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Zhengjun Ma,1 Yanmei Zhang,1 Yupu Zhu,2 Minxuan Cui,2 Yutao Liu,2 Yun-You Duan,1 Li Fan,2 Li Zhang1 1Department of Ultrasound Medicine, Tangdu Hospital, Air Force Medical University, Xi’an, People’s Republic of China; 2Department of Pharmaceutical Chemistry and Analysis, School of Pharmacy, Air Force Medical University, Xi’an, People’s Republic of ChinaCorrespondence: Li Fan; Li Zhang, Email xxfanny@fmmu.edu.cn; lilyzhang319_20@hotmail.comIntroduction: Recently, nanobubbles (NBs) have gained significant traction in the field of tumor diagnosis and treatment owing to their distinctive advantages. However, the application of NBs is limited due to their restricted size and singular reflection section, resulting in low ultrasonic reflection.Methods: We synthesized a nano-scale ultrasound contrast agent (IR783-SiO2NPs@NB) by encapsulating SiO2 nanoparticles in an IR783-labeled lipid shell using an improved film hydration method. We characterized its physicochemical properties, examined its microscopic morphology, evaluated its stability and cytotoxicity, and assessed its contrast-enhanced ultrasound imaging capability both in vitro and in vivo.Results: The results show that IR783-SiO2NPs@NB had a “donut-type” composite microstructure, exhibited uniform particle size distribution (637.2 ± 86.4 nm), demonstrated excellent stability (30 min), high biocompatibility, remarkable tumor specific binding efficiency (99.78%), and an exceptional contrast-enhanced ultrasound imaging capability.Conclusion: Our newly developed multiple scattering NBs with tumor targeting capacity have excellent contrast-enhanced imaging capability, and they show relatively long contrast enhancement duration in solid tumors, thus providing a new approach to the structural design of NBs.Keywords: ultrasound contrast agents, nanobubbles, CEUS, scattering cross-section, SiO2 NPs

Abstract: Objective: Velocity vector imaging (VVI) is widely used to quantify cardiac mechanical deformation. This study sought to determine whether VVI could be used to evaluate the stiffness of maternal peripheral arteries in women with pre-eclampsia. Study design: Twenty-four women with pre-eclampsia and 34 normotensive pregnant women were recruited. Longitudinal and circumferential peak velocity, strain and strain rate of the right common carotid artery (CCA) were measured. All measurements were averaged from three consecutive cardiac cycles and expressed as mean±standard deviation. Results: Longitudinal velocity, strain and strain rate of the anterior and posterior walls of the CCA were significantly lower in women with pregnancy-induced hypertension compared with normotensive pregnant women [velocity: 0.22±0.09cm/s vs 0.29±0.09cm/s (p <0.01) and 0.24±0.10cm/s vs 0.34±0.13cm/s (p <0.01); strain: 8.50±4.92% vs 12.2±6.21% (p <0.01) and 10.11±5.02% vs 14.21±6.48% (p <0.05); strain rate: 1.62±1.14s–1 vs 2.24±1.13s–1 (p <0.05) and 1.91±0.99s–1 vs 2.45±0.97s–1 (p <0.05)]. Similar results were also found for circumferential velocity, strain and strain rate of the anterior and posterior walls, and the interior and exterior lateral walls of the CCA. Conclusions: Stiffness of the maternal CCA was significantly greater in women with pre-eclampsia compared with normotensive pregnant women. VVI may have potential for quantitative assessment of vascular mechanical deformation in the clinical setting. [Copyright &y& Elsevier]

Background: Superior vena cava syndrome (SVCS) is a clinical expression of obstruction of blood flow through the superior vena cava. The patterns of the Doppler flow changes of superior vena cava (SVC), especially the respiratory effects on them have not yet been fully elucidated. This study was to examine SVC Doppler flow patterns and the respiratory effects on them in healthy subjects and patients with SVCS. Methods: The SVC Doppler flow patterns of 18 normal human subjects and 22 patients with SVCS were analyzed at initial diagnosis and were followed up every 2 months for at least 11 months. Results: Among the 22 patients, 5 patients with the tumor near the right atrium oppressing the inferior segment of the SVC had clear VR- and AR-waves, while in the other 17 patients the VR- and AR-waves disappeared or their outlines were vague. The respiratory variations of the S- and D-waves as a percentage change in inspiration compared to expiration in patient group were much lower than those in control group (S-wave: 1.67 +/- 3.32% vs. 15.65 +/- 16.15%, P = 0.0003; D-wave: 1.80 +/- 1.12% vs. 23.55 +/- 37%, P = 0.0087), which gradually became larger with treatment and showed no significant difference with those in control group after 7 months. Conclusions: The Doppler flows of the patients with SVCS correlate well with the images of CT scan of them. The respiratory variation of the S- and D-velocities could be used to evaluate the severity of SVC obstruction and its therapeutic effect. [ABSTRACT FROM AUTHOR]

This study was aimed to quantify the underestimation of cardiac Doppler measurements and to explore a method for correction. A dual pulse wave (PW)/Doppler tissue imaging (DTI) mode echocardiographic technique was used in the in vitro and in vivo studies. In the in vitro experiment, we have demonstrated how cardiac valvular motion might interfere with blood velocity estimation using conventional Doppler. When examining the participants, we observed that adding valvular annulus velocity to determine the relative velocity between blood and valvular annulus would result in an increment of 9.3 ± 1.3 cm/s and 6.3 ± 0.9 cm/s for aortic and pulmonary blood flow, 12.8 ± 1.9 cm/s and 8.9 ± 1.4 cm/s for mitral E and A wave, 12.9 ± 1.8 cm/s and 10.2 ± 2.4 cm/s for tricuspid E and A wave. The underestimations of the Doppler measurements markedly influence the hemodynamic parameters commonly used in the clinical practices and researches. This study provides a quantitative method for the correction and would make the Doppler measurement accurate. [ABSTRACT FROM AUTHOR]

Foraging tunnel disturbances by small subterranean herbivores can alter soil properties and nutrient dynamics in grasslands, potentially altering soil organic carbon (SOC). Examining the impact of foraging tunnel disturbances on mineral-associated organic carbon (MAOC) and particulate organic carbon (POC) is crucial for understanding SOC changes and its stability. However, the effects of these disturbances on POC and MAOC are not well documented. This study uses the plateau zokor (Eospalax baileyi) as a focal subterranean herbivore to investigate the effects of foraging tunnel disturbances on POC and MAOC in alpine steppes, alpine meadows, and alpine meadow steppes. Ninety paired quadrats were used for soil and plant sampling across three alpine grassland types. Results show that foraging tunnel disturbances consistently reduced POC concentrations across all grassland types, with reductions of 44.01 % in alpine steppes, 20.86 % in alpine meadows, and 29.58 % in alpine meadow steppes. MAOC concentrations decreased by 16.49 % in alpine steppes, while no significant changes in MAOC were observed in alpine meadows and alpine meadow steppes. The reduction in the POC to MAOC ratio indicates increased SOC stability. However, despite this increased stability, the change may lead to a decrease in overall carbon sequestration potential, as the total SOC in the soil declines. The main factors influencing POC and MAOC were soil moisture, belowground biomass, and microbial biomass carbon, with their influences varying by grassland type. The findings demonstrate that foraging tunnel disturbances by plateau zokors can lead to substantial modifications in SOC composition, influencing both its stability and sequestration potential. The disturbances necessitate tailored management strategies to mitigate their impacts, considering the unique characteristics of each grassland type to preserve carbon sequestration potential. This study contributes to a deeper understanding of the ecological role of small subterranean herbivores in the carbon cycle of alpine grassland ecosystems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Psoriasis, a persistent skin condition caused by the disorder of the immune system, impacts approximately 1.25 million individuals globally. Nevertheless, the presence of adverse effects in conventional clinical drugs necessitates further exploration of novel medications or combination therapies to mitigate these reactions and enhance their effectiveness., Methods: Hence, our intention here in this paper is to utilize the lipid nanoparticle delivery system for overcoming the volatility and hydrophobic properties of α-pinene, a naturally occurring compound renowned for its anti-inflammatory and antiviral effects, and further explore its potential pharmacological applications both in vitro and in vivo ., Results: The production of α-pinene lipid nanoparticles (APLNs) was achieved through the utilization of high pressure homogenization methods. APLNs was successfully fabricated with enhanced stability and water solubility. Meanwhile, the application of APLNs could drastically reduce the expression of lipopolysaccharide (LPS)-induced inflammation-related factors in THP-1 cells. Administration of APLNs to a mouse model of auricular swelling could effectively reduce redness and swelling in the auricles of mice as well. Furthermore, APLNs were also found to alleviate skin damage in mice with Imiquimod (IMQ)-induced psoriasis model, as well as decrease the levels of psoriasis-related protein nuclear factor kappa-B (NF-κB) and interleukin-17 (IL-17), interleukin-23 (IL-23), and other inflammation-related cytokines. More importantly, utilization of APLNs successfully mitigated the systemic inflammatory reactions in mice, resulting in the reduction of spleen-to-body ratio (wt%) and of inflammatory cytokines' expression in the serum., Discussion: Overall, our results suggest that with the help of lipid nanoparticle encapsulation, APLNs possess a better pharmacological effect in anti-inflammation and could potentially serve as an anti-psoriasis drug., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Liang, Zhao, Chen, Zhu, Duan, Zou, Huang, Li and Zhang.)

The e^{+}e^{-}→D&#95;{s}^{+}D&#95;{s1}(2536)^{-} and e^{+}e^{-}→D&#95;{s}^{+}D&#95;{s2}^{*}(2573)^{-} processes are studied using data samples collected with the BESIII detector at center-of-mass energies from 4.530 to 4.946 GeV. The absolute branching fractions of D&#95;{s1}(2536)^{-}→D[over ¯]^{*0}K^{-} and D&#95;{s2}^{*}(2573)^{-}→D[over ¯]^{0}K^{-} are measured for the first time to be (35.9±4.8±3.5)% and (37.4±3.1±4.6)%, respectively. The e^{+}e^{-}→D&#95;{s}^{+}D&#95;{s1}(2536)^{-} and e^{+}e^{-}→D&#95;{s}^{+}D&#95;{s2}^{*}(2573)^{-} cross sections are measured, and a resonant structure at around 4.6 GeV with a width of 50 MeV is observed in both processes with a statistical significance of 7.2σ and 15σ, respectively. The state is observed for the first time in e^{+}e^{-}→D&#95;{s}^{+}D&#95;{s2}^{*}(2573)^{-} and could be the Y(4626) found by the Belle oration in the D&#95;{s}^{+}D&#95;{s1}(2536)^{-} final state, since they have similar masses and widths. There is also evidence for a structure at around 4.75 GeV in both processes.

The high heterogeneity within and between breast cancer patients complicates treatment determination and prognosis assessment. Treatment decision-making is influenced by various factors, such as tumor subtype, histological grade, and genotype, necessitating personalized treatment strategies. Prognostic outcomes vary significantly depending on patient-specific conditions. As a critical branch of artificial intelligence, machine learning efficiently handles large datasets and automates decision-making processes. The introduction of machine learning offers new solutions for breast cancer treatment selection and prognosis assessment. In the field of cancer therapy, traditional methods for predicting treatment and survival outcomes often rely on single or few biomarkers, limiting their ability to capture the complexity of biological processes comprehensively. Machine learning analyzes patients' multi-omic data and the intricate patterns of variations during cancer initiation and progression to predict patients' survival and treatment outcomes. Consequently, it facilitates the selection of appropriate therapeutic interventions to implement early intervention and improve treatment efficacy for patients. Here, we first introduce common machine learning methods, and then elaborate on the application of machine learning in the field of survival prediction and prognosis from two aspects: evaluating survival and predicting treatment outcomes for breast cancer patients. The aim is to provide breast cancer patients with precise treatment strategies to improve therapeutic outcomes and quality of life.

Objective: This study aimed to evaluate and compare the effectiveness of knowledge base-optimized and unoptimized large language models (LLMs) in the field of orthopedics to explore optimization strategies for the application of LLMs in specific fields., Methods: This research constructed a specialized knowledge base using clinical guidelines from the American Academy of Orthopaedic Surgeons (AAOS) and authoritative orthopedic publications. A total of 30 orthopedic-related questions covering aspects such as anatomical knowledge, disease diagnosis, fracture classification, treatment options, and surgical techniques were input into both the knowledge base-optimized and unoptimized versions of the GPT-4, ChatGLM, and Spark LLM, with their generated responses recorded. The overall quality, accuracy, and comprehensiveness of these responses were evaluated by 3 experienced orthopedic surgeons., Results: Compared with their unoptimized LLMs, the optimized version of GPT-4 showed improvements of 15.3% in overall quality, 12.5% in accuracy, and 12.8% in comprehensiveness; ChatGLM showed improvements of 24.8%, 16.1%, and 19.6%, respectively; and Spark LLM showed improvements of 6.5%, 14.5%, and 24.7%, respectively., Conclusion: The optimization of knowledge bases significantly enhances the quality, accuracy, and comprehensiveness of the responses provided by the 3 models in the orthopedic field. Therefore, knowledge base optimization is an effective method for improving the performance of LLMs in specific fields., (© 2024. Huazhong University of Science and Technology.)

Rationale and Objectives: The aim of this study was to develop a deep learning radiomics nomogram (DLRN) based on B-mode ultrasound (BMUS) and color doppler flow imaging (CDFI) images for preoperative assessment of lymphovascular invasion (LVI) status in invasive breast cancer (IBC)., Materials and Methods: In this multicenter, retrospective study, 832 pathologically confirmed IBC patients were recruited from eight hospitals. The samples were divided into training, internal test, and external test sets. Deep learning and handcrafted radiomics features reflecting tumor phenotypes on BMUS and CDFI images were extracted. The BMUS score and CDFI score were calculated after radiomics feature selection. Subsequently, a DLRN was developed based on the scores and independent clinic-ultrasonic risk variables. The performance of the DLRN was evaluated for calibration, discrimination, and clinical usefulness., Results: The DLRN predicted the LVI with accuracy, achieving an area under the receiver operating characteristic curve of 0.93 (95% CI 0.90-0.95), 0.91 (95% CI 0.87-0.95), and 0.91 (95% CI 0.86-0.94) in the training, internal test, and external test sets, respectively, with good calibration. The DLRN demonstrated superior performance compared to the clinical model and single scores across all three sets (p < 0.05). Decision curve analysis and clinical impact curve confirmed the clinical utility of the model. Furthermore, significant enhancements in net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indicated that the two scores could serve as highly valuable biomarkers for assessing LVI., Conclusion: The DLRN exhibited strong predictive value for LVI in IBC, providing valuable information for individualized treatment decisions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Neurocognitive dysfunction is observationally associated with the risk of psychiatric disorders. Blood metabolites, which are readily accessible, may become highly promising biomarkers for brain disorders. However, the causal role of blood metabolites in neurocognitive function, and the biological pathways underlying their association with psychiatric disorders remain unclear., Methods: To explore their putative causalities, we conducted bidirectional two-sample Mendelian randomization (MR) using genetic variants associated with 317 human blood metabolites (n max  = 215,551), g-Factor (an integrated index of multiple neurocognitive tests with n max  = 332,050), and 10 different psychiatric disorders (n = 9,725 to 807,553) from the large-scale genome-wide association studies of European ancestry. Mediation analysis was used to assess the potential causal pathway among the candidate metabolite, neurocognitive trait and corresponding psychiatric disorder., Results: MR evidence indicated that genetically predicted acetylornithine was positively associated with g-Factor (0.035 standard deviation units increase in g-Factor per one standard deviation increase in acetylornithine level; 95% confidence interval, 0.021 to 0.049; P = 1.15 × 10 -6 ). Genetically predicted butyrylcarnitine was negatively associated with g-Factor (0.028 standard deviation units decrease in g-Factor per one standard deviation increase in genetically proxied butyrylcarnitine; 95% confidence interval, -0.041 to -0.015; P = 1.31 × 10 -5 ). There was no evidence of associations between genetically proxied g-Factor and metabolites. Furthermore, the mediation analysis via two-step MR revealed that the causal pathway from acetylornithine to bipolar disorder was partly mediated by g-Factor, with a mediated proportion of 37.1%. Besides, g-Factor mediated the causal pathway from butyrylcarnitine to schizophrenia, with a mediated proportion of 37.5%. Other neurocognitive traits from different sources provided consistent findings., Conclusion: Our results provide genetic evidence that acetylornithine protects against bipolar disorder through neurocognitive abilities, while butyrylcarnitine has an adverse effect on schizophrenia through neurocognition. These findings may provide insight into interventions at the metabolic level for risk of neurocognitive and related disorders., (© 2024. The Author(s).)

The J/ψ, ψ(3686)→Σ^{0}Σ[over ¯]^{0} processes and subsequent decays are studied using the world's largest J/ψ and ψ(3686) data samples collected with the BESIII detector. The parity-violating decay parameters of the decays Σ^{0}→Λγ and Σ[over ¯]^{0}→Λ[over ¯]γ, α&#95;{Σ^{0}}=-0.0017±0.0021±0.0018 and α[over ¯]&#95;{Σ^{0}}=0.0021±0.0020±0.0022, are measured for the first time. The strong CP symmetry is tested in the decays of the Σ^{0} hyperons for the first time by measuring the asymmetry A&#95;{CP}^{Σ}=α&#95;{Σ^{0}}+α[over ¯]&#95;{Σ^{0}}=(0.4±2.9±1.3)×10^{-3}. The weak CP test is performed in the subsequent decays of their daughter particles Λ and Λ[over ¯]. Also for the first time, the transverse polarizations of the Σ^{0} hyperons in J/ψ and ψ(3686) decays are observed with opposite directions, and the ratios between the S-wave and D-wave contributions of the J/ψ, ψ(3686)→Σ^{0}Σ[over ¯]^{0} decays are obtained. These results are crucial to understand the decay dynamics of the charmonium states and the production mechanism of the Σ^{0}-Σ[over ¯]^{0} pairs.

Ethnopharmacological Relevance: Sophorae tonkinensis Radix et Rhizoma (STR) is an extensively applied traditional Chinese medicine (TCM) in southwest China. However, its clinical application is relatively limited due to its hepatotoxicity effects., Aim of the Study: To understand the material foundation and liver injury mechanism of STR., Materials and Methods: Chemical compositions in STR and its prototypes in mice were profiled by ultra-performance liquid chromatography coupled quadrupole-time of flight mass spectrometry (UPLC-Q/TOF MS). STR-induced liver injury (SILI) was comprehensively evaluated by STR-treated mice mode. The histopathologic and biochemical analyses were performed to evaluate liver injury levels. Subsequently, network pharmacology and multi-omics were used to analyze the potential mechanism of SILI in vivo. And the target genes were further verified by Western blot., Results: A total of 152 compounds were identified or tentatively characterized in STR, including 29 alkaloids, 21 organic acids, 75 flavonoids, 1 quinone, and 26 other types. Among them, 19 components were presented in STR-medicated serum. The histopathologic and biochemical analysis revealed that hepatic injury occurred after 4 weeks of intragastric administration of STR. Network pharmacology analysis revealed that IL6, TNF, STAT3, etc. were the main core targets, and the bile secretion might play a key role in SILI. The metabolic pathways such as taurine and hypotaurine metabolism, purine metabolism, and vitamin B6 metabolism were identified in the STR exposed groups. Among them, taurine, hypotaurine, hypoxanthine, pyridoxal, and 4-pyridoxate were selected based on their high impact value and potential biological function in the process of liver injury post STR treatment., Conclusions: The mechanism and material foundation of SILI were revealed and profiled by a multi-omics strategy combined with network pharmacology and chemical profiling. Meanwhile, new insights were taken into understand the pathological mechanism of SILI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Using data samples collected with the BESIII detector operating at the BEPCII storage ring, the cross section of the inclusive process e^{+}e^{-}→η+X, normalized by the total cross section of e^{+}e^{-}→hadrons, is measured at eight center-of-mass energy points from 2.0000 to 3.6710 GeV. These are the first measurements with momentum dependence in this energy region. Our measurement shows a significant discrepancy compared to the existing fragmentation functions. To address this discrepancy, a new QCD analysis is performed at the next-to-next-to-leading order with hadron mass corrections and higher twist effects, which can explain both the established high-energy data and our measurements reasonably well.

Introduction: CD24 is a highly glycosylated glycosylphosphatidylinositol anchored membrane protein that plays an important role in tumor progression. The aim of this study was to investigate the effect of abnormal expression of CD24 on the proliferation, migration and invasion of breast cancer (BC) cells, and the molecular mechanism of regulating CD24 expression in breast cancer., Methodology: The bioinformatics method was used to predict the expression level of CD24 in BC and its relationship with the occurrence and development of BC. IHC, RT-qPCR and WB were used to detect the expression of CD24 in BC tissues and cells. The proliferation of CD24 was evaluated by CCK-8 and colony formation assay, and the migration and invasion of CD24 were evaluated by wound healing and transwell. In addition, the effect of CD24 on the malignancy of BC in vivo was further evaluated by subcutaneous tumorigenesis assay. Molecular mechanisms were measured by luciferase reporter assays, biotin-labeled miRNA pull-down assay, RIP, and western blotting., Results: The results show that CD24 is highly expressed in breast cancer tissues and cell lines, and knockdown of CD24 in vivo and in vitro can inhibit the proliferation, migration and invasion of BC cells. Mechanistically, the transcription factor ZNF460 promotes its expression by binding to the CD24 promoter, and the expression of ZNF460 is regulated by miR-125a-5p, which inhibits its expression by targeting the 3'UTR of ZNF460. In addition, LINC00525 acts as a ceRNA sponge to adsorb miR-125a-5p and regulate its expression., Conclusions: Overexpression of CD24 is involved in the development and poor prognosis of BC, which can be used as a potential target for the treatment of BC and provide a theoretical basis for the treatment of BC., (© 2024. The Author(s).)

Metal/dielectric multilayer films have important applications in energy-saving glass, stealth materials, solar energy utilization and other fields. In the current study, the thickness of each layer of TiO 2 /Ag/TiO 2 /Ag/TiO 2 film is optimized. The effects of the number of metal/dielectric multilayer films and the incident light angle on their optical properties were investigated. The TiO 2 /Ag/TiO 2 /Ag/TiO 2 film was prepared by electron beam evaporation coating technology, and their reflectance and transmittance were measured. The measurement results show that the visible light transmittance (380-780 nm) of the film can achieve 68.7%, and the infrared reflectance (780-2500 nm) can reach 95.9%. Compared with the traditional dielectric/metal/dielectric three-layer film, the visible light transmittance of the film is higher, and the solar infrared reflectance is greatly improved. In the solar radiation band (280-2500 nm), the average error between the experimental reflectance and transmittance and the theoretical prediction results is less than 0.03. The distribution of electric and magnetic fields inside the film was simulated by finite-difference time-domain method. The simulation results show that the high visible light transmittance is due to the interference resonance of electromagnetic waves inside the film. Taking Shanghai as an example, under our calculation conditions, compared with ordinary SiO 2 glass, TiO 2 /Ag/TiO 2 /Ag/TiO 2 film can reduce the total energy consumption of buildings by 14.3% and refrigeration energy consumption by 17.2%., (© 2024 IOP Publishing Ltd.)

The precise roles of chromatin organization at osteoporosis risk loci remain largely elusive. Here, we combined chromatin interaction conformation (Hi-C) profiling and self-transcribing active regulatory region sequencing (STARR-seq) to qualify enhancer activities of prioritized osteoporosis-associated single-nucleotide polymorphisms (SNPs). We identified 319 SNPs with biased allelic enhancer activity effect (baaSNPs) that linked to hundreds of candidate target genes through chromatin interactions across 146 loci. Functional characterizations revealed active epigenetic enrichment for baaSNPs and prevailing osteoporosis-relevant regulatory roles for their chromatin interaction genes. Further motif enrichment and network mapping prioritized several putative, key transcription factors (TFs) controlling osteoporosis binding to baaSNPs. Specifically, we selected one top-ranked TF and deciphered that an intronic baaSNP (rs11202530) could allele-preferentially bind to YY2 to augment PAPSS2 expression through chromatin interactions and promote osteoblast differentiation. Our results underline the roles of TF-mediated enhancer-promoter contacts for osteoporosis, which may help to better understand the intricate molecular regulatory mechanisms underlying osteoporosis risk loci., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Testicular torsion is the most common acute scrotum worldwide and mainly occurs in children and adolescents. Studies have demonstrated that the duration of symptoms and torsion grade lead to different outcomes in children diagnosed with testicular torsion., Aim: To predict the possibility of testicular salvage (TS) in patients with testicular torsion in a tertiary center., Methods: We reviewed the charts of 75 pediatric patients with acute testicular torsion during a 12-year period from November 2011 to July 2023 at the Suzhou Hospital of Anhui Medical University. Univariate and multivariate logistic regression analyses were used to determine independent predictors of testicular torsion. The data included clinical findings, physical examinations, laboratory data, color Doppler ultrasound findings, operating results, age, presenting institution status, and follow-up results., Results: Our study included 75 patients. TS was possible in 57.3% of all patients; testicular torsion occurred mostly in winter, and teenagers aged 11-15 years old accounted for 60%. Univariate logistic regression analyses revealed that younger age ( P = 0.09), body mass index ( P = 0.004), torsion angle ( P = 0.013), red blood cell count ( P = 0.03), neutrophil-to-lymphocyte ratio ( P = 0.009), and initial presenting institution ( P < 0.001) were associated with orchiectomy. In multivariate analysis, only the initial presenting institution predicted TS ( P < 0.05)., Conclusion: The initial presenting institution has a predictive value for predicting TS in patients with testicular torsion. Children with scrotal pain should be admitted to a tertiary hospital as soon as possible., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Fungal infections have become clinically challenging owing to the emergence of drug resistance in invasive fungi and the rapid increase in the number of novel pathogens. The development of drug resistance further restricts the use of antifungal agents. Therefore, there is an urgent need to identify alternative treatments for Cryptococcus neoformans ( C. neoformans ). Disulfiram (DSF) has a good human safety profile and promising applications as an antiviral, antifungal, antiparasitic, and anticancer agent. However, the effect of DSF on Cryptococcus is yet to be thoroughly investigated. This study investigated the antifungal effects and the mechanism of action of DSF against C. neoformans to provide a new theoretical foundation for the treatment of Cryptococcal infections. In vitro studies demonstrated that DSF inhibited Cryptococcus growth at minimum inhibitory concentrations (MICs) ranging from 1.0 to 8.0 μg/mL. Combined antifungal effects have been observed for DSF with 5-fluorocytosine, amphotericin B, terbinafine, or ketoconazole. DSF exerts significant protective effects and synergistic effects combined with 5-FU for Galleria mellonella infected with C. neoformans . Mechanistic investigations showed that DSF dose-dependently inhibited melanin, urease, acetaldehyde dehydrogenase, capsule and biofilm viability of C. neoformans . Further studies indicated that DSF affected C. neoformans by interfering with multiple biological pathways, including replication, metabolism, membrane transport, and biological enzyme activity. Potentially essential targets of these pathways include acetaldehyde dehydrogenase, catalase, ATP-binding cassette transporter (ABC transporter), and iron-sulfur cluster transporter. These findings provide novel insights into the application of DSF and contribute to the understanding of its mechanisms of action in C. neoformans ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Peng, Zhang, Duan, Liu, Peng, Wei, Chen, Sang and Kong.)

Objective: To investigate the abnormal radiomics features of the hippocampus in patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) and to explore the clinical implications of these features., Methods: 752 participants were recruited in this retrospective multicenter study (7 centers), which included 236 MS, 236 NMOSD, and 280 normal controls (NC). Radiomics features of each side of the hippocampus were extracted, including intensity, shape, texture, and wavelet features (N = 431). To identify the variations in these features, two-sample t-tests were performed between the NMOSD vs. NC, MS vs. NC, and NMOSD vs. MS groups at each site. The statistical results from each site were then integrated through meta-analysis. To investigate the clinical significance of the hippocampal radiomics features, we conducted further analysis to examine the correlations between these features and clinical measures such as Expanded Disability Status Scale (EDSS), Brief Visuospatial Memory Test (BVMT), California Verbal Learning Test (CVLT), and Paced Auditory Serial Addition Task (PASAT)., Results: Compared with NC, patients with MS exhibited significant differences in 78 radiomics features (P < 0.05/862), with the majority of these being texture features. Patients with NMOSD showed significant differences in 137 radiomics features (P < 0.05/862), most of which were intensity features. The difference between MS and NMOSD patients was observed in 47 radiomics features (P < 0.05/862), mainly texture features. In patients with MS and NMOSD, the most significant features related to the EDSS were intensity and textural features, and the most significant features related to the PASAT were intensity features. Meanwhile, both disease groups observed a weak correlation between radiomics data and BVMT., Conclusion: Variations in the microstructure of the hippocampus can be detected through radiomics, offering a new approach to investigating the abnormal pattern of the hippocampus in MS and NMOSD., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Toxoplasma gondii relies heavily on the de novo pyrimidine biosynthesis pathway for fueling the high uridine-5'-monophosphate (UMP) demand during parasite growth. The third step of de novo pyrimidine biosynthesis is catalyzed by dihydroorotase (DHO), a metalloenzyme that catalyzes the reversible condensation of carbamoyl aspartate to dihydroorotate. Here, functional analyses of TgDHO reveal that tachyzoites lacking DHO are impaired in overall growth due to decreased levels of UMP, and the noticeably growth restriction could be partially rescued after supplementation with uracil or high concentrations of L-dihydroorotate in vitro. When pyrimidine salvage pathway is disrupted, both DHO H35A and DHO D284E mutant strains proliferated much slower than DHO-expressing parasites, suggesting an essential role of both TgDHO His35 and Asp284 residues in parasite growth. Additionally, DHO deletion causes the limitation of bradyzoite growth under the condition of uracil supplementation or uracil deprivation. During the infection in mice, the DHO-deficient parasites are avirulent, despite the generation of smaller tissue cysts. The results reveal that TgDHO contributes to parasite growth both in vitro and in vivo. The significantly differences between TgDHO and mammalian DHO reflect that DHO can be exploited to produce specific inhibitors targeting apicomplexan parasites. Moreover, potential DHO inhibitors exert beneficial effects on enzymatic activity of TgDHO and T. gondii growth in vitro. In conclusion, these data highlight the important role of TgDHO in parasite growth and reveal that it is a promising anti-parasitic target for future control of toxoplasmosis., (© 2023 Federation of American Societies for Experimental Biology.)

Introduction: Insufficient withdrawal duration of antithrombotics leads to excessive bleeding after major surgery. We hypothesize that intraoperative hemoadsorption (HA) can reduce postoperative allogeneic transfusion requirements and excessive bleeding events (EBE), without an increase in ischemic/thromboembolic events (ITE) in patients who have taken antithrombotics and undergone nonelective cardiac surgery., Methods: A total of 460 patients admitted to our hospital from 2018 to 2022 were included in this study and divided into two groups: HA and non-HA. Because of the risk of bias due to differences in antithrombotic type, withdrawal duration, or basic coagulation function, propensity score matching was used for analyses., Results: Out of 154 cases in the HA group, 144 pairs were successfully matched. No HA safety events such as hemolysis, hypotension, or device failure occurred. After matching, the two groups were found to be comparable in preoperative antithrombotic type, withdrawal duration, platelets and coagulation function, and demographic and perioperative characteristics. Although the HA group did not have a reduced incidence of EBE, this group exhibited significant decreases in the transfusion rate and volume, the incidence of ITE, acute kidney injury, and central nervous system injury., Conclusions: For patients who have undergone nonelective cardiac surgery and taken antithrombotics, HA can simply and safely rebalance the postoperative coagulation system and have associations with reduced transfusion and postoperative ITE., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Aim: Genome-wide association studies (GWAS) have identified multiple susceptibility loci associated with insulin resistance (IR)-relevant phenotypes. However, the genes responsible for these associations remain largely unknown. We aim to identify susceptibility genes for IR-relevant phenotypes via a transcriptome-wide association study., Materials and Methods: We conducted a large-scale multi-tissue transcriptome-wide association study for IR (Insulin Sensitivity Index, homeostasis model assessment-IR, fasting insulin) and lipid-relevant traits (high-density lipoprotein cholesterol, triglycerides, low-density lipoprotein cholesterol and total cholesterol) using the largest GWAS summary statistics and precomputed gene expression weights of 49 human tissues. Conditional and joint analyses were implemented to identify significantly independent genes. Furthermore, we estimated the causal effects of independent genes by Mendelian randomization causal inference analysis., Results: We identified 1190 susceptibility genes causally associated with IR-relevant phenotypes, including 58 genes that were not implicated in the original GWAS. Among them, 11 genes were further supported in differential expression analyses or a gene knockout mice database, such as KRIT1 showed both significantly differential expression and IR-related phenotypic effects in knockout mice. Meanwhile, seven proteins encoded by susceptibility genes were targeted by clinically approved drugs, and three of these genes (H6PD, CACNB2 and DRD2) have been served as drug targets for IR-related diseases/traits. Moreover, drug repurposing analysis identified four compounds with profiles opposing the expression of genes associated with IR risk., Conclusions: Our study provided new insights into IR aetiology and avenues for therapeutic development., (© 2023 John Wiley & Sons Ltd.)

Over the past few years, developments in artificial intelligence (AI), especially in radiomics and deep learning, have enabled the extraction of pathophysiology-related information from varied medical imaging and are progressively transforming medical practice. AI applications are extending into domains previously thought to be accessible only to human experts. Recent research has demonstrated that ultrasound-derived radiomics and deep learning represent an enticing opportunity to benefit preoperative evaluation and prognostic monitoring of diffuse and focal liver disease. This review summarizes the application of radiomics and deep learning in ultrasound liver imaging, including identifying focal liver lesions and staging of liver fibrosis, as well as the evaluation of pathobiological properties of malignant tumors and the assessment of recurrence and prognosis. Besides, we identify important hurdles that must be overcome while also discussing the challenges and opportunities of radiomics and deep learning in clinical applications.

Objective To investigate the brain age differences between Alzheimer's disease(AD)and mild cognitive impairment(MCI)patients,and further explore the correlations between brain age gap(BAG)and clinical features.Methods The clinical data and radiologic findings of 132 probable AD and AD-derived MCI patients diagnosed at Beijing Tiantan Hospital,Capital Medical University from December 2018 to July 2021 were retrospectively analyzed.According to the diagnostic criteria for AD and MCI,the patients were assigned into AD and MCI groups.In addition,156 volunteers without neurological diseases and other severe diseases were recruited as the control group.The general data,Montreal cognitive assessment(MoCA)score,and mini-mental state examination(MMSE)score were compared among the three groups.The deep learning-based brain age prediction model was employed to calculate the BAGs of the three groups.Spearman correlation analysis was conducted to explore the correlations between BAG and clinical features.Results The 132 patients included 106 patients in the AD group and 26 patients in the MCI group.The MoCA and MMSE scores followed an ascending trend of AD group

Most of the single-nucleotide polymorphisms (SNPs) associated with insulin resistance (IR)-relevant phenotypes by genome-wide association studies (GWASs) are located in noncoding regions, complicating their functional interpretation. Here, we utilized an adapted STARR-seq to evaluate the regulatory activities of 5,987 noncoding SNPs associated with IR-relevant phenotypes. We identified 876 SNPs with biased allelic enhancer activity effects (baaSNPs) across 133 loci in three IR-relevant cell lines (HepG2, preadipocyte, and A673), which showed pervasive cell specificity and significant enrichment for cell-specific open chromatin regions or enhancer-indicative markers (H3K4me1, H3K27ac). Further functional characterization suggested several transcription factors (TFs) with preferential allelic binding to baaSNPs. We also incorporated multi-omics data to prioritize 102 candidate regulatory target genes for baaSNPs and revealed prevalent long-range regulatory effects and cell-specific IR-relevant biological functional enrichment on them. Specifically, we experimentally verified the distal regulatory mechanism at IRS1 locus, in which rs952227-A reinforces IRS1 expression by long-range chromatin interaction and preferential binding to the transcription factor HOXC6 to augment the enhancer activity. Finally, based on our STARR-seq screening data, we predicted the enhancer activity of 227,343 noncoding SNPs associated with IR-relevant phenotypes (fasting insulin adjusted for BMI, HDL cholesterol, and triglycerides) from the largest available GWAS summary statistics. We further provided an open resource (http://www.bigc.online/fnSNP-IR) for better understanding genetic regulatory mechanisms of IR-relevant phenotypes., Competing Interests: Declaration of interests The authors have declared that no conflict of interest exists., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWASs) have repeatedly reported multiple non-coding single-nucleotide polymorphisms (SNPs) at 2p14 associated with rheumatoid arthritis (RA), but their functional roles in the pathological mechanisms of RA remain to be explored. In this study, we integrated a series of bioinformatics and functional experiments and identified three intronic RA SNPs (rs1876518, rs268131, and rs2576923) within active enhancers that can regulate the expression of SPRED2 directly. At the same time, SPRED2 and ACTR2 influence each other as a positive feedback signal amplifier to strengthen the protective role in RA by inhibiting the migration and invasion of rheumatoid fibroblast-like synoviocytes (FLSs). In particular, the transcription factor CEBPB preferentially binds to the rs1876518-T allele to increase the expression of SPRED2 in FLSs. Our findings decipher the molecular mechanisms behind the GWAS signals at 2p14 for RA and emphasize SPRED2 as a potential candidate gene for RA, providing a potential target and direction for precise treatment of RA., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objective: This study aims to investigate the methods for rat spinal cord ischemia injury models with a high long-term survival rate., Methods: The rats were divided into three groups: the treatment group, the control group, and the sham operation group. The treatment group had a blocked thoracic aorta (landing zone 3 by Ishimaru - T11) + aortic bypass circulation for 20 min. In the control group, the thoracic aorta at the landing zone 3 was blocked for 20 min. In the sham operation group, only thoracotomy without thoracic aortic occlusion was performed. The mean arterial blood pressure (MABP) of the thoracic aorta and caudal artery before and after thoracic aortic occlusion was monitored intraoperatively. Spinal cord function was monitored by a transcranial motor evoked potential (Tc-MEP) during the operation. Spinal cord function was evaluated by the BBB scale (Basso, Beattie, & Bresnahan locomotor rating scale) scores at multiple postoperative time points. The spinal cord sections of the rats were observed for 7 days after surgery, and the survival curves were analyzed for 28 days after surgery., Results: After aortic occlusion, the MABP of thoracic aorta decreased to 6% of that before occlusion, and the MABP of caudal artery decreased to 63% of that before occlusion in the treatment group. In the control group, the MABP of both thoracic aorta and caudal artery decreased to 19% of that before occlusion. The Tc-MEP waveform of the treatment group disappeared after 6 min, and that of the control group disappeared after 8 min until the end of surgery. There was no change in the Tc-MEP waveform in the sham operation group. The BBB score of the treatment group decreased more obviously than the control group, and there was a significant difference. There was no decrease in the sham group. Spinal cord sections showed a large number of degeneration and necrosis of neurons, infiltration of inflammatory cells, and proliferation of surrounding glial cells in the treatment group. In the control group, multiple neurons were necrotic. The histology of the sham operation group was normal. The 28-day survival rate of the treatment group was 73.3%, which was higher than the control group (40.0%), and there was a significant difference ( p < 0.05)., Conclusion: Thoracic aortic occlusion combined with aortic bypass is an effective modeling method for rats with accurate modeling effects and high long-term survival rates.

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease with multiple environmental and genetic factors involved in its etiology. Although lots of genetic loci associated with AD have been reported by GWASs, only a small part of phenotypic variations can be explained. To identify additional susceptibility genes on AD, we conducted a large-scale transcriptome-wide association study using a joint-tissue imputation approach in ∼840,000 European individuals combined with six precomputed gene expression weights of four AD-relevant tissues, including skin fibroblast, lymphocyte, and whole blood. The Mendelian randomization causal inference analysis was performed to estimate the causal effect of transcriptome-wide association study‒identified genes. We identified 51 genes significantly associated with AD after Bonferroni corrections, and 19 genes showed putatively causal associations such as an established gene FLG (P = 3.98 × 10 ‒10 ) and seven genes that have not been implicated in previous transcriptome-wide association studies, such as AQP3 (P = 4.43 × 10 ‒7 ) and PDCD1 (P = 7.66 × 10 ‒7 ). Among them, four genes (AQP3, PDCD1, ADCY3, and DOLPP1) were further supported in differential expression analyses or the Mouse Genome Informatics database. Overall, our study identified susceptibility genes associated with AD, providing, to our knowledge, previously unreported clues in revealing the genetic mechanisms in AD., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Due to the limited effectiveness of existing drugs for the treatment of toxoplasmosis, there is a dire need for the discovery of new therapeutic options. Artemether is an important drug for malaria and several studies have indicated that it also exhibits anti- T. gondii activity. However, its specific effect and mechanisms are still not clear. To elucidate its specific role and potential mechanism, we first evaluated its cytotoxicity and anti- Toxoplasma effect on human foreskin fibroblast cells, and then analyzed its inhibitory activity during T. gondii invasion and intracellular proliferation. Finally, we examined its effect on mitochondrial membrane potential and reactive oxygen species (ROS) in T. gondii . The CC 50 value of artemether was found to be 866.4 μM, and IC 50 was 9.035 μM. It exhibited anti- T. gondii activity and inhibited the growth of T. gondii in a dose-dependent manner. We also found that the inhibition occurred primarily in intracellular proliferation, achieved by reducing the mitochondrial membrane integrity of T. gondii and stimulating ROS production. These findings suggest that the mechanism of artemether against T. gondii is related to a change in the mitochondrial membrane and the increase in ROS production, which may provide a theoretical basis for optimizing artemether derivatives and further improving their anti- Toxoplasma efficacy.

Objective: To explore the risk factors of pneumoconiosis patients' re-admission to provide a scientific basis for improving the treatment effect of pneumoconiosis, reducing the rate of re-admission, and reducing the burden of disease. Methods: In June 2020, The clinical data of 470 patients with pneumoconiosis who had hospitalization records from February 8, 2014, to February 8, 2020, in the Hunan Provincial Occupational Disease Prevention and Treatment Institute were retrospectively analyzed. The patients' general data and emotional state at the first admission were collected through questionnaires and telephone follow-ups. The entire group of patients completed at least one follow-up, with readmission as the end event. First, the Kaplan-Meier method was used for univariate analysis. The multivariate COX regression model analysis was performed on meaningful variables to explore the risk factors that affect the patient's re-admission. Results: A total of 470 patients with pneumoconiosis were included in this study, with an average age of 55.88 years (34-81 years old) and all the participants were male. During the first admission, the number of participants diagnosed as stage III pneumoconiosis, with complications of COPD, fatty liver, or severe pulmonary diffusion dysfunction was 215 (45.74%) , 179 (38.09%) , 51 (10.85%) , and 44 (9.36%) , respectively. Six patients (1.28%) have had suicidal tendencies almost every day since they became ill. A total of 345 patients (73.40%) were re-admitted to the hospital. Multivariate Cox regression model analysis showed that compared with the suspected pneumoconiosis group, patients in the first, second, and third-stage pneumoconiosis groups had an increased risk of readmission ( OR =2.43, 2.96, 2.35, P =0.000) . Compared with the age of 30-50 years old, 50-70 years old and ≥70 years old have an increased risk of readmission ( OR =1.28, 2.32, P <0.05) . Patients with tricuspid regurgitation ( OR =1.33, P <0.05) and elevated triglyceride level (>2.26 mmol/L) ( OR =1.40, P <0.05) have increased risks of readmission. Compared with the normal group, patients with severe pulmonary diffusion dysfunction in pneumoconiosis have an increased risk of readmission ( OR =1.96, P <0.05) . Compared with the normal group, pneumoconiosis patients in the suicidal group had an increased risk of re-admission to the hospital almost every day ( OR =2.92, P <0.05) . Conclusion Age of onset, stage of pneumoconiosis, tricuspid regurgitation, high triglycerides, severe diffuse pulmonary dysfunction, and suicidal tendency are independent risk factors that affect the readmission of patients with pneumoconiosis. The management of chronic diseases and mental health of patients with pneumoconiosis should be strengthened to reduce the risk of readmission. Conclusion: Age of onset, stage of pneumoconiosis, tricuspid regurgitation, high triglycerides, severe diffuse pulmonary dysfunction, and suicidal tendency are independent risk factors that affect the readmission of patients with pneumoconiosis. The management of chronic diseases and the mental health of patients with pneumoconiosis should be strengthened to reduce the risk of readmission.

Matrine (MT) is a major bioactive compound extracted from Sophorae tonkinensis . However, the clinical application of MT is relatively restricted due to its potentially toxic effects, especially hepatotoxicity. Although MT-induced liver injury has been reported, little is known about the underlying molecular mechanisms. In this study, transcriptomics and metabolomics were applied to investigate the hepatotoxicity of MT in mice. The results indicated that liver injury occurred when the administration of MT (30 or 60 mg/kg, i.g) lasted for 2 weeks, including dramatically increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), etc . The metabolomic results revealed that steroid biosynthesis, purine metabolism, glutathione metabolism, and pyruvate metabolism were involved in the occurrence and development of MT-induced hepatotoxicity. Further, the transcriptomic data indicated that the downregulation of NSDHL with CYP51, FDFT1, and DHCR7, involved in steroid biosynthesis, resulted in a lower level of cholic acid. Besides, Gstps and Nat8f1 were related to the disorder of glutathione metabolism, and HMGCS1 could be treated as the marker gene of the development of MT-induced hepatotoxicity. In addition, other metabolites, such as taurine, flavin mononucleotide (FMN), and inosine monophosphate (IMP), also made a contribution to the boosting of MT-induced hepatotoxicity. In this work, our results provide clues for the mechanism investigation of MT-induced hepatotoxicity, and several biomarkers (metabolites and genes) closely related to the liver injury caused by MT are also provided. Meanwhile, new insights into the understanding of the development of MT-induced hepatotoxicity or other monomer-induced hepatotoxicity were also provided.

Background: Neuronal intranuclear inclusion disease (NIID), which pathogenesis remains largely unclear, is a neurodegenerative disease caused by GGC repeat expansion in NOTCH2NLC gene. As case studies have reported dynamic cortical perfusion changes in NIID, this study aimed to explore the cerebral perfusion pattern in NIID patients., Materials and Methods: A total of 38 NIID patients and 34 healthy controls (HCs) were recruited, and 2 NIID patients who had had episodic symptoms within 2 months were excluded. Data on demographic characteristics and clinical features were collected. All participants underwent three-dimensional pseudo-continuous arterial spin labeling perfusion magnetic resonance imaging (MRI) scanning. Voxel-based comparisons of cerebral blood flow (CBF) were conducted., Results: NIID patients showed decreased perfusion in the cortex but increased perfusion in the deep brain regions compared with HCs. The regions with significant hypoperfusion were distributed in the bilateral frontal, temporal, parietal, and occipital gyri, with the left frontal gyrus being the most prominent. The regions with significant hyperperfusion included the bilateral basal ganglia, midbrain, pons, para-hippocampal, and parts of the bilateral cerebellum, fusiform, lingual, rectus, orbital, and cingulum anterior gyri, which were adjacent to the midline (all FDR-corrected p <0.05). When comparing the mean CBF value of the whole brain, no significant differences were observed between NIID patients and HCs (28.81 ± 10.1 vs. 27.99 ± 5.68 ml/100 g*min, p = 0.666). Voxel-based analysis showed no significant difference in cerebral perfusion between NIID patients with and without episodic symptoms. The perfusion within the bilateral middle frontal and anterior cingulate gyri showed positive correlations with MMSE and MoCA scores using age, sex, and education as covariates ( p <0.005 uncorrected)., Conclusion: NIID patients exhibited characteristic cortical hypoperfusion and deep brain hyperperfusion. The perfusion in the bilateral frontal lobe and cingulate gyrus was correlated with the severity of cognitive dysfunction. Cerebral perfusion change may be involved in NIID pathophysiology and serve as a potential indicator for monitoring NIID severity and progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tai, Hua, Zhang, Duan, Zhuo, Wang, Zhou, Liu and Lv.)

Characterizing the skin mycobiome is necessary to define its association with the host immune system, particularly in children. In this study, we describe the skin mycobiome on the face, ventral forearm, and calf of 72 prepubescent children (aged 1 to 10 years) and their mothers, based on internal transcribed spacer (ITS) amplicon sequencing. The age and delivery mode at birth are the most influential factors shaping the skin mycobiome. Compared with that of the vaginally born children, the skin mycobiome of caesarean-born children is assembled by predominantly deterministic niche-based processes and exhibits a more fragile microbial network at all three sampling sites. Moreover, vaginal delivery leads to clearer intra- and interindividual specialization of fungal structures with increasing age; this phenomenon is not observed in caesarean-born children. The maternal correlation with children also differs based on the mode of delivery; specifically, the mycobiomes of vaginally born children at younger ages are more strongly correlated with vagina-associated fungal genera (Candida and Rhodotorula), whereas those of caesarean-delivered children at elder age include more skin-associated and airborne fungal genera (Malassezia and Alternaria). Based on this ecological framework, our results suggest that the delivery mode is significantly associated with maturation of the skin fungal community in children. IMPORTANCE Human skin is permanently colonized by microbes starting at birth. The hygiene hypothesis suggests that a lack of early-life immune imprinting weakens the body's resilience against atopic disorders later in life. To better understand fungal colonization following early-life periods affected by interruption, we studied the skin mycobiomes of 73 children and their mothers. Our results suggest a differentiation of the skin mycobiomes between caesarean-born and vaginally born children. Caesarean-born children exhibit a mycobiome structure with more fitted deterministic niche-based processes, a fragile network, and an unchanged microbial dissimilarity over time. In vaginally born children, this dissimilarity increases with age. The results indicate that initial microbial colonization has a long-term impact on a child's skin mycobiome. We believe that these findings will inspire further investigations of the "hygiene hypothesis" in the human microbiome, especially in providing novel insights into influences on the development of the early-life microbiome.

Although naturally occurring flavonoids have shown beneficial effects on the side effects caused by cisplatin, there are few reports on the protective effect of dihydrochalcone on the cisplatin-induced toxicity. Trilobatin (TLB), as the major sweetener and active ingredient in Lithocarpus polystachyus Rehd, is a dihydrochalcone-like compound that can be present in concentrations of up to 10% or more in tender leaves. Herein, a cisplatin-induced acute kidney injury (AKI) model was established to investigate the protective effect and mechanism of TLB against the cisplatin-induced nephrotoxicity in mice. The results showed that TLB significantly reversed the inhibition of CRE, BUN, and MDA levels compared with the cisplatin group. Furthermore, TLB treatment (50 and 100 mg/kg) for 10 days significantly alleviated cisplatin-induced renal pathological changes. TUNEL staining showed that TLB administration can effectively improve the occurrence of apoptosis of renal tissue cells caused by cisplatin exposure. Importantly, western blot analysis verified that TLB alleviated cisplatin-induced nephrotoxicity by regulating the AKT/MAPK signaling pathway and apoptosis. In summary, our findings showed clearly that TLB has a significant preventive effect on cisplatin-induced AKI., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Aripiprazole (ARI), a second-generation atypical antipsychotic drug approved for schizophrenia treatment, shows good efficacy against depression. However, the poorly aqueous solubility of ARI leads to low bioavailability and increased dose-related side effects, seriously limiting its application in pharmaceutics. Herein, we demonstrated the fabrication of ARI and poly (methyl vinyl ether- co -maleic anhydride) (PVMMA) composite nanoparticles (PA NPs) using the supercritical antisolvent (SAS) process for enhancing its water-solubility and curative anti-depressant effects. Initially, the optimal experimental conditions (ARI/PVMMA mass ratio of 1:6, pressure of 10 MPa, and solution flow rate of 0.75 ml min -1 ) were determined by a 2 3 factorial experimental design, resulting in the PA NPs with an excellent particle morphology. In vitro cell experiments showed that PA NPs significantly inhibited the inflammatory response caused by the microglia activation induced by lipopolysaccharide (LPS). Similarly, mice behavioral tests demonstrated that PA NPs significantly improved LPS-induced depression-like behavior. Importantly, compared with free ARI, the LPS-induced activation of microglia in the mouse brain and the expression of inflammatory factors in serum were significantly reduced after treatment with PA NPs. Together, the innovative PA NPs designed by SAS process might provide a candidate for developing new ARI-based nano-formulations., (© The Author(s) 2022. Published by Oxford University Press.)

Aim: To investigate the performance of a generative adversarial network (GAN) model for staging liver fibrosis and its radiomics-based nomogram for predicting cirrhosis., Materials and Methods: This two-centre retrospective study included 434 patients for whom input data of ultrasound images and histopathological data (obtained within 1 month of ultrasound examinations) were assigned to the training cohort (249 patients), the internal cohort (92 patients), and the external (93 patients) cohort. A data augmentation method based on a GAN model was used. The discriminative performance was evaluated for classifying fibrosis of S4 and ≥S3. Deep-learning radiomics features were extracted for the prediction of cirrhosis (S4). To perform feature reduction and selection, the least absolute shrinkage and selection operator (LASSO) algorithm was applied. Radiomics scores, along with clinical factors, were incorporated into a nomogram using multivariable logistic regression analysis. The performance of the models was estimated with respect to discrimination power, calibration, and clinical benefits., Results: The areas under the receiver operating characteristic curve (AUCs) values of the GAN were 0.832/0.762 (≥S3), and 0.867/0.835 (S4) for internal/external test sets, respectively. The radiomics nomogram that intergrated radiomics scores and clinical factors showed good calibration and discrimination ability of 0.922 (AUC) in the training dataset, 0.896 in the internal dataset, and 0.861 in the external dataset. Decision curve analysis (DCA) demonstrated that the nomogram outperformed radiologist and haematological indices in terms of the most clinical benefits., Conclusions: The GAN model could be applied to discriminate fibrosis stages, and a favourable predictive accuracy for diagnosing cirrhosis was achieved using a deep-learning radiomics nomogram., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Objective: To investigate the application effect of sequential autologous hematopoietic stem cell transplantation (Auto-HSCT) with lenalidomide, bortezomib and dexamethasone (RVD) in the treatment of multiple myeloma (MM) evaluated by propensity score matching., Methods: The clinical data of 49 MM patients treated with RVD scheme and followed-up for 36 months in the hospital from January 2015 to January 2021 were retrospectively analyzed and included in the control group, the clinical data of 54 MM patients who received RVD scheme and sequential Auto-HSCT scheme and completed 36 months of follow-up in the hospital during the same period were collected and included in the observation group. PSM method (1∶1, caliper value=0.01) was used to match the control group with the observation group based on baseline data and laboratory indexes, covariate equilibrium samples were obtained between groups (40 cases in each group). The clinical efficacy of patients in the two groups after 18 weeks of treatment was compared; the incidence of toxic and side effects during treatment of patients in the two groups was compared; the survival of patients in the two groups was compared after 36 months of follow-up., Results: The ORR and DCR in the observation group were higher than those in the control group, the difference was statistically significant (P<0.05). Compared the incidence of fatigue, rash, thrombocytopenia, anemia and nausea of patients in the two groups, there was no statistical significant difference (P>0.05). After 36 months of follow-up (no loss during follow-up), 4 cases died from illness in the observation group, with a survival rate of 90% and an average survival time of 35.61 (95% CI: 35541-35.685) months, 10 cases died from illness in the control group, with a survival rate of 75% and an average survival time of 34.70 (95% CI: 34.559-34.832) months, the survival rate of the observation group was higher than that of the control group, the difference was statistically significant (P<0.05)., Conclusion: Sequential Auto-HSCT with RVD regimen in the treatment of MM can improve the short-term efficacy and increase the survival rate of patients, which will not increase toxic and side effects and has high safety.

Background: Carotid atherosclerosis by ultrasound scanning can be considered as an ideal window to reflect systemic artery atherosclerosis, which has aroused wide concern for predicting the severity of coronary artery atherosclerosis clinically. Ultrasound radio frequency (RF) data technology has enabled us to evaluate the carotid structure and elastic function precisely, for predicting the severity of coronary artery atherosclerosis., Methods: Patients with suspected coronary artery disease (CAD) underwent coronary angiography and were assigned to four groups according to whether atherosclerotic plaque was found or not and it caused stenosis. Carotid artery intima-media thickness (IMT) and arterial stiffness were investigated by quality intima-media thickness (QIMT) and quality arterial stiffness (QAS) techniques during ultrasound scanning. Univariable and multivariable modeling were used to investigate correlations of carotid parameters to coronary artery atherosclerosis. Receive operating characteristic (ROC) curves were used to evaluate diagnostic performance of these ultrasound variables., Results: Carotid IMT and stiffness variables pulse wave velocity (PWV), α, β and compliance coefficient (CC) were statistically different between every two-group's comparisons. IMT correlated with stiffness variables significantly with r = 0.70, 0.77, 0.63, and -0.39, respectively. All variables correlated with the severity of coronary atherosclerosis with the odd ratio (OR) of 1.73, 1.67, 1.19, 1.23, and 0.56 accordingly as IMT, PWV, α, β and CC were concerned. The AUC of IMT, PWV, α, β and CC were 0.9257, 0.8910, 0.8016, 0.9383, 0.8581 with correctly classified rate of 88.16%, 83.77%, 78.07%, 86.84%, and 81.58%, respectively., Conclusions: Carotid artery IMT and stiffness variable PWV, α, β and CC presented favorable predicting and differentiating values for patients with coronary atherosclerosis of different severity., (© 2022 The Authors. Echocardiography published by Wiley Periodicals LLC.)

Numerous epidemiological studies have shown a close relationship between outdoor air pollution and increased risks for cancer, infection, and cardiopulmonary diseases. However, very few studies have investigated the potential health effects of coexposure to airborne particulate matter (PM) and bioaerosols through the transmission of infectious agents, particularly under the current circumstances of the coronavirus disease 2019 pandemic. In this study, we aimed to identify urinary metabolite biomarkers that might serve as clinically predictive or diagnostic standards for relevant diseases in a real-time manner. We performed an unbiased gas/liquid chromatography-mass spectroscopy (GC/LC-MS) approach to detect urinary metabolites in 92 samples from young healthy individuals collected at three different time points after exposure to clean air, polluted ambient, or purified air, as well as two additional time points after air repollution or repurification. Subsequently, we compared the metabolomic profiles between the two time points using an integrated analysis, along with Kyoto Encyclopedia of Genes and Genomes-enriched pathway and time-series analysis. We identified 33 and 155 differential metabolites (DMs) associated with PM and bioaerosol exposure using GC/LC-MS and follow-up analyses, respectively. Our findings suggest that 16-dehydroprogesterone and 4-hydroxyphenylethanol in urine samples may serve as potential biomarkers to predict or diagnose PM- or bioaerosol-related diseases, respectively. The results indicated apparent differences between PM- and bioaerosol-associated DMs at five different time points and revealed dynamic alterations in the urinary metabolic profiles of young healthy humans with cyclic exposure to clean and polluted air environments. Our findings will help in investigating the detrimental health effects of short-term coexposure to airborne PM and bioaerosols in a real-time manner and improve clinically predictive or diagnostic strategies for preventing air pollution-related diseases., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Gastric cancer (GC) is the fifth most common cancer and the third deadliest cancer in the world, and the occurrence and development of GC are influenced by epigenetics. Methyltransferase-like 3 (METTL3) is a prominent RNA n6-adenosine methyltransferase (m6A) that plays an important role in tumor growth by controlling the work of RNA. This study aimed to reveal the biological function and molecular mechanism of METTL3 in GC. The expression level of METTL3 in GC tissues and cells was detected by qPCR, Western blot and immunohistochemistry, and the expression level and prognosis of METTL3 were predicted in public databases. CCK-8, colony formation, transwell and wound healing assays were used to study the effect of METTL3 on GC cell proliferation and migration. In addition, the enrichment effect of METTL3 on DEK mRNA was detected by the RIP experiment, the m6A modification effect of METTL3 on DEK was verified by the MeRIP experiment and the mRNA half-life of DEK when METTL3 was overexpressed was detected. The dot blot assay detects m6A modification at the mRNA level. The effect of METTL3 on cell migration ability in vivo was examined by tail vein injection of luciferase-labeled cells. The experimental results showed that METTL3 was highly expressed in GC tissues and cells, and the high expression of METTL3 was associated with a poor prognosis. In addition, the m6A modification level of mRNA was higher in GC tissues and GC cell lines. Overexpression of METTL3 in MGC80-3 cells and AGS promoted cell proliferation and migration, while the knockdown of METTL3 inhibited cell proliferation and migration. The results of in vitro rescue experiments showed that the knockdown of DEK reversed the promoting effects of METTL3 on cell proliferation and migration. In vivo experiments showed that the knockdown of DEK reversed the increase in lung metastases caused by the overexpression of METTL3 in mice. Mechanistically, the results of the RIP experiment showed that METTL3 could enrich DEK mRNA, and the results of the MePIP and RNA half-life experiments indicated that METTL3 binds to the 3'UTR of DEK, participates in the m6A modification of DEK and promotes the stability of DEK mRNA. Ultimately, we concluded that METTL3 promotes GC cell proliferation and migration by stabilizing DEK mRNA expression. Therefore, METTL3 is a potential biomarker for GC prognosis and a therapeutic target.

Thyroid dysfunction is a common endocrine disease measured by thyroid-stimulating hormone (TSH) level. Although >70 genetic loci associated with TSH have been reported through genome-wide association studies (GWASs), the variants can only explain a small fraction of the thyroid function heritability. To identify novel candidate genes for thyroid function, we conducted the first large-scale transcriptome-wide association study (TWAS) for thyroid function using GWAS-summary data for TSH levels in up to 119 715 individuals combined with precomputed gene expression weights of six panels from four tissue types. The candidate genes identified by TWAS were further validated by TWAS replication and gene expression profiles. We identified 74 conditionally independent genes significantly associated with thyroid function, such as PDE8B (P = 1.67 × 10-282), PDE10A (P = 7.61 × 10-119), NR3C2 (P = 1.50 × 10-92) and CAPZB (P = 3.13 × 10-79). After TWAS replication using UKBB datasets, 26 genes were replicated for significant associations with thyroid-relevant diseases/traits. Among them, 16 genes were causal for their associations to thyroid-relevant diseases/traits and further validated in differential expression analyses, including two novel genes (MFSD6 and RBM47) that did not implicate in previous GWASs. Enrichment analyses detected several pathways associated with thyroid function, such as the cAMP signaling pathway (P = 7.27 × 10-4), hemostasis (P = 3.74 × 10-4), and platelet activation, signaling and aggregation (P = 9.98 × 10-4). Our study identified multiple candidate genes and pathways associated with thyroid function, providing novel clues for revealing the genetic mechanisms of thyroid function and disease., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Acoustic structure quantification (ASQ) has been applied to evaluate liver histologic changes by analyzing the speckle pattern seen on B-mode ultrasound. We aimed to assess the severity of portal hypertension (PHT) through hepatic ultrasonography., Methods: Sixty patients diagnosed with PHT and underwent surgical treatment with portosystemic shunts were enrolled. Portal pressure (PP) was measured intraoperatively. Patients were divided into subgroups according to the severity of gastroesophageal varices and Child-Pugh class. Three difference ratio (C m 2 ) values on ASQ histogram mode were analyzed for their relationships with PP, degree of gastroesophageal varices and Child-Pugh liver function. Thirty healthy volunteers matched with the patients for gender and age were enrolled as controls. Comparisons among groups and correlation of the parameters with PP were analyzed. Area under the receive operating characteristic curve was used to evaluate the predicting value of ASQ parameters., Results: In the patients, the ASQ parameters peak C m 2 (C m 2 max ), mean C m 2 (C m 2 mean ) and the highest occurred C m 2 value of the obtained red curve (R max C m 2 ) were all greatly increased (P < 0.0001, P < 0.0001, P = 0.027). Multiple comparisons indicated that, regardless of Child-Pugh class and degree of gastroesophageal varices, the patients had significantly increased C m 2 max and C m 2 mean compared with the controls (all P < 0.0001). No differences among subgroups were observed. C m 2 max was significantly statistically correlated with PP (r = 0.3505, P < 0.01), degree of varices (r = 0.4998, P < 0.0001). Youden's index for C m 2 max with a cut-off value of 140.3 for predicting the presence of PHT, gastroesophageal varices and liver function equal to or worse than Child-Pugh class B were 0.8, 0.91 and 0.84, respectively., Conclusions: ASQ analysis of ultrasonographic images may have a role in the evaluation of the severity of PHT by detecting liver histologic changes in the speckle pattern caused by cirrhosis., (© 2022. The Author(s).)

Background: Accumulative evidences have shown that dysregulation of biological pathways contributed to the initiation and progression of malignant tumours. Several methods for pathway activity measurement have been proposed, but they are restricted to making comparisons between groups or sensitive to experimental batch effects., Methods: We introduced a novel method for individualized pathway activity measurement (IPAM) that is based on the ranking of gene expression levels in individual sample. Taking advantage of IPAM, we calculated the pathway activity of 318 pathways from KEGG database in the 10528 tumour/normal samples of 33 cancer types from TCGA to identify characteristic dysregulated pathways among different cancer types., Findings: IPAM precisely quantified the level of activity of each pathway in pan-cancer analysis and exhibited better performance in cancer classification and prognosis prediction over five widely used tools. The average ROC-AUC of cancer diagnostic model using tumour-educated platelets (TEPs) reached 92.84%, suggesting the potential of our algorithm in early diagnosis of cancer. We identified several pathways significantly deregulated and associated with patient survival in a large fraction of cancer types, such as tyrosine metabolism, fatty acid degradation, cell cycle, p53 signalling pathway and DNA replication. We also confirmed the dominant role of metabolic pathways in cancer pathway dysregulation and identified the driving factors of specific pathway dysregulation, such as PPARA for branched-chain amino acid metabolism and NR1I2, NR1I3 for fatty acid metabolism., Interpretation: Our study will provide novel clues for understanding the pathological mechanisms of cancer, ultimately paving the way for personalized medicine of cancer., Funding: A full list of funding can be found in the Acknowledgements section., Competing Interests: Declaration of interests The authors declare that there are no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)