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Abstract Background Empagliflozin (EMPA) has demonstrated efficacy in providing cardiovascular benefits in metabolic diseases. However, the direct effect of EMPA on autophagy in obesity-related cardiac dysfunction remains unclear. Therefore, this study aimed to determine changes in cardiac autophagy during diet-induced obesity and clarify the exact mechanism by which EMPA regulates autophagic pathways. Methods Male C57BL/6J mice were fed a 12-week high-fat diet (HFD) followed by 8 weeks of EMPA treatment. Body composition analysis and echocardiography were performed to evaluate metabolic alterations and cardiac function. Histological and immunofluorescence staining was used to evaluate potential enhancements in myocardial structure and biological function. Additionally, H9c2 cells were transfected with small interfering RNA targeting sirtuin 3 (SIRT3) and further treated with palmitic acid (PA) with or without EMPA. Autophagy-related targets were analyzed by western blotting and RT‒qPCR. Results EMPA administration effectively ameliorated metabolic disorders and cardiac diastolic dysfunction in HFD-fed mice. EMPA prevented obesity-induced myocardial hypertrophy, fibrosis, and inflammation through the activation of SIRT3-mediated autophagosome formation. The upregulation of SIRT3 triggered by EMPA promoted the initiation of autophagy by activating AMP-activated protein kinase (AMPK) and Beclin1. Furthermore, activated SIRT3 contributed to the elongation of autophagosomes through autophagy-related 4B cysteine peptidase (ATG4B) and autophagy-related 5 (ATG5). Conclusions EMPA promotes SIRT3-mediated autophagosome formation to alleviate damage to the cardiac structure and function of obese mice. Activated SIRT3 initiates autophagy through AMPK/Beclin1 and further stimulates elongation of the autophagosome membrane via ATG4B/ATG5. These results provide a new explanation for the cardioprotective benefits of EMPA in obesity.

Abstract Molecular imaging holds the potential for noninvasive and accurate grading of liver fibrosis. It is limited by the lack of biomarkers that strongly correlate with liver fibrosis grade. Here, we discover the grading potential of fibroblast activation protein alpha (FAPα) for liver fibrosis through transcriptional analysis and biological assays on clinical liver samples. The protein and mRNA expression of FAPα are linearly correlated with fibrosis grade (R2 = 0.89 and 0.91, respectively). A FAPα-responsive MRI molecular nanoprobe is prepared for quantitatively grading liver fibrosis. The nanoprobe is composed of superparamagnetic amorphous iron nanoparticles (AFeNPs) and paramagnetic gadoteric acid (Gd-DOTA) connected by FAPα-responsive peptide chains (ASGPAGPA). As liver fibrosis worsens, the increased FAPα cut off more ASGPAGPA, restoring a higher T1-MRI signal of Gd-DOTA. Otherwise, the signal remains quenched due to the distance-dependent magnetic resonance tuning (MRET) effect between AFeNPs and Gd-DOTA. The nanoprobe identifies F1, F2, F3, and F4 fibrosis, with area under the curve of 99.8%, 66.7%, 70.4%, and 96.3% in patients’ samples, respectively. This strategy exhibits potential in utilizing molecular imaging for the early detection and grading of liver fibrosis in the clinic.

Abstract Alpine natural heritage sites hold significant value due to their unique global resources. Studying land cover changes in these areas is crucial for maintaining and preserving multiple their values. This study takes Kalajun-Kuerdening, one of the components of Xinjiang Tianshan World Natural Heritage Site, as an example to analyze land cover changes and their driving factors in alpine heritage sites. Highlights include: (1) Between 1994 and 2023, Forest and Grassland increased by 55.96 km2 and 18.16 km2, with notable forest growth from 2007 to 2017. Trends in Forest changes align with forest protection policies, and a substantial amount of Bareland converted to Grassland indicates an increase in vegetation cover. (2) Elevation, precipitation, temperature, and evapotranspiration are key drivers of land cover changes, as validated by Random Forest algorithm and Geodetector model. (3) Favorable conditions for Grassland to Forest transition include annual precipitation between 275 and 375 mm, annual temperature between −2 and 3 °C, annual evapotranspiration between 580 and 750 mm, elevation between 1800 and 2600 m, and aspect between 0 to 110° and 220 to 259.9°. Continuous monitoring of land cover changes and their driving factors in mountain heritage sites contributes to the protection of the ecological environment and provides data and information support for addressing climate change, resource management, and policy making.

Abstract Background Obesity and its associated complications raise significant public concern, revealing gender disparities in the susceptibility to metabolic disorders, with females often displaying greater resistance to obesity-related metabolic disorder than males. Sestrin2 is a crucial protein involved in metabolism and energy balance. This study seeks to explore whether Sesn2 knockout (KO) exacerbates high-fat diet (HFD) induced obesity in female mice. Methods Female mice with wild-type (WT) and Sesn2 KO were subjected to a 12-week regimen of normal diet or HFD. Using a Body Composition Analyzer, body composition was gauged. Biochemical assays encompassed glucose, lipid, and liver function measurements, alongside 24-hour urine albumin excretion. Echocardiographic evaluation assessed cardiac function. Histopathological analysis of key metabolic tissues (liver, kidney, and heart tissues) were conducted. Western blotting or qRT-PCR evaluated key proteins and genes linked to inflammation, mitochondrial, and lipid metabolism in adipose tissues. Results In comparison to mice fed a regular diet, those on a HFD exhibited significant increases in body weight and fat mass. Notably, Sesn2 KO further aggravated obesity, showcasing the most pronounced metabolic anomalies: elevated body weight, fat mass, impaired glucose tolerance, and insulin sensitivity, alongside heightened levels of free fatty acids and triglycerides. Additionally, KO-HFD mice displayed exacerbated multi-tissue impairments, including elevated hepatic enzymes, increased urinary albumin excretion, compromised cardiac function, and accumulation of lipids in the liver, kidney, and heart. Moreover, adipose tissue showcased altered lipid dynamics and function, characterized by enhanced triglyceride breakdown and modified adipokine levels. Browning was diminished, along with decreased Pgc1α and Sirt1 in KO-HFD mice. Conclusion Sesn2 KO exacerbates HFD-induced obesity and metabolic disorders in female mice. These findings underscore Sestrin2’s novel role as a regulator of obesity in female mice.

Abstract This study, leveraging search engine data, investigates the dynamics of China's domestic tourism markets in response to the August 2022 epidemic outbreak in Xinjiang. It focuses on understanding the reaction mechanisms of tourist-origin markets during destination crises in the post-pandemic phase. Notably, the research identifies a continuous rise in the potential tourism demand from tourist origin cities, despite the challenges posed by the epidemic. Further analysis uncovers a regional disparity in the growth of tourism demand, primarily influenced by the economic stratification of origin markets. Additionally, the study examines key tourism attractions such as Duku Road, highlighting its resilient competitive system, which consists of distinctive tourism experiences, economically robust tourist origins, diverse tourist markets, and spatial pattern stability driven by economic factors in source cities, illustrating an adaptive response to external challenges such as crises. The findings provide new insights into the dynamics of tourism demand, offering a foundation for developing strategies to bolster destination resilience and competitiveness in times of health crises.

The Altai Mountains, spanning China, Russia, Kazakhstan, and Mongolia, are crucial habitats for many endemic, rare, and endangered species and are a vital migration corridor. However, the standards for establishing protected areas (PAs) differ among the four countries, resulting in suboptimal spatial arrangements and protection gaps in PAs. Therefore, here, by integrating the habitats of rare and endangered species and key ecosystem service areas, we identified potential conservation areas in the Altai Mountains. And we overlaid them with existing PAs in China, Russia, Kazakhstan, and Mongolia to determine the core habitats of the transboundary ecological networks for conservation. The identified core habitats covered 168,729.00 km2, representing 50.63 % of the Altai Mountains. Among these, potential conservation area not covered by existing PAs was approximately 82,833.50 km2 (24.86%). Additionally, 116 ecological corridors were identified with an average length of 38.15 km, including 8 transboundary corridors that connect the core conservation areas across different countries. Based on these findings, new PAs and other effective conservation measures (OECMs) in the Altai Mountains were proposed, along with a phased cooperation framework to gradually enhance the construction of transboundary ecological networks for conservation. Establishing the Altai Mountains’ transboundary ecological networks for conservation has the potential to become a model for transboundary conservation projects, providing valuable insights and guidance for developing conservation and collaborative management strategies in other transboundary regions.

Summary: Advanced glycation end products (AGEs) in diabetes can cause endothelial damage. Heparin, widely known as a recognized anticoagulant, is also a multifunctional therapeutic drug. This study investigated whether heparin could ameliorate AGEs-induced endothelial injury. Remarkably, heparin effectively attenuated this cellular damage and assumed a reparative role. Furthermore, heparin inhibited the AGEs-RAGE-NFκB axis, thereby mitigating endothelial inflammatory injury. Comprehensive proteome and knockdown experiments suggested that heparin may exert a positive influence on cell growth and further alleviate pathological damage by upregulating the expression of LYAR (cell growth-regulating nucleolar protein). Diabetic mouse model was also used to further verify the changes of endothelial tissue in diabetic state and heparin intervention. In summary, these findings demonstrate that heparin has the potential to ameliorate AGEs-induced endothelial injury, opening new avenues for exploring the expanded therapeutic roles of heparin and its potential application in the management of diabetes and its associated complications.

Edge computing has attracted wide attention due to its ultra-low latency services, as well as the prevalence of smart devices and intelligent applications. Edge server placement (ESP) is one of the key issues needed to be addressed for effective and efficient request processing, by deciding which edge stations to equip with limited edge resources. Due to NP-hardness of ESP, some works have designed meta-heuristic algorithms for solving it. While these algorithms either exploited only one kind of meta-heuristic search strategies or separately perform two different meta-heuristic algorithms. This can result in limit performance of ESP solutions due to the “No Free Lunch” theorem. In addition, existing algorithms ignored the computing delay of edge servers (ESs) on request process, resulting in overestimation of the service quality. To address these issues, in this article, we first formulate ESP problem with the objective of minimizing the overall response time, considering heterogeneous edge servers with various service capacity. Then, to search effective or even the best ESP solutions, we propose a hybrid meta-heuristic algorithm (named GP4ESP) by taking advantage of both the powerful global search ability of genetic algorithm (GA) and the fast convergence of particle swarm optimization (PSO). GP4ESP effectively fuses the merits of GA and PS by integrating the swarm cognition of PSO into the evolutionary strategy of GA. At last, we conducted extensive simulation experiments to evaluate the performance of GP4ESP, and results show that GP4ESP achieves 18.2%–20.7% shorter overall response time, compared with eleven up-to-date ESP solving algorithms, and the performance improvement is stable as the scale of ESP is varied.

Abstract Background Ketogenic diets are increasingly popular for addressing obesity, but their impacts on the gut microbiota and metabolome remain unclear. This paper aimed to investigate how a ketogenic diet affects intestinal microorganisms and metabolites in obesity. Methods Male mice were provided with one of the following dietary regimens: normal chow, high-fat diet, ketogenic diet, or high-fat diet converted to ketogenic diet. Body weight and fat mass were measured weekly using high-precision electronic balances and minispec body composition analyzers. Metagenomics and non-targeted metabolomics data were used to analyze differences in intestinal contents. Results Obese mice on the ketogenic diet exhibited notable improvements in weight and body fat. However, these were accompanied by a significant decrease in intestinal microbial diversity, as well as an increase in Firmicutes abundance and a 247% increase in the Firmicutes/Bacteroidetes ratio. The ketogenic diet also altered multiple metabolic pathways in the gut, including glucose, lipid, energy, carbohydrate, amino acid, ketone body, butanoate, and methane pathways, as well as bacterial secretion and colonization pathways. These changes were associated with increased intestinal inflammation and dysbiosis in obese mice. Furthermore, the ketogenic diet enhanced the secretion of bile and the synthesis of aminoglycoside antibiotics in obese mice, which may impair the gut microbiota and be associated with intestinal inflammation and immunity. Conclusions The study suggest that the ketogenic diet had an unfavorable risk–benefit trade-off and may compromise metabolic homeostasis in obese mice.

Abstract While the forests on Mount Taishan are predominantly man-made, there is a notable vertical variation in vegetation. This study employs the method of cloud model, quantifying uncertainty (fuzziness and randomness) of things. Utilizing digital elevation model (DEM) and vegetation distribution data, we constructed elevation cloud models for Mount Taishan’s deciduous broad-leaved, temperate coniferous, and mixed coniferous-broadleaved forests. Using three numerical features of the cloud model—Expectation (EX), Entropy (EN), and Hyper-entropy (HE)—we quantitatively analyzed the macro regularity and local heterogeneity of Mount Taishan’s forests vertical distribution from the perspective of uncertainty theory. The results indicate: (1) The EX of the core zone elevation of deciduous broad-leaved forest is 716.65 m, temperate coniferous forest is 1053.51 m, and mixed coniferous-broadleaved forest is 1384.09 m. The variation range of the core zone distribution height is smaller in the mixed coniferous-broadleaved forest (EN: 53.74 m) compared to deciduous broad-leaved forest (EN: 99.63 m) and temperate coniferous forest (EN: 121.70 m). (2) The fuzziness and randomness of the distribution height of the lower extension zones of deciduous broad-leaved forest and temperate coniferous forest (EN: 75.15 m, 184.56 m; HE: 24.09 m, 63.54 m) are greater than those of the upper extension zones (EN: 44.75 m, 42.49 m; HE: 14.48 m, 13.23 m). (3) The distribution fuzziness and randomness within temperate coniferous forests exceed those of deciduous broad-leaved forests. Within the core zones, the uncertainty regarding the vertical distribution of vegetation across different aspects remains consistent, which retains the characteristic of man-made forests. However, in transition areas, there is significant disparity, reflecting the adaptive relationship between vegetation and its environment to some extent. In the upper and lower extension zones of deciduous broad-leaved forests, the EX values for the vertical distribution height of mixed coniferous and broad-leaved forests differ significantly from those of deciduous broad-leaved forests (the difference is 22.82–39.15 m), yet closely resemble those of temperate coniferous forests (the difference is 4.79–7.94 m). This suggests a trend wherein deciduous broad-leaved tree species exhibit a proclivity to encroach upon coniferous forest habitats. The elevation cloud model of vertical vegetation zones provides a novel perspective and method for the detailed analysis of Mount Taishan’s vegetation vertical differentiation.

Biological experiments targeting the mammalian primary visual cortex have shown that neuronal response to a preferred orientation grating is cross-inhibited by an orthogonal orientation mask grating. The plaid formed by the overlap of the two gratings not only causes a decrease in the neuronal firing rate but also shifts the gamma oscillation to a weaker oscillation at a higher frequency. The mechanism for the above phenomena is unclarified. In this paper, a large-scale cortical neuronal network model with biological details is constructed. In this model, two modes of connectivity that may contribute to cross-inhibition are considered: the thalamo-cortical feedforward pathway and the push-pull organization of cortical layer 4. Based on this model, the modulation of firing rate and gamma oscillation by a plaid stimulation are successfully reproduced, which is consistent with biological experiments and suggests that it is the thalamo-cortical feedforward pathway that leads to cross-inhibition. Furthermore, our analysis of the neuronal spike clusters and current fluctuations suggests that the push-pull organization leads to an increase in gamma frequency during the transition of visual stimuli from grating to plaid by modulating the source of synaptic inhibition in local neuronal populations. Such results will help to understand the visual processing under multi-input integration.

The largemouth bass is a native species of North America that was first introduced to mainland China in the 1980s. In recent years, it has been extensively farmed in China due to its high meat quality and broad adaptability. In this study, we collected growth trait data from 1,066 largemouth bass individuals across two populations. We generated an average of approximately 7× sequencing coverage for these fish using Illumina sequencers. From the samples, we identified 2,695,687 SNPs and retained 1,809,116 SNPs for further analysis after filtering. To estimate the number of genome-wide effective SNPs, we performed LD pruning with PLINK software and identified 77,935 SNPs. Our GWAS revealed 15 SNPs associated with six growth traits. We identified a total of 24 genes related to growth, with three genes—igf1, myf5, and myf6—directly associated with skeletal muscle development and growth, located near the leading SNP on chromosome 23. Other candidate genes are involved in the development of tissues and organs or other physiological processes. These findings provide a valuable set of SNPs and genes that could be useful for genetic breeding programs aimed at enhancing growth in largemouth bass.

Microbial interactions are widespread and important processes that support the link between disease and microbial ecology. The gut microbiota is a major source of microbial stimuli that can have detrimental or beneficial effects on human health. It is also an endocrine organ that maintains energy homeostasis and host immunity. Obesity is a highly and increasingly prevalent metabolic disease and the leading cause of preventable death worldwide. An imbalance in the gut microbiome is associated with several diseases including obesity-related metabolic disorders. This review summarizes the complex association between the gut microbiome and obesity-associated metabolic diseases and validates the role and mechanisms of ecological dysregulation in the gut in obesity-associated metabolic disorders. Therapies that could potentially alleviate obesity-associated metabolic diseases by modulating the gut microbiota are discussed.

A high percentage of people worldwide complain of sleep disturbances; however, the vast majority do not meet the diagnostic criteria for insomnia or other classic sleep disorders. Therefore, the ‘classical’ concept of poor sleep remains undetected, and patients stay ignored and unidentified. Also, poor sleep has been strongly associated with increased daytime function impairment, morbidity and mortality and is considered a risk factor for developing mental disorders. Poor sleep is the individual experience of insufficient restorative sleep and/or sleep satisfaction in adults who do not fulfil the criteria for sleep disorders. This article provides a review on the impact of poor sleep on a healthy life within the multidimensional concept of sleep health, including the COVID-19-affected period. We propose a wide definition of poor sleep and the key characteristics of poor sleepers and tools for (self) detection. We discuss sleep assessment methods that combine the ability to capture the subjective perception of the sleep experience and measure objective sleep parameters. We then report selected strategies to improve sleep health, focusing on healthy sleep habits, cognitive behavioural therapy, diet, exercise, food supplements and other sleep aids. Considering the current megalopolis way of life, young people are following a 24/24 hours 7 days/week rhythm of life, with increased exposure to noise and light pollution, night-shift work, higher commute time, increased global temperature and overuse of smartphones and screens. Therefore, there is an urgent need for increasing awareness of poor sleep and stimulating educational efforts targeted at poor sleepers and primary care specialists.

IntroductionCorneal endothelial transplantation accounts for most of corneal transplantation for treating corneal diseases, however severe shortage of corneal donors is the biggest obstacle. In our previous study, we differentiated human skin-derived precursors (SKPs) into corneal endothelial cell (CEC)-like cells with a co-culture system. In this study, we aimed to investigate cell differentiation molecular mechanism and evaluate the function of CEC-like cells by developing tissue-engineered corneas in order to improve cell production efficiency and provide basic research for clinical transformation.MethodsWe performed transcriptome sequencing of SKPs and CEC-like cells. Further, we focused on the possible enriching pathways, including PI3K/Akt, MAPK/Erk, WNT/β-catenin, and important transcription factors Pitx2 and Foxc1. The PI3K and β-catenin inhibitors were also added to the culture system to observe the differentiation alteration. We developed a graft for a tissue-engineered cornea (TEC) using CEC-like cells and acellular porcine cornea matrix scaffold. The tissue-engineered corneas were transplanted into rabbits via penetrating keratoplasty.ResultsThe PI3K/Akt, MAPK/Erk, and WNT/β-catenin pathways play important roles during the differentiation of SKPs into CEC-like cells. Crosstalk existed between the PI3K/Akt and MAPK/Erk pathways. The PI3K/Akt and WNT/β-catenin pathways were connected. Pitx2 and Foxc1 were subject to temporal and spatial controls of the WNT/β-catenin pathway. The inhibition of the PI3K/Akt and WNT/β-catenin pathways both prevented cell differentiation. CEC-like cells grew well on the acellular porcine cornea matrix scaffold, and the tissue-engineered corneal graft performed well after transplantation into rabbits.ConclusionWe provide experimental basis for CEC-like cell industrial production and drive the cells to be clinically applied in cellular replacement therapy or alternative graft substitution for treating corneal diseases in the future.

Vibrio harveyi is a major pathogen in yellow drum (Nibea albiflora) aquaculture, causing significant mortality and economic losses. In this study, using the latest assembled reference genome of yellow drum by our laboratory, we conducted genome-wide association study (GWAS) analysis on 345 individuals (197 susceptible and 148 resistant). The analysis revealed 24 significant single nucleotide polymorphisms (SNPs) on chromosome 24 within a 217 Kb region. The estimated heritability for all genome-wide SNPs was 0.3578, while the heritability for the 24 significant SNPs was 0.0710. Four candidate genes were identified within this region: Suppressor of Cytokine Signaling 1 (SOCS1), C-type Lectin Domain Family 16A (CLEC16A), Major Histocompatibility Complex Class II Transactivator (CIITA), and Protein Kinase Cβ (PRKCB). Subsequently, expression quantitative trait loci (eQTL) analysis was performed on transcriptome sequencing data from spleen tissues of 78 individuals from the resistant group. On average, each chromosome harbored 49,396 eQTL loci, with an average of one SNP regulate 1.3 genes. Notably, 22.79% of SNPs showed significant associations with the expression of one or more genes. By integrating GWAS and eQTL data, seven SNPs were identified to have significant associations with regulated genes in the eQTL results. All seven SNPs were found to target the same gene, namely Zinc Finger Protein yd23210 in yellow drum. This study provides genetic markers and candidate genes for molecular breeding of yellow drum against V. harveyi infection, offering insights into the molecular immune mechanisms and potential pathways for genetic improvement of disease resistance traits in this species.

Magnetic graphene (Fe3O4@G) was synthesized as a magnetic solid phase extractor for the extraction and enrichment of organophosphorus pesticides in green tea by chemical coprecipitation method. Based on this, ultra high performance liquid chromatography tandem mass spectrometry method was developed for the determination of 19 organophosphorus pesticide residues in green tea. 40 mg adsorbent and 4 g sodium chloride were used in this experiment with the pH of sample solution at 7 for 20 min extraction time, 3.0 mL acetone desorption. The result showed that the prepared Fe3O4@G material had good stability and reusability with the linear correlation coefficients greater than 0.999 in the range of 5～500 μg/L. The limits of detection (LOD) and the limits of quantitation (LOQ) were 5.0～6.0 μg/kg and 15.0～20.0 μg/kg, respectively. The recoveries were between 61.2% and 94.9% with the relative standard deviations (RSD, n=6) in the range of 2.6%～10.2% when the samples were labeled at 20.0, 40.0 and 200.0 μg/kg. This method was safe and economy with a wide application range, easier control of pretreatment, less amount of organic solvent and reusable materials, which has a good application prospect in the enrichment and separation of pesticides in tea by the magnetic dispersion solid phase extraction technology.

Abstract Background There is a great challenge to sedation for infants with cleft lip and palate undergoing CT scan, because there is the younger age and no consensus on the type, dosage, and route of drug administration. Objective This study aimed to evaluate the efficacy of intranasal administration of dexmedetomidine combined with midazolam as a sedative option for infants with cleft lip and palate under imaging procedures. Methods Infants scheduled for cleft lip and palate repair surgery were randomly assigned to the IND group (intranasal dexmedetomidine 2 µg/kg alone) and the INDM group (intranasal dexmedetomidine 2 µg/kg combined with midazolam 0.05 mg/kg). The primary outcome was the proportion of infants underwent successful computed tomography (CT) scans under intranasal sedation. The secondary outcomes included onset time and duration of sedation, recovery time, Ramsay sedation scale, hemodynamic parameters during sedation, and adverse events. Data analyses involved the unpaired t-test, the repeated-measures analysis of variance test, and the continuity correction χ2 test. Results One hundred five infants were included in the analysis. The proportion of infants underwent successful CT scans under sedation was significantly greater in the INDM group than in the IND group (47 [95.9%] vs. 45 [80.4%], p = 0.016). Additionally, the INDM group had a shorter onset time and a longer duration of sedation statistically (12 [8.5, 17] min vs. 16 [12, 20] min, p = 0.001; 80 [63.6, 92.5] min vs. 68.5 [38, 89] min, p = 0.014, respectively), and their recovery time was significantly longer (43 [30, 59.5] min vs. 31.5 [20.5, 53.5] min, p = 0.006). The difference in Ramsay sedation scale values 20 min after administration was statistically significant between the groups. No statistically significant difference was found between the groups in changes in heart rate and respiratory rate. Conclusion Intranasal administration of dexmedetomidine in combination with midazolam resulted in higher sedation success in comparison with sole dexmedetomidine. However, it has a relatively prolonged duration of sedation and recovery time. Trial registration ChiCTR2100049122, Clinical trial first registration date: 21/07/2021.

Abstract The central nervous system (CNS) maintains homeostasis with its surrounding environment by restricting the ingress of large hydrophilic molecules, immune cells, pathogens, and other external harmful substances to the brain. This function relies heavily on the blood-cerebrospinal fluid (B-CSF) and blood-brain barrier (BBB). Although considerable research has examined the structure and function of the BBB, the B-CSF barrier has received little attention. Therapies for disorders associated with the central nervous system have the potential to benefit from targeting the B-CSF barrier to enhance medication penetration into the brain. In this study, we synthesized a nanoprobe ANG-PEG-UCNP capable of crossing the B-CSF barrier with high targeting specificity using a hydrocephalus model for noninvasive magnetic resonance ventriculography to understand the mechanism by which the CSF barrier may be crossed and identify therapeutic targets of CNS diseases. This magnetic resonance nanoprobe ANG-PEG-UCNP holds promising potential as a safe and effective means for accurately defining the ventricular anatomy and correctly locating sites of CSF obstruction.

This study investigates the alignment between the education of big data professionals in universities and the requirements of the labor market. Through the examination of data extracted from Chinese job advertisements, this study explores the multifaceted skill set sought by employers in the big data domain, with an emphasis on achieving a harmonious equilibrium between technical (“hard”) and soft skills. Employers expect a high level of proficiency in data processing and analysis coupled with capabilities in teamwork, communication, and leadership. The dynamic nature of big data, characterized by rapid technological advancements, underscores the importance of continuous learning. The demand for big data talent has various roles, including big data scientists, engineers, and workers, thus contributing to a diverse and competitive job market. Recognizing the potential gap between university education and the dynamic requirements of the job market, this study advocates the integration of practical skills with theoretical knowledge. It proposes that universities assert their autonomy in curriculum design while concurrently engaging with alumni and industry partners to afford students’ real-world experiences. In conclusion, this study underscores the significance of cultivating a sustainable talent development system. This encourages a curriculum that adeptly balances timeliness and innovation, producing graduates armed with contemporary tools and a comprehensive understanding of data science principles. This approach fosters versatile professionals capable of effectively addressing the myriad challenges within the diverse landscapes of the industry.

Purpose: Murine models of pancreatic cancer with damp-heat syndrome were established based on two methods to explore the differences in the composition of intestinal flora and to seek characteristic genera with potential for model evaluation. Methods: In our study, thirty-four C57BL/6J male mice were randomly divided into a control group (Con), a model group (Mod), a classic damp-heat syndrome group (CDHS), and a climate-chamber group (CC). CDHS and CC groups were fed with a high-fat diet and glucose water, while the CDHS group was given 2.4 g/kg alcohol by gavage for 10 days, and the CC group was placed in a climatic chamber with a set temperature of (32 ± 1) °C and humidity of (92 ± 2)% for 10 days. The Mod group, CDHS group, and CC group underwent tumor-building experiments on day 11. Tumorigenicity was then assessed twice a week. After 4 weeks, feces, colon tissue, and tumor tissue were taken from the mice and were tested, and the mice were euthanized afterwards. Results: Mice in the CDHS and CC groups showed symptoms similar to the clinical damp-heat syndrome observed in traditional Chinese medicine (TCM), and exhibited a worse general condition and more rapid tumor growth trend than those in the Mod group. The pathological examination indicated that inflammation was prevalent in the CDHS and CC groups. Both groups had a disrupted intestinal barrier and an overgrowth of pathogenic bacteria such as c_Gammaproteobacteria, o_Enterobacteriales, and g_Bacteroides. Their microbiota composition showed greater diversity. Conclusions: Intestinal flora may have a promising future in the discovery of indicators for evaluating a model of damp-heat syndrome in pancreatic cancer.

Telomeres, repetitive sequences located at the extremities of chromosomes, play a pivotal role in sustaining chromosomal stability. Telomerase is a complex enzyme that can elongate telomeres by appending telomeric repeats to chromosome ends and acts as a critical factor in telomere dynamics. The gradual shortening of telomeres over time is a hallmark of cellular senescence and cellular death. Notably, telomere shortening appears to result from the complex interplay of two primary mechanisms: telomere shelterin complexes and telomerase activity. The intricate interplay of genetic, environmental, and lifestyle influences can perturb telomere replication, incite oxidative stress damage, and modulate telomerase activity, collectively resulting in shifts in telomere length. This age-related process of telomere shortening plays a considerable role in various chronic inflammatory and oxidative stress conditions, including cancer, cardiovascular disease, and rheumatic disease. Existing evidence has shown that abnormal telomere shortening or telomerase activity abnormalities are present in the pathophysiological processes of most rheumatic diseases, including different disease stages and cell types. The impact of telomere shortening on rheumatic diseases is multifaceted. This review summarizes the current understanding of the link between telomere length and rheumatic diseases in clinical patients and examines probable telomere shortening in peripheral blood mononuclear cells and histiocytes. Therefore, understanding the intricate interaction between telomere shortening and various rheumatic diseases will help in designing personalized treatment and control measures for rheumatic disease.

The existing approaches for the design of tourist areas often lead to limited flexibility in project implementation. To realize a more flexible approach, in this study, we formulated a model for planning and designing tourist areas at the local level. Moreover, specific tools for analyzing tourist areas and ensuring sustainable development under changing conditions were developed. This study was conducted in two tourist regions, Biryuzovaya Katun tourist complex and Belokurikha destination (including Belokurikha City with Belokurikha 2 Gornaya tourist complex and surrounding areas), in the Altay Mountains. We employed the recreation opportunity spectrum and proposed a system-integrated programming approach for the design of tourist areas at the destination and site levels. The key of this approach was the collection and analysis of current spatial data, including the spatial distribution of attractions and visitor flows. We constructed heat maps using video recording and unmanned aerial vehicle (UAV) observation data. Moreover, we analyzed the video stream using an image-analyzing framework You Only Look Once (YOLO) v5 software. The heat map of visitor flows based on video recording data in the Andreevskaya Sloboda museum of Belokurikha 2 Gornaya tourist complex allowed us to highlight the most attractive sites in this area and classify them into one of three types: points of functional concentration, points of transitional concentration, and points of attractions. The heat maps in Biryuzovaya Katun tourist complex, created using UAV observation data, allowed us to determine the spatiotemporal patterns of visitor flows and tourists’ preferences throughout the day within four time intervals: 09:00–12:00, 13:00–14:00, 14:00–15:00, and 16:00–18:00 (LST). The maximum visitor flow density occurred from 16:00 to 18:00 in the beach area of the artificial lake. A comparison between the visitor-concentrated sites and the current facilities provided insights into the demand for attractions and facilities and the lacking areas. Heat maps are useful in analyzing the land use at the site level, while zoning based on the recreation opportunity spectrum can be used to design tourist areas at the destination level. The proposed methods for analyzing the use of tourist areas contribute to the development of adaptive tourism design.

Summary: The global burden of diseases and injuries poses complex and pressing challenges. This study analyzed 369 diseases and injuries attributed to 84 risk factors globally from 1990 to 2019, projecting trends to 2040. In 2019, global risks caused 35 million deaths. Non-communicable diseases were responsible for 8.2 million deaths, primarily from air pollution (5.5 million). Cardiovascular disease from air pollution had a high age-standardized disability-adjusted life year rate (1,073.40). Communicable, maternal, neonatal, and nutritional diseases caused 1.4 million deaths, mainly due to unsafe water and sanitation. Occupational risks resulted in 184,269 transport-related deaths. Behavioral risks caused 21.6 million deaths, with dietary factors causing 6.9 million cardiovascular deaths. Diabetes linked to sugar-sweetened beverages showed significant growth (1990–2019). Metabolic risks led to 18.6 million deaths. Projections to 2040 indicated persistent challenges, emphasizing the urgent need for targeted interventions and policies to alleviate the global burden of diseases and injuries.

Abstract 3D printing can produce intuitive, precise, and personalized anatomical models, providing invaluable support for precision medicine, particularly in areas like surgical training and preoperative planning. However, conventional 3D printed models are often significantly more rigid than human organs and cannot undergo repetitive resection, which severely restricts their clinical value. Here we report the stereolithographic 3D printing of personalized liver models based on physically crosslinked self-healing elastomers with liver-like softness. Benefiting from the short printing time, the highly individualized models can be fabricated immediately following enhanced CT examination. Leveraging the high-efficiency self-healing performance, these models support repetitive resection for optimal trace through a trial-and-error approach. At the preliminary explorative clinical trial (NCT06006338), a total of 5 participants are included for preoperative planning. The primary outcomes indicate that the negative surgery margins are achieved and the unforeseen injuries of vital vascular structures are avoided. The 3D printing of liver models can enhance the safety of hepatic surgery, demonstrating promising application value in clinical practice.

Abstract Introduction Tofacitinib, a selective inhibitor of JAK1 and/or JAK3, is considered to alleviate the pulmonary condition of primary Sjögren’s syndrome (pSS)-associated interstitial lung disease (ILD) through its anti-inflammatory and antifibrotic effects. Methods and analysis This is a single-center, prospective, randomized, open-label trial. The trial will compare a 52-week course of oral tofacitinib with traditional therapy cyclophosphamide (CYC) combined with azathioprine (AZA) in the treatment of pSS-ILD. A total of 120 patients will be randomly assigned into two treatment groups with a 1:1 ratio and followed for 52 weeks from the first dose. The primary endpoint of the study is the increase of forced vital capacity (FVC) at 52 weeks. Secondary endpoints include high-resolution computed tomography (HRCT), diffusion capacity for carbon monoxide of the lung (DLCO), the Mahler dyspnea index, the health-related quality of life (HARQoL) score, the cough symptom score, EULAR Sjögren's syndrome disease activity index (ESSDAI), and safety. Discussion This study will be the first randomized controlled trial to investigate tofacitinib compared to the traditional regimen of CYC in combination with AZA in the treatment of pSS-ILD, which will provide data on efficacy and safety and further elucidate the role of the JAK-STAT signaling pathway in the development of pSS-ILD. Ethics and dissemination Before starting the experiment, the research proposal, informed consent (ICF) and relevant documents in accordance with the ethical principles of the Helsinki Declaration and the relevant requirements of the local GCP rules for ethical approval shall be submitted to the ethics committee of the hospital. The ethical approval of this study is reviewed by the Ethics Committee of Tongji Hospital and the ethical approval number is 2021-LCYJ-007. When the experiment is completed, the results will also be disseminated to patients and the public through publishing papers in international medical journals. Trial registration The study was registered on the Chinese Clinical Trial Registry, www.chictr.org.cn ; ID ChiCTR2000031389.

The transcription factor activating protein 2α (AP2α) is a nuclear transcription factor that specifically binds to DNA and is involved in the regulation of animal embryonic development, cell growth, apoptosis, tumorigenesis, immunity, and other biological processes. In our previous study, the transcription factor AP2α was discovered as a key disease-resistance candidate gene in the yellow drum, Nibea albiflora, in response to a Vibrio harveyi infection through genome-wide association analysis. In the present study, the AP2α gene, which encodes a protein of 424 amino acids, was cloned from a yellow drum. The N-terminal is a trans-activation domain rich in proline and glutamine (P/Q-rich domain), and the middle is a central basic structure (central basic region), which is a highly conserved helix-span-helix motif responsible for DNA binding and protein dimerization. Multiple alignments of amino acid sequences showed that AP2α was highly conserved, with a homology of more than 84.63% among the detected fish, amphibians, birds, and mammals. Quantitative RT-PCR demonstrated that AP2α was widely distributed in the nine tested tissues, with the highest expression in the blood. Moreover, its transcription was significantly activated in the liver, spleen, and head kidney by V. harveyi infection, especially in the liver wherein the transcript level of AP2α reached a peak at 24 h post infection. Subcellular localization by constructing the recombinant eukaryotic expression plasmid pGEFP-AP2α and transfection into HEK293T cells revealed that AP2α was localized in the nucleus. In addition, the soluble GST-AP2α fusion protein was expressed in Escherichia coli BL21. These results demonstrate that AP2α plays an important role in the immune response against V. harveyi in N. albiflora. We provide new insights into the role of AP2α in the innate immunity of teleost fishes and provide a basis for studies on immune mechanisms and disease-resistant breeding in N. albiflora and other marine fish.

Landscape aesthetic quality (LAQ) evaluation is vital in territorial spatial planning. It helps to achieve the rational development and protection of territorial space and ensures the harmonious coexistence of developments and the ecological environment. Based on mapping and quantification, this paper took LAQ evaluation as the object, established a methodological framework for large-scale natural LAQ evaluation, excavated and identified key areas with outstanding landscape aesthetics service supply capabilities, and supported regional landscape planning and protection management. This paper took the Hengduan Mountains in China as an example to evaluate and identify the spatial distribution of the LAQ in mountainous areas. The results showed that the high-value LAQ areas are located east and south of the Hengduan Mountains, where high-quality natural landscapes are concentrated and have significant potential for establishing national parks. The evaluation results of the LAQ can provide a good reference for the spatial identification of future national parks in the Hengduan Mountains. Moreover, our research can provide a scientific basis for large-scale landscape spatial planning and decision-making for the classified protection and rational utilization of landscape resources and other mountain ecosystems.

Abstract Purpose In recent decades, diverse nomograms have been proposed to predict extraprostatic extension (EPE) in prostate cancer (PCa). We aimed to systematically evaluate the accuracy of MRI-inclusive nomograms and traditional clinical nomograms in predicting EPE in PCa. The purpose of this meta-analysis is to provide baseline summative and comparative estimates for future study designs. Materials and methods The PubMed, Embase, and Cochrane databases were searched up to May 17, 2023, to identify studies on prediction nomograms for EPE of PCa. The risk of bias in studies was assessed by using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). Summary estimates of sensitivity and specificity were obtained with bivariate random-effects model. Heterogeneity was investigated through meta-regression and subgroup analysis. Results Forty-eight studies with a total of 57 contingency tables and 20,395 patients were included. No significant publication bias was observed for either the MRI-inclusive nomograms or clinical nomograms. For MRI-inclusive nomograms predicting EPE, the pooled AUC of validation cohorts was 0.80 (95% CI: 0.76, 0.83). For traditional clinical nomograms predicting EPE, the pooled AUCs of the Partin table and Memorial Sloan Kettering Cancer Center (MSKCC) nomogram were 0.72 (95% CI: 0.68, 0.76) and 0.79 (95% CI: 0.75, 0.82), respectively. Conclusion Preoperative risk stratification is essential for PCa patients; both MRI-inclusive nomograms and traditional clinical nomograms had moderate diagnostic performance for predicting EPE in PCa. This study provides baseline comparative values for EPE prediction for future studies which is useful for evaluating preoperative risk stratification in PCa patients. Critical relevance statement This meta-analysis firstly evaluated the diagnostic performance of preoperative MRI-inclusive nomograms and clinical nomograms for predicting extraprostatic extension (EPE) in prostate cancer (PCa) (moderate AUCs: 0.72–0.80). We provide baseline estimates for EPE prediction, these findings will be useful in assessing preoperative risk stratification of PCa patients. Key points • MRI-inclusive nomograms and traditional clinical nomograms had moderate AUCs (0.72–0.80) for predicting EPE. • MRI combined clinical nomogram may improve diagnostic accuracy of MRI alone for EPE prediction. • MSKCC nomogram had a higher specificity than Partin table for predicting EPE. • This meta-analysis provided baseline and comparative estimates of nomograms for EPE prediction for future studies. Graphical Abstract

Abstract Background Sepsis-induced myocardial injury (SIMI) is a common organ dysfunction and is associated with higher mortality in patients with sepsis. We aim to construct a nomogram prediction model to assess the 28-day mortality in patients with SIMI. . Method We retrospectively extracted data from Medical Information Mart for Intensive Care (MIMIC-IV) open-source clinical database. SIMI was defined by Troponin T (higher than the 99th percentile of upper reference limit value) and patients with cardiovascular disease were excluded. A prediction model was constructed in the training cohort by backward stepwise Cox proportional hazards regression model. The concordance index (C-index), area under the receiver operating characteristics curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), calibration plotting and decision-curve analysis (DCA) were used to evaluate the nomogram. Results 1312 patients with sepsis were included in this study and 1037 (79%) of them presented with SIMI. The multivariate Cox regression analysis in all septic patients revealed that SIMI was independently associated with 28-day mortality of septic patients. The risk factors of diabetes, Apache II score, mechanical ventilation, vasoactive support, Troponin T and creatinine were included in the model and a nomogram was constructed based on the model. The C-index, AUC, NRI, IDI, calibration plotting and DCA showed that the performance of the nomogram was better than the single SOFA score and Troponin T. Conclusion SIMI is related to the 28-day mortality of septic patients. The nomogram is a well-performed tool to predict accurately the 28-day mortality in patients with SIMI.

Sjögren’s syndrome (SjS) is a systemic, highly diverse, and chronic autoimmune disease with a significant global prevalence. It is a complex condition that requires careful management and monitoring. Recent research indicates that epigenetic mechanisms contribute to the pathophysiology of SjS by modulating gene expression and genome stability. DNA methylation, a form of epigenetic modification, is the fundamental mechanism that modifies the expression of various genes by modifying the transcriptional availability of regulatory regions within the genome. In general, adding a methyl group to DNA is linked with the inhibition of genes because it changes the chromatin structure. DNA methylation changes the fate of multiple immune cells, such as it leads to the transition of naïve lymphocytes to effector lymphocytes. A lack of central epigenetic enzymes frequently results in abnormal immune activation. Alterations in epigenetic modifications within immune cells or salivary gland epithelial cells are frequently detected during the pathogenesis of SjS, representing a robust association with autoimmune responses. The analysis of genome methylation is a beneficial tool for establishing connections between epigenetic changes within different cell types and their association with SjS. In various studies related to SjS, most differentially methylated regions are in the human leukocyte antigen (HLA) locus. Notably, the demethylation of various sites in the genome is often observed in SjS patients. The most strongly linked differentially methylated regions in SjS patients are found within genes regulated by type I interferon. This demethylation process is partly related to B-cell infiltration and disease progression. In addition, DNA demethylation of the runt-related transcription factor (RUNX1) gene, lymphotoxin-α (LTA), and myxovirus resistance protein A (MxA) is associated with SjS. It may assist the early diagnosis of SjS by serving as a potential biomarker. Therefore, this review offers a detailed insight into the function of DNA methylation in SjS and helps researchers to identify potential biomarkers in diagnosis, prognosis, and therapeutic targets.

This study examined the determinants of sustainable development within national parks and ecotourism settlements across both Tajik National Park and Fann Mountains areas in the Republic of Tajikistan, as well as Zaamin National Park and Hisar State Reserve in the Republic of Uzbekistan. Primary data were gathered from surveys conducted in four distinct settlements across these nations, and subsequent analyses employed descriptive statistics, factor analysis, and Analysis of Variance (ANOVA). The levels of sustainable development varied among the four settlements. The following factors were the most important for sustainable development: active engagement from local authorities and the population, high levels of tourist satisfaction, and attractive sights. The findings of this study have important implications for policymakers and stakeholders involved in the development of national parks and ecotourism settlements in Tajikistan and Uzbekistan. The findings suggest that the following strategies are most effective in promoting sustainable development: encouraging active engagement from local authorities and the population, providing high-quality services to tourists, and protecting the environment.

Arid regions hold a prominent position as global tourist destination. However, their ecological fragility and sensitivity to economic and social factors make them more susceptible to various disruptive elements, thereby exacerbating the instability of the tourism socio-ecological system. Consequently, there has been a growing focus on tourism socio-ecological system resilience (TSESR) in arid regions. This study has developed a scientific and universally applicable assessment framework to evaluate TSESR in arid regions, considering the system's process mechanisms and dimensions. The framework encompasses four key domains: resistance, recovery, adaptation, and renewal, further divided into twelve criterion layers. This study conducted a case study in 14 prefecture-level units in Xinjiang, China, from 2010 to 2020. An improved TOPSIS model, Gini coefficient, Kernel density estimation, and Obstacle degree model were employed to investigate the levels, spatiotemporal variations, and obstacle factors of TSESR. The research findings indicate that during the study period, the resilience levels of the 14 prefecture-level cities exhibited an overall upward trend with fluctuations. There are notable spatial disparities, yet these disparities are diminishing. Furthermore, factors such as resource endowment, market potential, economic foundation, industrial environment, and human capital represented common obstacles, while unique regional impediments also existed. The TSESR assessment index system can scientifically and comprehensively evaluate resilience levels, offering an adaptive indicators framework for arid regions. It promotes the development of a resilient tourism socio-ecological system, thereby achieving sustainable tourism development.

This study addresses the critical need for regional tourism integration and sustainable development by identifying cooperation opportunities among tourist attractions within a region. We introduce a novel methodology that combines association rule mining with complex network analysis and utilizes search index data as a dynamic and contemporary data source to reveal cooperative patterns among tourist attractions. Our approach delineates a potential cooperative network within the destination ecosystem, categorizing tourist attractions into three distinct communities: core, intermediary, and periphery. These communities correspond to high, medium, and low tourist demand scales, respectively. The study uncovers a self-organizing network structure, driven by congruences in internal tourist demand and variances in external tourist experiences. Functionally, there is a directed continuum of cooperation prospects among these communities. The core community, characterized by significant tourist demand, acts as a catalyst, boosting demand for other attractions. The intermediary community, central in the network, links the core and periphery, enhancing cooperative ties and influence. Peripheral attractions, representing latent growth areas within the destination matrix, benefit from associations with the core and intermediary communities. Our findings provide vital insights into the dynamics, systemic characteristics, and fundamental mechanisms of potential cooperation networks among tourist attractions. They enable tourism management organizations to employ our analytical framework for real-time monitoring of tourism demand and flow trends. Additionally, the study guides the macro-control of tourism flows based on the tourism network, thereby improving the tourist experience and promoting coordinated development among inter-regional tourist attractions.

IntroductionPfeiffer syndrome is a rare genetic disorder characterized by craniosynostosis, broad thumbs and big toes, and partial syndactyly of the hands and feet. This case report presents the case of a girl diagnosed with type 2 Pfeiffer syndrome who experienced severe obstructive sleep apnea (OSA).Case reportThe patient had been using an oropharyngeal airway since the age of 4 months due to snoring and witnessed apnea during sleep. At 11 months old, she was referred to our sleep clinic because of growth limitation and gross motor ability issues. Polysomnography (PSG) showed severe obstructive hypopnea before any treatment, and revealed severe central sleep apnea with the oropharyngeal airway in place. Positive airway pressure (PAP) therapy was initiated, which improved both her sleep and gross motor ability.ConclusionThis case report emphasizes the importance of thorough sleep studies for diagnosing sleep and breathing disorders in Pfeiffer syndrome patients and highlights the effectiveness of PAP therapy in managing these conditions.

Abstract Background Ovarian cancer, particularly epithelial ovarian cancer (EOC), is the leading cause of cancer-related mortality among women. Our previous study revealed that high HMGB3 levels are associated with poor prognosis and lymph node metastasis in patients with high-grade serous ovarian carcinoma; however, the role of HMGB3 in EOC proliferation and metastasis remains unknown. Methods MTT, clonogenic, and EdU assays were used to assess cell proliferation. Transwell assays were performed to detect cell migration and invasion. Signaling pathways involved in HMGB3 function were identified by RNA sequencing (RNA-seq). MAPK/ERK signaling pathway protein levels were evaluated by western blot. Results HMGB3 knockdown inhibited ovarian cancer cell proliferation and metastasis, whereas HMGB3 overexpression facilitated these processes. RNA-seq showed that HMGB3 participates in regulating stem cell pluripotency and the MAPK signaling pathway. We further proved that HMGB3 promotes ovarian cancer stemness, proliferation, and metastasis through activating the MAPK/ERK signaling pathway. In addition, we demonstrated that HMGB3 promotes tumor growth in a xenograft model via MAPK/ERK signaling. Conclusions HMGB3 promotes ovarian cancer malignant phenotypes and stemness through the MAPK/ERK signaling pathway. Targeting HMGB3 is a promising strategy for ovarian cancer treatment that may improve the prognosis of women with this disease. Video Abstract

Sleep takes approximately 1/3 of a person’s lifetime; therefore, its quality profoundly affects learning, physical recovery, and metabolism. Clinically relevant human physiological data are collected using polysomnography, which is analyzed by sleep technologists to determine sleep stages. However, the manual method is prone to having a cumbersome workload due to a large amount of data analysis and different data formats. Simultaneously, manually analyzed results are influenced by doctors’ medical clinical experience, which may cause inconsistent diagnoses. Recently, with the development of artificial intelligence, computer science, other technologies, and their interdisciplinarity, a series of typical achievements have been accomplished in intelligent diagnosis, laying the foundation for medical artificial intelligence in the sleep medicine field. In sleep research, realizing automatic sleep signal analysis and recognition assists doctors in diagnosis and reduces their workload, thus having important clinical significance and application value. Although deep neural networks are becoming popular for automatic sleep stage classification with supervised learning, large-scale, labeled datasets remain difficult to acquire. Learning from raw polysomnography signals and derived time-frequency image representations has been an interesting solution. However, extracting features from only a single dimension leads to inadequate feature extraction and, thus, limited accuracy. Hence, this paper aims to learn multi-view representations for physiological signals with semi-supervised learning. Specifically, we make the following contributions: (1) We propose a multi-view, hybrid neural network model containing a multichannel view time-frequency domain feature extraction mechanism, an attention mechanism, and a feature fusion module. Among these aspects, the multichannel view time-frequency domain mechanism extracts time domain and frequency domain signal features to achieve multi-view feature extraction. The attention mechanism module enhances salience features and achieves interclass feature extraction in the frequency domain. The feature fusion module fuses and classifies the above features. (2) A semi-supervised learning strategy is used to learn unlabeled electroencephalogram (EEG) data, which solves the problem of sleep data underutilization due to insufficient labeling of EEG signals in clinical practice. (3) Extensive experiments conducted on sleep stage classification demonstrate state-of-the-art performance compared with supervised learning and a semi-supervised baseline. Experimental results on three public databases (Sleep−EDF, DOD−H, and DOD−O) and one private database show that our semi-supervised method achieves accuracies of 81.6%, 81.5%, 79.2%, and 75.4%. The results show that our proposed model is comparable to a fully supervised sleep staging model while substantially reducing the technician’s workload in data labeling.

Abstract Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

Recreational ecosystem services (RESs) are the subset of ecosystem services (ESs) that contribute to human society through recreation, recreation opportunities, and experiences. Existing RESs mostly focus on a single recreational landscape; alternatively, when mapping RESs, multiple types of landscapes are often drawn together, ignoring the differences in recreational landscape (RL) types and affecting the accuracy of the mapping. At the same time, quantifying the monetary value of RESs has been a challenge due to the lack of market substitutes that can approximate the prices associated with these non-excludable goods. This study used the MaxENT model, then classified and used recreational resource POI data, combined with environmental data on the existence or generation of different types of RL, mapped RES from the perspective of RL supply, and conducted monetization and evaluations of RL. The results show that the models’ AUC values are all greater than 0.7, and the distribution of RL supply can be drawn relatively accurately. The Qinghai–Tibet Plateau National Park Group (QTPNPG) has the largest high-quality geomorphic recreational landscape (69,081.02 km2), followed by a high-quality biological recreational landscape (59,348.65 km2) and a high-quality hydrological recreational landscape (33,251.20 km2). The national parks in the eastern part of the Qinghai–Tibet Plateau have a larger proportion of high-value areas of the RES. The total monetary value of the RES is CNY 8.323 billion, and the average monetary value of RES per unit area is CNY 20,200/km2. Our study optimizes the method of mapping RESs and provides a new way of quantifying the monetary value of RESs. The results can provide a reference for the recreational development of THE QTPNPG and its contribution to regional sustainable development.

The glycosylation levels of proteins in cancer cells are closely related to cancer invasion and migration. CD44 is a transmembrane glycoprotein that is significantly overexpressed in a variety of tumor cells and has been proven to promote the migration and motility of cancer cells, but the effect of its N-glycosylation modification on CD44 protein function in tumors is less studied. Here, we investigated the effect of six N-glycan chains (N25/57/100/110/120/255) on CD44s localization, function and stability in hepatocarcinoma cells. When the six sites were mutated, we found that CD44s lost its membrane localization in Huh7 and MHCC-97H cells. On this basis, we identified three glycosylation sites on CD44s (N57, N100 and N110) that played key roles in intracellular localization. When N57, N100 and N110 were mutated together, CD44 localized to the cytoplasm, while another three-site mutant (N25/N120/N255) was still anchored to the membrane. In addition, the ability of CD44-N57Q/N100Q/N110Q to promote the metastasis and invasion of Huh7 and 97H cells was weakened compared with that of CD44-N25Q/N120Q/N255Q. Furthermore, CD44-N57Q/N100Q/N110Q accumulated abnormally in the ER, and a high level of the ER stress (ERS) marker BiP was detected at the same time compared with wild-type CD44. When the lysosome inhibitor CQ was added, the content of mutant protein that triggered ERS significantly increased, which indicated that the degradation mode of CD44-N57Q/N100Q/N110Q after ERS was mainly through the lysosomal pathway (ERLAD). The results revealed that the N-glycosylation sites N57, N100 and N110 mutated on CD44s affected its function and degraded it by lysosomes after triggering ERS. These findings provide data for new studies on ER-related degradation, further promote the study of the glycan chain function of CD44 and furnish new ideas for the treatment of liver cancer metastasis.

Objective To analyse the trends of diseases burden attributed to high body mass index (BMI), including overweight and obesity, in Asia from 1990 to 2019.Design Observational study.Setting The data of 45 countries and regions in Asia were obtained from the Global Burden of Disease Study 2019 database.Main outcome measures Numbers, age-standardised rate (ASR) of deaths and disability-adjusted life years (DALYs), and the corresponding estimated annual percentage changes (EAPCs), attributable to high BMI in Asia from 1990 to 2019, were analysed by regions, genders and age. We also analysed changes in the causes of deaths and DALYs that are attributable to high BMI over this period.Results In 2019, all causes deaths attributable to high BMI in Asia were 2 329 503, with increases by 265% compared with 1990. Over three decades, DALYs related to high BMI have increased by 268%. The ASRs of deaths and DALYs in Asia both showed continuous upward trends during this period (EAPC 1.39; 95% certainty interval [95% CI] 1.35 to 1.43 for deaths; EAPC 1.8; 95% CI 1.76 to 1.84 for DALYs), while both were declined in high-income areas (EAPC −2.03 and −1.26). By geographical regions, disease burden in Central Asia and West Asia have been fluctuating at high levels, but high-income Asia Pacific showed decreasing trends of ASR of deaths (EAPC −2.03) and DALYs (EAPC −1.26). Over this period, disease burden in Asia was changing from women to men, and tends to ageing. In addition, diabetes were the diseases most affected by high BMI, and cancer burden was high in middle-aged and elderly people.Conclusions The disease burden attributed to high BMI in Asia has experienced great changes. It is necessary to promote the prevention of obesity and chronic diseases in a comprehensive manner, especially in low-income areas, men and elderly.

A method for simultaneous screening of 90 pesticide residues in blueberries by ultra-high pressure liquid chromatography high resolution mass spectrometry was developed. Target residues in blueberries were extracted by an improved QuEChERS protocol. Ultra-high pressure liquid chromatography coupled to quadrupole/orbitrap high-resolution mass spectrometry was employed for screening analysis with full mass scanning trigged data dependent fragment ion acquisition in positive and negative mode. The analytes were quantified by representative matrix-matched standard curve. The results showed that the optimized ratio of PSA vs C18 was 1:1 with amount of 150 mg respectively in the improved QuEChERS protocol. The limits of detection and limits of quantitation of the method were 0.1~18.7 μg/kg and 0.2~20.2 μg/kg as well. The linearities for 90 pesticides were fitted by regression calculation at the range of 0.005~0.1 mg/kg with determination coefficient R2≥0.992. With calibration of the representative matrix-matched standard curve, recoveries were calculated ranging from 50.1% to 130.9% and relative standard deviations were varied in the scope of 1.0%~14.9% at the three spiking levels of 0.01, 0.05 and 0.1 mg/kg. Five pesticides were detected in the real-life blueberry samples purchased in the market, evidencing the applicability of the developed method. The proposed approach is applicable for routine pesticide monitoring in blueberries with simple sample preparation, broad analyte coverage and powerful capability of quantification and qualification.

Temporal lobe epilepsy (TLE) is thought to be associated with neuronal hyperexcitability in the hippocampal-entorhinal cortical (EC) circuit. Due to the complexity of the hippocampal-EC network connections, the biophysical mechanisms of the different circuits in epilepsy generation and propagation are still not fully established. In this work, we propose a hippocampal-EC neuronal network model to explore the mechanism of epileptic generation. We demonstrate that enhanced excitability of pyramidal neurons in cornu ammonis 3 (CA3) can drive hippocampal-EC to produce a transition from background to seizure state and cause exaggerated phase-amplitude coupling (PAC) phenomenon of theta modulated high-frequency oscillations (HFO) in CA3, cornu ammonis 1 (CA1), dentate gyrus, and EC. Interestingly, PAC strength indirectly responds to the degree of CA3 pyramidal (PY) neuron hyperexcitability, suggesting that PAC can be used as a potential marker of seizures. Furthermore, we find that enhanced synaptic connectivity of mossy cells to granule cells and CA3 PY neurons drives the system to produce epileptic discharges. These two channels may play a key role in mossy fiber sprouting. In particular, the PAC phenomenon of delta-modulated HFO and theta-modulated HFO can be generated according to the different degrees of moss fiber sprouting. Finally, the results suggest that hyperexcitability of stellate cells in EC can lead to seizures, which supports the argument that EC can act as an independent source of seizures. Overall, these results highlight the key role of different circuits in seizures, providing a theoretical basis and new insights into the generation and propagation of TLE.

Abstract Background Compared with typical visceral fat deposits in obesity and metabolic syndrome, perirenal adipose tissue (PRAT) dysfunction is more closely linked to obesity-related chronic kidney disease (OB-CKD). The myokine irisin reportedly promotes positive outcomes in metabolic disease. This study investigated whether irisin could reduce urinary albumin excretion and demonstrate renoprotective effects through the regulation of PRAT function in obese mice. Methods C57BL/6 J mice received a high-fat diet (HFD) with or without concurrent administration of irisin. Glucose tolerance, plasma levels of free fatty acids, and urinary albumin excretion were assessed, along with renal morphology. The vascular endothelial growth factor and nitric oxide in glomeruli were also analyzed, in addition to PRAT function-associated proteins. Results Irisin administration significantly reduced the final body weight, fat mass, and free fatty acids, without reducing PRAT mass, in HFD mice. Furthermore, irisin decreased urinary albumin excretion and attenuated both renal fibrosis and lipid accumulation. Irisin administration led to increases in PRAT function-associated proteins, including sirtuin1, uncoupling protein-1, and heme-oxygenase-1. Ex vivo treatment of PRAT and glomeruli with irisin also restored PRAT function. Finally, irisin treatment restored the vascular endothelial growth factor–nitric oxide axis. Conclusions Irisin attenuated metabolic disorders and protected against OB-CKD by normalizing the PRAT–kidney axis. These results suggest that agents targeting PRAT activation might be useful for treatment of OB-CKD.

Abstract Physiological rapid eye movement (REM) sleep termination is vital for initiating non-REM (NREM) sleep or arousal, whereas the suppression of excessive REM sleep is promising in treating narcolepsy. However, the neuronal mechanisms controlling REM sleep termination and keeping sleep continuation remain largely unknown. Here, we reveal a key brainstem region of GABAergic neurons in the control of both physiological REM sleep and cataplexy. Using fiber photometry and optic tetrode recording, we characterized the dorsal part of the deep mesencephalic nucleus (dDpMe) GABAergic neurons as REM relatively inactive and two different firing patterns under spontaneous sleep–wake cycles. Next, we investigated the roles of dDpMe GABAergic neuronal circuits in brain state regulation using optogenetics, RNA interference technology, and celltype-specific lesion. Physiologically, dDpMe GABAergic neurons causally suppressed REM sleep and promoted NREM sleep through the sublaterodorsal nucleus and lateral hypothalamus. In-depth studies of neural circuits revealed that sublaterodorsal nucleus glutamatergic neurons were essential for REM sleep termination by dDpMe GABAergic neurons. In addition, dDpMe GABAergic neurons efficiently suppressed cataplexy in a rodent model. Our results demonstrated that dDpMe GABAergic neurons controlled REM sleep termination along with REM/NREM transitions and represented a novel potential target to treat narcolepsy.

Background: Patients with primary Sjögren’s syndrome (pSS) are at increased risk of cardiovascular morbidity as compared with the general population. Objectives: A retrospective study on 349 Chinese patients with pSS was conducted to identify potential risk factors for cardiovascular events and develop a cardiovascular risk nomogram. Design: This is a retrospective observational study. Methods: The study included 349 patients who were diagnosed with pSS at Tongji Hospital, School of Medicine, Tongji University, China from January 2010 to March 2022. The least absolute shrinkage and selection operator (LASSO) was used to select features for the cardiovascular risk model. The features selected in LASSO were used to build the cardiovascular risk model in a multivariate logistic regression analysis. C-index, receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis were used to assess the predictive model. Internal validation was performed by bootstrapping. Results: Sex, joint pain as an initial symptom, dry mouth, oral ulcers, dental caries, Raynaud’s phenomenon, fatigue, diabetes, elevated thyroid-stimulating hormone (TSH) level, and elevated systolic blood pressure were included in the nomogram for the prediction of cardiovascular risk. Our model had good discrimination (C-index: 0.824, 95% confidence interval: 0.712–0.936) and good calibration (C-index in the interval validation: 0.8). Decision curve analysis indicated that our nomogram demonstrated clinical usefulness for intervention in a cardiovascular disease possibility threshold of 3%. Conclusion: The cardiovascular risk nomogram incorporating sex, initial joint pain, dry mouth, oral ulcer, dental caries, Raynaud’s phenomenon, fatigue, diabetes, elevated TSH, and systolic blood pressure could be used in the prediction of cardiovascular risk in patients with pSS and the guidance of further treatment.

BackgroundFibroblast activation protein (FAP) is a cell-surface serine protease that has both dipeptidyl peptidase as well as endopeptidase activities and could cleave substrates at post-proline bond. Previous findings showed that FAP was hard to be detected in normal tissues but significantly up-regulated in remodeling sites like fibrosis, atherosclerosis, arthritis and embryonic tissues. Though increasing evidence has demonstrated the importance of FAP in cancer progression, no multifactorial analysis has been developed to investigate its function in gastrointestinal cancers until now.MethodsBy comprehensive use of datasets from The Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), scTIME Portal and Human Protein Atlas (HPA), we evaluated the carcinogenesis potential of FAP in gastrointestinal cancers, analyzing the correlation between FAP and poor outcomes, immunology in liver, colon, pancreas as well as stomach cancers. Then liver cancer was selected as example to experimentally validate the pro-tumor and immune regulative role of FAP in gastrointestinal cancers.ResultsFAP was abundantly expressed in gastrointestinal cancers, such as LIHC, COAD, PAAD and STAD. Functional analysis indicated that the highly-expressed FAP in these cancers could affect extracellular matrix organization process and interacted with genes like COL1A1, COL1A2, COL3A1 and POSTN. In addition, it was also observed that FAP was positively correlated to M2 macrophages infiltration across these cancers. To verify these findings in vitro, we used LIHC as example and over-expressed FAP in human hepatic stellate LX2 cells, a main cell type that produce FAP in tumor tissues, and then investigate its role on LIHC cells as well as macrophages. Results showed that the medium from FAP-over-expressed LX2 cells could significantly promote the motility of MHCC97H and SK-Hep1 LIHC cells, increase the invasion of THP-1 macrophages and induce them into pro-tumor M2 phenotype.ConclusionIn summary, we employed bioinformatic tools and experiments to perform a comprehensive analysis about FAP. Up-regulation of FAP in gastrointestinal cancers was primarily expressed in fibroblasts and contributes to tumor cells motility, macrophages infiltration and M2 polarization, revealing the multifactorial role of FAP in gastrointestinal cancers progression.

SubjectiveSleep-disordered breathing (SDB) is highly prevalent in polio survivors. Obstructive sleep apnea (OSA) is the most frequent type. Full polysomnography (PSG) is recommended for OSA diagnosis in patients with comorbidities by current practice guidelines, but it is not always accessible. The purpose of this study was to evaluate whether type 3 portable monitor (PM) or type 4 PM might be a viable alternative to PSG for the diagnosis of OSA in postpolio subjects.MethodsA total of 48 community-living polio survivors (39 men and 9 women) with an average age of 54.4 ± 5.3 years referred for the evaluation of OSA and who volunteered to participate were recruited. First, they completed the Epworth Sleepiness Scale (ESS) questionnaire and underwent pulmonary function testing and blood gas tests the day before PSG night. Then, they underwent an overnight in-laboratory PSG with a type 3 PM and type 4 PM recording simultaneously.ResultsThe AHI from PSG, respiratory event index (REI) from type 3 PM, and ODI3 from type 4 PM was 30.27 ± 22.51/h vs. 25.18 ± 19.11/h vs. 18.28 ± 15.13/h, respectively (P < 0.001). For AHI ≥ 5/h, the sensitivity and specificity of REI were 95.45 and 50%, respectively. For AHI ≥ 15/h, the sensitivity and specificity of REI were 87.88% and 93.33%, respectively. The Bland–Altman analysis of REI on PM vs. AHI on PSG showed a mean difference of −5.09 (95% confidence interval [CI]: −7.10, −3.08; P < 0.001) with limits of agreement ranging from −18.67 to 8.49 events/h. ROC curve analysis for patients with REI ≥ 15/h showed an area under the curve (AUC) of 0.97. For AHI ≥ 5/h, the sensitivity and specificity of ODI3 from type 4 PM were 86.36 and 75%, respectively. For patients with AHI ≥ 15/h, the sensitivity was 66.67%, and the specificity was 100%.ConclusionType 3 PM and Type 4 PM could be alternative ways to screen OSA for polio survivors, especially for moderate to severe OSA.

The landscape is one of the bases of tourism development. Natural heritage sites are the pinnacle of natural areas with outstanding universal value, but the landscapes are diverse and fragile. Heritage sites needs to be moderately utilized to protect the landscape. Based on the aesthetic value of the heritage site, this study proposed an evaluation system for the tourist landscape vulnerability of a mountainous natural area in three aspects “Integration-Ecology-Coordination”. The results are as follows: (1) The factors influencing the integrated vulnerability of the landscape of Karajun-Kurdening were natural conditions, landscape patterns, and human activities in descending order of strength. In terms of spatial distribution, the integrated vulnerability of the study area was high, and the vulnerability in the south was higher than that in the north. (2) The forest landscape and grassland landscape are the carriers of the aesthetic value of the Karajun-Kurdening heritage site. The vulnerability of patch integrity and structural abundance of the forest landscape were low, while the forest density had strong heterogeneity. In addition, the patch integrity of the grassland landscape was strong, while the area of low grassland coverage was large. (3) The current tourism development was compatible with the landscape. Through the quantitative and qualitative comprehensive assessment of tourist landscape vulnerability, this study can usefully inform local policy-, plan-, and decision-making for future landscape conservation in mountainous natural heritage sites.

Abstract Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) resistance remains a therapeutic challenge in ovarian cancer. High-mobility group box 3 (HMGB3) plays significant roles in the development of drug resistance of many cancers. However, the function of HMGB3 in PARPi resistance is poorly understood. In the current study, we clarified that HMGB3 was aberrantly overexpressed in high-grade serous ovarian carcinoma (HGSOC) tissues, and high HMGB3 levels indicated shorter overall survival and drug resistance in HGSOC. The overexpression of HMGB3 increased the insensitivity of ovarian cancer to PARPi, whereas HMGB3 knockdown reduced PARPi resistance. Mechanistically, PARP1 was identified as a novel interaction partner of HMGB3, which could be blocked using olaparib and was enhanced upon DNA damage conditions. We further showed that loss of HMGB3 induced PARP1 trapping at DNA lesions and inhibited the PARylation activity of PARP1, resulting in an increased DNA damage response and cell apoptosis. The PARPi-resistant role of HMGB3 was also verified in a xenograft mouse model. In conclusion, HMGB3 promoted PARPi resistance via interacting with PARP1, and the targeted inhibition of HMGB3 might overcome PARPi resistance in ovarian cancer therapy.