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Avian Pasteurella multocida infection, can cause serious economic losses to the poultry industry every year. The inactivated vaccines of avian Pasteurella multocida are used to prevent infection. Increasing the cell density of avian Pasteurella multocida is the key to the application of these inactivated vaccines. This can be achieved by controlling the feeding strategy. This study aimed to achieve high-cell-density cultivation of avian Pasteurella multocida by applying an appropriate medium and a rational feeding strategy based on viable cell growth and dissolved oxygen level variation during a fermentation process. An optimized medium suited for the growth of avian P. multocida was used. Meanwhile, besides the online real-time determination of viable cell density, the concentration of glucose was maintained at 1.5 g/L using a glucose-stat feeding strategy after 2 h. The selected nutrient mixture, including yeast extract, tryptone, betaine, VB1, and VH, was fed using a dissolved oxygen feedback feeding strategy after 4 h. As a result, the viable cell density and cell count of avian P. multocida under optimized conditions were increased to OD600: 9.38 and 4.58×1010 CFU/mL, which were higher by 7.27 and 7.26 times than those under the original conditions, respectively.

Abstract Background Neutral Lipid Storage Disease with Myopathy (NLSDM) is a rare lipid metabolism disorder caused by PNPLA2 gene mutations. Clinical manifestations are heterogeneous, and diagnosis is often delayed, usually gaining patients’ attention due to the increased risk of cardiomyopathy. Case presentation We herein report a 36-year-old Asian male presenting with progressive limb weakness, muscle atrophy of limbs and trunk, dysarthria, and heart failure. Electromyography indicated myogenic changes, and muscle biopsy results revealed characteristics of lipid storage myopathy. Genetic analysis of PNPLA2 revealed two heterozygous mutations: c.757 + 1G > T (chr11-823588, splice-5) on intron 6 and c.919delG (chr11-823854, p.A307Pfs*13) on exon 7. The patient improved limb strength, and dysarthria disappeared after the Medium Chain Fatty Acids diet. Conclusions In conclusion, we report for the first time that the two heterozygous mutations PNPLA2 c.919delG and c.757 + 1G > T together induced NLSDM, which was confirmed by muscle biopsy.

Abstract Few studies have focused on the risk factors for necrotizing enterocolitis (NEC) in small for gestational age (SGA) infants. The aim of this study was to identify the risk factors for NEC in SGA newborns. This study included consecutive SGA neonates admitted to a tertiary hospital in Jiangxi Province, China from Jan 2008 to Dec 2022. Patients with NEC (Bell’s stage ≥ II) were assigned to the NEC group. Gestational age- and birth weight-matched non-NEC infants born during the same period at the same hospital were assigned to the control group. The risk factors associated with NEC were analyzed with univariate and logistic regression models. During the study period, 2,912 SGA infants were enrolled, 150 (5.15%) of whom developed NEC. In total, 143 patients and 143 controls were included in the NEC and control groups, respectively. Logistic regression analysis revealed that sepsis (OR 2.399, 95% CI 1.271–4.527, P = 0.007) and anemia (OR 2.214, 95% CI 1.166–4.204, P = 0.015) might increase the incidence of NEC in SGA infants and that prophylactic administration of probiotics (OR 0.492, 95% CI 0.303–0.799, P = 0.004) was a protective factor against NEC. Therefore, sepsis, anemia and a lack of probiotic use are independent risk factors for NEC in SGA infants.

Abstract Objective Retinal vascular endothelial cell (RVECs) injury is a major cause of morbidity and mortality among the patients with diabetes. RVECs dysfunction is the predominant pathological manifestation of vascular complication in diabetic retinopathy. N6-methyladenosine (m6A) serves as the most prevalent modification in eukaryotic mRNAs. However, the role of m6A RNA modification in RVECs dysfunction is still unclear. Methods RT-qPCR analysis and western blot were conducted to detect the change of m6A RNA modification in diabetic retinopathy. CCK-8 assay, transwell experiment, wound healing assay, tube formation experiment, m6A-IP-qPCR were performed to determine the role of YTHDC1 in RVECs. Retinal trypsin digestion test and H&E staining were used to evaluate histopathological changes. Results The levels of m6A RNA methylation were significantly up-regulated in HG-induced RVECs, which were caused by increased expression of YTHDC1. YTHDC1 regulated the viability, proliferation, migration and tube formation ability in vitro. YTHDC1 overexpression impaired RVECs function by repressing CDK6 expression, which was mediated by YTHDC1-dependent mRNA decay. Moreover, it showed sh-YTHDC1 inhibited CDK6 nuclear export. Sh-YTHDC1 promotes the mRNA degradation of CDK6 in the nucleus but does not affect the cytoplasmic CDK6 mRNA. In vivo experiments showed that overexpression of CDK6 reversed the protective effect of sh-YTHDC1 on STZ-induced retinal tissue damage. Conclusion YTHDC1-mediated m6A methylation regulates diabetes-induced RVECs dysfunction. YTHDC1-CDK6 signaling axis could be therapeutically targeted for treating DR.

Abstract Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive pulmonary vascular disorder with substantial morbidity and mortality, also a disease underdiagnosed and undertreated. It is potentially curable by pulmonary endarterectomy (PEA) in patients with surgically accessible thrombi. Balloon pulmonary angioplasty (BPA) and targeted medical therapy are options for patients with distal lesions or persistent/recurrent pulmonary hypertension after PEA. There is an urgent need to increase the awareness of CTEPH. Qualified CTEPH centers are still quite limited. Baseline characteristics, management pattern and clinical outcome of CTEPH in China needs to be reported. Methods and design The CHinese reAl-world study to iNvestigate the manaGEment pattern and outcomes of chronic thromboembolic pulmonary hypertension (CHANGE) study is designed to provide the multimodality treatment pattern and clinical outcomes of CTEPH in China. Consecutive patients who are ≥ 14 year-old and diagnosed with CTEPH are enrolled. The diagnosis of CTEPH is confirmed in right heart catheterization and imaging examinations. The multimodality therapeutic strategy, which consists of PEA, BPA and targeted medical therapy, is made by a multidisciplinary team. The blood sample and tissue from PEA are stored in the central biobank for further research. The patients receive regular follow-up every 3 or 6 months for at least 3 years. The primary outcomes include all-cause mortality and changes in functional and hemodynamic parameters from baseline. The secondary outcomes include the proportion of patients experiencing lung transplantation, the proportion of patients experiencing heart and lung transplantation, and changes in health-related quality of life. Up to 31 December 2023, the study has enrolled 1500 eligible patients from 18 expert centers. Conclusions As a real-world study, the CHANGE study is expected to increase our understanding of CTEPH, and to fill the gap between guidelines and the clinical practice in the diagnosis, assessment and treatment of patients with CTEPH. Registration Number in ClinicalTrials.gov NCT05311072.

We present a rare case of a large parathyroid carcinoma (PC) characterized by severe hyperparathyroidism, hypercalcemia, and osteoporosis. Long-standing calcium loss resulted in thoracic and facial deformities, initially misdiagnosed as oral malignancy.

Physical activity (PA) offers extensive benefits for all children, including those with intellectual disabilities (ID), who face significant challenges in behavioral management and psycho-social well-being. This study investigates the effects of school-based PA on attention, academic performance, and relationships with teachers and parents in children with ID. A 12-week single-blind randomized controlled trial was conducted with 102 children with ID, aged 6 to 12 years (71 boys and 31 girls) from grades 1 to 5. Participants were divided into three groups: MVPA (moderate to vigorous PA), MPA (mild PA), and NPA (no PA). Each group engaged in PA three times a week for 45 min per session, with activities planned by a fitness trainer and supervised by the researcher. Outcome measures were assessed using SNAP-IV, STRS, CPRS, and APRS scales before and after the intervention. The results indicated that MVPA had a more significant positive impact on all outcomes compared to MPA and NPA. MPA also produced notable improvements relative to NPA. These findings underscore the importance of integrating PA into educational settings as a comprehensive strategy to enhance attention, academic performance, and social interactions for children with ID. This research highlights PA as a vital tool for addressing behavioral challenges and fostering better developmental outcomes in this population.

The ability to accurately encode the temporal information of sensory events and hence to make prompt action is fundamental to humans’ prompt behavioral decision-making. Here we examined the ability of ensemble coding (averaging multiple inter-intervals in a sound sequence) and subsequent immediate reproduction of target duration at half, equal, or double that of the perceived mean interval in a sensorimotor loop. With magnetoencephalography (MEG), we found that the contingent magnetic variation (CMV) in the central scalp varied as a function of the averaging tasks, with a faster rate for buildup amplitudes and shorter peak latencies in the “half” condition as compared to the “double” condition. ERD (event-related desynchronization) -to-ERS (event-related synchronization) latency was shorter in the ”half” condition. A robust beta band (15–23 Hz) power suppression and recovery between the final tone and the action of key pressing was found for time reproduction. The beta modulation depth (i.e., the ERD-to-ERS power difference) was larger in motor areas than in primary auditory areas. Moreover, results of phase slope index (PSI) indicated that beta oscillations in the left supplementary motor area (SMA) led those in the right superior temporal gyrus (STG), showing SMA to STG directionality for the processing of sequential (temporal) auditory interval information. Our findings provide the first evidence to show that CMV and beta oscillations predict the coupling between perception and action in time averaging.

In recent years, semantic segmentation in deep learning has been widely applied in medical image segmentation, leading to the development of numerous models. Convolutional Neural Network (CNNs) have achieved milestone achievements in medical image analysis. Particularly, deep neural networks based on U-shaped architectures and skip connections have been extensively employed in various medical image tasks. U-Net is characterized by its encoder-decoder architecture and pioneering skip connections, along with multi-scale features, has served as a fundamental network architecture for many modifications. But U-Net cannot fully utilize all the information from the encoder layer in the decoder layer. U-Net++ connects mid parameters of different dimensions through nested and dense skip connections. However, it can only alleviate the disadvantage of not being able to fully utilize the encoder information and will greatly increase the model parameters. In this paper, a novel BFNet is proposed to utilize all feature maps from the encoder at every layer of the decoder and reconnects with the current layer of the encoder. This allows the decoder to better learn the positional information of segmentation targets and improves learning of boundary information and abstract semantics in the current layer of the encoder. Our proposed method has a significant improvement in accuracy with 1.4 percent. Besides enhancing accuracy, our proposed BFNet also reduces network parameters. All the advantages we proposed are demonstrated on our dataset. We also discuss how different loss functions influence this model and some possible improvements.

Abstract Pyroptosis, a novel type of programmed cell death (PCD), which provides a feasible therapeutic option for the treatment of tumors. However, due to the hypermethylation of the promoter, the critical protein Gasdermin E (GSDME) is lacking in the majority of cancer cells, which cannot start the pyroptosis process and leads to dissatisfactory therapeutic effects. Additionally, the quick clearance, systemic side effects, and low concentration at the tumor site of conventional pyroptosis reagents restrict their use in clinical cancer therapy. Here, we described a combination therapy that induces tumor cell pyroptosis via the use of ultrasound-targeted microbubble destruction (UTMD) in combination with DNA demethylation. The combined application of UTMD and hydralazine-loaded nanodroplets (HYD-NDs) can lead to the rapid release of HYD (a demethylation drug), which can cause the up-regulation of GSDME expression, and produce reactive oxygen species (ROS) by UTMD to cleave up-regulated GSDME, thereby inducing pyroptosis. HYD-NDs combined with ultrasound (US) group had the strongest tumor inhibition effect, and the tumor inhibition rate was 87.15% (HYD-NDs group: 51.41 ± 3.61%, NDs + US group: 32.73%±7.72%), indicating that the strategy had a more significant synergistic anti-tumor effect. In addition, as a new drug delivery carrier, HYD-NDs have great biosafety, tumor targeting, and ultrasound imaging performance. According to the results, the combined therapy reasonably regulated the process of tumor cell pyroptosis, which offered a new strategy for optimizing the therapy of GSDME-silenced solid tumors.

Abstract Background Electronic health records (EHRs) are digital records of individual health information. However, their adoption and utilization remain low. This study explores the factors influencing the implementation of EHRs through a questionnaire survey to enhance individual awareness and adoption of EHRs. Methods A questionnaire and an expert rating scale were developed sequentially, and the consistency of the scores from five experts was calculated using Kendall’s W to generate a final questionnaire. A non-parametric test was utilized to analyze differences in continuous data that did not follow a normal distribution. Categorical variables were expressed as percentages (%), the chi-square test was employed for group comparisons, and multiple logistic regression was implemented to assess individuals’ awareness and adoption of EHRs. Results In total, 1,341 survey questionnaires were distributed between January and December 2022, with 1,337 valid responses (99.7%). The results indicated that the proportion of participants who were aware of EHRs and had a bachelor’s degree or higher education, an income of ≥$700 per month, residence in urban areas, possessed self-care abilities, and underwent annual physical examinations was significantly higher than that without awareness of EHRs (P

Breast cancer in the elderly presents distinct biological characteristics and clinical treatment responses compared with cancer in younger patients. Comprehensive Geriatric Assessment is recommended for evaluating treatment efficacy in elderly cancer patients based on physiological classification. However, research on molecular classification in older cancer patients remains insufficient. In this study, we identified two subgroups with distinct senescent clusters among geriatric breast cancer patients through multi-omics analysis. Using various machine learning algorithms, we developed a comprehensive scoring model called “Sene_Signature,” which more accurately distinguished elderly breast cancer patients compared with existing methods and better predicted their prognosis. The Sene_Signature was correlated with tumor immune cell infiltration, as supported by single-cell transcriptomics, RNA sequencing, and pathological data. Furthermore, we observed increased drug responsiveness in patients with a high Sene_Signature to treatments targeting the epidermal growth factor receptor and cell-cycle pathways. We also established a user-friendly web platform to assist investigators in assessing Sene_Signature scores and predicting treatment responses for elderly breast cancer patients. In conclusion, we developed a novel model for evaluating prognosis and therapeutic responses, providing a potential molecular classification that assists in the pre-treatment assessment of geriatric breast cancer.

AbstractBackground Anxiety and depression are common comorbidities in idiopathic pulmonary fibrosis (IPF) that impair health-related quality of life. However, there is a lack of studies focusing on the mental disorder of IPF after antifibrotic treatment and their related predictive factors.Methods Patients with an initial diagnosis of IPF were enrolled. Data on demographics, lung function, Generalized Anxiety Disorder-7 (GAD-7) Scale, Patient Health Questionnaire 9 (PHQ-9), Patient Health Questionnaire-15 (PHQ-15), and St. George's Respiratory Questionnaire total score(SGRQ-T) were collected. Changes in anxiety, depression, somatic symptoms, and quality of life scores before and after nintedanib treatment were compared, and the related predictive factors were analyzed.Results A total of 56 patients with a first diagnosis of IPF were enrolled, with 42 and 35 patients suffering from anxiety and depression, respectively. The GAD-7, PHQ-9, PHQ-15, and SGRQ scores were higher in the anxiety and depression groups. SGRQ total score (SGRQ-T) [OR = 1.075, 95%CI= (1.011, 1.142)] was an independent predictor of IPF combined with anxiety (p

AbstractObjective The association between nutritional status and prognosis of idiopathic pulmonary fibrosis (IPF) remains unclear. This systematic review and meta-analysis aimed to explore the effect of body mass index (BMI) and weight loss on the prognosis of IPF patients.Methods We accumulated studies on IPF, BMI, and weight loss from databases including PubMed, Embase, Web of science, Scopus, Ovid and Cochrane Library up to 4 August 2023. Using Cox proportional hazard regression model for subgroup analysis, hazard ratio (HR) and 95% confidence intervals (CI) for BMI in relation to mortality, acute exacerbation (AE), and hospitalization in IPF patients were calculated, and HR, odds ratio (OR), and 95% CI for weight loss corresponding to IPF patient mortality were assessed. Sensitivity analysis was peformed by eliminating every study one by one, and publication bias was judged by Egger’s test and trim-and-fill method.Results A total of 34 eligible studies involving 18,343 IPF patients were included in the meta-analysis. The pooled results by univariate Cox regression analysis showed that baseline BMI was a predictive factor for IPF mortality (HR = 0.93, 95%CI = [0.91, 0.94]). Furthermore, the results by the multivariable regression model indicated that baseline BMI was an independent risk factor for predicting IPF mortality (HR = 0.94, 95%CI = [0.91, 0.98]). Weight loss was identified as a risk factor for IPF mortality (HR = 2.74, 95% CI = [2.12, 3.54]; OR = 4.51, 95% CI = [1.72, 11.82]) and there was no predictive value of BMI for acute exacerbation (HR = 1.00, 95% CI= [0.93, 1.07]) or hospitalization (HR = 0.95, 95% CI = [0.89, 1.02]).Conclusion Low baseline BMI and weight loss in the course of IPF may indicate a high risk of mortality in patients with IPF, so it is meaningful to monitor and manage the nutritional status of IPF patients, and early intervention should be conducted for low BMI and weight loss.

Abstract Background X‐linked adrenoleukodystrophy (X‐ALD) is the most common peroxisomal disorder attributed to ABCD1 mutations. Case reports with predominant brainstem involvement are rare. Case Presentation In this study, we reported a plateau male worker of X‐ALD characterized by progressive weakness accompanied by gait instability, mild nystagmus, and constipation. After 2 years of onset, a brain Magnetic Resonance Image (MRI) scan showed no abnormality but genetic analysis revealed a heterozygous mutation (c.1534G>A) in the ABCD1 gene. After 7 years of onset, although the patient was given aggressive dietary and symptomatic treatment in the course of the disease, a brain MRI scan showed predominantly brainstem damage, but serum concentrations of very long‐chain fatty acids were normal, and he had been bedridden for almost 2 years with severe bladder dysfunction, forcing him to undergo cystostomy. The patient was discharged with improved urinary retention and renal function. Conclusions We reported an X‐ALD patient with a novel ABCD1 variation characterized by brainstem damage and retrospectively summarized the clinical manifestation, MRI features, and genetic features of X‐ALD patients with brainstem damage.

Summary: Biological nitrogen fixation catalyzed by nitrogenase contributes greatly to the global nitrogen cycle. Nitrogenase expression is subject to regulation in response to nitrogen availability. However, the mechanism through which the transcriptional activator NifA regulates nitrogenase expression by interacting with PII nitrogen regulatory proteins remains unclear in diazotrophic proteobacteria lacking NifL. Here, we demonstrate that in Rhodopseudomonas palustris grown with ammonium, NifA bound deuridylylated PII proteins to form an inactive NifA-PII complex, thereby inhibiting the expression of nitrogenase. Upon nitrogen limitation, the dissociation of uridylylated PII proteins from NifA resulted in the full restoration of NifA activity, and, simultaneously, uridylylation of the significantly up-regulated PII protein GlnK2 led to the increased expression of NifA in R. palustris. This insight into how NifA interacts with PII proteins and controls nitrogenase expression sets the stage for creating highly efficient diazotrophs, reducing the need for energy-intensive chemical fertilizers and helping to diminish carbon emissions.

IntroductionThe new topical formula is urgent needed to meet clinical needs for majority mild patients with psoriasis. Deucravacitinib exerts outstanding anti-psoriatic capacity as an oral TYK2 inhibitor; however, single therapy is insufficient to target the complicated psoriatic skin, including excessive reactive oxygen species (ROS) and persistent inflammation. To address this need, engineered smart nano-therapeutics hold potential for the topical delivery of deucravacitinib.Methodshydrophobic Deucravacitinib was loaded into polyethylene glycol block-polypropylene sulphide (PEG-b-PPS) for transdermal delivery in the treatment of psoriasis. The oxidative stress model of HaCaT psoriasis was established by TNF-α and IL-17A in vitro. JC-1 assay, DCFH-DA staining and mtDNA copy number were utilized to assess mitochondrial function. 0.75% Carbopol®934 was incorporated into SPMs to produce hydrogels and Rhb was labeled to monitor penetration by Immunofluorescence. In vivo, we established IMQ-induced psoriatic model to evaluate therapeutic effect of Car@Deu@PEPS.ResultsDeu@PEPS exerted anti-psoriatic effects by restoring mitochondrial DNA copy number and mitochondrial membrane potential in HaCaT. In vivo, Car@Deu@PEPS supramolecular micelle hydrogels had longer retention time in the dermis in the IMQ-induced ROS microenvironment. Topical application of Car@Deu@PEPS significantly restored the normal epidermal architecture of psoriatic skin with abrogation of splenomegaly in the IMQ-induced psoriatic dermatitis model. Car@Deu@PEPS inhibited STAT3 signaling cascade with a corresponding decrease in the levels of the differentiation and proliferative markers Keratin 17 and Cyclin D1, respectively. Meanwhile, Car@Deu@PEPS alleviated IMQ-induced ROS generation and subsequent NLRP3 inflammasome-mediated pyroptosis.ConclusionDeu@PEPS exerts prominent anti-inflammatory and anti-oxidative effects, which may offers a more patient-acceptable therapy with fewer adverse effects compared with oral deucravacitinib.

Abstract Proper subcellular localization is crucial for the functioning of biomacromolecules, including proteins and RNAs. Nuclear transport is a fundamental cellular process that regulates the localization of many macromolecules within the nuclear or cytoplasmic compartments. In humans, approximately 60 proteins are involved in nuclear transport, including nucleoporins that form membrane-embedded nuclear pore complexes, karyopherins that transport cargoes through these complexes, and Ran system proteins that ensure directed and rapid transport. Many of these nuclear transport proteins play additional and essential roles in mitosis, biomolecular condensation, and gene transcription. Dysregulation of nuclear transport is linked to major human diseases such as cancer, neurodegenerative diseases, and viral infections. Selinexor (KPT-330), an inhibitor targeting the nuclear export factor XPO1 (also known as CRM1), was approved in 2019 to treat two types of blood cancers, and dozens of clinical trials of are ongoing. This review summarizes approximately three decades of research data in this field but focuses on the structure and function of individual nuclear transport proteins from recent studies, providing a cutting-edge and holistic view on the role of nuclear transport proteins in health and disease. In-depth knowledge of this rapidly evolving field has the potential to bring new insights into fundamental biology, pathogenic mechanisms, and therapeutic approaches.

Effective construction project planning relies on addressing constraints related to materials, labor, equipment, and others. Planning meetings are typical venues for stakeholders to identify, communicate, and remove constraints. However, a critical gap exists in lacking an automated approach to identify, classify, analyze, and track constraint discussions during onsite planning meetings. Therefore, this research aims to 1. develop a natural language processing model to classify constraints in meeting discussions; 2. uncover the discussion patterns of managers and foremen regarding various constraints; and 3. extract the root causes for constraints, evaluate their impacts, and prepare managers to develop practical solutions for constraint removal. This research collected meeting transcripts from 94 onsite planning meetings of a building project, spanning 263,836 words. Next, this research leveraged a general pretrained transformer (GPT) to segment discussion dialogs into topics. A Bidirectional Encoder Representations from Transformers (BERT)-based model was developed to categorize constraint types for each topic. The constraint patterns among meeting attendees were assessed. Furthermore, a GPT-based tool was devised to track root causes, impacts, and solutions for various constraints. Test results revealed an 8.8% improvement in constraint classification accuracy compared with the traditional classification model. An occupational characteristic in constraint discussion was observed in that the management team tended to balance their focus on various constraints, while foremen concentrated on more practical issues. This research contributes to the body of knowledge by leveraging language models to analyze construction planning meetings. The findings facilitate project managers in establishing constraint logs for diagnosing and prognosticating planning issues.

Introduction: Wernicke encephalopathy (WE) is a potentially fatal condition caused by thiamine (vitamin B1) deficiency. Chronic alcoholism is the most common cause of WE; however, other conditions responsible for thiamine deficiency should also be considered. Case Report: We report the case of a 64-year-old woman with a history of diabetes who presented with confusion and apathy. Magnetic resonance imaging of the brain showed T2 hyperintensities involving dorsolateral medulla oblongata, tegmentum of the pons, vermis of the cerebellum, periaqueductal region, and the bilateral mammillary bodies. She had a history of intravenous glucose administration before her mental symptoms developed. On suspicion of WE, she was treated with a high dose of thiamine empirically. Her clinical condition improved rapidly in 2 weeks. Conclusion: Endogenous thiamine stores can be rapidly depleted in the case of enhanced glucose oxidation. Patients who receive glucose should also be prescribed thiamine to avoid inducing or exacerbating WE.

Abstract Background Compliance with colonoscopy among elderly individuals participating in colorectal cancer (CRC) screening programs is unsatisfactory, despite a high detection rate of bowel‐related diseases. In this study, our aim was to analyze the impact of risk factors on the trends of compliance and detection rates in colonoscopy among high‐risk individuals aged 60–74. Methods A retrospective study was conducted on the high‐risk individuals aged 60–74 participating in the 2021 CRC screening program in Tianjin, China. Logistic regression analyses, including both univariate and multivariate analyses, were performed to explore the impact of different risk factors on colonoscopy compliance among the high‐risk individuals. Besides, the study investigated the influence of various risk factors on the detection rates of bowel‐related diseases among the high‐risk individuals who underwent colonoscopy. Results A total of 24,064 high‐risk individuals were included, and 5478 individuals received a free colonoscopy, with an overall compliance of 22.76%. Among them, the adenoma detection rate was 55.46%. Males and individuals with a positive FIT had high compliance and detection rates for CRC, advanced adenomas (AA), advanced colorectal neoplasia (ACN), and colorectal neoplasm (CN). Individuals aged 70–74 were associated with low compliance but high CRC, ACN, and CN detection rates. Individuals who reported a history of chronic constipation, bloody mucous, and CRC in first‐degree relative showed high compliance but no significantwere associated with the detection rates of CRC, AA, and CN. Conclusion This study reported several risk factors associated with the screening behaviors for CRC. Patterns and trends in CRC, AA, ACN, and CN compliance and detection rates correlate with risk factors.

Abstract Introduction Ulcerative colitis (UC) is one of the most common diseases in the gastrointestinal tract related to abnormal inflammation. Pyroptosis, which is characterized by the formation of inflammasome, activation of caspase‐1, and separation of N‐ and C‐terminus of gasdermin D (GSDMD), and may be involved in the pathogenesis of IBD. Krüppel‐like factor 4 (KLF4) is a zinc finger transcription factor expressed in differentiated epithelial cells. KLF4 mediates proinflammatory signaling in macrophages. Here, we tested whether KLF4 is functional in pyroptosis of UC. Methods In human UC tissues and/or lipopolysaccharide (LPS)/adenosine 5‐triphosphate (ATP) stimulation human colon epithelial cells, KLF4, TXNIP, Cleave‐Caspase‐1, and GSDMD expression were detected through quantitative reverse transcription polymerase chain reaction (PCR), immunohistochemical and western blot assay. Interleukin (IL)‐1β and IL‐18 levels were quantified by enzyme‐linked immunosorbent assay. We successfully constructed a KLF4‐silenced colon epithelial cell line using an adenovirus vector. We apply the UCSC and JASPAR to predict the KLF4 binding sites in the promoter region of TXNIP. Results In human UC tissues and/or LPS/ATP stimulation human colon epithelial cells, KLF4, TXNIP, Caspase‐1, and GSDMD expression level were significantly elevated via quantitative reverse transcription PCR, immunohistochemical and western blot assay. Moreover, We identified that there is an interaction between KLF4 and TXNIP through Yeast double hybrid assay and CO‐IP assay. We successfully constructed a KLF4‐silenced human intestinal epithelial cell line. In LPS/ATP stimulation KLF4‐silenced human intestinal epithelial cells, KLF4, TXNIP, Cleave Caspase‐1, ASC, and GSDMD expression level were significantly decreased via quantitative reverse transcription PCR. Conclusion Our results confirm that KLF4 can positively regulate the expression of TXNIP and regulate the pyroptosis process of UC through the TXNIP/NLRP3 pathway.

Cyber-Physical-Social Systems (CPSS) epitomize the modern era’s intelligent connectivity. They integrate physical devices, computer networks, and social networks, forming an innovative paradigm for intelligent systems. Utilizing CPSS to enhance intelligence, automation, and remote services in healthcare represents a primary research focus. Pulmonary embolism, a prevalent condition resulting from the blockage of the pulmonary artery and its branches by emboli, leads to a spectrum of clinical syndromes marked by impaired pulmonary circulation and right heart dysfunction, contributing to sudden and unpredictable fatalities. Nevertheless, the diagnosis of pulmonary embolism remains challenging due to non-specific clinical presentations, constrained diagnostic capabilities, delayed diagnoses, insufficient physician knowledge, and suboptimal diagnostic techniques. Consequently, we introduce the innovative LSCU-Net architecture within the CPSS framework, designed to develop an automated segmentation and intelligent assessment system for pulmonary embolism, facilitating its automated and intelligent detection. The experimental findings demonstrate that the model accurately segments pulmonary embolism, evidenced by a Jaccard index of 0.6958, a Dice coefficient of 0.8193, a Mean Pixel Accuracy (mPA) of 0.8519, and an accuracy of 0.9993. Empirical studies reveal that our proposed model substantially surpasses existing models in performance. Consequently, this model can aid physicians in the diagnosis of pulmonary embolism during clinical practice. The established pulmonary embolism automatic segmentation and assessment system also showcases the application successes of CPSS in intelligent remote healthcare. The system’s development and deployment not only streamline physicians’ diagnostic processes but also elevate public health standards and advance CPSS research within the medical domain.

Purpose: To investigate whether erythropoietin (EPO) can treat pulmonary arterial hypertension (PAH) in rats by regulating the differentiation and homing of bone marrow mesenchymal stem cells (BMSCs) through Notch1/Jagged signaling pathway. Materials & methods: BMSCs were isolated from the bone marrow of 6-week-old male SD rats by whole bone marrow method and identified. BMSCs were treated with 500 IU/mL EPO, and the proliferation, migration, invasion and differentiation ability, and the expression of MMP-2 and MMP-9 protein of BMSCs were detected in vitro. After the establishment of the pulmonary hypertension model in rats, BMSCs were intervened with different concentrations of EPO and injected into the rats through intravenous injection. The levels of TNF-α, IL-1β and IL-6 in lung tissue, the expression of SRY CXCR4, CCR2, Notch1 and Jagged protein in lung tissue, and the levels of TGF-α, vascular endothelial factor (VEGF), IGF-1 and HGF in serum were detected. Immunofluorescence (IF) staining was used to detect the co-localization of CD34. Results: EPO promoted the proliferation, migration, and invasion of BMSCs by inhibiting Notch1/Jagged pathway in vitro, and induced BMSCs to differentiate into vascular smooth muscle cells and vascular endothelial cells. EPO inhibited Notch1/Jagged pathway in PAH rats, induced BMSCs homing and differentiation, increased the levels of TGF-α, VEGF, IGF-1 and HGF, and decreased the levels of TNF-α, IL-1β and IL-6. Discussion & conclusion: EPO can inhibit the Notch1/Jagged pathway and promote the proliferation, migration, invasion, homing and differentiation of BMSCs to treat pulmonary hypertension in rats in vitro and in vivo.

BackgroundThe level at which cumulative blood pressure (BP) can increase the risk of ASCVD in different age groups remains unclear. This study aimed to investigate the association of 10-year cumulative BP levels with the long-term risk of ASCVD of different age groups.MethodsCumulative BP exposure was assessed using the time-weighted average (TWA) BP divided into four BP groups. The participants were also divided into four groups according to their baseline age (

Abstract Background Cathepsin C (Cat C) is involved in the inflammatory-immune system and can be degraded by cathepsin D (Cat D). Preeclampsia (PE) and the inflammation-immunity relationship is currently a hot research topic, but there are still few studies. The aim was to investigate the expression and significance of Cat C and D in the serum of nonpregnant women, patients in various stages of pregnancy and patients with PE, and in the placenta of patients with normal pregnancy and PE. Methods Sixty young healthy nonpregnant women were selected: 180 normal pregnant women, including 60 each in the first, second, and third trimesters, and 100 women with PE, including 39 women with severe preeclampsia. The levels of Cat C and D in serum were detected by enzyme-linked immunosorbent assay (ELISA), and the expression levels of Cat C and D in placentas were detected by immunohistochemistry (IHC). Results The serum of Cat C in the first trimester was significantly lower than that in the nonpregnant group (P

Abstract Background A large number of researchers have devoted to accelerating the speed of genome sequencing and reducing the cost of genome sequencing for decades, and they have made great strides in both areas, making it easier for researchers to study and analyze genome data. However, how to efficiently store and transmit the vast amount of genome data generated by high-throughput sequencing technologies has become a challenge for data compression researchers. Therefore, the research of genome data compression algorithms to facilitate the efficient representation of genome data has gradually attracted the attention of these researchers. Meanwhile, considering that the current computing devices have multiple cores, how to make full use of the advantages of the computing devices and improve the efficiency of parallel processing is also an important direction for designing genome compression algorithms. Results We proposed an algorithm (LMSRGC) based on reference genome sequences, which uses the suffix array (SA) and the longest common prefix (LCP) array to find the longest matched substrings (LMS) for the compression of genome data in FASTA format. The proposed algorithm utilizes the characteristics of SA and the LCP array to select all appropriate LMSs between the genome sequence to be compressed and the reference genome sequence and then utilizes LMSs to compress the target genome sequence. To speed up the operation of the algorithm, we use GPUs to parallelize the construction of SA, while using multiple threads to parallelize the creation of the LCP array and the filtering of LMSs. Conclusions Experiment results demonstrate that our algorithm is competitive with the current state-of-the-art algorithms in compression ratio and compression time.

BackgroundThe prevalence of osteoporosis and osteopenia is higher among underground coal miners than surface workers. The special underground work environment and unhealthy habits such as smoking, drinking, and a high-salt diet may lead to changes in bone metabolism, increasing the risk of fragility fractures and placing a heavy economic burden on individuals and society. ObjectiveTo identify potential factors influencing fragility fractures among coal miners in different working environments and to provide a basis for targeted preventive measures to reduce the occurrence of fragility fractures.MethodsMale participants who attended at least one of the physical examinations in Kailuan Group between June 2006 and December 2020 were included in the study. The participants were divided into two groups based on their working environment: surface or underground. A case-control study was conducted, where patients with new fragility fractures served as the case group and participants without fragility fractures served as the control group. The two groups were matched with a case:control ratio of 1:4 by age (±1 year) and the same year of physical examination. The matching process was repeated twice, once for the surface working population and once for the underground working population. The analysis of risk factors was conducted using conditional logistic regression models.ResultsAmong a total of 113138 employees in Kailuan Group, 82631 surface workers and 30507 underground workers were included, respectively. The number of individuals who suffered fragility fractures was 1375, accounting for 1.22% of the total population. The incidence of fragility fractures in underground workers was significantly higher than that in surface workers (1.63%>1.07%, P

Abstract A transmitarray adopting dual‐layer polarisation rotating (PR) elements is proposed. The element comprises a pair of perpendicularly placed C‐shaped slots etched on the two sides of a single‐layer substrate and orthogonally rotates transmission wave polarisation with regard to the incidence. By adjusting C‐shaped slot's dimension as well as mirroring the bottom layer of the element, a 360° phase shift with a high transmission magnitude is achieved. Based on the proposed unit‐cell, a dual‐layer transmitarray composed of 529 elements is designed and developed. The experimental 1‐dB gain bandwidth and peak aperture efficiency are 13% and 44% respectively. Furthermore, sidelobe level of 20 dB and cross polarisation level of 26 dB are obtained at 10 GHz. These promising properties demonstrate the superiority of the element for transmitarray designs. In addition, this element can be also a good candidate for folded transmitarray designs.

Abstract Despite rapid advances in metabolic therapies over the past decade, their efficacy in melanoma has been modest, largely due to the interaction between cancer-associated fibroblasts (CAFs) and cancer cells to promote cancer growth. Altering the tumor microenvironment (TME) is challenging and elusive. CAFs is critical for glutamine deprivation survival in melanoma. In this research, we assembled a CAFs-targeted, controlled-release nanodroplets for the combined delivery of the amino acid transporter ASCT2 (SLC1A5) inhibitor V9302 and GLULsiRNA (siGLUL). The application of ultrasound-targeted microbubble disruption (UTMD) allows for rapid release of V9302 and siGLUL, jointly breaking the glutamine metabolism interaction between CAFs and cancer cells on one hand, on the other hand, blocking activated CAFs and reducing the expression of extracellular matrix (ECM) to facilitate drug penetration. In addition, ultrasound stimulation made siGLUL more accessible to tumor cells and CAFs, downregulating GLUL expression in both cell types. FH-V9302-siGLUL-NDs also serve as contrast-enhanced ultrasound imaging agents for tumor imaging. Our study developed and reported FH-NDs as nanocarriers for V9302 and siGLUL, demonstrating that FH-V9302-siGLUL-NDs have potential bright future applications for integrated diagnostic therapy. Graphical Abstract

Abstract Background The Chinese visceral adiposity index (CVAI), a simple surrogate measure of visceral fat, is significantly associated with cardiovascular disease (CVD) risk in the general population. This study aimed to evaluate the association of cumulative CVAI (cumCVAI) exposure and its accumulation time course with CVD risk among patients with hypertension. Methods This prospective study involved 15,350 patients with hypertension from the Kailuan Study who were evaluated at least three times in the observation period of 2006 to 2014 (2006–2007, 2010–2011, and 2014–2015) and who were free of myocardial infarction and stroke before 2014. The cumCVAI was calculated as the weighted sum of the mean CVAI for each time interval (value × time). The time course of CVAI accumulation was categorized by splitting the overall accumulation into early (cumCVAI06 − 10) and late (cumCVAI10 − 14) accumulation, or the slope of CVAI versus time from 2006 to 2014 into positive and negative. Results During the 6.59-year follow-up period, 1,184 new-onset CVD events were recorded. After adjusting for confounding variables, the hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD were 1.35 (1.13–1.61) in the highest quartile of cumCVAI, 1.35 (1.14–1.61) in the highest quartile of the time-weighted average CVAI, 1.26 (1.12–1.43) in those with a cumulative burden > 0, and 1.43 (1.14–1.78) for the group with a 10-year exposure duration. When considering the time course of CVAI accumulation, the HR (95% CI) for CVD was 1.33 (1.11–1.59) for early cumCVAI. When considering the combined effect of cumCVAI accumulation and its time course, the HR (95% CI) for CVD was 1.22 (1.03–1.46) for cumCVAI ≥ median with a positive slope. Conclusions In this study, incident CVD risk depended on both long-term high cumCVAI exposure and the duration of high CVAI exposure among patients with hypertension. Early CVAI accumulation resulted in a greater risk increase than later CVAI accumulation, emphasizing the importance of optimal CVAI control in early life.

Abstract Background and Aims Colonoscopy is an important colorectal cancer (CRC) screening modality; however, not all high‐risk groups identified by fecal immunochemical test (FIT) and/or high‐risk factor questionnaire (HRFQ) undergo colonoscopy in time. The impact of delays in colonoscopy on CRC detection among high‐risk populations remains poorly understood, warranting further clarification. Methods A retrospective study was conducted among CRC high‐risk population identified by Tianjin CRC screening program. According to the colonoscopy results after HRFQ and FIT, patients were classified into CRC, advanced adenoma, non‐advanced adenoma, and normal groups. The time interval between CRC screening and colonoscopy was investigated and its relationship with colonoscopy results. Logistic regression was performed to explore the risk factors of CRC detection. Results Among the high‐risk population without a history of CRC or polyps, 49,810 underwent HRFQ, FIT, and colonoscopy, and a time interval of fewer than 6 months was found for 79.56% of patients (n = 39,630). People with positive FIT were more likely to undergo colonoscopy within 6 months, and detection rates of CRC and/or advanced adenoma were positively related to time intervals. Similar results were found in people with a negative FIT but positive HRFQ. A time interval longer than 6 months was a significant predictor of CRC detection in high‐risk populations. Conclusion For high‐risk people identified by CRC screening, especially those with a positive FIT, a time interval of 6 months was associated with an increased probability of CRC detection. Our findings emphasize that populations at high risk should undergo colonoscopy at least within 6 months.

Abstract Purpose Stroke is a documented risk factor for hip fracture(HF). However, no data is currently available on this issue in mainland China, we therefore assessed the risk of hip fracture after new-onset stroke using a cohort study. Methods This study included 165,670 participants without a history of stroke at baseline from the Kailuan study. All participants were followed biennially until December 31, 2021. During follow-up, a total of 8,496 new-onset stroke cases were identified. For each case subject, four control subjects was randomly selected, matched for age (± 1 years) and sex. The final analysis comprised 42,455 pair-matched cases and controls. A multivariate Cox proportional hazard regression model was used to estimate the effect of new-onset stroke on the risk of hip fracture. Results During an average follow-up of 8.87 (3.94) years, a total of 231 hip fracture cases occurred, 78 cases in the stroke group and 153 cases in the control group, with incidence rates of 1.12 and 0.50 per 1000 person-years, respectively. The cumulative incidence of the stroke group was higher than that of the controls (P

The uncertainty of parameters will have a significant impact on slope stability, where sensitivity analysis is a commonly used method in uncertainty research. However, traditional sensitivity analysis method costs much computation time. When calculating the sensitivity index of one parameter, all other parameters are taken as fixed values, and the uncertainty of all parameters cannot be considered simultaneously. Therefore, the variance-based and the moment-independent global sensitivity analysis (GSA) methods are both introduced to determine the influence of geotechnical parameters on slope stability in this study. To solve the importance index of GSA, the least angle regression algorithm, the kernel density estimation, and orthogonal polynomial estimation methods are developed to obtain variance-based importance index and the moment-independent importance index, respectively. The proposed methods allow all variables to change simultaneously within their variation range and have high computational efficiency. The results are in good at with those obtained by the variance-based Monte Carlo simulation method, which is considered as the exact solution forobtaining the importance index. The influence of the correlation between the shear strength parameters (c and φ) on the importance index is also studied, which indicates that the negative correlation will have a great impact on the importance index, which in turn affects the safety assessment of slope. Three engineering cases have been studied for engineering application, and the compared results indicate that the impact of the geotechnical parameters uncertainty on the safety factor (Fs) and failure probability (pf) are different. Therefore, the approaches based on GSA which can integrate the Fs with pf will be a promising approach for slope stability evaluation.

ObjectiveTo investigate the association between cumulative remnant cholesterol (cumRC) and the risk of new-onset fragility fractures.MethodsThis study included individuals who participated in the 2006, 2008, and 2010 Kailuan health examinations. Baseline characteristics were compared between groups according to cumRC quartiles. The incidence density was calculated, and the log-rank test was used to compare the cumulative incidence. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI), and restricted cubic spline was used to examine the possibly non-linear relation between cumRC and the risk of fragility fractures. Additional analyses were performed with stratification by age (≥ or

Abstract With the advancements in radiotherapy (RT) in recent years, several studies have shown that RT can significantly prolong the survival of patients with hepatocellular carcinoma (HCC). As a noninvasive treatment option, the application of RT for the treatment of HCC is garnering increasing attention. In this retrospective study, we included data from 13,878 patients with HCC from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2019 and 325 patients with HCC treated in three tertiary hospitals in China between 2015 and 2021. Patient data were divided into RT and non-RT groups based on whether the patients underwent RT. Propensity score matching analysis was performed to minimize the deviation between the RT and non-RT groups, and the Kaplan–Meier method, Cox proportional hazard model, and nomogram were used to assess the efficacy of undergoing RT. The median overall survival (mOS) of the RT group was significantly longer compared with that of the non-RT group for the SEER data (16 months versus 9 months, p

In this study, an axicon metalens comprising a large central disc surrounded by nanoposts for energy harvesting in composite metal-oxide semiconductor sensors was designed, fabricated, and experimentally characterized. The main role of the central disc is focusing light; the nanoposts of various diameters deflect light to form a Bessel-like beam. The spatial distribution of the optical transmission was measured using micro-hyperspectral imaging. The axicon metalens concentrates the light to the sensitive area of the sensor and also harvests light from adjacent pixels. After adding an axicon metalens, the normalized peak transmission is up to 250% at λ = 700 nm as compared to a blank TiO2 film. The experimental results had fair agreement with the finite-difference-time-domain simulation. The ultra-broadband energy-harvesting performance of the sensor suggests that it could be applied in surveillance and Internet of Things applications.

Abstract Nanosized drug delivery systems have rapidly emerged as a promising approach to tumor therapy, which still have many challenges in clinical application. In this study, doxorubicin-loaded O-carboxymethyl chitosan/perfluorohexane nanodroplets (O-CS-DOX NDs) were synthesized and functionally tested as an effective drug delivery system in vitro and in vivo. O-CS-DOX NDs with small size (159.6 nm) and good doxorubicin encapsuling ability showed pH- and ultrasound-dependent drug release profile and satisfying ultrasound imaging performance. With high biocompatibility and biosafety, these nanodroplets could accumulate in the tumor sites and exhibit high efficiency in inhibiting tumor growth with ultrasound irradiation. These stable, safe and smart O-CS-DOX NDs showed promising potential as a smart dual-responsive bomb for tumor ultrasonic imaging and treatment.

BackgroundThe optimal local treatment for HCC with tumor diameter ≥ 5 cm is not well established. This research evaluated the effectiveness of external beam radiation therapy (EBRT) versus transcatheter arterial chemoembolization (TACE) for HCC with tumor diameter ≥ 5 cm.MethodsA total of 1210 HCC patients were enrolled in this study, including 302 and 908 patients that received EBRT and TACE, respectively. Propensity score matching (PSM) was used to identify patient pairs with similar baseline characteristics. Overall survival (OS) was the primary study endpoint.ResultsWe identified 428 patients using 1:1 PSM for survival comparison. Compared with the TACE group, the EBRT group had a significantly longer median OS (mOS) before (14.9 vs. 12.3 months, p = 0.0085) and after (16.8 vs. 11.4 months, p = 0.0026) matching. In the subgroup analysis, compared with the TACE group, the EBRT group had a significantly longer mOS for HCC with tumor diameters of 5-7 cm (34.1 vs. 14.3 months, p = 0.04) and 7-10 cm (34.4 vs. 10 months, p = 0.00065), whereas for HCC with tumor diameters ≥ 10 cm, no significant difference in mOS was observed (11.2 vs. 11.2 months, p = 0.83). In addition, the multivariable Cox analysis showed that Child-A, alkaline phosphatase < 125 U/L, and EBRT were independent prognostic indicators for longer survival.ConclusionEBRT is more effective than TACE as the primary local treatment for HCC with tumor diameter ≥ 5 cm, especially for HCC with tumor diameter of 5-10 cm.

Abstract Liver metastasis is the main cause of death in patients with colorectal cancer (CRC); thus, necessitating effective biomarkers and therapeutic targets for colorectal cancer liver metastasis (CRLM). Fibroblast growth factor 19 (FGF19) is a protumorigenic gene in numerous human malignancies. In this study, it is shown that FGF19 plays an indispensable role in CRLM. FGF19 expression and secretion are markedly correlated with liver metastasis and lower overall survival rates of patients with CRC. An in vivo metastasis model shows that FGF19 overexpression confers stronger liver‐metastatic potential in CRC cells. Mechanistically, FGF19 exerts an immunomodulatory function that creates an environment conducive for metastasis in CRLM. FGF19 mediates the polarization of hepatic stellate cells to inflammatory cancer‐associated fibroblasts (iCAFs) by activating the autocrine effect of IL‐1α via the FGFR4‐JAK2‐STAT3 pathway. FGF19‐induced iCAFs promote neutrophil infiltration and mediate neutrophil extracellular trap (NET) formation in liver metastatic niches via the production of complement C5a and IL‐1β, which in turn accelerates the liver colonization of CRC cells. Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19‐induced liver metastasis in a mouse model. In summary, this study describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention.

Background and purpose: Sex difference in cerebral atherosclerosis has been noted in previous studies, but the precise characteristics remain incompletely elucidated. This study aims to identify the sex difference in patients with asymptomatic cerebrovascular stenosis. Materials and methods: The image and clinical data of 1305 consecutive patients who had head and neck computed tomography angiography (CTA) were collected. Fifty hundred and seventy-three patients (287 males) with asymptomatic atherosclerotic stenosis in cerebral arteries were finally included. The stenosis number, distribution, severity and their changes with age were analyzed and compared between males and females. Simple linear regression was used to assess the change in lesions with age. Results: A total of 2097 stenoses were identified in 573 patients, males had more stenoses than females (3 [2, 5] vs 3 [2, 4], p=0.015). The number of stenoses in extracranial arteries was much higher in males (p = 0.001). Females had higher percentage of stenosis in anterior (89.6% vs 85.9%, p = 0.012) and intracranial arteries (63.3% vs 57.1%, p = 0.004) than males. Males had higher percentage of moderate-severe stenosis (5.1% vs 3.2%, p = 0.026). Age (OR = 1.67; 95% CI 1.24–2.25; p

Abstract Immunotherapy had demonstrated inspiring effects in tumor treatment, but only a minority of people could benefit owing to the hypoxic and immune-suppressed tumor microenvironment (TME). Therefore, there was an urgent need for a strategy that could relieve hypoxia and increase infiltration of tumor lymphocytes simultaneously. In this study, a novel acidity-responsive nanoscale ultrasound contrast agent (L-Arg@PTX nanodroplets) was constructed to co-deliver paclitaxel (PTX) and L-arginine (L-Arg) using the homogenization/emulsification method. The L-Arg@PTX nanodroplets with uniform size of about 300 nm and high drug loading efficiency displayed good ultrasound diagnostic imaging capability, improved tumor aggregation and achieved ultrasound-triggered drug release, which could prevent the premature leakage of drugs and thus improve biosafety. More critically, L-Arg@PTX nanodroplets in combination with ultrasound targeted microbubble destruction (UTMD) could increase cellular reactive oxygen species (ROS), which exerted an oxidizing effect that converted L-Arg into nitric oxide (NO), thus alleviating hypoxia, sensitizing chemotherapy and increasing the CD8 + cytotoxic T lymphocytes (CTLs) infiltration. Combined with the chemotherapeutic drug PTX-induced immunogenic cell death (ICD), this promising strategy could enhance immunotherapy synergistically and realize powerful tumor treatment effect. Taken together, L-Arg@PTX nanodroplets was a very hopeful vehicle that integrated drug delivery, diagnostic imaging, and chemoimmunotherapy. Graphical Abstract

The construction of multifunctional oncotherapy nanoplatforms that combine diagnosis and treatment remains challenging. Nanodroplets (NDs), which simultaneously enhance ultrasound imaging and therapeutic effects, are a potential strategy for non-invasive drug delivery. To achieve the goals of precise medicine, novel SP94 peptide-modified and doxorubicin-loaded ultrasonic NDs (SP94-DOX-NDs) for castration-resistant prostate cancer (CRPC) targeting and treatment were constructed in this study. The characteristics, contrast-enhanced ultrasound imaging (CEUI), targeting ability to glucose-regulated protein 78 (GRP78)-overexpressing CRPC and anticancer effect of the SP94-DOX-NDs were assessed. The desired SP94-NDs were successfully prepared using the nanoemulsification method using a certain proportion of SP94-PEG-chitosan, perfluoropentane (PFP), Tween 20, and lecithin. SP94-NDs with a size of ∼300 nm showed great biocompatibility and CEUI ability. Compared with blank NDs, SP94-NDs exhibited higher tumor-specific targeting ability due to conjugation between the SP94 peptide and GRP78-overexpressing 22RV1 cells. Most importantly, in vitro and in vivo investigations showed that SP94-DOX-NDs combined with ultrasound could specifically deliver DOX into 22RV1 cells and thereby demonstrated a stronger anticancer effect than DOX-NDs and DOX. Thus, SP94-DOX-NDs may provide an efficient approach for the real-time imaging of tumors and triggered, accurate drug delivery to tumors.

Ultrasound nanodroplets (NDs) have been reported as a promising nanocarrier for siRNA delivery depending on its unique strengths of sonoporation. Presently, common means for NDs-mediated siRNA delivery is through electrostatic interaction, but challenges like cationic toxicity still exist. In this study, we demonstrated a novel strategy to construct negatively charged and ultrasound (US)-responsive O-carboxymethyl chitosan (O-CMS) NDs as a siRNA targeted delivery system through three-way junction of bacteriophage phi29 DNA packaging motor (3WJ-pRNA) nanotechnology. 39nt A10-3.2 aptamer targeting prostate specific membrane antigen (PSMA) and 21nt siRNA against cationic amino acid transporter 1 (siCAT-1) were annealed to 3WJ-pRNA scaffold via complementation with an extended sequence. The cholesterol molecule attached to one branch facilitates the 3WJ-pRNA nanoparticles anchoring onto NDs. The desired O-CMS NDs with siRNA-loading and RNA-aptamer modification (A10-3.2/siCAT-1/3WJ-NDs) were successfully prepared, which were with spherical shapes, core–shell structures and uniform in sizes (198 nm with PDI 0.3). As a main proportion of shell, O-CMC showed a certain anti-tumor effects. In vitro studies demonstrated that A10-3.2/siCAT-1/3WJ-NDs exhibited good contrast-enhanced US imaging, buffering capacity and high bio-safety, were able to deliver siCAT-1 to PSMA-overexpressed prostate cancer cells under US irradiation, thus silence the CAT-1 expression, and consequently suppressing 22RV1 cell proliferation and migration. Taken overall, our findings provide a promising strategy to develop negatively charged and US-responsive NDs for tumor-targeted siRNA delivery.

Glutaric aciduria type I (GA-I) is an autosomal recessive genetic disorder caused by a deficiency in glutaryl-CoA dehydrogenase (GCDH). Patients who do not receive proper treatment may die from acute encephalopathic crisis. Current treatments for GA-I include a low-lysine diet combined with oral supplementation of L-carnitine. A mouse model of Gcdhc.422_428del/c.422_428del (Gcdh−/−) was generated in our laboratory using CRISPR/Cas9. Gcdh−/− mice had significantly higher levels of glutaric acid (GA) in the plasma, liver, and brain than those in wild-type C57BL/6 mice. When given a high-protein diet (HPD) for two days, approximately 60% of Gcdh−/− mice did not survive the metabolic stress. To evaluate whether GCDH gene replacement therapy could be used to provide sustained treatment for patients with GA-1, we prepared a recombinant adeno-associated virus (rAAV) carrying a human GCDH expression cassette and injected it into Gcdh−/− neonates for a proof-of-concept (PoC) study. Our study demonstrated that delivering rAAV to the central nervous system (CNS), but not the peripheral system, significantly increased the survival rate under HPD exposure. Our study also demonstrated that rAAVPHP.eB mediated a higher efficiency than that of rAAV9 in increasing the survival rate. Surviving mice showed dose-dependent GCDH protein expression in the CNS and downregulation of GA levels. Our study demonstrated that AAV-based gene replacement therapy was effective for GA-I treatment and provided a feasible solution for this unmet medical need.

Abstract The seepage is completed under the control of the action. There is a definite relationship between the seepage and its controlling factors. The recharge flow, seepage flow and water level change are unified. In this paper, the exact and complete relationship among seepage flow, recharge flow and water level change is discussed in detail through field observation and repeated tests, and a new equation for clarifying seepage flow law and water level change law is established, it provides more accurate, more convenient and more reliable theoretical basis for solving the problem of seepage flow. At the same time, through the study of seepage movement law, it is found that the method of parameter introduction has some disadvantages, and then a new method is established to study the law of seepage movement.

There are problems in rural energy consumption, such as extensive management, poor economy and high gas emission. A multi-objective operation optimization method is proposed, in this paper, to solve the problems of economic and environmental protection operation of rural decentralized integrated energy system. The basic structure of rural decentralized integrated energy system was studied. The energy system was composed of solar collector, air source heat pump, heat storage water tank and electric boiler, which is composed of solar energy as the main energy source and air energy as the auxiliary energy source. A multi-objective operation optimization model of integrated energy system was constructed under the constraints of energy supply and demand balance and equipment capacity balance, taking economy and environmental protection as dual objectives. NSGA-II algorithm with dynamic congestion degree was selected to solve the optimization model. The economy and environmental protection of the optimized integrated energy heating system have been improved in the operation process through simulation analysis.

As an acute and highly lethal infectious disease, there is no specific therapeutic drug for canine distemper (CD). Although the process of large-scale production of canine distemper virus (CDV) vaccine of mink has been greatly improved, there are still many deficiencies to be perfected. As one of the most promising technologies for large-scale vaccine production, microcarrier suspension culture technology needs to be further improved. In this study, the application effect of the new Cephodex microcarrier in CDV culture was evaluated to establish a set of technical process for DF-1 cell high-density growth and CDV efficient proliferation. To perfect the large-scale CDV production process, Cephodex was used to suspension culture DF-1 cells for proliferating CDV. In a shake flasks culture system, the optimal culture conditions were established by optimizing culture temperature, virus inoculation and harvest time. Therefore, mink CD vaccine high-efficiency production was laid on the preliminarily established technology of CDV microcarrier suspension culture. The cell density could reach over 3×106 cells/mL after 72 h cultured with Cephodex microcarrier at 37°C. Proliferated at 35°C, the CDV titer after 72 h was about 100.5 TCID50/0.1ml higher than that at 33°C and 37°C. These results show that the Cephodex microcarrier could be used for large-scale culture of DF-1 cells and efficient proliferation of CDV.

On the basis of metal crystal structures, the theoretical models of effective elastic Young's modulus of body centered cubic (BCC) and face-centered cubic (FCC) lattice materials were established by using Timoshenko beam model, and the flexibility matrix of lattice materials was determined. The effect of nodal and shear on the Young's modulus of lattice materials was analyzed. The results show that the theoretical model is in good agreement with the finite element numerical simulation. Moreover, the lattice nodal has a great influence on the equivalent Young's modulus and shear modulus of BCC and FCC lattices, and the elastic properties of lattice materials will be underestimated if the nodal effect is ignored. FCC has a higher specific Young's modulus than BCC lattice, while BCC has a higher specific shear modulus than FCC lattice. Furthermore, FCC lattice materials have higher compression stiffness than most of lattice materials.