Repeat it without me: Crowdsourcing the T1 mapping common ground via the ISMRM reproducibility challenge.

PURPOSE: T1 mapping is a widely used quantitative MRI technique, but its tissue-specific values remain inconsistent across protocols, sites, and vendors. The ISMRM Reproducible Research and Quantitative MR study groups jointly launched a challenge to assess the reproducibility of a well-established inversion-recovery T1 mapping technique, using acquisition details from a seminal T1 mapping paper on a standardized phantom and in human brains. METHODS: The challenge used the acquisition protocol from Barral et al. (2010). Researchers collected T1 mapping data on the ISMRM/NIST phantom and/or in human brains. Data submission, pipeline development, and analysis were conducted using open-source platforms. Intersubmission and intrasubmission comparisons were performed. RESULTS: Eighteen submissions (39 phantom and 56 human datasets) on scanners by three MRI vendors were collected at 3 T (except one, at 0.35 T). The mean coefficient of variation was 6.1% for intersubmission phantom measurements, and 2.9% for intrasubmission measurements. For humans, the intersubmission/intrasubmission coefficient of variation was 5.9/3.2% in the genu and 16/6.9% in the cortex. An interactive dashboard for data visualization was also developed: https://rrsg2020.dashboards.neurolibre.org. CONCLUSION: The T1 intersubmission variability was twice as high as the intrasubmission variability in both phantoms and human brains, indicating that the acquisition details in the original paper were insufficient to reproduce a quantitative MRI protocol. This study reports the inherent uncertainty in T1 measures across independent research groups, bringing us one step closer to a practical clinical baseline of T1 variations in vivo.

Efficient pulse sequence design framework for high-dimensional MR fingerprinting scans using systematic error index.

PURPOSE: For effective optimization of MR fingerprinting (MRF) pulse sequences, estimating and minimizing errors from actual scan conditions are crucial. Although virtual-scan simulations offer an approximation to these errors, their computational demands become expensive for high-dimensional MRF frameworks, where interactions between more than two tissue properties are considered. This complexity makes sequence optimization impractical. We introduce a new mathematical model, the systematic error index (SEI), to address the scalability challenges for high-dimensional MRF sequence design. METHODS: By eliminating the need to perform dictionary matching, the SEI model approximates quantification errors with low computational costs. The SEI model was validated in comparison with virtual-scan simulations. The SEI model was further applied to optimize three high-dimensional MRF sequences that quantify two to four tissue properties. The optimized scans were examined in simulations and healthy subjects. RESULTS: The proposed SEI model closely approximated the virtual-scan simulation outcomes while achieving hundred- to thousand-times acceleration in the computational speed. In both simulation and in vivo experiments, the optimized MRF sequences yield higher measurement accuracy with fewer undersampling artifacts at shorter scan times than the heuristically designed sequences. CONCLUSION: We developed an efficient method for estimating real-world errors in MRF scans with high computational efficiency. Our results illustrate that the SEI model could approximate errors both qualitatively and quantitatively. We also proved the practicality of the SEI model of optimizing sequences for high-dimensional MRF frameworks with manageable computational power. The optimized high-dimensional MRF scans exhibited enhanced robustness against undersampling and system imperfections with faster scan times.

Molybdenum disulfide nanosheets promote the plasmid-mediated conjugative transfer of antibiotic resistance genes.

The environmental safety of nanoscale molybdenum disulfide (MoS2) has attracted considerable attention, but its influence on the horizontal migration of antibiotic resistance genes and the ecological risks entailed have not been reported. This study addressed the influence of exposure to MoS2 at different concentrations up to 100 mg/L on the conjugative transfer of antibiotic resistance genes carried by RP4 plasmids with two strains of Escherichia coli. As a result, MoS2 facilitated RP4 plasmid-mediated conjugative transfer in a dose-dependent manner. The conjugation of RP4 plasmids was enhanced as much as 7-fold. The promoting effect is mainly attributable to increased membrane permeability, oxidative stress induced by reactive oxygen species, changes in extracellular polymer secretion and differential expression of the genes involved in horizontal gene transfer. The data highlight the distinct dose dependence of the conjugative transfer of antibiotic resistance genes and the need to improve awareness of the ecological and health risks of nanoscale transition metal dichalcogenides.

Combining magnetic resonance fingerprinting with voxel-based morphometric analysis to reduce false positives for focal cortical dysplasia detection.

OBJECTIVE: We aim to improve focal cortical dysplasia (FCD) detection by combining high-resolution, three-dimensional (3D) magnetic resonance fingerprinting (MRF) with voxel-based morphometric magnetic resonance imaging (MRI) analysis. METHODS: We included 37 patients with pharmacoresistant focal epilepsy and FCD (10 IIa, 15 IIb, 10 mild Malformation of Cortical Development [mMCD], and 2 mMCD with oligodendroglial hyperplasia and epilepsy [MOGHE]). Fifty-nine healthy controls (HCs) were also included. 3D lesion labels were manually created. Whole-brain MRF scans were obtained with 1 mm3 isotropic resolution, from which quantitative T1 and T2 maps were reconstructed. Voxel-based MRI postprocessing, implemented with the morphometric analysis program (MAP18), was performed for FCD detection using clinical T1w images, outputting clusters with voxel-wise lesion probabilities. Average MRF T1 and T2 were calculated in each cluster from MAP18 output for gray matter (GM) and white matter (WM) separately. Normalized MRF T1 and T2 were calculated by z-scores using HCs. Clusters that overlapped with the lesion labels were considered true positives (TPs); clusters with no overlap were considered false positives (FPs). Two-sample t-tests were performed to compare MRF measures between TP/FP clusters. A neural network model was trained using MRF values and cluster volume to distinguish TP/FP clusters. Ten-fold cross-validation was used to evaluate model performance at the cluster level. Leave-one-patient-out cross-validation was used to evaluate performance at the patient level. RESULTS: MRF metrics were significantly higher in TP than FP clusters, including GM T1, normalized WM T1, and normalized WM T2. The neural network model with normalized MRF measures and cluster volume as input achieved mean area under the curve (AUC) of .83, sensitivity of 82.1%, and specificity of 71.7%. This model showed superior performance over direct thresholding of MAP18 FCD probability map at both the cluster and patient levels, eliminating ≥75% FP clusters in 30% of patients and ≥50% of FP clusters in 91% of patients. SIGNIFICANCE: This pilot study suggests the efficacy of MRF for reducing FPs in FCD detection, due to its quantitative values reflecting in vivo pathological changes. © 2024 International League Against Epilepsy.

Melt-quenched glass formation of a family of metal-carboxylate frameworks.

Metal-organic framework (MOF) glasses are an emerging class of glasses which complement traditional inorganic, organic and metallic counterparts due to their hybrid nature. Although a few zeolitic imidazolate frameworks have been made into glasses, how to melt and quench the largest subclass of MOFs, metal carboxylate frameworks, into glasses remains challenging. Here, we develop a strategy by grafting the zwitterions on the carboxylate ligands and incorporating organic acids in the framework channels to enable the glass formation. The charge delocalization of zwitterion-acid subsystem and the densely filled channels facilitate the coordination bonding mismatch and thus reduce the melting temperature. Following melt-quenching realizes the glass formation of a family of carboxylate MOFs (UiO-67, UiO-68 and DUT-5), which are usually believed to be un-meltable. Our work opens up an avenue for melt-quenching porous molecular solids into glasses.

ß-Sitosterol targets ASS1 for Nrf2 ubiquitin-dependent degradation, inducing ROS-mediated apoptosis via the PTEN/PI3K/AKT signaling pathway in ovarian cancer.

The exploration of drugs derived from natural sources holds significant promise in addressing current limitations in ovarian cancer (OC) treatments. While previous studies have highlighted the remarkable anti-cancer properties of the natural compound ß-sitosterol (SIT) across various tumors, its specific role in OC treatment remains unexplored. This study aims to investigate the anti-tumor activity of SIT in OC using in vitro and in vivo models, delineate potential mechanisms, and establish a preclinical theoretical foundation for future clinical trials, thus fostering further research. Utilizing network pharmacology, we pinpoint SIT as a promising candidate for OC treatment and predict its potential targets and pathways. Through a series of in vitro and in vivo experiments, we unveil a novel mechanism through which SIT mitigates the malignant biological behaviors of OC cells by modulating redox status. Specifically, SIT selectively targets argininosuccinate synthetase 1 (ASS1), a protein markedly overexpressed in OC tissues and cells. Inhibiting ASS1, SIT enhances the interaction between Nrf2 and Keap1, instigating the ubiquitin-dependent degradation of Nrf2, subsequently diminishing the transcriptional activation of downstream antioxidant genes HO-1 and NQO1. The interruption of the antioxidant program by SIT results in the substantial accumulation of reactive oxygen species (ROS) in OC cells. This, in turn, upregulates PTEN, exerting negative regulation on the phosphorylation activation of AKT. The suppression of AKT signaling disrupted downstream pathways associated with cell cycle, cell survival, apoptosis, migration, and invasion, ultimately culminating in the death of OC cells. Our research uncovers new targets and mechanisms of SIT against OC, contributing to the existing knowledge on the anti-tumor effects of natural products in the context of OC. Additionally, this research unveils a novel role of ASS1 in regulating the Nrf2-mediated antioxidant program and governing redox homeostasis in OC, providing a deeper understanding of this complex disease.

Intervertebral disc-intrinsic Hedgehog signaling maintains disc cell phenotypes and prevents disc degeneration through both cell autonomous and non-autonomous mechanisms.

Intervertebral disc degeneration is closely related to abnormal phenotypic changes in disc cells. However, the mechanism by which disc cell phenotypes are maintained remains poorly understood. Here, Hedgehog-responsive cells were found to be specifically localized in the inner annulus fibrosus and cartilaginous endplate of postnatal discs, likely activated by Indian Hedgehog. Global inhibition of Hedgehog signaling using a pharmacological inhibitor or Agc1-CreERT2-mediated deletion of Smo in disc cells of juvenile mice led to spontaneous degenerative changes in annulus fibrosus and cartilaginous endplate accompanied by aberrant disc cell differentiation in adult mice. In contrast, Krt19-CreER-mediated deletion of Smo specifically in nucleus pulposus cells led to healthy discs and normal disc cell phenotypes. Similarly, age-related degeneration of nucleus pulposus was accelerated by genetic inactivation of Hedgehog signaling in all disc cells, but not in nucleus pulposus cells. Furthermore, inactivation of Gli2 in disc cells resulted in partial loss of the vertebral growth plate but otherwise healthy discs, whereas deletion of Gli3 in disc cells largely corrected disc defects caused by Smo ablation in mice. Taken together, our findings not only revealed for the first time a direct role of Hedgehog-Gli3 signaling in maintaining homeostasis and cell phenotypes of annuls fibrosus and cartilaginous endplate, but also identified disc-intrinsic Hedgehog signaling as a novel non-cell-autonomous mechanism to regulate nucleus pulposus cell phenotype and protect mice from age-dependent nucleus pulposus degeneration. Thus, targeting Hedgehog signaling may represent a potential therapeutic strategy for the prevention and treatment of intervertebral disc degeneration.

Piperlongumine, a Piper longum-derived amide alkaloid, protects mice from ovariectomy-induced osteoporosis by inhibiting osteoclastogenesis via suppression of p38 and JNK signaling.

Postmenopausal osteoporosis (PMOP) is a metabolic bone disease that results from overproduction and hyperactivation of osteoclasts caused by insufficient estrogen in women after menopause. Current therapeutic strategies are mainly focused on treating PMOP patients who have already developed severe bone loss or even osteoporotic fractures. Obviously, a better strategy is to prevent PMOP from occurring in the first place. However, such reagents are largely lacking. Piperlongumine (PLM), an amide alkaloid extracted from long pepper Piper longum, exhibits the anti-osteoclastogenic effect in normal bone marrow macrophages (BMMs) and the protective effect against osteolysis induced by titanium particles in mice. This study examined the preventive effect of PLM on PMOP and explored the potential mechanism of this effect using both ovariectomized mice and their primary cells. The result showed that PLM (5 and 10 mg kg-1) administered daily for 6 weeks ameliorated ovariectomy-induced bone loss and osteoclast formation in mice. Further cell experiments showed that PLM directly suppressed osteoclast formation, F-actin ring formation, and osteoclastic resorption pit formation in BMMs derived from osteoporotic mice, but did not obviously affect osteogenic differentiation of bone marrow stromal cells (BMSCs) from these mice. Western blot analysis revealed that PLM attenuated maximal activation of p38 and JNK pathways by RANKL stimulation without affecting acute activation of NF-κB, AKT, and ERK signaling. Furthermore, PLM inhibited expression of key osteoclastogenic transcription factors NFATc1/c-Fos and their target genes (Dcstamp, Atp6v0d2, Acp5, and Oscar). Taken together, our findings suggest that PLM inhibits osteoclast formation and function by suppressing RANKL-induced activation of the p38/JNK-cFos/NFATc1 signaling cascade, thereby preventing ovariectomy-induced osteoporosis in mice. Thus, PLM can potentially be used as an anti-resorption drug or dietary supplement for the prevention of PMOP.

Metal Nanoparticles Assisted Ultrafast Laser Plasmonic Microwelding of Oxide-Semiconductor Interconnects.

Integration of wafer-scale oxide and semiconductor materials meets the difficulties of residual stress and materials incompatibility. In this work, Ag NPs thin film is contributed as an energy confinement layer between oxide (Sapphire) and semiconductor (Si) wafers to localize the materials interaction during ultrafast laser irradiation. Due to the plasmonic effects generated within constructed dielectric-metal-dielectric structures (i.e., Sapphire-Ag-Si), thermal diffusion and chemical reaction between Ag and its neighboring materials facilitate the microwelding of Sapphire and Si wafers. Ag NPs can be totally sintered within the junction area to bridge oxide and semiconductor, while Al─O─Ag bond and Ag─Si bond are formed at Ag-Sapphire and Ag─Si interfaces, respectively. As-received heterogeneous joint exhibits a high shear strength up to 5.4 MPa, with the fracture occurring inside Si wafer. Meanwhile, insertion of metal nanolayer can greatly relieve the residual stress-induced microcracking inside the brittle materials. Such wafer-scale Sapphire and Si interconnects thus show robust strength and excellent impermeability even after thermal shocking (-40 °C to 120 °C) for 200 cycles. This metal NPs layer-assisted plasmonic microwelding technology can extend to broad materials integration, which is promising for high-performance microdevices development in MEMS, MOEMS, or microfluidics.

Irritable bowel syndrome in children: the placebo response rate and influencing factors a meta-analysis.

BACKGROUND: Irritable bowel syndrome is common in children and exhibits a high placebo response. This study was to explore the placebo response rate and its influencing factors in children with irritable bowel syndrome. METHODS: A systematic search was performed on Pubmed, Embase, MEDLINE, Cochrane Library, CNKI, Wanfang, and CBM from database inception to March 2022. Randomized controlled trials of irritable bowel syndrome in children were included in the study. The primary outcome was the placebo response rate of improvement. RESULTS: Thirteen studies were included, with 445 patients in the placebo group. The rate of improvement and abdominal pain disappearance were 28.2% (95% CI, 16.6-39.9%) and 5% (95% CI, 0-18.4%). The placebo response based on the abdominal pain score was 0.675 (95% CI, 0.203-1.147). The mode of administration (P < 0.01), dosing schedule (P < 0.01), and clinical outcome assessor (P = 0.04) have a significant impact on the magnitude of placebo effect. CONCLUSIONS: The placebo response rate for pediatric irritable bowel syndrome was 28.2%. In clinical trials, reducing dosing frequency, selecting appropriate dosage forms, and using patient-reported outcomes can help mitigate the placebo effect. IMPACT: This is the first meta-analysis to assess the placebo response rates for improvement and disappearance in children with IBS. The finding suggested that the mode of administration, dosing schedule, and clinical outcome assessor could potentially influence the magnitude of the placebo effect in children with IBS. This study would provide a basis for estimating sample size in clinical trial design with a placebo control.

Recent advances and clinical translation of liposomal delivery systems in cancer therapy.

The limitations of conventional cancer treatment are driving the emergence and development of nanomedicines. Research in liposomal nanomedicine for cancer therapy is rapidly increasing, opening up new horizons for cancer treatment. Liposomal nanomedicine, which focuses on targeted drug delivery to improve the therapeutic effect of cancer while reducing damage to normal tissues and cells, has great potential in the field of cancer therapy. This review aims to clarify the advantages of liposomal delivery systems in cancer therapy. We describe the recent understanding of spatiotemporal fate of liposomes in the organism after different routes of drug administration. Meanwhile, various types of liposome-based drug delivery systems that exert their respective advantages in cancer therapy while reducing side effects were discussed. Moreover, the combination of liposomal agents with other therapies (such as photodynamic therapy and photothermal therapy) has demonstrated enhanced tumor-targeting efficiency and therapeutic efficacy. Finally, the opportunities and challenges faced by the field of liposome nanoformulations for entering the clinical treatment of cancer are highlighted.

Inter-individual, hemispheric and sex variability of brain activations during numerosity processing.

Numerosity perception is a fundamental and innate cognitive function shared by both humans and many animal species. Previous research has primarily focused on exploring the spatial and functional consistency of neural activations that were associated with the processing of numerosity information. However, the inter-individual variability of brain activations of numerosity perception remains unclear. In the present study, with a large-sample functional magnetic resonance imaging (fMRI) dataset (n = 460), we aimed to localize the functional regions related to numerosity perceptions and explore the inter-individual, hemispheric, and sex differences within these brain regions. Fifteen subject-specific activated regions, including the anterior intraparietal sulcus (aIPS), posterior intraparietal sulcus (pIPS), insula, inferior frontal gyrus (IFG), inferior temporal gyrus (ITG), premotor area (PM), middle occipital gyrus (MOG) and anterior cingulate cortex (ACC), were delineated in each individual and then used to create a functional probabilistic atlas to quantify individual variability in brain activations of numerosity processing. Though the activation percentages of most regions were higher than 60%, the intersections of most regions across individuals were considerably lower, falling below 50%, indicating substantial variations in brain activations related to numerosity processing among individuals. Furthermore, significant hemispheric and sex differences in activation location, extent, and magnitude were also found in these regions. Most activated regions in the right hemisphere had larger activation volumes and activation magnitudes, and were located more lateral and anterior than their counterparts in the left hemisphere. In addition, in most of these regions, males displayed stronger activations than females. Our findings demonstrate large inter-individual, hemispheric, and sex differences in brain activations related to numerosity processing, and our probabilistic atlas can serve as a robust functional and spatial reference for mapping the numerosity-related neural networks.

MiR-143-3p/FNDC5 axis: a novel regulator of insulin sensitivity.

PURPOSE: Insulin resistance is a key hallmark in type 2 diabetes. In recent decades, there have been numerous studies of the causes of insulin resistance. microRNAs (miRNAs) participate in the regulation of multiple aspects of energy metabolism and miR-143-3p has been shown to induce insulin resistance. We aimed to predict the downstream targets of miR-143-3p and found a miR-143-3p binding site on the 3'-untranslated region of FNDC5 (Fibronectin type III domain containing 5) mRNA. METHODS: We first confirmed that FNDC5 mRNA is a target of miR-143-3p using a double luciferase experiment, then constructed a prokaryotic expression system for the mature form of FNDC5, irisin, and expressed and purified irisin protein. We transfected a miR-143-3p mimic into HepG2-NTCP (Na+-taurocholate cotransporting polypeptide) cells using an NTCP targeting vector, then 24 h later, the glucose concentration of the culture medium, western blot analysis was analyzed. We next co-incubated the cells transfected with the miR-143-3p mimic with irisin for 12 h following by the assay of glucose uptake and AKT phosphorylation. RESULTS: The glucose concentration of the culture medium was higher than that associated with control miRNA-transfected cells (p < 0.01). Western blot analysis showed that the miR-143-3p mimic significantly reduced the expression of FNDC5 (p < 0.05) and the phosphorylation of AKT (Protein kinase B) (p < 0.05), implying impaired insulin signaling. which increased the glucose uptake (p < 0.0001) and AKT phosphorylation in the cells (p < 0.05). CONCLUSION: We conclude that FNDC5 is a direct target of miR-143-3p and that miR-143-3p induces insulin resistance by reducing its expression.

Motion Robust MR Fingerprinting Scan to Image Neonates With Prenatal Opioid Exposure.

PURPOSE: To explore whether MR fingerprinting (MRF) scans provide motion-robust and quantitative brain tissue measurements for non-sedated infants with prenatal opioid exposure (POE). STUDY TYPE: Prospective. POPULATION: 13 infants with POE (3 male; 12 newborns (age 7-65 days) and 1 infant aged 9-months). FIELD STRENGTH/SEQUENCE: 3T, 3D T1-weighted MPRAGE, 3D T2-weighted TSE and MRF sequences. ASSESSMENT: The image quality of MRF and MRI was assessed in a fully crossed, multiple-reader, multiple-case study. Sixteen image quality features in three types-image artifacts, structure and myelination visualization-were ranked by four neuroradiologists (8, 7, 5, and 8 years of experience respectively), using a 3-point scale. MRF T1 and T2 values in 8 white matter brain regions were compared between babies younger than 1 month and babies between 1 and 2 months. STATISTICAL TESTS: Generalized estimating equations model to test the significance of differences of regional T1 and T2 values of babies under 1 month and those older. MRI and MRF image quality was assessed using Gwet's second order auto-correlation coefficient (AC2) with confidence levels. The Cochran-Mantel-Haenszel test was used to assess the difference in proportions between MRF and MRI for all features and stratified by the type of features. A P value <0.05 was considered statistically significant. RESULTS: The MRF of two infants were excluded in T1 and T2 value analysis due to severe motion artifact but were included in the image quality assessment. In infants under 1 month of age (N = 6), the T1 and T2 values were significantly higher compared to those between 1 and 2 months of age (N = 4). MRF images showed significantly higher image quality ratings in all three feature types compared to MRI images. CONCLUSIONS: MR Fingerprinting scans have potential to be a motion-robust and efficient method for nonsedated infants. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

Does clinical experience affect the bracket bonding accuracy of guided bonding devices in vitro?

OBJECTIVES: To study whether and how the clinical experience of the operator affects the accuracy of bracket placement using guided bonding devices (GBDs) in vitro. MATERIALS AND METHODS: Five resin models were bonded virtually with brackets, and the corresponding GBDs were generated and three-dimensionally printed. Nine operators, which included three dental students, three orthodontic students, and three orthodontists, bonded the brackets on the resin models using GBDs on a dental mannequin. After being bonded with brackets, the models were scanned, and the actual and designed positions of the brackets were compared. RESULTS: There was no immediate debonding. The orthodontists spent a significantly shorter time (22.36 minutes) in bracket bonding than the dental students (24.62 minutes; P < .05). The brackets tended to deviate to the buccal side in the dental student group. Linear deviations tended to be smallest in the orthodontic student group, but no significant difference was found among operators with different clinical experience (P > .5). All linear and angular deviations in each group were under 0.5 mm and 2°, respectively. CONCLUSIONS: Clinical experience was positively related to the bonding accuracy using GBDs, especially in the buccolingual dimension. Inexperience also led to longer bonding duration. However, bonding accuracy was clinically acceptable in general.

Self-calibrated subspace reconstruction for multidimensional MR fingerprinting for simultaneous relaxation and diffusion quantification.

PURPOSE: To propose a new reconstruction method for multidimensional MR fingerprinting (mdMRF) to address shading artifacts caused by physiological motion-induced measurement errors without navigating or gating. METHODS: The proposed method comprises two procedures: self-calibration and subspace reconstruction. The first procedure (self-calibration) applies temporally local matrix completion to reconstruct low-resolution images from a subset of under-sampled data extracted from the k-space center. The second procedure (subspace reconstruction) utilizes temporally global subspace reconstruction with pre-estimated temporal subspace from low-resolution images to reconstruct aliasing-free, high-resolution, and time-resolved images. After reconstruction, a customized outlier detection algorithm was employed to automatically detect and remove images corrupted by measurement errors. Feasibility, robustness, and scan efficiency were evaluated through in vivo human brain imaging experiments. RESULTS: The proposed method successfully reconstructed aliasing-free, high-resolution, and time-resolved images, where the measurement errors were accurately represented. The corrupted images were automatically and robustly detected and removed. Artifact-free T1, T2, and ADC maps were generated simultaneously. The proposed reconstruction method demonstrated robustness across different scanners, parameter settings, and subjects. A high scan efficiency of less than 20 s per slice has been achieved. CONCLUSION: The proposed reconstruction method can effectively alleviate shading artifacts caused by physiological motion-induced measurement errors. It enables simultaneous and artifact-free quantification of T1, T2, and ADC using mdMRF scans without prospective gating, with robustness and high scan efficiency.

The IL-31/TRPV1 pathway mediates allergic asthma exacerbated by DINP dermal exposure in OVA-sensitized Balb/c mice.

BACKGROUND: The potential role of dermal exposure diisononyl phthalate (DINP) as an adjuvant in allergic inflammation and asthma has been suggested. However, the current findings do not provide enough evidence to support this claim. OBJECTIVES: The purpose of this investigation was to examine the impact and mechanisms of allergic asthma exacerbation through the dermal exposure to DINP. METHODS: The study was undertaken using OVA-sensitized mice. Lung histopathology and airway hyperreactivity (AHR) were assessed. Expression levels of immunoglobulins (t-IgE, OVA-IgE and OVA-IgG1), cytokines (IL-31, IL-4, IL-5, IL-6, IL-13 and INF-γ), and TRPV1 were measured. To investigate the mechanism by which allergic asthma worsens due to dermal exposure to DINP, the blockade analysis using the IL-31 antagonist SB-431542 and the TRPV1 antagonist capsazepine (CZP) were performed. RESULTS: The findings of the study revealed that the simultaneous exposure to DINP and OVA resulted in an increase in inspiratory resistance (Ri) and expiratory resistance (Re), a decrease in the minimum value of lung dynamic compliance (Cldyn), and worsened airway remodeling. Additionally, it was found that this exposure led to an increase in the levels of IL-31 and TRPV1, which are biomarkers of Th2 cytokines (IL-4, IL-5, IL-6, and IL-13), as well as immunoglobulins (Total IgE, OVA-lgE, and OVA-IgG1), while decreasing the biomarker of Th1 cytokines (IFN-γ). However, these impairments showed improvement after the administration of SB-431542 or CZP. CONCLUSION: The findings of this research indicate that the IL-31/TRPV1 pathway plays a moderating function in OVA-induced allergic asthma worsened by dermal exposure to DINP.

[Mechanism of ferroptosis in chronic heart failure based on theory of "harmful hyperactivity and responding inhibition"].

Chronic heart failure is the end stage of heart diseases caused by multiple causes. Myocardial cell injury is the key cause of cardiac function deterioration. Ferroptosis, an iron-dependent programmed death mode, is characterized by iron overload and excessive accumulation of lipid peroxides. Studies have demonstrated that inhibiting ferroptosis has a protective effect on myocardial cells. The theory of "harmful hyperactivity and responding inhibition" is an important rule developed by physicians to explain the generation and restriction of the five elements and the pathological imbalance of the human body, and can guide medication. Correlating with the nature, humans need to rely on the law of responding inhibition to maintain the harmony of five Zang-organs and the steady state of Fu-organs. The pathogenesis of ferroptosis in chronic heart failure highly coincides with the process of failing to "inhibition and hyperactivity becoming harmful". The initial factor of ferroptosis is the deficiency of heart Qi, which results in the inability to maintain the balance of cardiomyocyte redox system. The involvement of the five Zang-organs leads to the loss of distribution of body fluid and blood. As a result, the phlegm turbidity, blood stasis, and water retention in the meridians occur, which are manifested as the accumulation of iron and lipid peroxides, which is the aggravating factor of ferroptosis. The two factors interact with each other, leading to the spiral development and thus aggravating heart failure. According to the traditional Chinese medicine(TCM) pathogenesis of ferroptosis, the authors try to treat the chronic heart failure by stages in accordance with the general principle of restraining excess and alleviating hyperactivity. The early-stage treatment should "nourish heart Qi, regulate the five Zang-organs, so as to restrain excess". The middle-stage treatment should "active blood, resolve phlegm, dispel pathogen, and eliminate turbidity", so as to alleviate hyperactivity. The late-stage treatment should "warm Yang, replenish Qi, active blood, and excrete water". Following the characteristics of pathogenesis, the TCM intervention can reduce iron accumulation and promote the clearance of lipid peroxide, thus inhibiting ferroptosis and improving cardiac function.

Effect of Danhong injection on heart failure in rats evaluated by metabolomics.

Background: Heart failure (HF) is characterized by reduced ventricular filling or ejection function due to organic or non-organic cardiovascular diseases. Danhong injection (DHI) is a medicinal material used clinically to treat HF for many years in China. Although prior research has shown that Danhong injection can improve cardiac function and structure, the biological mechanism has yet to be determined. Methods: Serum metabolic analysis was conducted via ultra-high-performance liquid chromatography-quadrupole time-of-flight/mass spectrometry (UHPLC-QE/MS) to explore underlying protective mechanisms of DHI in the transverse aortic constriction (TAC)-induced heart failure. Multivariate statistical techniques were used in the research, such as unsupervised principal component analysis (PCA) and orthogonal projection to latent structures discriminant analysis (OPLS-DA). MetaboAnalyst and Kyoto Encyclopedia of Genes and Genomes (KEGG) were employed to pinpoint pertinent metabolic pathways. Results: After DHI treatment, cardiac morphology and function as well as the metabolism in model rats were improved. We identified 17 differential metabolites and six metabolic pathways. Two biomarkers, PC(18:3(6Z,9Z,12Z)/24:0) and L-Phenylalanine, were identified for the first time as strong indicators for the significant effect of DHI. Conclusion: This study revealed that DHI could regulate potential biomarkers and correlated metabolic pathway, which highlighted therapeutic potential of DHI in managing HF.

AUV Path Planning Considering Ocean Current Disturbance Based on Cloud Desktop Technology.

In the field of ocean energy detection, Autonomous Underwater Vehicles (AUVs) offer significant advantages in terms of manpower, resource, and energy efficiency. However, the unpredictable nature of the ocean environment, particularly the real-time changes in ocean currents, poses navigational risks for AUVs. Therefore, effective path planning in dynamic environments is crucial for AUVs to perform specific tasks. This paper addresses the static path planning problem and proposes a model called the noise net double DQN network with prioritized experience replay (N-DDQNP). The N-DDQNP model combines a noise network and a prioritized experience replay mechanism to address the limited exploration and slow convergence speed issues of the DQN algorithm, which are caused by the greedy strategy and uniform sampling mechanism. The proposed approach involves constructing a double DQN network with a priority experience replay and an exploration mechanism using the noise network. Second, a compound reward function is formulated to take into account ocean current, distance, and safety factors, ensuring prompt feedback during the training process. Regarding the ocean current, the reward function is designed based on the angle between the current direction and the AUV's heading direction, considering its impact on the AUV's speed. As for the distance factor, the reward is determined by the Euclidean distance between the current position and the target point. Furthermore, the safety factor considers whether the AUV may collide with obstacles. By incorporating these three factors, the compound reward function is established. To evaluate the performance of the N-DDQNP model, experiments were conducted using real ocean data in various complex ocean environments. The results demonstrate that the path planning time of the N-DDQNP model outperforms other algorithms in different ocean current scenarios and obstacle environments. Furthermore, a user console-AUV connection has been established using spice cloud desktop technology. The cloud desktop architecture enables intuitive observation of the AUV's navigation posture and the surrounding marine environment, facilitating safer and more efficient underwater exploration and marine resource detection tasks.