversion efficiency. At a wind speed of 9 m/s, the duty ratios of a single set of coils (SC), two sets of coils (TC), and multiple sets of coils (MC) are 30%, 51%, and 100%, respectively. The total output powers are 0.4 mW, 0.62 mW, and 0.72 mW. However, the rate of output growth has decreased from 55% to 16%. The position of the coils affects the initial electromagnetic damping of the energy harvester. Changing the position can reduce the initial electromagnetic damping, thereby decreasing the critical wind speed. The critical wind speed of the MEGEH decreases as the induction coil is positioned further away from the vibration center. When the distance is sufficiently large, the electromagnetic damping force becomes negligible. When the induction coil is positioned centrally, the MEGEH demonstrates its maximum critical wind speed, which has been measured at 4.01 m/s. When the initial distance between the induction coil and the vibrating component is increased to 10 mm, the critical wind speed reaches its minimum value of 2.23 m/s. Therefore, it is necessary to optimize the arrangement of the coils. The coils of the MEGEH should be arranged with the MC and a 10 mm offset from the center.

Previous studies have focused on the reduction effect of regulation-based instruments and economic-based instruments on air pollution, ignoring the importance of environmental information disclosure. Based on the Ambient Air Quality Standards (AAQS), a quasi-natural policy implemented in 2012, this paper assesses the effect of environmental information disclosure on air pollution through a dynamic spatial difference-in-difference (DID) model using panel data of 269 cities from 2006 to 2017 in China. We find that the implementation of the AAQS results in a 3% reduction of local PM2.5 concentration and a 3.3% reduction of PM2.5 concentration in the surrounding cities. Further analysis suggests that environmental information disclosure reduces air pollution through enhancing public environmental concerns, green innovation, and industrial upgrading. We also explore the moderating effect of government environmental regulation and heterogeneity analysis in different regions. Our findings suggest that government should further develop the scope and quality of environmental quality information disclosure. Moreover, the local government should provide more support for the green transformation of enterprises and provide necessary support during the transition period. In addition, long-term sustainable environmental protection policies must be able to mobilize regional initiatives for green development.

Abstract Patients with Parkinson’s disease (PD) exhibit systemic deficits, including arthritis and osteoporosis-like symptoms. However, the questions, how the deficits in periphery organs or tissues occur in PD patients, and what are the relationship (s) of the periphery tissue deficits with the brain pathology (e.g., dopamine neuron loss), are at the beginning stage to be investigated. Notice that both PD and osteoporosis are the products of a complex interaction of genetic and environmental risk factors. Genetic mutations in numerous genes have been identified in patients either with recessive or autosomal dominant PD. Most of these PD risk genes are ubiquitously expressed; and many of them are involved in regulation of bone metabolism. Here, we review the functions of the PD risk genes in regulating bone remodeling and homeostasis. The knowledge gaps in our understanding of the bone-to-brain axis in PD development are also outlined.

Phosphorothioate (PT) modification by the dnd gene cluster is the first identified DNA backbone modification and has been shown to constitute a multifunctional epigenetic system. Despite a variety of advantages for hosting dnd systems, these systems are surprisingly distributed sporadically among contemporary microbial genomes. To address this ecological paradox, Jian et al. systematically investigated the occurrence and phylogeny of dnd systems in prokaryotes, and provided evidence to suggest that dnd systems have originated in ancient Cyanobacteria (probably Nostocales) after the Great Oxygenation Event.

Jin-Xiu Pan et al. report that an osteoblast-specific expression of Swedish mutant amyloid precursor protein (APPswe) induces ER stress-driven senescence, leading to systemic inflammation and inflammation in the cortex that drives behavioral changes. The results demonstrate a previously unrecognized function of osteoblastic APPswe to brain axis in AD development.

Drawing on expectancy theory, this study explains how founders’ succession intentions might influence family firms’ environmental environments. Using a nationally representative sample of Chinese private firms, we find that family firms make more environmental investments when founders have succession intentions. We also find that the relationship between founders’ succession intentions and family firms’ environmental investments is negatively moderated by the founders’ subjective social status. Moreover, the results show that, compared with ownership succession intentions, the positive role of founders’ management succession intentions on family firms’ environmental investments is more prominent. This study helps us to better understand the impact of succession intentions on family business decision-making from a psychological perspective. It enriches the research on succession intentions and provides practical implications for family firms’ sustainable development.

With the rapid development of artificial intelligence, machine vision and other information technologies in the construction of smart power plants, the requirements of power plants for the state monitoring of hydro-generator units (HGU) are becoming higher and higher. Based on this, this paper applies YOLOv5 to the state monitoring scenario of HGU, and proposes a method for rotor speed measurement (RSM) and operating state identification (OSI) of HGUs based on the YOLOv5. The proposed method is applied to the actual RSM and OSI of HGUs. The experimental results show that the Precision and Recall of the proposed method for rotor image are 99.5% and 100%, respectively. Compared with the traditional methods, the online image monitoring based on machine vision not only realizes high-precision RSM and the real-time and accurate determination of operating states, but also realizes video image monitoring of the rotor, the operation trend prediction of the rotor and the early warning of abnormal operating states, so that staff can find the hidden dangers in time and ensure the safe operation of the HGU.

ABSTRACT Phosphorothioate (PT) modification, a sequence-specific modification that replaces the nonbridging oxygen atom with sulfur in a DNA phosphodiester through the gene products of dndABCDE or sspABCD, is widely distributed in prokaryotes. DNA PT modification functions together with gene products encoded by dndFGH, pbeABCD, or sspE to form defense systems that can protect against invasion by exogenous DNA particles. While the functions of the multiple enzymes in the PT system have been elucidated, the exact role of DndE in the PT process is still obscure. Here, we solved the crystal structure of DndE from the haloalkaliphilic archaeal strain Natronorubrum bangense JCM10635 at a resolution of 2.31 Å. Unlike the tetrameric conformation of DndE in Escherichia coli B7A, DndE from N. bangense JCM10635 exists in a monomeric conformation and can catalyze the conversion of supercoiled DNA to nicked or linearized products. Moreover, DndE exhibits preferential binding affinity to nicked DNA by virtue of the R19- and K23-containing positively charged surface. This work provides insight into how DndE functions in PT modification and the potential sulfur incorporation mechanism of DNA PT modification. IMPORTANCE DndABCDE proteins have been demonstrated to catalyze DNA PT modification with the nonbridging oxygen in the DNA sugar-phosphate backbone replaced by sulfur. In the PT modification pathway, DndA exerts cysteine desulfurase activity capable of catalyzing the mobilization of sulfur from l-cysteine, which involves the ion-sulfur cluster assembly of DndC. This is regarded as the initial step of the DNA PT modification. Moreover, DndD has ATPase activity in vitro, which is believed to provide energy for the oxygen-sulfur swap, while the function of DndE is unknown. However, the exact function of the key enzyme DndE remains to be elucidated. By determining the structure of DndE from the haloalkaliphilic strain Natronorubrum bangense JCM10635, we showed that the archaeal DndE adopts a monomer conformation. Notably, DndE can introduce nicks to supercoiled DNA and exhibits a binding preference for nicked DNA; the nicking is believed to be the initial step for DNA to facilitate the sulfur incorporation.

IntroductionPhosphodiesterase type 5-inhibitors (PDE5is) are the first-line treatment for patients with diabetes mellitus-induced erectile dysfunction (DMED), however, some patients are non-responser to PDE5is. We performed a perspective, randomized, comparative study to explore the efficacy of low intensity extracorporeal shock wave treatment (Li-ESWT) combined with vacuum erectile device (VED) in the treatment of DMED patients who were unresponsive to PDE5is.MethodsOne hundred and five eligible patients were randomly divided into three groups: group A (VED), group B (Li-ESWT) and group C (VED plus Li-ESWT). Follow-up was conducted at 4 weeks, 8 weeks and 12 weeks after the end of treatment. The erectile function was estimated by the international index of erectile function-erectile function domain (IIEF-EF), erection hardness score (EHS), sexual encounter profile questions 2 and 3 (SEP2 and SEP3) and global assessment question 1 and 2 (GAQ1 and GAQ2) before and after treatment. The changes of five points in IIEF-EF were calculated as the minimal clinical important difference (MCID), which was considered as the main index of efficacy.ResultsThe MCID was achieved in 14.7%, 14.7% and 17.6% patients in group A at the follow up on 4 weeks, 8 weeks and 12 weeks, respectively (36.4%, 39.4% and 36.4% in group B; 36.4%, 51.5%, and 66.7% in group C). There were significant differences in the percentage of MCID cases between group A and group C at the follow up on 12 weeks (P

Strokes are mainly caused by thromboembolic obstruction of a major cerebral artery. Major clinical manifestations include paralysis hemiplegia, aphasia, memory, and learning disorders. In the case of ischemic stroke (IS), hyperactive platelets contribute to advancing an acute thrombotic event progression. Therefore, the principal goal of treatment is to recanalize the occluded vessel and restore cerebral blood flow by thrombolysis or mechanical thrombectomy. However, antiplatelets or thrombolytic therapy may increase the risk of bleeding. Beyond the involvement in thrombosis, platelets also contribute to the inflammatory process induced by cerebral ischemia. Platelet-mediated thrombosis and inflammation in IS lie primarily in the interaction of platelet receptors with endothelial cells and immune cells, including T-cells, monocytes/macrophages, and neutrophils. Following revascularization, intervention with conventional antiplatelet medicines such as aspirin or clopidogrel does not substantially diminish infarct development, most likely due to the limited effects on the thrombo-inflammation process. Emerging evidence has shown that T cells, especially regulatory T cells (Tregs), maintain immune homeostasis and suppress immune responses, playing a critical immunomodulatory role in ischemia-reperfusion injury. Hence, considering the deleterious effects of inflammatory and immune responses, there is an urgent need for more targeted agents to limit the thrombotic-inflammatory activity of platelets and minimize the risk of a cerebral hemorrhage. This review highlights the involvement of platelets in neuroinflammation and the evolving role of Tregs and platelets in IS. In response to all issues, preclinical and clinical strategies should generate more viable therapeutics for preventing and managing IS with immunotherapy targeting platelets and Tregs.

Background: Dental follicle cells (DFCs) are promising candidates for tissue engineering. However, the molecular mechanisms that regulate the biological characteristics of DFCs are still unclear. Transient receptor potential melastatin 7 (TRPM7) is a Ca2+- and Mg2+-permeable cation channel. The aim of this study was to determine the impact of TRPM7 on the proliferation, migration and osteogenic differentiation of DFCs. Methods: PCR, Western blotting, Immunocytochemical staining and Patch clamp methods were used to identify the gene and protein expression of TRPM7 in DFCs. DFCs were infected with lentiviruses that expressed either TRPM7 specific shRNA or scrambled non-effective shRNA to investigate its functional role. Cell proliferation and migration were assessed using Cell Counting Kit-8 assays and transwell cell culture chambers separately. Cell osteogenic differentiation were determined by ALP assay kit and Alizarin Red staining. Results: Gene and protein expression of TRPM7 were detected in DFCs, but not of TRPM6, which is a closely related channel with similar function. In the absence of Mg2+, typical whole cell TRPM7-like currents were recorded by patch clamp. These were inhibited by low concentrations of 2-APB, but activated by high concentrations of 2-APB. Functional studies demonstrated that suppression of TRPM7 expression inhibited the proliferation and migration of DFCs, and promoted their osteogenic differentiation. Furthermore, Mg2+ deficiency mimicked the effects of TRPM7 knockdown in terms of osteogenic differentiation of DFCs. Conclusions: These results demonstrate that TRPM7 is involved in regulating the proliferation, migration and osteogenic differentiation of DFCs.

In order to improve the output characteristics of the electromagnetic energy harvester in a high-speed flow field, a spring-coupling electromagnetic energy harvester (SEGEH) is proposed, based on the galloping characteristics of a large amplitude. The electromechanical model of the SEGEH was established, the test prototype was made, and the experiments were conducted using a wind tunnel platform. The coupling spring can convert the vibration energy consumed by the vibration stroke of the bluff body without inducing an electromotive force into the elastic energy of the spring. This not only reduces the galloping amplitude, but it also provides elastic force for the return of the bluff body, and it improves the duty cycle of the induced electromotive force and the output power of the energy harvester. The stiffness of the coupling spring and the initial distance between the coupling spring and the bluff body will affect the output characteristics of the SEGEH. At a wind speed of 14 m/s, the output voltage was 103.2 mV and the output power was 0.79 mW. Compared with the energy harvester without a coupling spring (EGEH), the output voltage increases by 29.4 mV, with an increase of 39.8%. The output power was increased by 0.38 mW, with an increase of 92.7%.

Many insects, including the Plutella xylostella (L.), have developed varying degrees of resistance to many insecticides, including Bacillus thuringiensis (Bt) toxins, the bioinsecticides derived from Bt. The polycalin protein is one of the potential receptors for Bt toxins, and previous studies have confirmed that the Cry1Ac toxin can bind to the polycalin protein of P. xylostella, but whether polycalin is associated with the resistance of Bt toxins remains controversial. In this study, we compared the midgut of larvae from Cry1Ac-susceptible and -resistant strains, and found that the expression of the Pxpolycalin gene was largely reduced in the midgut of the resistant strains. Moreover, the spatial and temporal expression patterns of Pxpolycalin showed that it was mainly expressed in the larval stage and midgut tissue. However, genetic linkage experiments showed that the Pxpolycalin gene and its transcript level were not linked to Cry1Ac resistance, whereas both the PxABCC2 gene and its transcript levels were linked to Cry1Ac resistance. The larvae fed on a diet containing the Cry1Ac toxin showed no significant change in the expression of the Pxpolycalin gene in a short term. Furthermore, the knockout of polycalin and ATP-binding cassette transporter subfamily C2 (ABCC2) genes separately by CRISPR/Cas9 technology resulted in resistance to decreased susceptibility to Cry1Ac toxin. Our results provide new insights into the potential role of polycalin and ABCC2 proteins in Cry1Ac resistance and the mechanism underlying the resistance of insects to Bt toxins.

Proton exchange membranes (PEMs) are an important type of vanadium redox flow battery (VRFB) separator that play the key role of separating positive and negative electrolytes while transporting protons. In order to lower the vanadium ion permeability and improve the proton selectivity of PEMs for enhancing the Coulombic efficiency of VRFBs, herein, various amounts of nano-sized SiO2 particles were introduced into a previously optimized sulfonated poly(arylene ether) (SPAE) PEMs through the acid-catalyzed sol-gel reaction of tetraethyl orthosilicate (TEOS). The successful incorporation of SiO2 was confirmed by FT-IR spectra. The scanning electron microscopy (SEM) images revealed that the SiO2 particles were well distributed in the SPAE membrane. The ion exchange capacity, water uptake, and swelling ratio of the PEMs were decreased with the increasing amount of SiO2, while the mechanical properties and thermal stability were improved significantly. The proton conductivity was reduced gradually from 93.4 to 76.9 mS cm−1 at room temperature as the loading amount of SiO2 was increased from 0 to 16 wt.%; however, the VO2+ permeability was decreased dramatically after the incorporation of SiO2 and reached a minimum value of 2.57 × 10−12 m2 s−1 at 12 wt.% of SiO2. As a result, the H+/VO2+ selectivity achieved a maximum value of 51.82 S min cm−3 for the composite PEM containing 12 wt.% of SiO2. This study demonstrates that the properties of PEMs can be largely tuned by the introduction of SiO2 with low cost for VRFB applications.

Fresh-cut fruit requires an edible and water-resistant coating to remain fresh. This article investigated the effects of transglutaminase (TGase) and sunflower oil on the water-resistant characteristics, mechanical properties, and microstructure of a whey protein-based film. The whey protein-based emulsion coating’s preservation effect on fresh-cut apples was confirmed. According to the findings, sunflower oil (added at 1.5% w/w) could interact with β-lactoglobulin, α-lactoglobulin dimer, and β-lactoglobulin dimer to form emulsion droplets that are evenly dispersed throughout the protein film. This effect, combined with the covalent cross-linking of TGase, significantly improves the films’ microstructure, mechanical properties, and water resistance. However, too much and unevenly distributed sunflower oil (add 3% w/w) partially prevented the covalent cross-linking of TGase, reducing the elongation at the break of the composite film. In the fresh-cut apple storage experiment, the whey protein-based emulsion coating treatment significantly reduced the weight loss rate and browning index of fresh-cut apples by 26.55% and 46.39%, respectively. This was accomplished by the coating treatment significantly inhibiting the respiration rate increase, PPO and CAT activity enhancement, H2O2 production, and MDA accumulation. This research provides practical, technical, and theoretical guidance for the preservation of fresh-cut fruit.

Cell-free DNA (cfDNA) exists in various types of bodily fluids, including plasma, urine, bile, and others. Bile cfDNA could serve as a promising liquid biopsy for biliary tract cancer (BTC) patients, as bile directly contacts tumors in the biliary tract system. However, there is no commercial kit or widely acknowledged method for bile cfDNA extraction. In this study, we established a silica-membrane-based method, namely 3D-BCF, for bile cfDNA isolation, exhibiting effective recovery of DNA fragments in the spike-in assay. We then compared the 3D-BCF method with four other commercial kits: the BIOG cfDNA Easy Kit (BIOG), QIAamp DNA Mini Kit (Qiagen), MagMAXTM Cell-Free DNA Isolation Kit (Thermo Fisher), and NORGEN Urine Cell-Free Circulating DNA Purification Mini Kit (Norgen Biotek). The proposed 3D-BCF method exhibited the highest cfDNA isolation efficiency (p < 0.0001) from patient bile samples, and bile cfDNA of short, medium or long fragments could all be extracted effectively. To test whether the extracted bile cfDNA from patients carries tumor-related genomic information, we performed next-generation sequencing on the cfDNA and verified the gene-mutation results by polymerase chain reaction (PCR)-Sanger chromatograms and copy-number-variation (CNV) detection by fluorescence in situ hybridization (FISH) of tumor tissues. The 3D-BCF method could efficiently extract cfDNA from bile samples, providing technical support for bile cfDNA as a promising liquid biopsy for BTC patient diagnosis and prognosis.

A built environment with high-quality esthetic expression can positively contribute to key agendas of urban development. Environmental design is the design of physical environments that mainly respond to people’s behavioral needs and sensory preferences based on environment–behavior relations. Practitioners in this industry often work on esthetic quality improvement. Although previous studies have provided valuable knowledge about important elements of built environment esthetic expression, limited research efforts have been devoted to building a systematic framework that comprises key evaluation elements with high local adaptability and the influence relationships among them. The standards and preferences of esthetic expression in environmental design scheme evaluation are context-based. Providing an effective way to clarify evaluation elements with high local adaptability and the relationships among them may help reduce ambiguity, enhance consensus, and increase efficiency in the decision-making process. Therefore, this study adopted the esthetic expression evaluation of environmental design in China as an example and produced a hybrid decision analysis model by integrating the fuzzy Delphi method (FDM), exploratory factor analysis (EFA), analytic hierarchy process (AHP), and decision-making trial and evaluation laboratory (DEMATEL) method to evaluate the esthetic expression of environmental design schemes. A hierarchical evaluation framework composed of 5 dimensions and 18 evaluation elements was constructed in this study. The key design elements under each dimension and the influence relationships among them were also identified. This paper offers insights into the theoretical investigation and practical development of a systematic evaluation of the esthetic expression of environmental design schemes.

Mood disorders, also often referred to as affective disorders, are a group of psychiatric illnesses that severely impact mood and its related functions. The high medical expenditures have placed a significant financial burden on patients and their families. Aromatherapy is an alternative and complementary treatment that utilizes essential oils (EOs) or volatile oils (VOs) to achieve major therapeutic goals. In general, EOs are volatile chemicals that enter the body primarily through skin absorption and/or nasal inhalation. In addition, they can work through oral administration. Inhalation aromatherapy has shown unique advantages for treating mood disorders, especially depression, anxiety and mental disorders such as sleep disorder, which have been validated over the last decade through clinical and animal studies. Accumulating evidence has shown that EOs or VOs can bypass the blood-brain barrier to target brain tissue through the nasal-brain pathway. Subsequently, they act on the cerebral cortex, thalamus, and limbic system in the brain to improve symptoms of anxiety, depression and improve sleep quality. Here, we review the natural aromatic plants’ volatiles or essential oils used commonly as adjuncts to manage mood disorders and illustrate the mechanisms of inhalation aromatherapy, and mainly summarized the application of transnasal inhalation aromatherapy in depression, anxiety, and sleep disorders. We conclude that aromatherapy does not cause side-effects, which is vastly different from commonly used psychotropic drugs. Inhalation aromatherapy via brain-targeted nasal delivery offers potentially efficacious treatment for mental disorders and merits further study.

Anomaly detection for hydraulic turbine unit has an important role in hydropower system. In hydropower systems, different components will produce n-dimensional heterogeneous time series with different characteristics at all times. Due to the characteristic evolution and time dependence, vibration-based anomaly detection for hydraulic turbine unit is extremely challenging. In this paper, we propose a conditional quantile regression based recurrent neural network (QRNN), which models the time dependence and probability distribution between random variables. The proposed method aims to extract the actual representation patterns from the fitted models and it can effectively detect anomalies in the non-uniform time series of feature evolution. The experimental results show that the proposed method has better accuracy in anomaly detection (error reduction by 34%) than the traditional method, and saves at least 25.6% of execution time.

Summary: Background: Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with an extremely poor prognosis. Effective targets for anticancer therapy confirmed in PDAC are limited. However, the characteristics of genomics have not been fully elucidated in large-scale patients with PDAC from China. Methods: We collected both blood and tissue samples from 1080 Chinese patients with pancreatic cancer and retrospectively investigated the genomic landscape using next-generation sequencing (NGS). Findings: We found recurrent somatic mutations in KRAS (83.2%), TP53 (70.6%), CDKN2A (28.8%), SMAD4 (23.0%), ARID1A (12.8%) and CDKN2B (8.9%) in Chinese PDAC patients. Compared with primary pancreatic cancers, more genomic alterations accumulated especially cell cycle regulatory gene variants (45.4% vs 31.6%, P < 0.001) were observed in metastatic tumors. The most common mutation site of KRAS is p.G12D (43.6%) in pancreatic cancer. Patients with KRAS mutations were significantly associated with older age and mutations in the other three driver genes, while KRAS wild-type patients contained more fusion mutations and alternative mechanisms of RTK/Ras/MAPK pathway including a number of clinically targetable mutations. KRAS mutations in Chinese cohort were significantly lower than those in Western cohorts (all P < 0.05). A total of 252 (23.3%) patients with the core DNA damage response (DDR) gene mutations were detected. ATM (n =59, 5.5%) was the most frequent mutant DDR gene in patients with pancreatic cancer from China. Patients with germline DDR gene mutations were younger (P = 0.018), while patients with somatic DDR gene mutations were more likely to accumulate in metastatic lesions (P < 0.001) and had higher TMB levels (P < 0.001). In addition, patients with mutant DDR genes and patients carrying TP53 mutation were observed mutually exclusive (P < 0.001). Interpretation: We demonstrated the real-world genomic characteristics of large-scale patients with pancreatic cancer from China which may have promising implications for further clinical significance and drug development. Funding: The funders are listed in the Acknowledgement.

Qinglong Zhidong Decoction (QLZDD), a traditional Chinese medicine (TCM) prescription, has been effectively used to alleviate Tourette syndrome (TS) in children. However, the therapeutic mechanism of QLZDD on TS has not been evaluated. The present study aims to elucidate the therapeutic effect and the possible therapeutic mechanism of QLZDD on TS in mouse model. A 3,3-iminodipropionitrile (IDPN, 350 mg/kg)-induced-TS mouse model was established. The mice were randomly divided into the control group, the model group, the haloperidol group (14 mg/kg), the low-, middle-, or high-QLZDD-dose groups (6.83 g/kg, 13.65 g/kg, 27.3 g/kg). QLZDD was administrated orally once a day for 4 weeks. The tic-like behavior was recorded weekly. Then, neurotransmitters and neurotransmitter receptors were analyzed by ELISA, immunohistochemistry (IHC), and quantitative reverse transcription PCR in striatum. Further, the alteration to intestinal flora was monitored by 16s rRNA sequencing, and the role of gut microbiota in the alleviation of TS by QLZDD was investigated. QLZDD ameliorated the tic-like behavior, and decreased the level of excitatory neurotransmitters such as Glu and DA and increased the level of the inhibitory neurotransmitter GABA significantly. Moreover, QLZDD significantly blocked the mRNA expression and the protein expression of D1R and D2R in the striatum, while activated the levels of DAT and GABAR. Interestingly, QLZDD mediated the composition of gut microbiota by increasing the abundance of Lactobacillus and Bacteroides but decreasing the abundance of Alloprevotella and Akkermansia. Taken together, QLZDD ameliorated the tic-like behavior in TS mouse, its mechanism of action may be associated with restoring the balance of gut microbiota and neurotransmitters. The study indicated a promising role of QLZDD in alleviating TS and a therapeutic strategy for fighting TS in clinical settings.