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The rapid growth of urban traffic has intensified daily congestion, affecting both traffic flow and parking. Accurate parking prediction plays a vital role in effectively managing limited parking resources and is essential for the successful implementation of advanced intelligent systems. In an effort to comprehensively assess the latest developments in parking prediction, we curated a dataset of 639 articles spanning from 2010 to the present, using the Scopus database. Initially, we performed a bibliometric analysis utilizing VOSviewer software. These findings not only illuminate emerging trends within the parking prediction field but also provide strategic guidance for its progression. Subsequently, we categorized advancements in three focal areas: behavior prediction, demand prediction, and parking space prediction. A comprehensive overview of the present research status and future directions was then provided. The findings underscore the substantial progress achieved in current parking prediction models, achieved through diverse avenues like multi-source data integration, multi-variable feature extraction, nonlinear relationship modeling, deep learning techniques application, and ensemble model utilization. These innovative endeavors have not only pushed the theoretical boundaries of parking prediction but also significantly heightened the precision and applicability of predictive models in practical scenarios. Prospective research should explore avenues such as processing unstructured parking datasets, developing predictive models for small-scale data, mitigating noise interference in parking data, and harnessing potent platform fusion techniques. This study's significance transcends guiding and catalyzing advancement in academic and practical domains; it holds paramount relevance across academic research, technological innovation, decision-making support, business applications, and policy formulation.

Abstract Background Depressive symptoms often occur in patients with Alzheimer's disease (AD) and exacerbate the pathogenesis of AD. However, the neural circuit mechanisms underlying the AD-associated depression remain unclear. The serotonergic system plays crucial roles in both AD and depression. Methods We used a combination of in vivo trans-synaptic circuit-dissecting anatomical approaches, chemogenetic manipulations, optogenetic manipulations, pharmacological methods, behavioral testing, and electrophysiological recording to investigate dorsal raphe nucleus serotonergic circuit in AD-associated depression in AD mouse model. Results We found that the activity of dorsal raphe nucleus serotonin neurons (DRN5-HT) and their projections to the dorsal hippocampal CA1 (dCA1) terminals (DRN5-HT-dCA1CaMKII) both decreased in brains of early 5×FAD mice. Chemogenetic or optogenetic activation of the DRN5-HT-dCA1CaMKII neural circuit attenuated the depressive symptoms and cognitive impairments in 5×FAD mice through serotonin receptor 1B (5-HT1BR) and 4 (5-HT4R). Pharmacological activation of 5-HT1BR or 5-HT4R attenuated the depressive symptoms and cognitive impairments in 5×FAD mice by regulating the DRN5-HT-dCA1CaMKII neural circuit to improve synaptic plasticity. Conclusions These findings provide a new mechanistic connection between depression and AD and provide potential pharmaceutical prevention targets for AD.

Abstract Background Extended contact with silica particles can lead to Silicosis, a chronic lung condition lacking established treatment protocols or clear mechanisms of development. The urgency for innovative treatments arises from the unavailability of effective treatment methodologies. The origin of silica-induced pulmonary fibrosis includes essential processes such as macrophage activation and the conversion of fibroblasts into myofibroblasts, with oxidative stress playing a pivotal role. Shionone (SHI), a triterpenoid extracted from the Aster tataricus plant, is recognized for its extensive health benefits. This study explores the capability of SHI to alleviate the effects of silica-induced lung fibrosis in mice. Methods This investigation explored the impact of SHI on lung inflammation and fibrosis at different stages (early and late) triggered by silica in mice, focusing specifically on the initial and more developed phases. It comprised an analysis of isolated peritoneal macrophages and fibroblasts extracted from mice to elucidate SHI's therapeutic potential and its underlying mechanism. The methodology employed encompassed quantitative PCR, immunofluorescence, flow cytometry, and western blotting to examine macrophage activity and their transition into myofibroblasts. The activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by SHI was confirmed via immunofluorescence and western blot studies. SHI's antioxidative properties were evidenced by the measurement of reactive oxygen species (ROS) and mitochondrial ROS within both macrophages and fibroblasts, using 2′, 7′-dichlorodihydrofluorescein diacetate and MitoSOX, respectively. The relevance of SHI was further underscored by applying ML385 and Nrf2 siRNA to gauge its effectiveness. Results Starting SHI treatment early countered the harmful effects of lung inflammation and fibrosis caused by silica, while initiating SHI at a later phase decelerated the advancement of fibrosis. SHI's action was linked to the activation of the Nrf2 signaling pathway, a boost in antioxidant enzyme levels, and a decrease in oxidative stress and inflammation in macrophages affected by silica. Furthermore, SHI prevented the conversion of fibroblasts into myofibroblasts prompted by TGF-β, along with the resultant oxidative stress. The beneficial outcomes of SHI were negated when ML385 and Nrf2 siRNA were applied, highlighting the pivotal role of the Nrf2 pathway in SHI's efficacy. Conclusion SHI plays a significant role in stimulating the Nrf2 pathway, thereby defending against silica-induced oxidative stress and inflammatory reactions in macrophages, and inhibiting the conversion of fibroblasts to myofibroblasts due to TGF-β. This suggests that SHI is a viable option for treating lung inflammation and fibrosis in mice suffering from silicosis.

ABSTRACTBackground Tongue coating microbiota has aroused particular interest in profiling oral and digestive system cancers. However, little is known on the relationship between tongue coating microbiome and colorectal cancer (CRC).Methods Metagenomic shotgun sequencing was performed on tongue coating samples collected from 30 patients with CRC, 30 patients with colorectal polyps (CP), and 30 healthy controls (HC). We further validated the potential of the tongue coating microbiota to predict the CRC by a random forest model.Results We found a greater species diversity in CRC samples, and the nucleoside and nucleotide biosynthesis pathway was more apparent in the CRC group. Importantly, various species across participants jointly shaped three distinguishable fur types.The tongue coating microbiome profiling data gave an area under the receiver operating characteristic curve (AUC) of 0.915 in discriminating CRC patients from control participants; species such as Atopobium rimae, Streptococcus sanguinis, and Prevotella oris aided differentiation of CRC patients from healthy participants.Conclusion These results elucidate the use of tongue coating microbiome in CRC patients firstly, and the fur-types observed contribute to a better understanding of the microbial community in human. Furthermore, the tongue coating microbiota-based biomarkers provide a valuable reference for CRC prediction and diagnosis.

Introduction: Frailty has an important impact on the health outcomes of older patients, and frailty screening is recommended as part of perioperative evaluation. The Hospital Frailty Risk Score (HFRS) is a validated tool that highlights frailty risk using 109 International Classification of Diseases, 10th revision (ICD-10) codes. In this study, we aim to compare HFRS to the Charlson Comorbidity Index (CCI) and validate HFRS as a predictor of adverse outcomes in Asian patients admitted to surgical services. Method: A retrospective study of electronic health records (EHR) was undertaken in patients aged 65 years and above who were discharged from surgical services between 1 April 2022 to 31 July 2022. Patients were stratified into low (HFRS 15) risk of frailty. Results: Those at high risk of frailty were older and more likely to be men. They were also likely to have more comorbidities and a higher CCI than those at low risk of frailty. High HFRS scores were associated with an increased risk of adverse outcomes, such as mortality, hospital length of stay (LOS) and 30-day readmission. When used in combination with CCI, there was better prediction of mortality at 90 and 270 days, and 30-day readmission. Conclusion: To our knowledge, this is the first validation of HFRS in Singapore in surgical patients and confirms that high-risk HFRS predicts long LOS (≥7days), increased unplanned hospital readmissions (both 30-day and 270-day) and increased mortality (inpatient, 10-day, 30-day, 90-day, 270-day) compared with those at low risk of frailty.

Predicting the wideband radiation of the high-power interconnection cable network within the system is necessary for the electromagnetic compatibility design verification of power electronic systems, and it is urgent to accurately model and analyze its radiation characteristics. The current modeling methods, such as the equivalent dipole method, have numerous constraints, making it difficult to effectively analyze multi-core cable network with connectors, transmission lines of arbitrary arrangement, and large-scale branches. To address this problem, this paper proposes a hybrid modeling method, which integrates multi-conductor transmission line (MTL) equations, dipole radiation theory, and multi-port network theory. Firstly, by using multi-port network theory, this method creates an equivalent circuit for the connection by extracting the S-parameters of the connector. Then, a cascaded transmission model is established using MTL equations, which can analyze the radiation characteristics of various interconnecting cable networks between electromechanical devices, including both straight and bent configurations. Next, the current distribution along the cable network is solved through termination conditions. Furthermore, dipole array radiation theory is used to calculate the radiated field of the complicated cable network with connectors, large-scale branches, and transmission lines of arbitrary layout. Finally, some examples are used to validate the validity and accuracy of this method.

Heat stress resulting from global climate change has been demonstrated to adversely affect growth, development, and reproduction of marine organisms. The Zhikong scallop (Chlamys farreri), an important economical mollusk in China, faces increasing risks of summer mortality due to the prolonged heat waves. The heart, responsible for transporting gas and nutrients, is vital in maintaining homeostasis and physiological status in response to environmental changes. In this study, the effect of heat stress on the cardiac function of C. farreri was investigated during the continuous 30-day heat stress at 27 °C. The results showed the heart rate of scallops increased due to stress in the initial phase of high temperature exposure, peaking at 12 h, and then gradually recovered, indicating an acclimatization at the end of the experiment. In addition, the levels of catalase (CAT), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC) exhibited an initial increase followed by recovery in response to heat stress. Furthermore, transcriptome analysis of the heart identified 3541 differentially expressed genes (DEGs) in response to heat stress. Subsequent GO and KEGG enrichment analysis showed that these genes were primarily related to signal transduction and oxidative stress, such as the phosphatidylinositol signaling system, regulation of actin cytoskeleton, MAPK signaling pathway, FoxO signaling pathway, etc. In addition, two modules were identified as significant responsive modules according to the weighted gene co-expression network analysis (WGCNA). The upregulation of key enzymes within the base excision repair and gap junction pathways indicated that the heart of C. farreri under heat stress enhanced DNA repair and maintained cellular integrity. In addition, the variable expression of essential signaling molecules and cytoskeletal regulators suggested that the heart of C. farreri modulated cardiomyocyte contraction, intracellular signaling, and heart rate through complex regulation of phosphorylation and calcium dynamics in response to heat stress. Collectively, this study enhances our understanding of cardiac function and provides novel evidence for unraveling the mechanism underlying the thermal response in mollusks.

Pharmacogenomic analysis based on drug transcriptome characteristics is widely used to identify mechanisms of action. The purpose of this study was to elucidate the molecular mechanism of protective effect against adriamycin (ADM)-induced mpc5 cell injury of Chinese cordyceps aqueous extracts (WCCs) by a systematic transcriptomic analysis. The phytochemicals of WCCs were analyzed via the “phenol–sulfuric acid method”, high-performance liquid chromatography (HPLC), and HPLC–mass spectrometry (MS). We analyzed the drug-reaction transcriptome profiles of mpc5 cell after treating them with WCCs. RNA-seq analysis revealed that WCCs alleviated ADM-induced mpc5 cell injury via restoring the expression of certain genes to normal level mainly in the one-carbon pool by the folate pathway, followed by the relaxin, apelin, PI3K-Akt, and nucleotide-binding, oligomerization domain (NOD)-like receptor signaling pathway, enhancing DNA synthesis and repair, cell proliferation, fibrosis reduction, and immune regulation. Otherwise, WCCs also modulated the proliferation and survival of the mpc5 cell by regulating metabolic pathways, and partially restores the expression of genes related to human disease pathways. These findings provide an innovative understanding of the molecular mechanism of the protective effect of WCCs on ADM-induced mpc5 cell injury at the molecular transcription level, and Mthfd2, Dhfr, Atf4, Creb5, Apln, and Serpine1, etc., may be potential novel targets for treating nephrotic syndrome.

Previous studies have shown that post-thaw sperm performance is affected by multiple stressors during cryopreservation, such as those induced by physical, chemical, mechanical and physiological changes. One of these is the balance disturbance between the antioxidant defense system and reactive oxygen species (ROS) production. This study investigated whether this disturbance could be alleviated by the addition of different antioxidants to cryoprotective solution [8% dimethyl sulfoxide (DMSO) in 1 µm filtered seawater] optimized for the sperm in dwarf surf clam Mulinia lateralis, the model bivalve species used in many different types of studies. Results showed that the addition of 20 μM coenzyme Q10 (Q10) to 8% DMSO achieved a D-stage larval rate similar to that of the fresh control at a sperm-to-egg ratio at least 50% less than the 8% DMSO treatment alone. The addition of other antioxidants (glycine, melatonin and polyvinylpyrrolidone) did not have any positive effects. The improvement in post-thaw sperm quality by Q10 could be due to its ability to significantly decrease ROS production and lipid peroxidation and significantly increase the motility, plasma membrane integrity, mitochondrial membrane potential, acrosome integrity, DNA integrity and activities of catalase and glutatione. In this study, 37 fatty acids (FAs) were quantified in dwarf surf clam sperm, with 21 FAs being significantly impacted by the cryopreservation with 8% DMSO. Thirteen of these 21 FAs were changed due to the addition of 20 μM Q10 to 8% DMSO, with approximately half of them being improved significantly toward the levels of fresh control, while the remaining half extended further from the trends shown with 8% DMSO treatment. However, no significant difference was found in the percentage of each FA category sum and the ratio of unsaturated/saturated FAs between the two treated groups. In conclusion, the antioxidant Q10 has shown the potential to further improve the sperm cryopreservation technique in bivalves.

Summary: Depressive symptoms usually precede the cognitive decline in Alzheimer disease (AD) and worsen the clinical outcome. However, the neural circuitry mediating early emotional dysfunction, especially depressive symptoms in AD, remains elusive. Anterior cingulate cortex (ACC) is closely related to depression and vulnerable in AD. By quantitative whole-brain mapping and electrophysiological recording, we found that the decreased axonal calcium activity in neurons of ACC and the glutamatergic projection from ACC to the ventral hippocampal CA1 (vCA1) is significantly impaired in 3-month-old 5×FAD mice, which exhibit depressive-like phenotype before cognition defects in early stage. The activation of ACC-vCA1 circuit by chemogenetic manipulation efficiently ameliorated the early depressive-like behaviors in 5×FAD mice. We further identified the upregulated neuregulin-1 (Nrg1) in ACC impaired the excitatory synaptic transmission from the ACC to vCA1 in AD. Our work reveals the role of ACC-vCA1 circuit in regulating AD associated depression symptom in a mouse model of AD.

Abstract Quantifying atmospheric CO2 over long periods from space is crucial in understanding the carbon cycle's response to climate change. However, a single satellite offers limited spatiotemporal coverage, making comprehensive monitoring challenging. Moreover, biases among various satellite retrievals hinder their direct integration. This study proposed a machine learning framework for fusing the column‐averaged dry‐air mole fraction of CO2 (XCO2) retrievals from Greenhouse Gases Observing Satellite (GOSAT) and OCO‐2 satellites. The best model (R2 = 0.85) presented improved consistency of GOSAT retrievals by reducing 71.5% of the average monthly bias while using OCO‐2 retrievals as a benchmark, indicating the fusion data set's potential to enhance observation coverage. Incorporating the adjusted GOSAT XCO2 retrievals into the OCO‐2 data set added an average of 84.7 thousand observations annually, enhancing the yearly temporal coverage by 53.6% (from 14 to 21.5 days per grid). This method can be adapted to other satellites, maximizing satellite resources for a more robust carbon flux inversion.

Abstract Background Acute lung injury (ALI) is a severe disease that can lead to acute respiratory distress syndrome (ARDS), characterized by intractable hypoxemia, poor lung compliance, and respiratory failure, severely affecting patients' quality of life. The pathogenesis of ALI has not been fully elucidated yet, and sepsis is an important cause of ALI. Among the organ injuries caused by sepsis, the lungs are the earliest damaged ones. Radix cyathulae is reported to have analgesic, anti-inflammatory, and anti-aging effects. Cyasterone is extracted from Radix cyathulae. However, it is not known whether cyasterone has protective effects for ALI. This study aims to investigate the effect of cyasterone on sepsis-related ALI and its mechanism. Methods We used the cecal ligation peferation (CLP) method to establish a mouse sepsis model, and cyasterone was given intraperitoneally on days 1–3 to observe its preventive effect on sepsis-related acute lung injury. Primary murine peritoneal macrophages were used to investigate the molecular mechanism of cyasterone in vitro. Results Cyasterone pretreatment inhibits pro-inflammatory cytokine production, NLRP3 inflammasome activation, and oxidative stress in vivo and in vitro. In addition, cyasterone attenuates sepsis-induced ALI by activating nuclear factor erythroid2-related factor (Nrf2), which may be associated with AKT(Ser473)/GSK3β(Ser9) pathway activation. Conclusions Cyasterone defends against sepsis-induced ALI by inhibiting inflammatory responses and oxidative stress, which depends heavily on the upregulation of the Nrf2 pathway through phosphorylation of AKT(Ser473)/GSK3β(Ser9). These results suggest cyasterone may be a valuable drug candidate for preventing sepsis-related ALI.

Abstract Cardiogenic growth factors play important roles in heart development. Placental growth factor (PLGF) has previously been reported to have angiogenic effects; however, its potential role in cardiogenesis has not yet been determined. We analyze single-cell RNA-sequencing data derived from human and primate embryonic hearts and find PLGF shows a biphasic expression pattern, as it is expressed specifically on ISL1+ second heart field progenitors at an earlier stage and on vascular smooth muscle cells (SMCs) and endothelial cells (ECs) at later stages. Using chemically modified mRNAs (modRNAs), we generate a panel of cardiogenic growth factors and test their effects on enhancing cardiomyocyte (CM) and EC induction during different stages of human embryonic stem cell (hESC) differentiations. We discover that only the application of PLGF modRNA at early time points of hESC-CM differentiation can increase both CM and EC production. Conversely, genetic deletion of PLGF reduces generation of CMs, SMCs and ECs in vitro. We also confirm in vivo beneficial effects of PLGF modRNA for development of human heart progenitor-derived cardiac muscle grafts on murine kidney capsules. Further, we identify the previously unrecognized PLGF-related transcriptional networks driven by EOMES and SOX17. These results shed light on the dual cardiomyogenic and vasculogenic effects of PLGF during heart development.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease for which there is a lack of effective pharmacological treatments. Hirudin, a natural peptide extracted from leeches, has been used for broad pharmacological purposes. In this study, we investigated the therapeutic effects of hirudin on IPF and its related mechanism of action. By constructing a mouse model of pulmonary fibrosis and treating it with hirudin in vivo, we found that hirudin exerted anti-fibrotic, anti-oxidative, and anti-fibroblast senescence effects. Moreover, using an in vitro model of stress-induced premature senescence in primary mouse lung fibroblasts and treating with hirudin, we observed inhibition of fibroblast senescence and upregulation of PGC1-alpha and Sirt3 expression. However, specific silencing of PGC1-alpha or Sirt3 suppressed the anti-fibroblast senescence effect of hirudin. Thus, the PGC1-alpha/Sirt3 pathway mediates the anti-fibroblast senescence effect of hirudin, potentially serving as a molecular mechanism underlying its anti-fibrosis and anti-oxidative stress effects exerted on the lungs.

Abstract The dwarf surf clam, Mulinia lateralis, is considered as a model species for bivalves because of its rapid growth and short generation time. Recently, successful breeding of this species for multiple generations in our laboratory revealed its acquisition of adaptive advantages during artificial breeding. In this study, 310 individuals from five different generations were genotyped with 22,196 single nucleotide polymorphisms (SNPs) with the aim of uncovering the genetic basis of their adaptation to laboratory conditions. Results revealed that M. lateralis consistently maintained high genetic diversity across generations, characterized by high observed heterozygosity (Ho: 0.2733–0.2934) and low levels of inbreeding (Fis: −0.0244–0.0261). Population analysis indicated low levels of genetic differentiation among generations of M. lateralis during artificial breeding (Fst

Sperm cryopreservation technique has been published in many farmed bivalve species. One of the key factors preventing its application in aquaculture and/or cryobanking is the knowledge gap on the performance of resultant progeny at late developmental stages and subsequent generations. An effective strategy to overcome these challenges is to use a model species with a short generation interval, such as the dwarf surfclam Mulinia lateralis (three months). This study evaluated the parameters key to the development of a non-programmable sperm cryopreservation technique in this species, with a D-stage larval rate similar to control being achieved when the sperm were cryopreserved under the conditions (cryoprotectant agent: 8% dimethyl sulfoxide; equilibration period: 10 min; rack height: 4 cm; thawing temperature: 60°C and sperm to egg ratio: 1100:1) optimized. This technique is the most common method applied in bivalve and the results from this study were all within the ranges published for other bivalve species, indicating this species would be an ideal bivalve model species for addressing cryopreservation evaluation issues that need a long extended time to collect data and/or challenging field experiments.

Idiopathic pulmonary fibrosis is a fatal interstitial lung disease for which effective drug therapies are lacking. Senegenin, an effective active compound from the traditional Chinese herb Polygala tenuifolia Willd, has been shown to have a wide range of pharmacological effects. In this study, we investigated the therapeutic effects of senegenin on pulmonary fibrosis and their associated mechanisms of action. We found that senegenin inhibited the senescence of epithelial cells and thus exerted anti-pulmonary-fibrosis effects by inhibiting oxidative stress. In addition, we found that senegenin promoted the expression of Sirt1 and Pgc-1α and that the antioxidative and antisenescent effects of senegenin were suppressed by specific silencing of the Sirt1 and Pgc–1α genes, respectively. Moreover, the senegenin-induced effects of antioxidation, antisenescence of epithelial cells, and antifibrosis were inhibited by treatment with Sirt1 inhibitors in vivo. Thus, the Sirt1/Pgc-1α pathway exerts its antifibrotic effect on lung fibrosis by mediating the antioxidative and antisenescent effects of senegenin.

Recently, the increase in marine temperatures has become an important global marine environmental issue. The ability of energy supply in marine animals plays a crucial role in avoiding the stress of elevated temperatures. The investigation into anaerobic metabolism, an essential mechanism for regulating energy provision under heat stress, is limited in mollusks. In this study, key enzymes of four anaerobic metabolic pathways were identified in the genome of scallop Chlamys farreri, respectively including five opine dehydrogenases (CfOpDHs), two aspartate aminotransferases (CfASTs) divided into cytoplasmic (CfAST1) and mitochondrial subtype (CfAST2), and two phosphoenolpyruvate carboxykinases (CfPEPCKs) divided into a primitive type (CfPEPCK2) and a cytoplasmic subtype (CfPEPCK1). It was surprising that lactate dehydrogenase (LDH), a key enzyme in the anaerobic metabolism of the glucose–lactate pathway in vertebrates, was absent in the genome of scallops. Phylogenetic analysis verified that CfOpDHs clustered according to the phylogenetic relationships of the organisms rather than substrate specificity. Furthermore, CfOpDHs, CfASTs, and CfPEPCKs displayed distinct expression patterns throughout the developmental process and showed a prominent expression in muscle, foot, kidney, male gonad, and ganglia tissues. Notably, CfASTs displayed the highest level of expression among these genes during the developmental process and in adult tissues. Under heat stress, the expression of CfASTs exhibited a general downregulation trend in the six tissues examined. The expression of CfOpDHs also displayed a downregulation trend in most tissues, except CfOpDH1/3 in striated muscle showing significant up-regulation at some time points. Remarkably, CfPEPCK1 was significantly upregulated in all six tested tissues at almost all time points. Therefore, we speculated that the glucose–succinate pathway, catalyzed by CfPEPCK1, serves as the primary anaerobic metabolic pathway in mollusks experiencing heat stress, with CfOpDH3 catalyzing the glucose–opine pathway in striated muscle as supplementary. Additionally, the high and stable expression level of CfASTs is crucial for the maintenance of the essential functions of aspartate aminotransferase (AST). This study provides a comprehensive and systematic analysis of the key enzymes involved in anaerobic metabolism pathways, which holds significant importance in understanding the mechanism of energy supply in mollusks.

The senescence of alveolar epithelial cells (AECs) and fibroblasts plays a pivotal role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a condition lacking specific therapeutic interventions. Curculigoside (CCG), a prominent bioactive constituent of Curculigo, exhibits anti-osteoporotic and antioxidant activities. Our investigation aimed to elucidate the anti-senescence and anti-fibrotic effects of CCG in experimental pulmonary fibrosis and delineate its underlying molecular mechanisms. Our findings demonstrate that CCG attenuates bleomycin-induced pulmonary fibrosis and lung senescence in murine models, concomitantly ameliorating lung function impairment. Immunofluorescence staining for senescence marker p21, alongside SPC or α-SMA, suggested that CCG’s mitigation of lung senescence correlates closely with the deceleration of senescence in AECs and fibroblasts. In vitro, CCG mitigated H2O2-induced senescence in AECs and the natural senescence of primary mouse fibroblasts. Mechanistically, CCG can upregulate SIRT1 expression, downregulating P300 expression, enhancing Trim72 expression to facilitate P300 ubiquitination and degradation, reducing the acetylation levels of antioxidant enzymes, and upregulating their expression levels. These actions collectively inhibited endoplasmic reticulum stress (ERS) and alleviated senescence. Furthermore, the anti-senescence effects and mechanisms of CCG were validated in a D-galactose (D-gal)-induced progeroid model. This study provides novel insights into the mechanisms underlying the action of CCG in cellular senescence and chronic diseases, offering potential avenues for the development of innovative drugs or therapeutic strategies.

BackgroundNowadays, researchers are using advanced multimodal neuroimaging techniques to construct the brain network connectome to elucidate the complex relationship among the networks of brain functions and structure. The objective of this study was to evaluate the coupling of structural connectivity (SC) and functional connectivity (FC) in the entire brain of healthy controls (HCs), and to investigate modifications in SC–FC coupling in individuals suffering from temporal lobe epilepsy (TLE).MethodsWe evaluated 65 patients with TLE matched for age and gender with 48 healthy controls. The SC–FC coupling between regions was determined, based on which whole-brain nodes were clustered. Differences in the coupling among the three groups of nodes were compared. To further validate the results obtained, the within-cluster coupling indices of the three groups were compared to determine the inter-group differences.ResultsNodes were divided into five clusters. Cluster 1 was primarily located in the limbic system (n = 9/27), whereas cluster 5 was mainly within the visual network (n = 12/29). By comparing average cluster SC–FC coupling in each cluster of the three groups, we identified marked discrepancies within the three cohorts in Cluster 3 (p = 0.001), Cluster 4 (p < 0.001), and Cluster 5 (p < 0.001). Post-hoc analysis revealed that the SC–FC coupling strengths in LTLE and RTLE were significantly lower than that in HCs in Cluster 3 (PL = 0.001/PR = 0.003), Cluster 4 (PL = 0.001/PR < 0.001), and Cluster 5 (PL < 0.001/PR < 0.001). We also observed that the within-cluster SC–FC coupling in cluster 5 of left- and right TLE was significantly lower than in HCs (PL = 0.0001, PR = 0.0005).ConclusionThe SC and FC are inconsistently coupled across the brain with spatial heterogeneity. In the fifth cluster with the highest degree of coupling in HCs, the average SC–FC coupling index of individuals with TLE was notably less than that of HCs, manifesting that brain regions with high coupling may be more delicate and prone to pathological disruption.

Measurement(s) carbon dioxide emissions Technology Type(s) fossil fuel consumption

Measurement(s) carbon dioxide emissions Technology Type(s) carbon monitor Sample Characteristic - Environment city Sample Characteristic - Location worldwide

Gases are the vital nutrition of all organisms as the precursor of metabolism pathways. As a potential biological process, protein synthesis is inevitably regulated by gas transport and utilization. However, the effect of carbon dioxide (CO2) present in many metabolic pathways on protein synthesis has not been studied well. In this work, carbon dioxide combined with oxygen was employed for cell-free protein synthesis (CFPS) in the tube-in-tube reactor with precise control of gas concentration. In this in vitro system, gases could directly affect the protein synthesis process without transmembrane transport. Varied concentrations of carbon dioxide (0–1%) and constant oxygen concentration (21%) were employed for CFPS to assess the effects. The cell-free reactions with 0.3% CO2 and 21% O2 showed the highest protein yields. The combined effect of CO2 and O2 also resulted in relatively high protein expression under high oxygen conditions (0.3% CO2 and 100% O2). Moreover, metabolomics assays were performed to gain insight into metabolic changes, which showed that CO2 slightly improved energy metabolism and redox balance. In particular, the extra supplied CO2 activated the decarboxylating reactions and removed toxic metabolites to recover the protein synthesis activity. The exploration of CO2 on protein synthesis could provide guiding implications for basic studies and biomanufacturing.

BackgroundFalls and fear of falling (FOF) are independent risk factors for functional limitations in older adults. However, the combined effect of falls and FOF on functional limitations and the moderating role of living alone or not is unclear. We aimed to examine (1) the independent and combined effect of falls and FOF on functional limitations in older adults and (2) whether living alone moderates these associations.MethodsWe used data from the National Health and Aging Trends Study (NHATS) and included 5,950 U.S. community-dwelling older adults aged 65 and older from Round 1 (Year 2011) and Round 2 (Year 2012). Falls and FOF were ascertained by asking participants whether they had any falls in the last year and whether they had worried about falling in the previous month at R1. Assessed functional limitations included any difficulties with mobility, self-care, or household activities at R2. Poisson regression models were used to examine the longitudinal associations of falls and FOF with functional limitations and the moderation effects of baseline living alone.ResultsOf the 5,950 participants, 16.3% had falls only; 14.3% had FOF only; 14.3% had both, and 55.1% had neither at baseline. In the adjusted model, those who experienced concurrent falls and FOF in R1 had a higher risk of functional limitations at R2 than those with neither (Mobility: Incidence risk ratio [IRR] = 1.34, 95% CI: 1.24–1.45; Self-care: IRR = 1.18, 95% CI: 1.11–1.26; Household: IRR = 1.20, 95% CI: 1.11–1.30). Moreover, living alone significantly moderated the longitudinal associations of concurrent falls and FOF with mobility activity limitations.ConclusionThe findings suggest that strategies to improve falls and FOF together could potentially help prevent functional limitations. Older adults who live with others and have falls or FOF should receive interventions to promote their mobility activities.

OBJECTIVES The aim of this study was to evaluate the disease burden of prostate cancer (PC) and assess key influencing factors associated with the disease expenditures of PC in the United States. METHODS The total deaths, incidence, prevalence, and disability-adjusted life-years of PC were obtained from the Global Burden of Disease Study 2019. The Medical Expenditure Panel Survey was used to estimate healthcare expenditures and productivity loss and to investigate patterns of payment and use of healthcare resources in the United States. A multivariable logistic regression model was conducted to identify key factors influencing expenditures. RESULTS For patients aged 50 and older, the burden for all age groups showed a modest increase over the 6-year period. Annual medical expenditures were estimated to range from US$24.8 billion to US$39.2 billion from 2014 to 2019. The annual loss in productivity for patients was approximately US$1,200. The top 3 major components of medical costs were hospital inpatient stays, prescription medicines, and office-based visits. Medicare was the largest source of payments for survivors. In terms of drug consumption, genitourinary tract agents (57.0%) and antineoplastics (18.6%) were the main therapeutic drugs. High medical expenditures were positively associated with age (p=0.005), having private health insurance (p=0.016), more comorbidities, not currently smoking (p=0.001), and patient self-perception of fair/poor health status (p

Objective Rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone, once every 3 weeks (R-CHOP21) is commonly used in non-Hodgkin’s lymphoma (NHL), but accompanied by Pneumocystis carinii pneumonia (PCP) as a fatal treatment complication. This study aims to estimate the specific effectiveness and cost-effectiveness of PCP prophylaxis in NHL undergoing R-CHOP21.Design A two-part decision analytical model was developed. Prevention effects were determined by systemic review of PubMed, Embase, Cochrane Library and Web of Science from inception to December 2022. Studies reporting results of PCP prophylaxis were included. Enrolled studies were quality assessed with Newcastle-Ottawa Scale. Costs were derived from the Chinese official websites, and clinical outcomes and utilities were obtained from published literature. Uncertainty was evaluated through deterministic and probabilistic sensitivity analyses (DSA and PSA). Willingness-to-pay (WTP) threshold was set as US$31 315.23/quality-adjusted life year (QALY) (threefold the 2021 per capita Chinese gross domestic product).Setting Chinese healthcare system perspective.Participants NHL receiving R-CHOP21.Interventions PCP prophylaxis versus no prophylaxis.Main outcome measures Prevention effects were pooled as relative risk (RR) with 95% CI. QALYs and incremental cost-effectiveness ratio (ICER) were calculated.Results A total of four retrospective cohort studies with 1796 participants were included. PCP risk was inversely associated with prophylaxis in NHL receiving R-CHOP21 (RR 0.17; 95% CI 0.04 to 0.67; p=0.01). Compared with no prophylaxis, PCP prophylaxis would incur an additional cost of US$527.61, and 0.57 QALYs gained, which yielded an ICER of US$929.25/QALY. DSA indicated that model results were most sensitive to the risk of PCP and preventive effectiveness. In PSA, the probability that prophylaxis was cost-effective at the WTP threshold was 100%.Conclusion Prophylaxis for PCP in NHL receiving R-CHOP21 is highly effective from retrospective studies, and routine chemoprophylaxis against PCP is overwhelmingly cost-effective from Chinese healthcare system perspective. Large sample size and prospective controlled studies are warranted.

Currently, the treatment for sepsis-induced acute lung injury mainly involves mechanical ventilation with limited use of drugs, highlighting the urgent need for new therapeutic options. As a pivotal aspect of acute lung injury, the pathologic activation and apoptosis of endothelial cells related to oxidative stress play a crucial role in disease progression, with NOX4 and Nrf2 being important targets in regulating ROS production and clearance. Echinacoside, extracted from the traditional Chinese herbal plant Cistanche deserticola, possesses diverse biological activities. However, its role in sepsis-induced acute lung injury remains unexplored. Moreover, although some studies have demonstrated the regulation of NOX4 expression by SIRT1, the specific mechanisms are yet to be elucidated. Therefore, this study aimed to investigate the effects of echinacoside on sepsis-induced acute lung injury and oxidative stress in mice and to explore the intricate regulatory mechanism of SIRT1 on NOX4. We found that echinacoside inhibited sepsis-induced acute lung injury and oxidative stress while preserving endothelial function. In vitro experiments demonstrated that echinacoside activated SIRT1 and promoted its expression. The activated SIRT1 was competitively bound to p22 phox, inhibiting the activation of NOX4 and facilitating the ubiquitination and degradation of NOX4. Additionally, SIRT1 deacetylated Nrf2, promoting the downstream expression of antioxidant enzymes, thus enhancing the NOX4-Nrf2 axis and mitigating oxidative stress-induced endothelial cell pathologic activation and mitochondrial pathway apoptosis. The SIRT1-mediated anti-inflammatory and antioxidant effects of echinacoside were validated in vivo. Consequently, the SIRT1-regulated NOX4-Nrf2 axis may represent a crucial target for echinacoside in the treatment of sepsis-induced acute lung injury.

Secretome is involved in almost all physiological, developmental, and pathological processes, but to date there is still a lack of highly-efficient research strategy to comprehensively study the secretome of invertebrates. Adhesive secretion is a ubiquitous and essential physiological process in aquatic invertebrates with complicated protein components and unresolved adhesion mechanisms, making it a good subject for secretome profiling studies. Here we proposed a computational pipeline for systematic profiling of byssal secretome based on spatiotemporal transcriptomes of scallop. A total of 186 byssus-related proteins (BRPs) were identified, which represented the first characterized secretome of scallop byssal adhesion. Scallop byssal secretome covered almost all of the known structural elements and functional domains of aquatic adhesives, which suggested this secretome-profiling strategy had both high efficiency and accuracy. We revealed the main components of scallop byssus (including EGF-like domain containing proteins, the Tyr-rich proteins and 4C-repeats containing proteins) and the related modification enzymes primarily contributing to the rapid byssus assembly and adhesion. Spatiotemporal expression and co-expression network analyses of BRPs suggested a simultaneous secretion pattern of scallop byssal proteins across the entire region of foot and revealed their diverse functions on byssus secretion. In contrast to the previously proposed “root-initiated secretion and extension-based assembly” model, our findings supported a novel “foot-wide simultaneous secretion and in situ assembly” model of scallop byssus secretion and adhesion. Systematic analysis of scallop byssal secretome provides important clues for understanding the aquatic adhesive secretion process, as well as a common framework for studying the secretome of non-model invertebrates.

Abstract Background This study was designed for the research and development (R&D) and application of a storage inflow and outflow management system enabling departments to perform efficient, scientific, and information-based consumable management. Methods In the endocrinology department of a hospital, expert and R&D teams in consumable management were set up, and an information-based storage inflow and outflow management system for consumables was designed and developed. The system was operated on a personal computer and was divided into three modules: public consumables, bed consumables, and quality control management. The functions of the system included storage inflow and outflow, early warnings, response to user queries, and statistics on consumables. Data were derived from the hospital information system (HIS,ZHIY SOFTWARE HIS VERSION4.0) and a questionnaire survey. Economic indicators, work efficiency of consumable management, nurse burnout, consumable stockroom management, and staff satisfaction were compared under manual management, Excel-based management, and the consumable storage inflow and outflow management system. The results of the questionnaire were analysed using the R software, version 4.1.0. Results Dates were obtained from manual management, Excel-based management and the consumable storage inflow and outflow management system. Under these three methods, the daily prices of department consumables per bed were 53.43 ± 10.27 yuan, 38.65 ± 8.56 yuan, and 31.98 ± 7.36 yuan, respectively, indicating that the new management system reduced costs for the department. The time spent daily on consumable management was shortened from 119.5 (106.75, 123.5) min to 56.5 (48.5, 60.75) to 20 (17.25, 24.25) min. Nurses’ emotional fatigue and job indifference scores, respectively, decreased from 22.90 ± 1.65 and 8.75 ± 1.25 under manual management to 19.70 ± 1.72 and 6.90 ± 1.37 under Excel-based management and to 17.20 ± 2.04 and 6.00 ± 1.30 under the novel system; the satisfaction of the warehouse keeper and collection staff, respectively, increased from 76.62% and 80.78% to 91.6% and 90.5% to 98.8% and 98.5% under the three successive systems. Conclusions The storage inflow and outflow management system achieved produced good results in the storage and classification of consumables.

Background: Life expectancy for patients with malignant tumors has been significantly improved since the presence of the programmed cell death protein-1/programmed cell death protein ligand-1 (PD-1/PD-L1) inhibitors in 2014, but they impose heavy financial burdens for patients, the healthcare system and the nations. The objective of this study was to determine the survival benefits, toxicities, and monetary of programmed cell death protein-1/programmed cell death protein ligand-1 inhibitors and quantify their values.Methods: Randomized controlled trials (RCTs) of PD-1/PD-L1 inhibitors for malignant tumors were identified and clinical benefits were quantified by American Society of Clinical Oncology Value Framework (ASCO-VF) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). The drug price in Micromedex REDBOOK was used to estimate monthly incremental drug costs (IDCs) and the correlation between clinical benefits and incremental drug costs of experimental and control groups in each randomized controlled trial, and the agreement between two frameworks were calculated.Results: Up to December 2022, 52 randomized controlled trials were included in the quantitative synthesis. All the randomized controlled trials were evaluated by American society of clinical oncology value framework, and 26 (50%) met the American society of clinical oncology value framework “clinical meaningful value.” 49 of 52 randomized controlled trials were graded by European society for medical oncology magnitude of clinical benefit scale, and 30 (61.2%) randomized controlled trials achieved European Society for Medical Oncology criteria of meaningful value. p-values of Spearman correlation analyses between monthly incremental drug costs and American society of clinical oncology value framework/European society for medical oncology magnitude of clinical benefit scale scores were 0.9695 and 0.3013, respectively. In addition, agreement between two framework thresholds was fair (κ = 0.417, p = 0.00354).Conclusion: This study suggests that there might be no correlation between the cost and clinical benefit of programmed cell death protein-1/programmed cell death protein ligand-1 inhibitors in malignancy, and the same results were observed in subgroups stratified by drug or indication. The results should be a wake-up call for oncologists, pharmaceutical enterprises and policymakers, and meanwhile advocate the refining of American Society of Clinical Oncology and European Society for Medical Oncology frameworks.

A major challenge in the field of diabetic wound healing is to confirm the body's intrinsic mechanism that could sense the immune system damage promptly and protect the wound from non-healing. Accumulating literature indicates that macrophage, a contributor to prolonged inflammation occurring at the wound site, might play such a role in hindering wound healing. Likewise, other immune cell dysfunctions, such as persistent neutrophils and T cell infection, may also lead to persistent oxidative stress and inflammatory reaction during diabetic wound healing. In this article, we discuss recent advances in the immune cellular components in wounds under the diabetic milieu, and the role of key signaling mechanisms that compromise the function of immune cells leading to persistent wound non-healing.

Summary: In this perspective, we proposed an innovative strategy that coupled near-real-time emission data with satellite observations to make a reliable and precise global carbon-monitoring system.

Background: CKLF like MARVEL transmembrane domain containing 6 (CMTM6) is an important programmed cell death 1 ligand 1 regulator (PD-L1). CMTM6 was reported as an important regulator of PD-L1 by promoting PD-L1 expression in tumor cells against T cells. However, the function of CMTM6 in cervical cancer is not well characterized. In addition, the role of CMTM6 in the induction of epithelial-mesenchymal transition (EMT) in the context of cervical cancer is unknown.Methods: In this study, we evaluated the role of CMTM6, including gene expression analysis, miRNA target regulation, and methylation characteristic, using multiple bioinformatics tools based on The Cancer Genome Atlas (TCGA) database. The expression of CMTM6 in cervical cancer tissues and non-cancerous adjacent tissues was assessed using immunohistochemistry. In vitro and in vivo function experiments were performed to explore the effects of CMTM6 on growth and metastasis of cervical cancer.Results: Human cervical cancer tissues showed higher expression of CMTM6 than the adjacent non-cancerous tissues. In vitro assays showed that CMTM6 promoted cervical cancer cell invasion, migration, proliferation, and epithelial-mesenchymal transition via activation of mitogen-activated protein kinase (MAPK) c-jun N-terminal kinase (JNK)/p38 signaling pathway. We identified transcription factors (TFs), miRNAs, and immune cells that may interact with CMTM6.Conclusion: These results indicate that CMTM6 is a potential therapeutic target in the context of cervical cancer.

The COVID-19 pandemic has severely impacted the tourism and hospitality industries worldwide. Tourism destination marketing has been an heated focus in tourism and hospitality academia, it is widely believed that it can promote the revival of industries in the post-pandemic era. But there is a lack of research on different graphic presentation forms in tourism advertisements. To bridge the gap in the related literature, this study aims at studying the impact of the image and text presentation forms of the scenic spot’s name in tourism advertisements on tourists’ visit intention to the tourist destination city by combining the theory of constructivism in cognitive psychology, SOR model, and affective-cognitive model to conduct a 2 × 2 between-group experiment. The study found that when the text part contains the scenic spot’s name, the tourism advertisement has a significant impact on tourists’ perceived advertising effectiveness, destination affective image, and visit intention. The results of eye tracking analysis also showed that fixation points are primarily distributed in the text part. Furthermore, this study explored the chain mediating mechanism of perceived advertising effectiveness and destination affective image and discovered that the impact of the text presentation form on the visit intention can be realized through the mediating effect of perceived advertising effectiveness and destination affective image. This study puts forward some suggestions for the tourism advertising and destination marketing of scenic spots with high-familiarity of destination cities with low-familiarity and improving the image of tourist destination cities.

Diabetic wound, one of the most common serious complications of diabetic patients, is an important factor in disability and death. Much of the research on the pathophysiology of diabetic wound healing has long focused on mechanisms mediated by hyperglycemia, chronic inflammation, microcirculatory and macrocirculatory dysfunction. However, recent evidence suggests that defensins may play a crucial role in the development and perpetuation of diabetic wound healing. The available findings suggest that defensins exert a beneficial influence on diabetic wound healing through antimicrobial, immunomodulatory, angiogenic, tissue regenerator effects, and insulin resistance improvement. Therefore, summarizing the existing research progress on defensins in the diabetic wound may present a promising strategy for diabetic patients.

As heritage is the precious treasure of human society, heritage also carries the genes of culture. It is of vital importance to effectively develop heritage tourism resources and explore the mechanisms that influence tourists’ cultural identity. This study has integrated the stimulus-organism-response (SOR) framework with the attitude-behavior-context (ABC) theory to construct a hypothetical model of heritage tourism aesthetics, tourist involvement, mental experience, and cultural identity so as to figure out their relationships. The questionnaires were collected to investigate the impact paths and mechanisms between heritage aesthetics, tourist involvement, mental experience, and cultural identity. The structural equation model was used to examine the relationship between heritage tourism aesthetics, tourist involvement, mental experience, and cultural identity. The main findings include: (1) the positive impact of aesthetics driving mental experience and cultural identity is significant; (2) the impact of tourist involvement on mental experience and cultural identity is also significant; (3) the impact of aesthetics on cultural identity is not significant, but mental experience mediates the relationship between aesthetics and cultural identity in heritage tourism. This study provides a new research framework and perspective for the aesthetics, tourist involvement, mental experience, and cultural identity of tourists in heritage tourism. This study also provides practical implications for government culture sectors to propagandize culture and for heritage destination managers to better manage heritage sites.

Vine tea (Ampelopsis grossedentata) is a plant resource with good nutritional and medicinal, and is widely consumed in China. This study aimed to develop a functional vine tea fermentation broth using microbial fermentation and cellulase degradation. First, the most suitable probiotics for vine tea fermentation were screened, and the fermentation conditions were optimized. Then, a new cellulase (Cel 906, MW076177) was added to evaluate the changes in the contents of effective substances and to study its efficacy. The results show that saccharomyces cerevisiae Y-401 was identified as the best strain, the optimal fermentation conditions were a time of 94.60 h, feeding concentration of 115.21 g/L, and temperature of about 34.97°C. The vine tea fermentation broth has a strong inhibitory ability on 2,2′-azinobis3-ethylbenzothiazoline-6-sulfonic acid (ABTS) (99.73%), peroxyl (53.15%), superoxide anion radicals (84.13%), and 1,1-Diphenyl-2-trinitrophenylhydrazine (DPPH) (92.48%). It has a decent inhibitory impact on the cell viability, tyrosinase activity (32.25%), and melanin synthesis (63.52%) of B16-F10 melanoma cells induced by α-MSH. Inflammatory cell recruitment was reduced in a zebrafish inflammation model. Therefore, this vine tea fermented broth has strong antioxidant, anti-melanoma, and anti-inflammatory effects, and has healthcare potential as a probiotic tea.

In order to deal with the complex situation that parametric uncertainty and correlation coexist in the automotive powertrain mounting system (PMS),an uncertainty analysis method for calculating the natural frequency and decoupling rate of PMS was proposed.In the proposed method,the multi-dimensional parallelepiped model was firstly constructed to describe the PMS parameters with uncertainty and correlation.Then,the uncertain responses of the natural frequency and decoupling rate were calculated by integrating the regulation technique,Taylor series expansion and central difference method.Next,the analysis procedure of the proposed method was presented.Finally,the Monte Carlo method was used as a reference method for comparison and verification.The numerical analysis results show that the correlation of uncertain parameters of PMS has a certain influence on the inherent characteristics of the system.The method presents acceptable computational accuracy and higher computational efficiency in solving the uncertain response of PMS,which provides important reference for the calculation,evaluation and optimization design of the inherent characteristics of automotive PMS.

Diabetic ulcers are one of the major complications of diabetes, and patients usually suffer from amputation and death due to delayed ulcer wound healing. Persistent inflammation and oxidative stress at the wound site are the main manifestations of delayed wound healing in diabetic ulcers. In addition, chronic hyperglycemia in patients can lead to circulatory accumulation of lipid peroxidation products and impaired iron metabolism pathways leading to the presence of multiple free irons in plasma. Ferroptosis, a newly discovered form of cell death, is characterized by intracellular iron overload and accumulation of iron-dependent lipid peroxides. These indicate that ferroptosis is one of the potential mechanisms of delayed wound healing in diabetic ulcers and will hopefully be a novel therapeutic target for delayed wound healing in diabetic patients. This review explored the pathogenesis of diabetic ulcer wound healing, reveals that oxidative stress and lipid peroxidation are common pathological mechanisms of ferroptosis and delayed wound healing in diabetic ulcers. Based on strong evidence, it is speculated that ferroptosis and diabetic ulcers are closely related, and have value of in-depth research. We attempted to clarify prospective associations between ferroptosis and diabetic ulcers in terms of GPX4, iron overload, ferroptosis inhibitors, AGEs, and HO-1, to provide new ideas for exploring the clinical treatment of diabetic ulcers.

The anomalous vortex beam (AVB), whose paraxial local topological charge varies with propagation, has potential applications in quantum information, laser beam shaping, and other fields. However, there are currently no efficient optical devices to generate AVBs. In this paper, we propose an efficient pure-phase device called spiral axicons. We theoretically analyze the spiral axicon, and then experimentally verify its performance by implementing a spiral axicon on spatial light modulator. Our work provides an alternative method for generating AVB, which will facilitate its application in different fields.

BackgroundIn the era of immunotherapy, predictive or prognostic biomarkers for head and neck squamous cell carcinoma (HNSCC) are urgently needed. Metabolic reprogramming in the tumor microenvironment (TME) is a non-negligible reason for the low therapeutic response to immune checkpoint inhibitor (ICI) therapy. We aimed to construct a metabolism-related gene prognostic index (MRGPI) for HNSCC bridging metabolic characteristics and antitumor immune cycling and identified the immunophenotype, genetic alternations, potential targeted inhibitors, and the benefit of immunotherapy in MRGPI-defined subgroups of HNSCC.MethodsBased on The Cancer Genome Atlas (TCGA) HNSCC dataset (n = 502), metabolism-related hub genes were identified by the weighted gene co-expression network analysis (WGCNA). Seven genes were identified to construct the MRGPI by using the Cox regression method and validated with an HNSCC dataset (n = 270) from the Gene Expression Omnibus (GEO) database. Afterward, the prognostic value, metabolic activities, genetic alternations, gene set enrichment analysis (GSEA), immunophenotype, Connectivity map (cMAP), and benefit of immunotherapy in MRGPI-defined subgroups were analyzed.ResultsThe MRGPI was constructed based on HPRT1, AGPAT4, AMY2B, ACADL, CKM, PLA2G2D, and ADA. Patients in the low-MRGPI group had better overall survival than those in the high-MRGPI group, consistent with the results in the GEO cohort (cutoff value = 1.01). Patients with a low MRGPI score display lower metabolic activities and an active antitumor immunity status and more benefit from immunotherapy. In contrast, a higher MRGPI score was correlated with higher metabolic activities, more TP53 mutation rate, lower antitumor immunity ability, an immunosuppressive TME, and less benefit from immunotherapy.ConclusionThe MRGPI is a promising indicator to distinguish the prognosis, the metabolic, molecular, and immune phenotype, and the benefit from immunotherapy in HNSCC.

Abstract Background CKLF like MARVEL transmembrane domain containing 6 (CMTM6) has been associated with the development in many kinds of cancers. However, the roles of CMTM6 in hepatocellular carcinoma (HCC) are largely unknown. Thus, the present study aimed to investigate the function of CMTM6 in HCC. Methods We analysed CMTM6 levels and functions using human HCC cell lines, paired HCC and adjacent non-tumorous tissues, and a tissue microarray. CMTM6 expression was silenced using short hairpin RNAs and its was overexpressed from a lentivirus vector. CMTM6 mRNA and protein levels were determined using quantitative real-time reverse transcription PCR and western blotting, respectively. Proliferation, colony formation, migration, and invasion were assessed using a Cell counting kit-8, colony formation, wound-healing, and Matrigel invasion assays, respectively. Immunohistochemistry was used to score the expression of CMTM6 in tissue samples. The localization and binding partners of CMTM6 were investigated using immunofluorescence and coimmunoprecipitation experiments, respectively. A mouse xenograft model was used for in vivo studies. Results Compared with that in adjacent, non-cancerous tissue, Here, CMTM6 levels were increased in HCC tissue samples. Silencing of CMTM6 suppressed the proliferation, migration, and invasion of HCC cells. Conversely, CMTM6 overexpression enhanced HCC cell invasion, migration, and proliferation. Mechanistically, CMTM6 physically interacts with and stabilizes vimentin, thus inducing epithelial–mesenchymal transition (EMT), which promotes proliferation, migration and invasion. Importantly, in HCC tissues, CMTM6 expression correlated positively with vimentin levels. Poor prognosis of HCC was associated significantly with higher CMTM6 expression. Conclusions CMTM6 has an important function in HCC proliferation, migration, and invasion, via its interaction with and stabilization of vimentin. CMTM6 might represent a potential biomarker and therapeutic target to treat HCC.

ObjectiveRecently, the significant improvement of atezolizumab and pembrolizumab over chemotherapy for treatment-naïve stage IV non-small cell lung cancer (NSCLC) has been demonstrated, but the cost-effectiveness of these regimens remains unknown.MethodsA Markov model was adapted from the US healthcare perspective to assess the cost-effectiveness of atezolizumab, pembrolizumab, and chemotherapy in treatment-naïve NSCLC. Pseudo-individual patient data were generated from digitized Kaplan–Meier curves. Direct medical costs and utility values were sourced from the database and literature. Quality-adjusted life-years (QALYs), total costs, and incremental cost-effectiveness ratios (ICERs) were computed. Sensitivity analyses and budgetary impact analyses were calculated.ResultsIn any and high programmed cell death 1-ligand 1 (PD-L1) expression populations, with chemotherapy, atezolizumab provided ICERs of $234,990 and $130,804 per QALY, while pembrolizumab yielded ICERs of $424,797 and $140,873 per QALY. The ICER of atezolizumab vs. pembrolizumab was $56,635 and $115,511.82 in any and high PD-L1 expression population, respectively. The critical drivers of ICERs included the cost of atezolizumab and pembrolizumab. The accumulated incremental budgetary impact of atezolizumab vs. chemotherapy increased to approximately $39.1 million in high PD-L1 expression patients over 5 years.ConclusionsIn the high PD-L1 expression population, both atezolizumab and pembrolizumab were cost-effective for stage IV NSCLC compared to chemotherapy, which is contrary to that in any PD-L1 expression population. Atezolizumab shows a higher acceptability in both populations. Treating with immune checkpoint inhibitors (ICIs) has a substantial budgetary impact on the medical burden. The PD-L1 expression level has the potential to be a predictor for the economics of ICIs.

Background: Eukaryotic Translation Initiation Factor 4E Binding Protein 1 (4EBP1) involved in inhibition of protein translation and synthesis. However, the phosphoprotein of 4EBP1 (p-4EBP1) promotes the translation and synthesis of several proteins, including multiple classic oncogenic proteins. The prognostic significance of 4EBP1 mRNA, 4EBP1 protein, and p-4EBP1 in Pan-cancer are still unclear.Methods: In this study, we provided a multi-Omics investigation for the prognostic value of 4EBP1 mRNA, 4EBP1 protein, and different 4EBP1 phosphoproteins in a Pan-cancer manner based on the TCGA projects. We explored the correlation between 4EBP1 expression and the cancer-associated fibroblast (CAFs) infiltration, respectively using the EPIC, MCPCOUNTER, and TIDE algorithms. The functional states of 4EBP1 were explored using single-cell sequencing analysis in Pan-Cancer. Immunohistochemistry staining was used to detect and verify the expression of 4EBP1 in several cancers.Results: 4EBP1 mRNA was aberrantly overexpressed in most cancers, and was associated with the poor prognosis in ten cancers. Notably, increased 4EBP1 mRNA expression significantly correlated with tumor staging and worse prognosis in BRCA, KIRC, and KIRP, while having the opposite effect in STAD. 4EBP1 expression was associated with the CAFs infiltration level in ten cancer types. Interestingly, the correlation between 4EBP1 and CAFs infiltration had pronounced heterogeneity in digestive system tumors and urinary system tumors. In BLCA, KIRC, and ACC as well as BRCA, 4EBP1 was significantly positively correlated with CAFs infiltration and was associated with a poor prognosis. In STAD and COAD, 4EBP1 is negatively correlated with CAFs infiltration and was associated with a better prognosis. Lastly, the expression and prognostic significance of 4EBP1 protein and different p-4EBP1 varied enormously among cancers.Conclusion: Our multi-omics study indicates that 4EBP1-driven CAFs infiltration is associated with cancer prognosis and 4EBP1 mRNA, 4EBP1 protein, and p-4EBP1 proteins may serve as potential prognostic biomarkers and therapeutic targets in diverse cancer.

The overall survival of patients with lower grade glioma (LGG) that might develop into high-grade malignant glioma shows marked heterogeneity. The currently used clinical evaluation index is not sufficient to predict precise prognostic outcomes accurately. To optimize survival risk stratification and the personalized management of patients with LGG, there is an urgent need to develop an accurate risk prediction model. The TCGA-LGG dataset, downloaded from The Cancer Genome Atlas (TCGA) portal, was used as a training cohort, and the Chinese Glioma Genome Atlas (CGGA) dataset and Rembrandt dataset were used as validation cohorts. The levels of various cancer hallmarks were quantified, which identified glycolysis as the primary overall survival-related risk factor in LGGs. Furthermore, using various bioinformatic and statistical methods, we developed a strong glycolysis-related gene signature to predict prognosis. Gene set enrichment analysis showed that in our model, high-risk glioma correlated with the chemoradiotherapy resistance and poor survival. Moreover, based on established risk model and other clinical features, a decision tree and a nomogram were built, which could serve as useful tools in the diagnosis and treatment of LGGs. This study indicates that the glycolysis-related gene signature could distinguish high-risk and low‐risk patients precisely, and thus can be used as an independent clinical feature.

Background: The discovery of reliable cancer biomarkers could tune a diagnosis and improve the way patients are treated. However, many cancers lack robust biomarkers. C1QTNF6 has been preliminarily elucidated for its role in some tumors. However, no pan-cancer analysis has been performed to comprehensively explore the value of C1QTNF6.Methods: Data from the TCGA database, GTEx database stored in the USUC Xena were used for analyzing the profiles of C1QTNF6 expression in normal and tumor tissues in pan-cancer. Subsequently, the gene alteration rates of C1QTNF6 were acquired on the online web cBioportal. With the aid of the TCGA data, the association between C1QTNF6 mRNA expression and copy number alterations (CNA) and methylation was determined. Survival analyses of C1QTNF6 were carried out. Moreover, the tumor biological and immunological characteristics of C1QTNF6 were clarified in the forms of the correlation between C1QTNF6 expression and hallmark Pathway scores in MsigDB database, immune cell infiltration, immune-related genes. We conducted a GSEA of C1QTNF6 to illustrate its potential biological functions. In addition, GDSC2 data with 198 drugs were adopted to explore drug sensitivity with the change of C1QTNF6 expression.Result:C1QTNF6 was overexpressed in many types of cancer, Survival analysis showed that C1QTNF6 independently served as a prognostic indicator for poor survival in many tumors. Besides, we also identified a positive correlation between C1QTNF6 and cancer hallmark pathway score, tumor microenvironment related pathways score (TMEp score), and immune characteristic. In terms of drug sensitivity analysis, we found higher expression level of C1QTNF6 predicts a high IC50 value for most of 198 drugs which predicts drug resistance.Conclusions: Our study provides a new biological marker for pan-cancer, which is beneficial to the diagnosis and treatment of cancer, which bring a new therapeutic target for tumors.

Abstract Background Lymphovascular invasion (LOI), a key pathological feature of head and neck squamous cell carcinoma (HNSCC), is predictive of poor survival; however, the associated clinical characteristics and underlying molecular mechanisms remain largely unknown. Methods We performed weighted gene co-expression network analysis to construct gene co-expression networks and investigate the relationship between key modules and the LOI clinical phenotype. Functional enrichment and KEGG pathway analyses were performed with differentially expressed genes. A protein–protein interaction network was constructed using Cytoscape, and module analysis was performed using MCODE. Prognostic value, expression analysis, and survival analysis were conducted using hub genes; GEPIA and the Human Protein Atlas database were used to determine the mRNA and protein expression levels of hub genes, respectively. Multivariable Cox regression analysis was used to establish a prognostic risk formula and the areas under the receiver operating characteristic curve (AUCs) were used to evaluate prediction efficiency. Finally, potential small molecular agents that could target LOI were identified with DrugBank. Results Ten co-expression modules in two key modules (turquoise and pink) associated with LOI were identified. Functional enrichment and KEGG pathway analysis revealed that turquoise and pink modules played significant roles in HNSCC progression. Seven hub genes (CNFN, KIF18B, KIF23, PRC1, CCNA2, DEPDC1, and TTK) in the two modules were identified and validated by survival and expression analyses, and the following prognostic risk formula was established: [risk score = EXPDEPDC1 * 0.32636 + EXPCNFN * (− 0.07544)]. The low-risk group showed better overall survival than the high-risk group (P