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BackgroundThe lack of understanding of molecular pathologies of the solitary functioning kidney makes improving and strengthening the continuity of care between pediatric and adult nephrological patients difficult. Copy number variations (CNVs) account for a molecular cause of solitary functioning kidney, but characterization of the pathogenic genes remains challenging.MethodsIn our prospective cohort study, 99 fetuses clinically diagnosed with a solitary functioning kidney were enrolled and evaluated using chromosomal microarray analysis (CMA). The genetic drivers for the pathogenic CNVs were analyzed. We characterized QPRT localization in fetal kidneys using immunohistochemistry and its expression in adult kidneys using quantitative RT-PCR. Further, QPRT was knocked down using siRNA in human embryonic kidney (HEK293T) cells, and the cell cycle and proliferation were tested.ResultsBesides one Triple X syndrome and one Down syndrome, we identified a total of 45 CNVs out of 34 subjects. Among the 14 pathogenic CNVs, CNV 16p11.2 reached the highest number of records with the phenotype of kidney anomalies in the Decipher database. Among the 26 genes within the 16p11.2 region, as a key enzyme for nicotinamide adenine dinucleotide (NAD+) biosynthesis, QPRT was distinctly localized in renal tubules but was barely observed in renal interstitial and glomeruli in fetal kidneys. The loss of QPRT prevented cells’ efficient transition into S phase, affected cell-cycle progression, and abrogated proliferation of human embryonic kidney cells.ConclusionOur data suggest that QPRT is a candidate gene associated with susceptibility for solitary functioning kidney. The CNVs discovered in our study exhibit great potential for future applications in genetic counseling and pregnancy management.

BackgroundAbnormal eye movements occur at the early stages of Alzheimer’s disease (AD). However, the characteristics of abnormal eye movements of patients with AD and their relationship with clinical symptoms remain inconsistent, and their predictive value for diagnosing and monitoring the progression of AD remains unclear.MethodsA total of 42 normal controls, 63 patients with mild cognitive impairment due to AD (AD-MCI), and 49 patients with dementia due to AD (AD-D) were recruited. Eye movements were assessed using the EyeKnow eye-tracking and analysis system. Cognitive function, neuropsychiatric symptoms, and activities of daily living were evaluated using various rating scales, and correlation analyses and receiver operating characteristic curves were performed.ResultsPatients with AD exhibited increased number of offsets and offset degrees, prolonged offset duration, and decreased accuracy in lateral fixation; reduced accuracy, prolonged saccadic duration, and decreased velocity in prosaccade; decreased accuracy and corrected rate, prolonged corrected antisaccadic duration, and reduced velocity in antisaccade; and reduced accuracy and increased inhibition failures in memory saccade. Eye movement parameters were correlated with global cognition and the cognitive domains of memory, language, attention, visuospatial ability, execution function, and activities of daily living. Subgroup analysis indicated that the associations between eye movements and clinical symptoms in patients with AD were influenced by disease severity and history of diabetes. In the AD-D and AD with diabetes groups, these associations diminished. Nevertheless, the associations persisted in the AD-MCI and AD without diabetes groups. The areas under the curves for predicting AD, AD-MCI, and AD-D were 0.835, 0.737, and 0.899, respectively (all p

IntroductionAcupuncture is beneficial in improving visual function for myopi periocular acupoints Taiyang can improve contrast sensitivity (CS). In this study, we aim to further investigate the impact of acupuncture at the limbs acupoints-Guangming(GB37) acupoint on visual function, and the neural mechanism of acupuncture at the GB37 acupoint improving visual function through electroencephalography (EEG) microstate.MethodsA total of 22 myopia were recruited. Uncorrected distance visual acuity (UDVA) and CS of myopic patients were tested before and after acupuncture, and EEG data were recorded throughout the entire acupuncture procedure.ResultsOur study found that compared with pre-acupuncture, the UDVA and CS of both eyes at each spatial frequency were improved; compared with the resting state of pre-acupuncture, the duration, occurrence and contribution of microstate A were significantly increased, while those of microstate D were decreased during the post-acupuncture state. The duration of microstate A was positively correlated with the CS. There was no correlation between UDVA and EEG microstates.DiscussionAcupuncture at GB37 can improve the UDVA and CS in myopic patients, which may be related to microstate A.

Ozone formation is closely tied to emissions of precursors, meteorological conditions, and atmospheric chemistry. In June 2024, Xuzhou City, located at the intersection of Jiangsu, Shandong, Henan, and Anhui provinces in East China, experienced a series of ozone pollution events. The continuous pollution episodes were characterized by consistently high levels of ozone, with daytime peaks reaching 130 ppb. By combining observations of atmospheric oxidation and the use of the Observation-Based Model model, it was determined that the pollution was the result of a “heatwave-ozone” co-occurring extreme event triggered by elevated temperatures, low humidity, and intense radiation. The heatwave led to increased emissions of VOCs from both natural and human-related sources, with more pronounced contribution from Bio-alkenes and OVOCs. This, in turn, resulted in higher levels of oxidizing agents and ozone formation potential, exacerbating the co-occurrence of heatwaves and ozone extremes. Sensitivity tests on enhanced controls showed that reducing NOx had a significant adverse effect on ozone levels, whereas reducing VOCs had positive benefits, particularly for controlling alkenes. Despite ongoing reductions in anthropogenic VOCs, the elevated temperatures led to an increase in natural VOCs emissions. On average, a 1°C temperature decrease could reduce the reactivity ratio of VOCs to NOx (VOCR/NOxR) by 0.12, thereby enhancing the advantages of emission reductions. Therefore, implementing measures to alleviate extreme heatwaves, such as limiting high-energy consumption and inducing artificial rainfall, can simultaneously reduce the intensity and reactivity of VOC emissions, aiding in the effective implementation of ozone pollution control policies.

The malignant mesothelioma mainly develops in the pleura and peritoneum, while primary ovarian mesothelioma is very rare. Here, we report the first case of primary ovarian mesothelioma (clear cell variant) with VHL mutations in the world based on the results of histomorphology, immunohistochemistry, and genetic testing. This is an extremely rare type of tumor that has not been reported so far. Through the literature search, we reviewed primary ovarian mesothelioma, focusing on its differential diagnosis and molecular genetics. The purpose of this paper is to deepen the flexible selection and application of immunohistochemical markers in mesothelioma, so as to reduce missed diagnosis and misdiagnosis.

ObjectiveOur study was conducted to explore the link between oxidative balance score (OBS) and rheumatoid arthritis (RA).MethodsA total of 21,415 participants were included in our research from five cycles (2011–2012, 2013–2014, 2015–2016, 2017–2018, and 2017–2020) of the National Health and Nutrition Examination Survey (NHANES). Moreover, 20 elements related to diet as well as lifestyle were combined to calculate OBS. The relationship between OBS and RA was assessed by employing multivariable regression analysis, and further exploration was carried out through subgroup analysis, restricted cubic spline analysis, and sensitivity analysis. Multiple covariates were selected to adjust the model for more robust results.ResultsIn our cross-sectional study, a higher OBS has a protective effect on the development of RA (OR = 0.98, 95% CI: 0.97 to 0.99). In contrast to individuals aged ≥60, the result is more prominent in the population aged 20–60 (OR = 0.97, 95% CI: 0.96 to 0.98). Marital status appears to introduce interference in the relationship between OBS and RA, and unmarried individuals exhibited different outcomes (OR = 1.02, 95% CI: 0.99 to 1.04) compared to others. The positive influence of OBS was more evident in patients with chronic kidney disease and cardiovascular disease, while it was stronger in individuals without diabetes and liver disease.ConclusionA higher OBS correlates with a reduced odd of RA. Further studies are needed to shoot more sights on improving dietary habits and lifestyles to gain proper OBS and explore whether OBS can be one of the measurements utilized to measure the risk of RA.

AimThyroid dysfunction is closely associated with periodontitis. We aim to explore the association between sensitivity to thyroid hormones (THs) and periodontitis and to investigate the mediating role of serum 25-hydroxyvitamin D[25(OH)D] in this relationship in Chinese euthyroid populations.MethodsThis population-based retrospective study included 2,530 euthyroid participants. Central sensitivity to THs was assessed by the thyroid feedback quantile-based index (TFQI), parametric thyroid feedback quantile-based index (PTFQI), thyrotrophic thyroxine resistance index (TT4RI) and thyroid-stimulating hormone index (TSHI), while FT3/FT4 was evaluated to assess peripheral sensitivity. Multivariable regression analysis and restricted cubic spline were performed to explore the association between sensitivity to THs and periodontitis. Threshold effect and subgroup analysis were also conducted. Mediation analysis was performed to estimate direct and indirect effects through 25(OH)D.ResultsMultivariable regression analysis indicated that central sensitivity to THs indices(per SD increase) were positively associated with periodontitis risk [TFQI: OR=1.19,95% CI (1.09, 1.31); PTFQI: OR=1.22, 95% CI(1.12,1.34); TSHI: OR=1.36, 95% CI (1.21,1.52); TT4RI: OR=1.43, 95% CI (1.25,1.63)](all P value

IntroductionThe oil and gas production industry requires rapid changing. As oil and gas companies around the world are called upon to decarbonize, several sectors within the industry are attempting to find new ways of working to achieve decarbonization. One of those sectors is spare parts warehousing. During the past decades of oil and gas production, spare parts warehousing has not been prioritized in optimization measures. Warehouses have been filled with material, all activities have been performed manually, and financial expenditure has been high. Now, a large oil and gas production company in Norway is looking to optimize its spare parts warehousing to streamline its logistics activities and increase sustainability.MethodThis study addresses the optimization ambitions of the company and proposes key design elements of a smart warehouse management system using Industry 4.0 technology implementation. The study is conducted by performing a review of relevant literature and company ambitions, before embarking on a qualitative design measure to contribute to the company’s innovative success.ResultsThe study proposes optimization of the warehouse activities goods receipt, issuing of stocked goods, and inventory count. Additionally, the digital supply chain of tomorrow and the technical architecture of a track and trace system in the warehouse is suggested.DiscussionThe study’s results can be used in practical implications and provide a foundation for future research. Future research is suggested to include extensive visual simulations, practical implementation studies, and studies on long-term effects of implementation.

Toxoplasma gondii (T. gondii), an obligate intracellular protozoan parasite, is increasingly recognized for its role in various human diseases, including periodontal diseases. Periodontal diseases comprise a wide range of inflammatory conditions that not only affect the supporting structures of the teeth and oral health but also contribute to systemic diseases. The parasite’s ability to modulate the host’s immune response and induce chronic inflammation within the periodontium is a key factor in periodontal tissue damage. Through its virulence factors, T. gondii disrupts the balance of inflammatory cytokines, leading to dysregulated immune responses, and exacerbates oxidative stress in periodontal tissues. And T. gondii invasion could affect specific proteins in host cells including HSP70, BAGs, MICs, ROPs, SAGs, and GRAs leading to periodontal tissue damage. The indirect role of the host immune response to T. gondii via natural killer cells, monocytes, macrophages, neutrophils, dendritic cells, T cells, and B cells also contributes to periodontal diseases. Understanding these complex interactions of T. gondii with host cells could unravel disease mechanisms and therapeutic targets for periodontal diseases. This review delves into the pathogenic mechanisms of T. gondii in periodontal diseases, offering a detailed exploration of both direct and indirect pathways of its impact on periodontal health.

BackgroundPrenatal drug use may cause toxicity to bone health in newborns. We aimed to examine whether birth outcomes mediate the association between medication use and neonatal metabolic bone disease (MBD).MethodsA prospective cohort of 10,801 pregnant women (17–49 years) and their infants followed at a single center from 1 January 2012 to 31 December 2021 were included. Based on four single drugs, comprehensive medication use was determined and categorized into three groups using latent-class analysis: group 1 included antibiotics and furosemide or less than two drugs except for MgSO4; group 2 included MgSO4 without antibiotics or furosemide; and group 3 encompassed dexamethasone and antibiotics. Mediation analysis was conducted to assess the mediating effects of prematurity, low birth weight (LBW), and small for gestational age (SGA).ResultsThere were 138 (1.3%) infants with MBD; 2,701 (25%) were born preterm, 1717 (15.9%) had LBW, and 303 (2.8%) were SGA. Pregnant women in groups 2 and 3 were 2.52 to 14.66 times more likely to deliver an infant with MBD than those in group 1. Only LBW showed a significant mediating effect on the association between comprehensive medication use and MBD, with a mediation proportion of 51.8% (45.0–64.1%, p

A tunable continuous wave (CW) Yb:CaWO4 laser operating in near infrared (NIR) spectral region is demonstrated by pumping with a diode laser. Continuously broadband tunable wavelengths are obtained in two polarizations by rotating the Lyot filter. The tuning widths of the output wavelengths in the π- and σ-polarizations are 42 nm (from 1005.2 nm to 1047.2 nm) and 41.8 nm (from 1005.1 nm to 1046.9 nm), respectively. At an absorbed pump power of 15.6 W at 976 nm, the maximum output powers in the π- and σ-polarizations are 5.2 W at 1026.2 nm and 4.7 W at 1028.1 nm, respectively. To the best of our knowledge, this is the first tunable laser operation by using Yb:CaWO4 crystal.

BackgroundRestricting salt, caffeine, and alcohol intake is commonly recommended as a first-line treatment for patients with Ménière’s disease (MD). However, it remains unclear whether these interventions effectively improve symptoms of MD. Therefore, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis to evaluate the relationship between these dietary modifications and MD.MethodsSummary statistics for salt added to food, alcohol consumption, coffee consumption, and MD were sourced from the United Kingdom Biobank, GSCAN, and the FinnGen study, involving up to 941,280 participants. The main analyses were performed using the random-effects inverse-variance weighted (IVW) approach and were complemented by four additional methods. Multiple sensitivity analyses were performed to validate the findings, and both forward and reverse MR analyses were employed to address potential reverse causality bias.ResultsThe primary MR results using the IVW method revealed that salt added to food (OR = 0.719, 95% CI: 0.429–1.206; p = 0.211), alcohol consumption (OR = 0.834, 95% CI: 0.427–1.628; p = 0.595), and coffee consumption (OR = 0.852, 95% CI: 0.555–1.306; p = 0.461) were not significantly correlated with MD. In reverse analysis, no evidence of significant effect was found from MD to salt added to food (OR = 1.000, 95% CI: 0.993–1.007; p = 0.957), alcohol consumption (OR = 0.998, 95% CI: 0.987–1.008; p = 0.682), and coffee consumption (OR = 0.998, 95% CI: 0.985–1.011; p = 0.72).ConclusionThis MR analysis did not identify convincing evidence to support the idea that restricting salt, caffeine, and alcohol intake is beneficial for the treatment of MD.

BackgroundHigh-risk double-expressor diffuse large B-cell lymphoma has an inferior prognosis following standard first-line therapy. After failure of second-line therapy, treatment options are limited if accompanied by localized compressive symptoms. Chimeric Antigen Receptor T cell (CAR-T) therapy preceded by bridging radiotherapy may be an effective emerging therapy.Case presentationWe report a 66-year-old female patient diagnosed with stage IV double-expressor diffuse large B-cell lymphoma. The patient achieved progressive disease after two cycles of rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone and continued to develop cervical lymph node recurrence after second-line therapy. The patient was infused with CAR-T cells after receiving focal bridging radiotherapy and remained in complete response more than 9 months after treatment. In addition, the patients did not experience serious adverse reactions related to radiotherapy as well as CAR-T cell therapy.ConclusionsIn this article, we describe a patient with double-expressor diffuse large B-cell lymphoma with localized compression symptoms after second-line treatment failure who benefited from CAR-T combined with focal bridging radiotherapy.

IntroductionFetal membrane inflammation is an integral event of parturition. However, excessive pro-inflammatory cytokines can impose threats to the fetus. Coincidentally, the fetal membranes express abundant 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), which generates biologically active cortisol to promote labor through induction of prostaglandin synthesis. Given the well-recognized anti-inflammatory actions of glucocorticoids, we hypothesized that cortisol regenerated in the fetal membranes might be engaged in restraining fetus-hazardous pro-inflammatory cytokine production for the safety of the fetus, while reserving pro-labor effect on prostaglandin synthesis to ensure safe delivery of the fetus.MethodsThe hypothesis was examined in human amnion tissue and cultured primary human amnion fibroblasts as well as a mouse model.Results11β-HSD1 was significantly increased in the human amnion in infection-induced preterm birth. Studies in human amnion fibroblasts showed that lipopolysaccharide (LPS) induced 11β-HSD1 expression synergistically with cortisol. Cortisol completely blocked NF-κB-mediated pro-inflammatory cytokine expression by LPS, but STAT3-mediated cyclooxygenase 2 expression, a crucial prostaglandin synthetic enzyme, remained. Further studies in pregnant mice showed that corticosterone did not delay LPS-induced preterm birth, but alleviated LPS-induced fetal organ damages, along with increased 11β-HSD1, cyclooxygenase 2, and decreased pro-inflammatory cytokine in the fetal membranes.DiscussionThere is a feed-forward cortisol regeneration in the fetal membranes in infection, and cortisol regenerated restrains pro-inflammatory cytokine expression, while reserves pro-labor effect on prostaglandin synthesis. This dual role of cortisol regeneration can prevent excessive pro-inflammatory cytokine production, while ensure in-time delivery for the safety of the fetus.

Colorectal cancer is the third most common cancer and the second most lethal cancer in the world. The main cause of the disease is due to dietary and behavioral factors. The treatment of this complex disease is mainly based on traditional treatments, including surgery, radiotherapy, and chemotherapy. Due to its high prevalence and high morbidity, more effective treatments with fewer side effects are urgently needed. In recent years, immunotherapy has become a potential therapeutic alternative and one of the fastest-developing treatments. Immunotherapy inhibits tumor growth by activating or enhancing the immune system to recognize and attack cancer cells. This review presents the latest immunotherapies for immune checkpoint inhibitors, cell therapy, tumor-infiltrating lymphocytes, and oncolytic viruses. Some of these have shown promising results in clinical trials and are used in clinical treatment.

Riparian vegetation always grows on both sides of a natural river during a dam-break event, while the river typically retains some water instead of completely drying out. The RNG k-ϵ turbulence model is employed to examine the evolutionary characteristics of the dam-break flow in the downstream vegetated channel. This model facilitates the analysis of water-level fluctuations, velocity distributions, and the retardation effects of vegetation on the dam-break flow by varying the initial water depth (IWD) in the downstream channel. Results indicates that as the water depth in the downstream channel increases, the dam-break wave tends to form more readily, possesses a larger amplitude, and the duration of rapid congestion in the dam-break current decreases. Hence, the surface velocity gradually declines and shows an intermittent distribution. Vegetation impedes the flow evolution in the vegetated area, an effect that diminishes progressively with increasing IWD. In contrast, vegetation hastens the evolution of water flow in the main channel, which remains minimally affected by the IWD.

BackgroundSpontaneous preterm birth (sPTB) is a global disease that is a leading cause of death in neonates and children younger than 5 years of age. However, the etiology of sPTB remains poorly understood. Recent evidence has shown a strong association between metabolic disorders and sPTB. To determine the metabolic alterations in sPTB patients, we used various bioinformatics methods to analyze the abnormal changes in metabolic pathways in the preterm placenta via existing datasets.MethodsIn this study, we integrated two datasets (GSE203507 and GSE174415) from the NCBI GEO database for the following analysis. We utilized the “Deseq2” R package and WGCNA for differentially expressed genes (DEGs) analysis; the identified DEGs were subsequently compared with metabolism-related genes. To identify the altered metabolism-related pathways and hub genes in sPTB patients, we performed multiple functional enrichment analysis and applied three machine learning algorithms, LASSO, SVM-RFE, and RF, with the hub genes that were verified by immunohistochemistry. Additionally, we conducted single-sample gene set enrichment analysis to assess immune infiltration in the placenta.ResultsWe identified 228 sPTB-related DEGs that were enriched in pathways such as arachidonic acid and glutathione metabolism. A total of 3 metabolism-related hub genes, namely, ANPEP, CKMT1B, and PLA2G4A, were identified and validated in external datasets and experiments. A nomogram model was developed and evaluated with 3 hub genes; the model could reliably distinguish sPTB patients and term labor patients with an area under the curve (AUC) > 0.75 for both the training and validation sets. Immune infiltration analysis revealed immune dysregulation in sPTB patients.ConclusionThree potential hub genes that influence the occurrence of sPTB through shadow participation in placental metabolism were identified; these results provide a new perspective for the development and targeting of treatments for sPTB.

BackgroundNumerous studies have investigated the relationship between gut microbiota (GM) and multiple sclerosis(MS), highlighting the significant role of GM in MS. However, there is a lack of systematic Scientometric analyses published in this specific research area to provide an overall understanding of the current research status.MethodsPerform a scientometric analysis on research conducted between 2010 and 2023 concerning the link between GM and MS using quantitative and visual analysis software (CiteSpace and VOSviewer.)ResultsFrom January 1, 2010, and December 31, 2023, a total of 1019 records about GM and MS were retrieved. The number of publications exhibited a consistent upward trend annually. The United States led in publications, showed the strongest level of collaboration among countries. The University of California, San Francisco stands as the top institution in terms of output, and the most prolific and cited authors were Lloyd H. Kasper and Javier Ochoa-Reparaz from the USA. The research in this field primarily centers on investigating the alterations and associations of GM in MS or EAE, the molecular immunological mechanisms, and the potential of GM-based interventions to provide beneficial effects in MS or EAE. The Keywords co-occurrence network reveals five primary research directions in this field. The most frequently occurring keywords are inflammation, probiotics, diet, dysbiosis, and tryptophan. In recent years, neurodegeneration and neuropsychiatric disorders have been prominent, indicating that the investigation of the mechanisms and practical applications of GM in MS has emerged as a current research focus. Moreover, GM research is progressively extending into the realm of neurodegenerative and psychiatric diseases, potentially becoming future research hotspots.ConclusionsThis study revealed a data-driven systematic comprehension of research in the field of GM in MS over the past 13 years, highlighted noteworthy research within the field, provided us with a clear understanding of the current research status and future trends, providing a valuable reference for researchers venturing into this domain.

IntroductionThyroid function during pregnancy fluctuates with gestational weeks, seasons and other factors. However, it is currently unknown whether there is a fetal sex-specific thyroid function in pregnant women. The purpose of this study was to investigate the fetal sex differences of maternal thyroid-stimulating hormone (TSH) and free thyroxine (FT4) in pregnant women.MethodsThis single-center retrospective real-world study was performed by reviewing the medical records of pregnant women who received regular antenatal health care and delivered liveborn infants in Shanghai First Maternity and Infant Hospital (Pudong branch), from Aug. 18, 2013 to Jul. 18, 2020. Quantile regression was used to evaluate the relationship between various variables and TSH and FT4 concentrations. The quantile regression also evaluated the sex impact of different gestational weeks on the median of TSH and FT4.ResultsA total of 69,243 pregnant women with a mean age of 30.36 years were included. 36197 (52.28%) deliveries were boys. In the three different trimesters, the median levels (interquartile range) of TSH were 1.18 (0.66, 1.82) mIU/L and 1.39 (0.85, 2.05) mIU/L, 1.70 (1.19, 2.40) mIU/L; and the median levels (interquartile range) of FT4 were 16.63 (15.16, 18.31) pmol/L, 14.09 (12.30, 16.20) pmol/L and 13.40 (11.52, 14.71) pmol/L, respectively. The maternal TSH upper limit of reference ranges was decreased more in mothers with female fetuses during gestational weeks 7 to 12, while their FT4 upper limit of the reference ranges was increased more than those with male fetuses. After model adjustment, the median TSH level was 0.11 mIU/L lower (P

BackgroundSpeech analysis has been expected to help as a screening tool for early detection of Alzheimer’s disease (AD) and mild-cognitively impairment (MCI). Acoustic features and linguistic features are usually used in speech analysis. However, no studies have yet determined which type of features provides better screening effectiveness, especially in the large aging population of China.ObjectiveFirstly, to compare the screening effectiveness of acoustic features, linguistic features, and their combination using the same dataset. Secondly, to develop Chinese automated diagnosis model using self-collected natural discourse data obtained from native Chinese speakers.MethodsA total of 92 participants from communities in Shanghai, completed MoCA-B and a picture description task based on the Cookie Theft under the guidance of trained operators, and were divided into three groups including AD, MCI, and heathy control (HC) based on their MoCA-B score. Acoustic features (Pitches, Jitter, Shimmer, MFCCs, Formants) and linguistic features (part-of-speech, type-token ratio, information words, information units) are extracted. The machine algorithms used in this study included logistic regression, random forest (RF), support vector machines (SVM), Gaussian Naive Bayesian (GNB), and k-Nearest neighbor (kNN). The validation accuracies of the same ML model using acoustic features, linguistic features, and their combination were compared.ResultsThe accuracy with linguistic features is generally higher than acoustic features in training. The highest accuracy to differentiate HC and AD is 80.77% achieved by SVM, based on all the features extracted from the speech data, while the highest accuracy to differentiate HC and AD or MCI is 80.43% achieved by RF, based only on linguistic features.ConclusionOur results suggest the utility and validity of linguistic features in the automated diagnosis of cognitive impairment, and validated the applicability of automated diagnosis for Chinese language data.

BackgroundPolycyclic aromatic hydrocarbons (PAHs), as organic pollutants widely present in daily environments, have been shown by existing epidemiological studies to be significantly associated with deficits in learning and memory functions in children and adults. However, the association between exposure to PAHs and cognitive function in older adults remains unclear. Additionally, existing related studies have only assessed the association between individual PAH exposures and cognitive assessments, overlooking the risks posed by mixed exposures. This study aims to use three statistical models to investigate the individual and overall effects of mixed PAH exposures on the cognition of older adults in the United States.MethodsThe study cohort was obtained from the NHANES database, which included individuals aged 60 and older from 2011 to 2014. Weighted generalized linear models (GLM), weighted quantile sum (WQS) models, and Bayesian kernel machine regression (BKMR) models were utilized to evaluate the connections between urinary PAH metabolites and the standardized Z-scores of four cognitive tests: Immediate Recall Test (IRT), Delayed Recall Test (DRT), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST).ResultsOur analysis involved 899 individuals aged 60 and above. In the fully adjusted GLM, 2-hydroxynaphthalene (2-OHNa), 3-hydroxyfluorene (3-OHFlu), and 2-hydroxyfluorene (2-OHFlu) demonstrated negative associations with DSST Z-scores. In the WQS model, six urinary PAH metabolites were negatively linked to AFT Z-scores (β (95% confidence intervals [CI]): −0.120 (−0.208, −0.033), p = 0.007) and DSST Z-scores (β (95% CI): −0.182 (−0.262, −0.103), p

The CBL (Casitas B-lineage lymphoma) family, as a class of ubiquitin ligases, can regulate signal transduction and activate receptor tyrosine kinases through various tyrosine kinase-dependent pathways. There are three members of the family: c-CBL, CBL-b, and CBL-c. Numerous studies have demonstrated the important role of CBL in various cellular pathways, particularly those involved in the occurrence and progression of cancer, hematopoietic development, and regulation of T cell receptors. Therefore, the purpose of this review is to comprehensively summarize the function and regulatory role of CBL family proteins in different human tumors, as well as the progress of drug research targeting CBL family, so as to provide a broader clinical measurement strategy for the treatment of tumors.

The quadriceps tendon, crucial for body movement, is among the body's strongest tendons. Factors like diabetes or hormone use can weaken it, making even minor trauma potentially causing rupture. Bilateral spontaneous quadriceps tendon rupture, where both tendons tear simultaneously, is rare. Prompt diagnosis and treatment are crucial. We present a case of a 44-year-old woman who experienced bilateral rupture after falling while doing chores. She had immediate pain and limited knee movement. Diagnosis via physical examination and CT/MRI scans confirmed the rupture. Surgical repair followed by rehabilitation led to significant pain reduction and improved function within two months. Overall, her postoperative outcome was satisfactory. This study underscores the importance of clear diagnosis, timely surgery, and thorough rehabilitation for optimal patient recovery from bilateral quadriceps tendon rupture.

The type I interferon (IFN) pathway is important for eukaryotic cells to resist viral infection, as well as an impediment to efficient virus replication. Therefore, this study aims to create an IFNAR1 knockout (KO) Madin-Darby bovine kidney (MDBK) cell line using CRISPR/Cas9 and investigate its application and potential mechanism in increasing viral replication of bovines. The IFNAR1 KO cells showed increased titers of bovine viral diarrhea virus (BVDV) (1.5 log10), with bovine enterovirus and bovine parainfluenza virus type 3 (0.5–0.8 log10). RNA-seq revealed reduced expression of the genes related IFN-I pathways including IFNAR1, STAT3, IRF9, and SOCS3 in IFNAR1 KO cells compared with WT cells. In WT cells, 306 differentially expressed genes (DEGs) were identified between BVDV-infected and -uninfected cells. Of these, 128 up- and 178 down-regulated genes were mainly associated with growth cycle and biosynthesis, respectively. In IFNAR1 KO cells, 286 DEGs were identified, with 82 up-regulated genes were associated with signaling pathways, and 204 down-regulated genes. Further, 92 DEGs were overlapped between WT and IFNAR1 KO cells including ESM1, IL13RA2, and SLC25A34. Unique DEGs in WT cells were related to inflammation and immune regulation, whereas those unique in IFNAR1 KO cells involved in cell cycle regulation through pathways such as MAPK. Knocking down SLC25A34 and IL13RA2 in IFNAR1 KO cells increased BVDV replication by 0.3 log10 and 0.4 log10, respectively. Additionally, we constructed an IFNAR1/IFNAR2 double-knockout MDBK cell line, which further increased BVDV viral titers compared with IFNAR1 KO cells (0.6 log10). Overall, the IFNAR1 KO MDBK cell line can support better replication of bovine viruses and therefore provides a valuable tool for bovine virus research on viral pathogenesis and host innate immune response.

BackgroundWith the increase in the aging population worldwide, Alzheimer’s disease has become a rapidly increasing public health concern. In the Global Burden of Disease Study 2019, there are three risk factors judged to have evidence for a causal link to Alzheimer’s disease and other dementias: smoking, high body-mass index (HBMI), and high fasting plasma glucose (HFPG).ObjectiveThis study aimed to analyze trends in AD mortality and the relevant burden across China from 1990 to 2019, as well as their correlation with age, period, and birth cohort.MethodsThe data were extracted from the GBD 2019. Trends in AD mortality attributable to metabolic risks (HFPG and HBMI) and smoking were analyzed using Joinpoint regression. The age-period-cohort (APC) model was used to evaluate cohort and period effects.ResultsFrom 1990 to 2019, the overall age-standardized mortality rate of AD increased, especially in women. There was an increase in AD mortality due to smoking in the net drift, and it was more significant in women (0.46, 95%CI = [0.09, 0.82]) than men (−0.03, 95%CI = [−0.11, 0.05]). For the cause of HFPG, the net drift values for men and women were 0.82% and 0.43%. For HBMI, the values were 3.14% and 2.76%, respectively, reflecting substantial increases in AD mortality.ConclusionTime trends in AD mortality caused by metabolic risks and smoking in China from 1990 to 2019 have consistently increased. Therefore, it is necessary to prevent excessive weight gain and obesity during the later stages of life, especially for females.

IntroductionWorkplace violence against healthcare workers has become a serious global public health problem. The incidence of workplace violence towards Psychiatric nurses is higher than in all other medical institutions, up to 84.2% per year. It not only negatively affects many aspects of healthcare workers’ lives, but also destroys the harmony of the nurse–patient relationship and reduces the quality of nursing care. The number of psychiatric nurses in China was approximately 96,000, far lower than most other countries and unable to meet the growing demand for mental health. However, the increase in workplace violence has future exacerbates the current shortage of nurses. Therefore, it is necessary to develop effective strategies to prevent psychiatric nurses from suffering from workplace violence, thereby to reduce nurse turnover and improve the quality of nursing care. A comprehensive understanding of psychiatric nurses’ preferences and priorities for preventing workplace violence is an important prerequisite before formulating strategies and taking measures. Unfortunately, to date, no research has investigated the psychiatric nurses’ preferences. Therefore, a discrete choice experiment (DCE) is conducting to explore the psychiatric nurses’ preferences for workplace violence prevention. This article reports on methodological details of the DCE.Methods and analysisSix attributes were developed through a literature review, one-on-one interviews and focus group discussions. D-efficient design in NGENE was used to generate choice sets. SPSS 24.0 will be used for descriptive analysis of social Demography, and Stata 16.0 will be used for analysis of DCE data. A multinomial logit model will be used to preliminarily explore trade-offs between workplace violence prevention characteristics included in the choice tasks. Then, in a mixed logit model, we plan to choose some arbitrarily defined base violence prevention program and will use the nlcom command to evaluate the probability of an alternative violence prevention program.Ethics and disseminationThe study was approved by the relevant ethics committees. Our findings will emphasize priority intervention areas based on the preferences of psychiatric nurses and provide references for hospitals to develop and improve workplace violence prevention strategies. The results will be shared through seminars, policy briefs, peer-reviewed journal articles and online blogs.

Human regulatory T cells (Treg) suppress other immune cells. Their dysfunction contributes to the pathophysiology of autoimmune diseases, including type 1 diabetes (T1D). Infusion of Tregs is being clinically evaluated as a novel way to prevent or treat T1D. Genetic modification of Tregs, most notably through the introduction of a chimeric antigen receptor (CAR) targeting Tregs to pancreatic islets, may improve their efficacy. We evaluated CAR targeting of human Tregs to monocytes, a human β cell line and human islet β cells in vitro. Targeting of HLA-A2-CAR (A2-CAR) bulk Tregs to HLA-A2+ cells resulted in dichotomous cytotoxic killing of human monocytes and islet β cells. In exploring subsets and mechanisms that may explain this pattern, we found that CD39 expression segregated CAR Treg cytotoxicity. CAR Tregs from individuals with more CD39low/- Tregs and from individuals with genetic polymorphism associated with lower CD39 expression (rs10748643) had more cytotoxicity. Isolated CD39− CAR Tregs had elevated granzyme B expression and cytotoxicity compared to the CD39+ CAR Treg subset. Genetic overexpression of CD39 in CD39low CAR Tregs reduced their cytotoxicity. Importantly, β cells upregulated protein surface expression of PD-L1 and PD-L2 in response to A2-CAR Tregs. Blockade of PD-L1/PD-L2 increased β cell death in A2-CAR Treg co-cultures suggesting that the PD-1/PD-L1 pathway is important in protecting islet β cells in the setting of CAR immunotherapy. In summary, introduction of CAR can enhance biological differences in subsets of Tregs. CD39+ Tregs represent a safer choice for CAR Treg therapies targeting tissues for tolerance induction.

Cerebrospinal fluid-contacting neurons (CSF-cNs) represent a distinct group of interneurons characterized by their prominent apical globular protrusions penetrating the spinal cord’s central canal and their basal axons extending towards adjacent cells. Identified nearly a century back, the specific roles and attributes of CSF-cNs have just started to emerge due to the historical lack of definitive markers. Recent findings have confirmed that CSF-cNs expressing PKD2L1 possess attributes of neural stem cells, suggesting a critical function in the regeneration processes following spinal cord injuries. This review aims to elucidate the molecular markers of CSF-cNs as potential neural stem cells during spinal cord development and assess their roles post-spinal cord injury, with an emphasis on their potential therapeutic implications for spinal cord repair.

Plant protection unmanned aerial vehicles (UAVs) have become popular in mountain orchards, but due to the differences in planting structures, the chances of heavy spraying, missed spraying and pesticide drift are increasing. To mitigate the adverse effects of these phenomena, it is necessary to clarify the effective deposition range of aerial spray droplets. This study proposed an effective spray swath determination method for the effective spraying range of mountainous orchards with UAVs equipped with a mist nozzle (bilateral 1% coverage). This approach focused on exploring the effects of flight height (unidirectional flight modes of 2, 3 and 4 m), spray nozzle atomization performance (reciprocating flight modes of 20, 30 and 40 µm) and flight route (treetop flying and inter-row flying) on the spraying range in a mountain setting. In addition, the study analysed the relationship between the droplet-size spectrum and the effective swath position. The results showed that it is feasible to use the bilateral 1% coverage evaluation method to determine the effective spray swath of a UAV adapted with a mist nozzle for aerial operation in a mountainous Nangguo Pear orchard. With the increase in UAV flight height (2–4 m), the effective unidirectional spray swath also increased, and with the increase in atomization level (20–40 μm), the effective reciprocating spray swath showed a decreasing trend. Moreover, the average effective swath width measured by the UAV for treetop flight was greater than that measured for inter-row flight. The study also found that the proportion of small droplets (droplet size less than 100 µm) below the UAV route was lower (approximately 50%) than along the sides of the route (approximately 80%), and the spray swath was not symmetrically distributed along the flight route but shifted laterally by approximately 3 to 4 m in the downhill direction.

BackgroundLimited research has explored the association between dietary soy products and colorectal polyps and adenomas, with insufficient attention given to cooking methods and subtypes of polyps. This study aimed to comprehensively assess the relationship between soy intake, its cooking methods, and the risk of colorectal polyps and adenomas within a high-incidence population of colorectal cancer (CRC) in China.MethodsData were derived from 14,903 participants aged 40–80 years, enrolled in the extended Lanxi Pre-colorectal Cancer Cohort (LP3C) between March 2018 and December 2022. This cross-sectional study is based on the participants’ baseline information. Long-term dietary information was collected through a validated food frequency questionnaire (FFQ), and colorectal polyps and adenomas were identified through electronic colonoscopy. Employing multivariate logistic regression, results were expressed as odds ratios (ORs) with their corresponding 95% confidence intervals (95% CIs).Results4,942 cases of colorectal polyps and 2,678 cases of adenomas were ascertained. A significant positive association was found between total soy intake and the occurrence of polyps/adenomas. Considering cooking methods, a notable increase in polyp risk was associated with the consumption of fried soys while no association was detected for boiled or marinated soys. Furthermore, total soy intake demonstrated associations with large and multiple polyps, polyps Yamade-typed less than II, and polyps across all anatomical subsites.ConclusionWithin the high-risk CRC population in China, increased soy product intake was linked to a higher risk of polyps, primarily attributed to the consumption of fried soys. This suggests that modifying cooking methods to avoid fried soys may serve as a preventive strategy for colorectal polyps.

ObjectiveTo evaluate parental knowledge of myopia control, investigate its association with children’s practice and refractive status, and explore their change under the outbreak of COVID-19 pandemic.MethodsIn this web-based survey, a self-administered questionnaire was made online available during the COVID-19 outbreak between February 1th, 2022 and August 31th, 2022 in China. Participants were recruited via social media by convenience and snowball sampling. Parents of both sexes whose children aged between 3 and 18 were eligible. The overall questionnaire was composed of four categories: demographic information, parental knowledge of myopia, children’s myopia-related behaviors and their change after the COVID-19 pandemic, and children’s refractive status. SPSS version 18.0 was applied to perform the statistics analysis and p 0.05). We found discordance phenomenon between parents’ knowledge and children’s behaviors, with parental knowledge being irrelevant to children’s sleeping time (p = 0.159, r = 0.069), the frequency of lying reading (p = 0.462, r = −0.036) and keeping nutrition diet (p = 0.142, r = 0.072), and positively correlated with daily homework time (p = 0.012, r = 0.123). After the outbreak of COVID-19, 77.8% (329/423) of parents admitted that their children’s daily routine had been changed, with children spending more time on sleeping (p

ObjectiveWe investigated the temporal trends and examined age-, period-, and cohort-specific effects of injury-related deaths among residents in Jiangsu to provide evidence for future injury prevention.MethodsThis study included 406,936 injury deaths from the Jiangsu provincial population death registration system. The average annual percent change (AAPC) in age-standardized mortality rates (ASMRs) was analyzed using joinpoint regression. Age-period-cohort models were generated to explore the effects of age, period, and birth cohort effects on mortality risk.ResultsASMRs for all injuries (AAPC = −2.3%), road traffic accidents (AAPC = −5.3%), suicide (AAPC = −3.8%), and drowning (AAPC = −3.9%) showed a downward trend during 2012–2021(all p

IntroductionThis study examined the impact of 5’-(N- ethylcarboxamido)adenosine (NECA) in the peripheral blood of healthy individuals, those with diabetes mellitus, diabetic retinopathy (DR), and C57BL/6 mice, both in vivo and in vitro.MethodsEnzyme-linked immunosorbent assay (ELISA) and flow cytometry (FCM) were used to evaluate the effects of NECA on dendritic cells (DCs) and mouse bone marrow-derived dendritic cells (BMDCs) and the effects of NECA-treated DCs on Treg and Th17 cells. The effect of NECA on the Toll-like receptor (TLR) pathway in DCs was evaluated using polymerase chain reaction (PCR) and western blotting (WB).ResultsFCM and ELISA showed that NECA inhibited the expression of surface markers of DCs and BMDCs, increased anti-inflammatory cytokines and decreased proinflammatory cytokines. PCR and WB showed that NCEA decreased mRNA transcription and protein expression in the TLR-4-MyD88-NF-kβ pathway in DCs and BMDCs. The DR severity in streptozocin (STZ) induced diabetic mice was alleviated. NECA-treated DCs and BMDCs were co-cultivated with CD4+T cells, resulting in modulation of Treg and Th17 differentiation, along with cytokine secretion alterations.ConclusionNECA could impair DCs’ ability to present antigens and mitigate the inflammatory response, thereby alleviating the severity of DR.

ObjectiveInjectable skin fillers offer a wider range of options for cutaneous anti-aging and facial rejuvenation. PLLA microspheres are increasingly favored as degradable and long-lasting fillers. The present study focused solely on the effect of PLLA on dermal collagen, without investigating its impact on the epidermis. In this study, we investigated the effects of PLLA microspheres on epidermal stem cells (EpiSCs).MethodsDifferent concentrations of PLLA microspheres on epidermal stem cells (EpiSCs) in vitro through culture, and identification of primary rat EpiSCs. CCK-8 detection, apoptosis staining, flow cytometry, Transwell assay, wound healing assay, q-PCR analysis, and immunofluorescence staining were used to detect the effects of PLLA on EpiSCs. Furthermore, we observed the effect on the epidermis by injecting PLLA into the dermis of the rat skin in vivo.ResultsPLLA microspheres promote cell proliferation and migration while delaying cell senescence and maintaining its stemness. In vitro, Intradermal injection of PLLA microspheres in the rat back skin resulted in delayed aging, as evidenced by histological and immunohistochemical staining of the skin at 2, 4, and 12 weeks of follow-up.ConclusionThis study showed the positive effects of PLLA on rat epidermis and EpiSCs, while providing novel insights into the anti-aging mechanism of PLLA.

BackgroundThe association between depression and musculoskeletal diseases has long been a subject of contentious debate. However, the causal relationship between the two remains uncertain. This study employs a two-sample Mendelian randomization (MR) analysis to investigate the causality between depression and six musculoskeletal diseases.MethodsIn this study, we performed MR analysis to systematically explore the causal relationship between depression and six musculoskeletal disorders. Single nucleotide polymorphisms (SNPs) that are linked to depression were employed as instrumental variables. To ensure robust and reliable conclusions, multiple analytical approaches were utilized, including inverse variance weighting(IVW), weighted median, and MR-Egger regression. Additionally, sensitivity analysis methods such as the MR-Egger intercept test, Cochran’s Q test, leave-one-out analysis, and funnel plot were employed.ResultsOur MR analysis revealed a significant association between depression and cervical spondylosis (depression: OR 1.003, 95% CI 1.002–1.005, P = 8.32E-05; major depressive disorder: OR 1.003, 95% CI 1.001–1.005, P = 0.0052). Furthermore, a strong correlation was noted between major depressive disorder (MDD) and knee osteoarthritis (KOA) (OR 1.299, 95% CI 1.154–1.463, P = 1.50E−5). Sensitivity analysis confirmed the robustness of these findings. Our independent validation study also corroborated these results.ConclusionThe MR analysis conducted in this study provides evidence supporting a genetic link between depression and cervical spondylosis, as well as KOA. Targeted interventions to manage depression in susceptible populations may contribute to lowering the risk of cervical spondylosis and KOA in these cohorts.

Transglutaminase (EC 2.3.2.13, TGase), an enzyme that catalyzes the formation of covalent cross-links between protein or peptide molecules, plays a critical role in commercial food processing, medicine, and textiles. TGase from Streptomyces is the sole commercial enzyme preparation for cross-linking proteins. In this study, we revealed that the SOS response repressor protein LexA in Streptomyces mobaraensis not only triggers morphological development but also enhances TGase synthesis. The absence of lexA significantly diminished TGase production and sporulation. Although LexA does not bind directly to the promoter region of the TGase gene, it indirectly stimulates transcription of the tga gene, which encodes TGase. Furthermore, LexA directly enhances the expression of genes associated with protein synthesis and transcription factors, thus favorably influencing TGase synthesis at both the transcriptional and posttranscriptional levels. Moreover, LexA activates four crucial genes involved in morphological differentiation, promoting spore maturation. Overall, our findings suggest that LexA plays a dual role as a master regulator of the SOS response and a significant contributor to TGase regulation and certain aspects of secondary metabolism, offering insights into the cellular functions of LexA and facilitating the strategic engineering of TGase overproducers.

BackgroundExplore the efficacy and safety of donor-derived CLL-1 chimeric antigen receptor T-cell therapy (CAR-T) for relapsed/refractory acute myeloid leukemia (R/R AML) bridging to allogeneic hematopoietic stem cell transplantation (allo-HSCT) after remission.Case presentationAn adult R/R AML patient received an infusion of donor-derived CLL-1 CAR-T cells, and the conditioning regimen bridging to allo-HSCT was started immediately after remission on day 11 after CAR-T therapy upon transplantation. Then, routine post-HSCT monitoring of blood counts, bone marrow (BM) morphology, flow cytometry, graft-versus-host disease (GVHD) manifestations, and chimerism status were performed.ResultAfter CAR-T therapy, cytokine release syndrome was grade 1. On day 11 after CAR-T therapy, the BM morphology reached complete remission (CR), and the conditioning regimen bridging to allo-HSCT started. Leukocyte engraftment, complete donor chimerism, and platelet engraftment were observed on days +18, +23, and +26 post-allo-HSCT, respectively. The BM morphology showed CR and flow cytometry turned negative on day +23. The patient is currently at 4 months post-allo-HSCT with BM morphology CR, negative flow cytometry, complete donor chimerism, and no extramedullary relapse/GVHD.ConclusionDonor-derived CLL-1 CAR-T is an effective and safe therapy for R/R AML, and immediate bridging to allo-HSCT after remission may better improve the long-term prognosis of R/R AML.

In high-altitude environments characterized by low pressure and oxygen levels, the intestinal microbiota undergoes significant alterations. Whether individuals are subjected to prolonged exposure or acute altitude changes, these conditions lead to shifts in both the diversity and abundance of intestinal microbiota and changes in their composition. While these alterations represent adaptations to high-altitude conditions, they may also pose health risks through certain mechanisms. Changes in the intestinal microbiota induced by high altitudes can compromise the integrity of the intestinal mucosal barrier, resulting in gastrointestinal dysfunction and an increased susceptibility to acute mountain sickness (AMS). Moreover, alterations in the intestinal microbiota have been implicated in the induction or exacerbation of chronic heart failure. Targeted modulation of the intestinal microbiota holds promise in mitigating high-altitude-related cardiac damage. Dietary interventions, such as adopting a high-carbohydrate, high-fiber, low-protein, and low-fat diet, can help regulate the effects of intestinal microbiota and their metabolic byproducts on intestinal health. Additionally, supplementation with probiotics, either through dietary sources or medications, offers a means of modulating the composition of the intestinal microbiota. These interventions may offer beneficial effects in preventing and alleviating AMS following acute exposure to high altitudes.

Introduction: Human topoisomerase 1 (TOP1) is an important target of various anticancer compounds. The design and discovery of inhibitors targeting TOP1 are of great significance for the development of anticancer drugs. Evodiamine and thieno [2,3-d] pyridine hybrids show potential antitumor activity. Herein, the anti-gastric cancer activities of these hybrids were investigated.Methods: The inhibitory effects of different concentrations of ten evodiamine derivatives on the gastric cancer cell line SGC-7901 were assessed using a methyl thiazolyl tetrazolium assay. Compounds EVO-1 and EVO-6 strongly inhibited gastric cancer cell proliferation, with inhibition rates of 81.17% ± 5.08% and 80.92% ± 2.75%, respectively. To discover the relationship between the structure and activity of these two derivatives, density functional theory was used to investigate their optimized geometries, natural population charges, frontier molecular orbitals, and molecular electrostatic potentials. To clarify their anti-gastric cancer mechanisms, molecular docking, molecular dynamics simulations, and binding free energy calculations were performed against TOP1.Results: The results demonstrated that these compounds could intercalate into the cleaved DNA-binding site to form a TOP1–DNA–ligand ternary complex, and the ligand remained secure at the cleaved DNA-binding site to form a stable ternary complex. As the binding free energy of compound EVO-1 with TOP1 (−38.33 kcal·mol−1) was lower than that of compound EVO-6 (−33.25 kcal·mol−1), compound EVO-1 could be a more potent anti-gastric cancer agent than compound EVO-6.Discussion: Thus, compound EVO-1 could be a promising anti-gastric cancer drug candidate. This study may facilitate the design and development of novel TOP1 inhibitors.

Invariant Natural Killer T cell therapy is an emerging platform of immunotherapy for cancer treatment. This unique cell population is a promising candidate for cell therapy for cancer treatment because of its inherent cytotoxicity against CD1d positive cancers as well as its ability to induce host CD8 T cell cross priming. Substantial evidence supports that iNKT cells can modulate myelomonocytic populations in the tumor microenvironment to ameliorate immune dysregulation to antagonize tumor progression. iNKT cells can also protect from graft-versus-host disease (GVHD) through several mechanisms, including the expansion of regulatory T cells (Treg). Ultimately, iNKT cell-based therapy can retain antitumor activity while providing protection against GVHD simultaneously. Therefore, these biological properties render iNKT cells as a promising “off-the-shelf” therapy for diverse hematological malignancies and possible solid tumors. Further the introduction of a chimeric antigen recetor (CAR) can further target iNKT cells and enhance function. We foresee that improved vector design and other strategies such as combinatorial treatments with small molecules or immune checkpoint inhibitors could improve CAR iNKT in vivo persistence, functionality and leverage anti-tumor activity along with the abatement of iNKT cell dysfunction or exhaustion.

BackgroundMetagenomic next-generation sequencing (mNGS) is a novel non-invasive and comprehensive technique for etiological diagnosis of infectious diseases. However, its practical significance has been seldom reported in the context of hematological patients with high-risk febrile neutropenia, a unique patient group characterized by neutropenia and compromised immune responses.MethodsThis retrospective study evaluated the results of plasma cfDNA sequencing in 164 hematological patients with high-risk febrile neutropenia. We assessed the diagnostic efficacy and clinical impact of mNGS, comparing it with conventional microbiological tests.ResultsmNGS identified 68 different pathogens in 111 patients, whereas conventional methods detected only 17 pathogen types in 36 patients. mNGS exhibited a significantly higher positive detection rate than conventional methods (67.7% vs. 22.0%, P < 0.001). This improvement was consistent across bacterial (30.5% vs. 9.1%), fungal (19.5% vs. 4.3%), and viral (37.2% vs. 9.1%) infections (P < 0.001 for all comparisons). The anti-infective treatment strategies were adjusted for 51.2% (84/164) of the patients based on the mNGS results.ConclusionsmNGS of plasma cfDNA offers substantial promise for the early detection of pathogens and the timely optimization of anti-infective therapies in hematological patients with high-risk febrile neutropenia.

IntroductionThis study investigated the effects of storage japonica brown rice (SJBR) and bile acids (BA) on the growth performance, meat quality, and intestinal microbiota of growing–finishing Min pigs.MethodsA total of 24 healthy Min pigs with a similar body weight of 42.25 ± 2.13 kg were randomly divided into three groups with eight replicates of one pig each. The groups were as follows: CON (50% corn), SJBR (25% corn +25% SJBR), and SJBR + BA (25% corn +25% SJBR +0.025% hyodeoxycholic acid). The experimental period lasted from day 90 (the end of the nursery phase) to day 210 (the end of the finishing phase).ResultsThe results showed the following: (1) Compared with the CON group, there was no significant difference in the average daily gain (ADG) and average daily feed intake (ADFI) of the SJBR and SJBR + BA groups, and the feed conversion ratio (FCR) was significantly decreased (p < 0.05). (2) Compared with the CON group, the total protein (TP) content in the serum was significantly increased, and the blood urea nitrogen (BUN) content was significantly decreased (p < 0.05) in the SJBR and SJBR + BA groups; moreover, HDL-C was significantly higher by 35% (p < 0.05) in the SJBR + BA group. (3) There were no significant differences in carcass weight, carcass length, pH, drip loss, cooking loss, and shear force among the groups; the eye muscle area was significantly increased in the SJBR group compared with the CON group (p < 0.05); back fat thickness was significantly decreased in the SJBR + BA group compared with the SJBR group (p < 0.05); and the addition of SJBR significantly increased the mRNA expression of MyHC I in the longissimus dorsi (LD) muscle of growing–finishing Min pigs (p < 0.05). (4) The cecal bacteria were detected using 16S rDNA, and the proportion of Lactobacillus was increased gradually at the genus level, but there was no significant difference among the different groups.ConclusionIn conclusion, 25% SJBR can improve the growth performance and increase the abundance of intestinal beneficial bacteria, and based on this, adding bile acids can reduce the back fat thickness of growing–finishing Min pigs.

ObjectivesThe characteristics of multimorbidity in the Chinese population are currently unclear. We aimed to determine the temporal change in multimorbidity prevalence, clustering patterns, and the association of multimorbidity with mortality from all causes and four major chronic diseases.MethodsThis study analyzed data from the China Kadoorie Biobank study performed in Wuzhong District, Jiangsu Province. A total of 53,269 participants aged 30–79 years were recruited between 2004 and 2008. New diagnoses of 15 chronic diseases and death events were collected during the mean follow-up of 10.9 years. Yule's Q cluster analysis method was used to determine the clustering patterns of multimorbidity. A Cox proportional hazards model was used to estimate the associations of multimorbidity with mortalities.ResultsThe overall multimorbidity prevalence rate was 21.1% at baseline and 27.7% at the end of follow-up. Multimorbidity increased more rapidly during the follow-up in individuals who had a higher risk at baseline. Three main multimorbidity patterns were identified: (i) cardiometabolic multimorbidity (diabetes, coronary heart disease, stroke, and hypertension), (ii) respiratory multimorbidity (tuberculosis, asthma, and chronic obstructive pulmonary disease), and (iii) mental, kidney and arthritis multimorbidity (neurasthenia, psychiatric disorders, chronic kidney disease, and rheumatoid arthritis). There were 3,433 deaths during the follow-up. The mortality risk increased by 24% with each additional disease [hazard ratio (HR) = 1.24, 95% confidence interval (CI) = 1.20–1.29]. Compared with those without multimorbidity at baseline, both cardiometabolic multimorbidity and respiratory multimorbidity were associated with increased mortality from all causes and four major chronic diseases. Cardiometabolic multimorbidity was additionally associated with mortality from cardiovascular diseases and diabetes, with HRs of 2.64 (95% CI = 2.19–3.19) and 28.19 (95% CI = 14.85–53.51), respectively. Respiratory multimorbidity was associated with respiratory disease mortality, with an HR of 9.76 (95% CI = 6.22–15.31).ConclusionThe prevalence of multimorbidity has increased substantially over the past decade. This study has revealed that cardiometabolic multimorbidity and respiratory multimorbidity have significantly increased mortality rates. These findings indicate the need to consider high-risk populations and to provide local evidence for intervention strategies and health management in economically developed regions.

ObjectiveMetabolic risks (MRs) are the primary determinants of breast cancer (BC) mortality among women. This study aimed to examine the changing trends in BC mortality associated with MRs and explore how they related to age, time period, and birth cohorts in Chinese women aged 25 and above.MethodsData were sourced from the Global Burden of Disease Study 2019 (GBD2019). The BC mortality trajectories and patterns attributable to MRs were assessed using Joinpoint regression. The age-period-cohort (APC) model was employed to evaluate cohort and time period effects.ResultsThe age-standardized mortality rate (ASMR) of BC mortality linked to MRs displayed an escalating trend from 1990 to 2019, demonstrating an average annual percentage change (AAPC) of 1.79% (95% CI: 1.69~1.87). AAPCs attributable to high fasting plasma glucose (HFPG) and high body mass index (HBMI) were 0.41% (95% CI: 0.32~0.53) and 2.75% (95% CI: 2.68~2.82), respectively. APC analysis revealed that BC mortality due to HBMI in women aged 50 and above showed a rise with age and mortality associated with HFPG consistently demonstrated a positive correlation with age. The impact of HBMI on BC mortality significantly outweighed that of HFPG. The risk of BC mortality linked to HBMI has steadily increased since 2005, while HFPG demonstrated a trend of initial increase followed by a decrease in the period effect. Regarding the cohort effect, the relative risk of mortality was greater in the birth cohort of women after the 1960s of MRs on BC mortality, whereas those born after 1980 displayed a slight decline in the relative risk (RR) associated with BC mortality due to HBMI.ConclusionThis study suggests that middle-aged and elderly women should be considered as a priority population, and control of HBMI and HFPG should be used as a primary tool to control metabolic risk factors and effectively reduce BC mortality.

BackgroundBacterial vaginosis (BV) is a most common microbiological syndrome. The use of molecular methods, such as multiplex real-time PCR (mPCR) and next-generation sequencing, has revolutionized our understanding of microbial communities. Here, we aimed to use a novel multiplex PCR test to evaluate the microbial composition and dominant lactobacilli in non-pregnant women with BV, and combined with machine learning algorithms to determine its diagnostic significance.MethodsResidual material of 288 samples of vaginal secretions derived from the vagina from healthy women and BV patients that were sent for routine diagnostics was collected and subjected to the mPCR test. Subsequently, Decision tree (DT), random forest (RF), and support vector machine (SVM) hybrid diagnostic models were constructed and validated in a cohort of 99 women that included 74 BV patients and 25 healthy controls, and a separate cohort of 189 women comprising 75 BV patients, 30 intermediate vaginal microbiota subjects and 84 healthy controls, respectively.ResultsThe rate or abundance of Lactobacillus crispatus and Lactobacillus jensenii were significantly reduced in BV-affected patients when compared with healthy women, while Lactobacillus iners, Gardnerella vaginalis, Atopobium vaginae, BVAB2, Megasphaera type 2, Prevotella bivia, and Mycoplasma hominis were significantly increased. Then the hybrid diagnostic models were constructed and validated by an independent cohort. The model constructed with support vector machine algorithm achieved excellent prediction performance (Area under curve: 0.969, sensitivity: 90.4%, specificity: 96.1%). Moreover, for subjects with a Nugent score of 4 to 6, the SVM-BV model might be more robust and sensitive than the Nugent scoring method.ConclusionThe application of this mPCR test can be effectively used in key vaginal microbiota evaluation in women with BV, intermediate vaginal microbiota, and healthy women. In addition, this test may be used as an alternative to the clinical examination and Nugent scoring method in diagnosing BV.

Hydrofoil, as the basic shape of the fluid blade, is widely used in fluid transport and energy conversion. However, friction resistance and pressure differential resistance are generated in the hydrofoil flow process, resulting in substantial energy consumption and negatively affecting the economy. On this basis, we propose two drag-reducing structures based on Clark-Y hydrofoil. In the design process of the jet structure, we considered the bionic jet velocity, jet angle and jet structure position as the design parameters and obtained the optimal jet structure by using Taguchi method. Finally, the two schemes (Clark-Yori and Clark-Yopt) are numerically simulated using large eddy simulation. Results show that when Ujet = 1.44 m/s, θ = 3° and x = 18.6 mm, the jet structure can play a significant drag reduction effect. Compared with Clark-Yori, the drag coefficient of Clark-Yopt is reduced by 26.5%, and the lift drag ratio is increased by 16.4%. Compared with Clark-Yori, Clark-Yopt can reduce the wall shear stress of the leading edge of the hydrofoil, thereby diminishing the frictional resistance. Meanwhile, the jet structure can effectively balance the area of the low-pressure region on the suction side of the hydrofoil, significantly reducing the pressure differential resistance. Clark-Yopt can accelerate the vortex collapse that decreases turbulence intensity and turbulence resistance. Moreover, it can effectively block the near-wall reflux of hydrofoil and reduce the internal friction between the reflux and the main flow.