Quantifying uncertainty in graph neural network explanations.

In recent years, analyzing the explanation for the prediction of Graph Neural Networks (GNNs) has attracted increasing attention. Despite this progress, most existing methods do not adequately consider the inherent uncertainties stemming from the randomness of model parameters and graph data, which may lead to overconfidence and misguiding explanations. However, it is challenging for most of GNN explanation methods to quantify these uncertainties since they obtain the prediction explanation in a post-hoc and model-agnostic manner without considering the randomness of graph data and model parameters. To address the above problems, this paper proposes a novel uncertainty quantification framework for GNN explanations. For mitigating the randomness of graph data in the explanation, our framework accounts for two distinct data uncertainties, allowing for a direct assessment of the uncertainty in GNN explanations. For mitigating the randomness of learned model parameters, our method learns the parameter distribution directly from the data, obviating the need for assumptions about specific distributions. Moreover, the explanation uncertainty within model parameters is also quantified based on the learned parameter distributions. This holistic approach can integrate with any post-hoc GNN explanation methods. Empirical results from our study show that our proposed method sets a new standard for GNN explanation performance across diverse real-world graph benchmarks.

rAAV capsid mutants eliminate leaky expression from DNA donor template for homologous recombination.

Precise genomic editing through the combination of CRISPR/Cas systems and recombinant adeno-associated virus (rAAV)-delivered homology directed repair (HDR) donor templates represents a powerful approach. However, the challenge of effectively suppressing leaky transcription from the rAAV vector, a phenomenon associated to cytotoxicity, persists. In this study, we demonstrated substantial promoter activities of various homology arms and inverted terminal repeats (ITR). To address this issue, we identified a novel rAAV variant, Y704T, which not only yields high-vector quantities but also effectively suppresses in cis mRNA transcription driven by a robust promoter. The Y704T variant maintains normal functionality in receptor interaction, intracellular trafficking, nuclear entry, uncoating, and second-strand synthesis, while specifically exhibiting defects in transcription. Importantly, this inhibitory effect is found to be independent of ITR, promoter types, and RNA polymerases. Mechanistic studies unveiled the involvement of Valosin Containing Protein (VCP/p97) in capsid-mediated transcription repression. Remarkably, the Y704T variant delivers HDR donor templates without compromising DNA replication ability and homologous recombination efficiency. In summary, our findings enhance the understanding of capsid-regulated transcription and introduce novel avenues for the application of the rAAV-CRISPR/Cas9 system in human gene therapy.

Correlation and risk factors of peripheral and cervicocephalic arterial atherosclerosis in patients with ischemic cerebrovascular disease.

Patients with ischemic cerebrovascular disease (ICVD) frequently develop concomitant peripheral artery disease (PAD) or renal artery stenosis (RAS), and multiterritorial atherosclerotic patients usually have a worse prognosis. We aimed to evaluate the status of peripheral atherosclerosis (AS) and cervicocephalic AS (CAS) in ICVD patients with AS, their correlation, and related risk factors contributing to coexisting cervicocephalic-peripheral AS (CPAS). Based on the severity and extent of AS evaluated by computed tomography angiography and ultrasound, the degree of AS was triple categorized to assess the correlation between CAS and PAD/RAS. CAS and PAD/RAS were defined as the most severe stenosis being ≥ 50% luminal diameter in cervicocephalic or lower limb arteries, and a peak systolic velocity at the turbulent site being ≥ 180 cm/s in the renal artery. Among 403 patients with symptom onset within 30 days, CAS, PAD, and RAS occurrence rates were 68.7%, 25.3%, and 9.9%, respectively. PAD was independently associated with the degree of extracranial and intracranial CAS (p = 0.042, OR = 1.428, 95% CI 1.014-2.012; p = 0.002, OR = 1.680, 95% CI 1.206-2.339), while RAS was independently associated with the degree of extracranial CAS (p = 0.001, OR = 2.880, 95% CI 1.556-5.329). Independent CPAS risk factors included an ischemic stroke history (p = 0.033), increased age (p < 0.01), as well as elevated fibrinogen (p = 0.021) and D-dimer levels (p = 0.019). In conclusion, the occurrence rates of RAS and PAD in ICVD patients with AS is relatively high, and with the severity of RAS or PAD increase, the severity of CAS also increase. Strengthening the evaluation of peripheral AS and controlling elevated fibrinogen might be crucial for preventing and delaying the progression of multiterritorial AS in ICVD patients with AS, thereby improving risk stratification and promoting more effective prevention and treatment strategies.

Enhanced transgene expression from single-stranded AAV vectors in human cells in vitro and in murine hepatocytes in vivo.

We identified that distal 10 nucleotides in the D-sequence in AAV2 inverted terminal repeat (ITR) share partial sequence homology to 1/2 binding site of glucocorticoid receptor-binding element (GRE). Here, we describe that (1) purified GR binds to AAV2 D-sequence, and the D-sequence competes with GR binding to its cognate binding site; (2) dexamethasone-mediated activation of GR pathway significantly increases the transduction efficiency of AAV2 vectors in human cells; (3) human osteosarcoma cells, U2OS, which lack expression of GR, are poorly transduced by AAV2 vectors, but stable transfection with a GR expression plasmid restores vector-mediated transgene expression; (4) replacement of the distal 10 nucleotides in the D-sequence of the AAV2 ITR with a full-length GRE consensus sequence significantly enhances transgene expression in human cells in vitro and in murine hepatocytes in vivo; and (5) none of the ITRs in AAV1, AAV3, AAV4, AAV5, and AAV6 genomes contains the GRE 1/2 binding site, and insertion of a full-length GRE consensus sequence in the AAV6-ITR also significantly enhances transgene expression from AAV6 vectors, both in vitro and in vivo. These novel vectors, termed generation Y AAV vectors, which are serotype, transgene, or promoter agnostic, should be useful in human gene therapy.

Overexpression of wild-type HRAS drives non-alcoholic steatohepatitis to hepatocellular carcinoma in mice.

Hepatocellular carcinoma (HCC), a prevalent solid carcinoma of significant concern, is an aggressive and often fatal disease with increasing global incidence rates and poor therapeutic outcomes. The etiology and pathological progression of non-alcoholic steatohepatitis (NASH)-related HCC is multifactorial and multistage. However, no single animal model can accurately mimic the full NASH-related HCC pathological progression, posing considerable challenges to transition and mechanistic studies. Herein, a novel conditional inducible wild-type human HRAS overexpressed mouse model (HRAS-HCC) was established, demonstrating 100% morbidity and mortality within approximately one month under normal dietary and lifestyle conditions. Advanced symptoms of HCC such as ascites, thrombus, internal hemorrhage, jaundice, and lung metastasis were successfully replicated in mice. In-depth pathological features of NASH- related HCC were demonstrated by pathological staining, biochemical analyses, and typical marker gene detections. Combined murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival, further confirming the accuracy and reliability of the model. Based on protein-protein interaction (PPI) network and RNA sequencing analyses, we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis, with subsequent progression to HCC. Collectively, our study successfully duplicated natural sequential progression in a single murine model over a very short period, providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.

Impact of perinatal factors on meconium aspiration syndrome in full-term newborns and the construction of a column chart prediction model: An observational study.

To explore the influence of perinatal-related factors on meconium aspiration syndrome (MAS) in full-term neonates and construct a nomogram prediction model for risk stratification of neonatal MAS and adoption of preventive measures. A total of 424 newborns and their mothers who were regularly examined at our hospital between January 2020 and December 2023 who had meconium-contaminated amniotic fluid during delivery were retrospectively selected as participants. Neonates were divided into MAS and non-MAS groups based on whether MAS occurred within 3 days after birth. Data from the 2 groups were analyzed, and factors influencing MAS were screened using multivariate logistic regression analysis. The R3.4.3 software was used to construct a nomogram prediction model for neonatal MAS risk. Receiver operating characteristic (ROC) curve analysis and the Hosmer-Lemeshow goodness-of-fit test were used to evaluate the performance of the model, and its clinical effectiveness was evaluated using a decision curve. Among the 424 neonates with meconium-stained amniotic fluid, 51 developed MAS within 3 days of birth (12.03%). Multivariate logistic regression analysis showed that a low amniotic fluid index before delivery (OR = 2.862, P = .019), advanced gestational age (OR = 0.526, P = .034), cesarean section (OR = 2.650, P = .013), severe amniotic fluid contamination (OR = 4.199, P = .002), low umbilical cord blood pH (OR = 2.938, P = .011), and low neonatal Apgar 1-min score (OR = 3.133, P = .006) were influencing factors of MAS in full-term neonates. Based on the above indicators, a nomogram prediction model for MAS risk of full-term newborns was constructed. The area under the ROC curve of the model was 0.931. The model was also tested for goodness-of-fit deviation (χ2 = 3.465, P = .903). Decision curve analysis found that the model was clinically effective in predicting the net benefit of MAS risk in neonates with meconium-stained amniotic fluid. The construction of a column chart prediction model for neonatal MAS risk based on prenatal amniotic fluid index, gestational age, delivery method, amniotic fluid contamination level, newborn umbilical blood pH value, and Apgar 1-min score has a certain application value.

Dynamic Mechanical Properties and Modified Johnson-Cook Model Considering Recrystallization Softening for Nickel-Based Powder Metallurgy Superalloys.

The material undergoes high temperature and high strain rate deformation process during the cutting process, which may induce the dynamic recrystallization behavior and result in the evolution of dynamic mechanical properties of the material to be machined. In this paper, the modified Johnson-Cook (J-C) model for nickel-based powder metallurgy superalloy considering dynamic recrystallization behavior in high strain rate and temperature is proposed. The dynamic mechanical properties of the material under different strain rates and temperature conditions are obtained by quasi-static compression test and split Hopkinson pressure bar (SHPB) test. The coefficients of the modified J-C model are obtained by the linear regression method. The modified model is verified by comparison with experimental and model prediction results. The results show that the modified J-C model proposed in this paper can accurately describe the mechanical properties of nickel-based powder metallurgy superalloys at high temperatures and high strain rates. This provides help for studying the cutting mechanism and finite element simulation of nickel-based powder metallurgy superalloy.

A visceral organ function-focused therapeutic strategy using a 6-hour time window for patients with acute type a aortic dissection complicated by mesenteric malperfusion.

BACKGROUND: Acute type A aortic dissection (ATAAD) complicated by mesenteric malperfusion is a critical and complicated condition. The optimal treatment strategy remains controversial, debate exists as to whether aortic dissection or mesenteric malperfusion should be addressed first, and the exact time window for mesenteric ischemia intervention is still unclear. To solve this problem, we developed a new concept based on the pathophysiological mechanism of mesenteric ischemia, using a 6-hour time window to divide newly admitted patients by the time from onset to admission, applying different treatment protocols to improve the clinical outcomes of patients with ATAAD complicated by mesenteric malperfusion. METHODS: This was a retrospective study that covered a five-year period. From July 2018 to December 2020(phase I), all patients underwent emergency open surgery. From January 2021 to June 2023(phase II), patients with an onset within 6 h all underwent open surgical repair, followed by immediately postoperative examination if the malperfusion is suspected, while the restoration of mesenteric perfusion and visceral organ function was performed first, followed by open repair, in patients with an onset beyond 6 h. RESULTS: There were no significant differences in baseline and surgical data. In phase I, eleven patients with mesenteric malperfusion underwent open surgery, while in phase II, our novel strategy was applied, with sixteen patients with an onset greater than 6 h and eleven patients with an onset less than 6 h. During the waiting period, none died of aortic rupture, but four patients died of organ failure, twelve patients had organ function improvement and underwent surgery successfully survived. The overall mortality rate decreased with the use of this novel strategy (54.55% vs. 18.52%, p = 0.047). Furthermore, the surgical mortality rate between the two periods showed even stronger statistical significance (54.55% vs. 4.35%, p = 0.022). Moreover, the proportions of patients with sepsis and multiorgan failure also showed differences. CONCLUSIONS: Our novel strategy for patients with ATAAD complicated by mesenteric malperfusion not only improves the surgical success rate but also reduces the overall mortality rate.

Fusing Diverse Decision Rules in 3D-Radiomics for Assisting Diagnosis of Lung Adenocarcinoma.

This study aimed to develop an interpretable diagnostic model for subtyping of pulmonary adenocarcinoma, including minimally invasive adenocarcinoma (MIA), adenocarcinoma in situ (AIS), and invasive adenocarcinoma (IAC), by integrating 3D-radiomic features and clinical data. Data from multiple hospitals were collected, and 10 key features were selected from 1600 3D radiomic signatures and 11 radiological features. Diverse decision rules were extracted using ensemble learning methods (gradient boosting, random forest, and AdaBoost), fused, ranked, and selected via RuleFit and SHAP to construct a rule-based diagnostic model. The model's performance was evaluated using AUC, precision, accuracy, recall, and F1-score and compared with other models. The rule-based diagnostic model exhibited excellent performance in the training, testing, and validation cohorts, with AUC values of 0.9621, 0.9529, and 0.8953, respectively. This model outperformed counterparts relying solely on selected features and previous research models. Specifically, the AUC values for the previous research models in the three cohorts were 0.851, 0.893, and 0.836. It is noteworthy that individual models employing GBDT, random forest, and AdaBoost demonstrated AUC values of 0.9391, 0.8681, and 0.9449 in the training cohort, 0.9093, 0.8722, and 0.9363 in the testing cohort, and 0.8440, 0.8640, and 0.8750 in the validation cohort, respectively. These results highlight the superiority of the rule-based diagnostic model in the assessment of lung adenocarcinoma subtypes, while also providing insights into the performance of individual models. Integrating diverse decision rules enhanced the accuracy and interpretability of the diagnostic model for lung adenocarcinoma subtypes. This approach bridges the gap between complex predictive models and clinical utility, offering valuable support to healthcare professionals and patients.

Microbleeds in Heterozygous HTRA1-Related Cerebral Small Vessel Disease.

This case report describes the evaluation of a 44-year-old man with a history of headache, dizziness, and imbalance and imaging that showed lacunar infarctions and bilateral white matter hyperintensities.

An integrated framework for prognosis prediction and drug response modeling in colorectal liver metastasis drug discovery.

BACKGROUND: Colorectal cancer (CRC) is the third most prevalent cancer globally, and liver metastasis (CRLM) is the primary cause of death. Hence, it is essential to discover novel prognostic biomarkers and therapeutic drugs for CRLM. METHODS: This study developed two liver metastasis-associated prognostic signatures based on differentially expressed genes (DEGs) in CRLM. Additionally, we employed an interpretable deep learning model utilizing drug sensitivity databases to identify potential therapeutic drugs for high-risk CRLM patients. Subsequently, in vitro and in vivo experiments were performed to verify the efficacy of these compounds. RESULTS: These two prognostic models exhibited superior performance compared to previously reported ones. Obatoclax, a BCL-2 inhibitor, showed significant differential responses between high and low risk groups classified by prognostic models, and demonstrated remarkable effectiveness in both Transwell assay and CT26 colorectal liver metastasis mouse model. CONCLUSIONS: This study highlights the significance of developing specialized prognostication approaches and investigating effective therapeutic drugs for patients with CRLM. The application of a deep learning drug response model provides a new drug discovery strategy for translational medicine in precision oncology.

Preoperative supine pelvic incidence predicts standing pelvic incidence following S2AI fixation in patients with adult spinal deformity: a prospective study.

STUDY DESIGN: A prospective study. OBJECTIVE: The aim of this study was to investigate the PI change in different postures and before and after S2­alar­iliac (S2AI) screw fixation, and to investigate whether pre-op supine PI could predict post-op standing PI. Previous studies have reported PI may change with various positions. Some authors postulated that the unexpected PI change in ASD patients could be due to sacroiliac joint laxity, S2-alar-iliac (S2AI) screw placement, or aggressive sagittal cantilever technique. However, there was a lack of investigation on how to predict post-op standing PI when making surgical strategy. METHODS: A prospective case series of ASD patients undergoing surgical correction with S2AI screw placement was conducted. Full-spine X-ray films were obtained at pre-op standing, pre-op supine, pre-op prone, as well as post-op standing postures. Pelvic parameters were measured. Spearman correlation analysis was used to determine relationships between each parameter. RESULTS: A total of 83 patients (22 males, 61females) with a mean age of 58.4 ± 9.5 years were included in this study. Pre-op standing PI was significantly lower than post-op standing PI (p = 0.004). Pre-op prone PI was significantly lower than post-op standing PI (p = 0.001). By contrast, no significant difference was observed between pre-op supine and post-op standing PI (p = 0.359) with a mean absolute difference of 2.2° ± 1.9°. Correlation analysis showed supine PI was significantly correlated with post-op standing PI (r = 0.951, p < 0.001). CONCLUSION: This study revealed the PI changed after S2AI screw fixation. The pre-op supine PI can predict post-op standing PI precisely, which facilitates to provide correction surgery strategy with a good reference for ideal sagittal alignment postoperatively.

Decreased retinal vascular density is associated with cognitive impairment in CADASIL: an optical coherence tomography angiography study.

PURPOSE: This study aimed to assess alterations in retinal vascular density in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients using optical coherence tomography angiography (OCTA) and investigate their association with MRI and cognitive features. METHODS: Twenty-five patients with CADASIL and forty healthy controls were evaluated by Cirrus HD-OCT 5000 with AngioPlex OCTA to determine changes in macular retinal vasculature. Retinal vasculature parameters between two groups were compared. The MRI lesion burden and neuropsychological scales were also examined in patients. The association between OCTA parameters and MRI/cognitive features was evaluated using partial Spearman rank correlation. RESULTS: The vessel density and perfusion density of whole image in macular region (vessel density: t = - 2.834, p = 0.005; perfusion density: t = - 2.691, p = 0.007) were significantly decreased in patients with CADASIL. Moreover, vessel density of whole image in macular region was negatively associated with Fazekas scores (ρ = - 0.457; p = 0.025) and the number of lacunar infractions (ρ = - 0.425, p = 0.038) after adjustment for age. Decreased macular vessel density and perfusion density of whole image were also associated with MoCA scores (vessel density: ρ = 0.542, p = 0.006; perfusion density: ρ = 0.478, p = 0.018) and other domain-specific neuropsychological tests (p < 0.05) after adjustment for age. CONCLUSION: Decreased retinal vascular density was associated with increased MRI lesion burden and cognitive impairment in patients with CADASIL. Our findings suggest that the degree of retinal vascular involvement, as demonstrated by OCTA, may be consistent with the severity of MRI lesions and the degree of cognitive impairment in patients.

Potential impairment of spinal cord around the apical vertebral level in hyperkyphotic patients: findings from diffusion tensor imaging.

PURPOSE: To evaluate the neuronal metrics/microstructure of the spinal cord around apical region in patients with hyperkyphosis using diffusion tensor imaging (DTI). METHODS: Thirty-seven patients with hyperkyphosis aged 45.5 ± 19.6 years old who underwent 3.0 T magnetic resonance imaging (MRI) examination with DTI sequence were prospectively enrolled from July 2022 to July 2023. Patients were divided into three groups according to spinal cord/ cerebrospinal fluid (CSF) architecture on sagittal-T2 MRI of the thoracic apex (the axial spinal cord classification): Group A-circular cord with visible CSF, Group B-circular cord without visible CSF at apical dorsal, and Group C-spinal cord deformed without intervening CSF. The fractional anisotropy (FA) values acquired from DTI were compared among different groups. Correlations between DTI parameters and global kyphosis (GK)/sagittal deformity angular ratio (sagittal DAR) were evaluated using Pearson correlation coefficients. RESULTS: In all patients, FA values were significantly lower at apical level as compared with those at one level above or below the apex (0.548 ± 0.070 vs. 0.627 ± 0.056 versus 0.624 ± 0.039, P < 0.001). At the apical level, FA values were significantly lower in Group C than those in Group B (0.501 ± 0.052 vs. 0.598 ± 0.061, P < 0.001) and Group A (0.501 ± 0.052 vs. 0.597 ± 0.019, P < 0.001). Moreover, FA values were significantly lower in symptomatic group than those in non-symptomatic group (0.498 ± 0.049 v. 0.578 ± 0.065, P < 0.001). Pearson correlation analysis showed that GK (r2 = 0.3945, P < 0.001) and sagittal DAR (r2 = 0.3079, P < 0.001) were significantly correlation with FA values at apical level. CONCLUSION: In patients with hyperkyphosis, the FA of spinal cord at apical level was associated with the neuronal metrics/microstructure of the spinal cord. Furthermore, the DTI parameter of FA at apical level was associated with GK and sagittal DAR.

Insomnia and Alexithymia in Chinese Adolescents with Major Depressive Disorder: A Cross-Sectional Study of Sex Differences and Associations.

Purpose: Insomnia is related to alexithymia in adults, but the relationship between insomnia and alexithymia in adolescents with major depressive disorder remains unclear. This study aimed to investigate the sex differences and the association between insomnia and alexithymia in adolescents with major depressive disorder. Patients and Methods: From October 2020 to April 2022, adolescent patients with major depressive disorder were recruited from psychiatric departments of seven hospitals in Anhui Province, China. Their general demographic and clinical information were collected. The 20-item Toronto Alexithymia Scale, the Center for Epidemiologic Studies of Depression Scale, and the Insomnia Severity Index Scale were used to assess their alexithymia, depression, and insomnia symptoms, respectively. The analysis of variance (ANOVA), Student's t-test and Mann-Whitney U-test were used for continuous variables and chi-square tests for categorical variables. Pearson's correlation analysis and Spearman correlation analysis were used to examine the correlation between ISI and demographic and clinical variables. Multiple binary logistic regression analyses with the "Enter" method were carried out to explore the correlations of insomnia. Results: The prevalence of insomnia in female adolescent patients was similar to that of male patients (χ2=1.84, p = 0.175). Compared with those without insomnia, patients with insomnia had worse family relationships (F = 7.71, p = 0.021), perceived heavier academic stress (F = 6.32, p = 0.012), more likely to take sedative-hypnotics (F = 5.51, p = 0.019), had higher levels of depression (F = 81.57, p < 0.001) and alexithymia (F = 28.57, p < 0.001). Correlation analysis showed that alexithymia was significantly associated with insomnia in adolescent patients (r = 0.360, p < 0.01). Binary logistic regression analyses showed that, alexithymia was significantly associated with insomnia in female patients (OR = 1.050, p < 0.05) but not male patients. Conclusion: In female adolescent patients, alexithymia is a risk factor of insomnia, which is of great importance in the understanding of the psychopathological mechanisms, treatments and psychological interventions of insomnia in adolescents with major depressive disorder.

Breast ultrasound image despeckling using multi-filtering DFrFT and adaptive fast BM3D.

Improving the quality of breast ultrasound images is of great significance for clinical diagnosis which can greatly boost the diagnostic accuracy of ultrasonography. However, due to the influence of ultrasound imaging principles and acquisition equipment, the collected ultrasound images naturally contain a large amount of speckle noise, which leads to a decrease in image quality and affects clinical diagnosis. To overcome this problem, we propose an improved denoising algorithm combining multi-filter DFrFT (Discrete Fractional Fourier Transform) and the adaptive fast BM3D (Block Matching and 3D collaborative filtering) method. Firstly, we provide the multi-filtering DFrFT method for preprocessing the original breast ultrasound image so as to remove some speckle noise early in fractional transformation domain. Based on the fractional frequency spectrum characteristics of breast ultrasound images, three types of filters are designed correspondingly in low, medium, and high frequency domains. And by integrating filtered images, the enhanced images are obtained which not only remove some speckle noise in background but also preserve the details of breast lesions. Secondly, for further enhancing the image quality on the basis of multi-filter DFrFT, we propose the adaptive fast BM3D method by introducing the DBSCAN-based super pixel segmentation to block matching process, which utilizes super pixel segmentation labels to provide a reference on how similar it is between target block and retrieval blocks. It reduces the number of blocks to be retrieved and make the matched blocks with more similar features. At last, the local noise parameter estimation is also adopted in the hard threshold filtering process of traditional BM3D algorithm to achieve local adaptive filtering and further improving the denoising effect. The synthetic data and real breast ultrasound data examples show that this combined method can improve the speckle suppression level and keep the fidelity of structure effectively without increasing time cost.

Mitochondrial dysfunction mediated by thioredoxin-interacting protein: A crucial determinant in di(2-ethylhexyl) phthalate-induced liver failure.

Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer that can interfere with the endocrine system and cause liver damage. However, the molecular mechanism of DEHP-induced liver injury is unclear. This study aimed to investigate the effects of DEHP on liver function and its relationship with thioredoxin-interacting protein (TXNIP) and mitochondrial oxidative stress pathway. We used C57BL/6 J mice and THLE-2 liver cells as in vivo and in vitro models, respectively, and treated them with different doses of DEHP, and measured the relevant biochemical indicators and molecular markers. We found that DEHP significantly increased the expression of TXNIP and NLRP3, while decreasing the expression of mitochondrial functional proteins, such as PGC-1α, TFAM, NRF1, NDUHA9, SDHA, MFN1. This resulted in mitochondrial dysfunction, manifested by reduced ATP generation, increased inflammatory factor release, elevated liver enzyme indicators, decreased mitochondrial membrane potential and increased oxidative stress. We further demonstrated that TXNIP upregulation activated NF-κB and MAPK signaling pathways, such as NF-κB, IκB, TAB2, TRAF6, ERK1, JNK, p38 MAPK, MEK1, which exacerbated oxidative stress and inflammation, leading to liver damage. Additionally, we found that treatment with the antioxidant MitoQ partially alleviated DEHP-induced liver toxicity, while silencing TXNIP more effectively restored mitochondrial function. Our study supports the hypothesis that DEHP induces mitochondrial oxidative stress through the TXNIP signaling pathway, resulting in liver dysfunction in mice, and suggests possible links between endocrine-disrupting chemicals and human diseases.

Associations of sleep-related variables with reverse dipping patterns of blood pressure in α-synucleinopathies.

INTRODUCTION: The reverse dipping blood pressure (BP) pattern is very common in α-synucleinopathies. We aimed to explore the associations of sleep-related variables with abnormal BP circadian rhythms in Parkinson's disease (PD) and multiple system atrophy (MSA). METHODS: A total of 126 patients, 76 with PD and 50 with MSA, were included. All participants underwent ambulatory BP monitoring and full-night polysomnography (PSG). We analyzed abnormal dipping patterns and sleep-related parameters, including moderate to severe obstructive sleep apnea (OSA), rapid eye movement behavior disorder (RBD), average oxygen saturation (SaO2%), lowest SaO2%, duration of SaO2% <90%, and apnea-hypopnea index (AHI). Binary logistic regression was performed to explore the associations between paraclinical variables, sleep-related variables, and reverse dipping patterns. RESULTS: Reverse dipping patterns were predominant in patients with PD (58.5 %) and MSA (68.0 %). Patients with MSA had higher AHI, RBD, and lower average SaO2% than those with PD. Taking both diseases together as a whole group of α-synucleinopathies, logistic regression analysis indicates the Hoehn-Yahr stage (odds ratio [OR] = 2.00 for reverse systolic and 2.34 for reverse diastolic dipping patterns), moderate to severe OSA (OR = 2.71 for reverse systolic and 2.53 for reverse diastolic dipping patterns), average SaO2% (OR = 1.35 for reverse systolic dipping patterns), and male sex (OR = 2.70 for reverse diastolic dipping patterns) were independently associated with reverse dipping patterns. CONCLUSIONS: Reverse dipping patterns were common in patients with PD and MSA. Hoehn-Yahr stage, moderate to severe OSA, average SaO2%, and male sex were associated with reverse dipping patterns in α-synucleinopathy.

Gut Microbiota Alterations in Adolescent Idiopathic Scoliosis Are Associated with Aberrant Bone Homeostasis.

OBJECTIVE: Low bone mineral density is the major prognostic factor for adolescent idiopathic scoliosis (AIS), but the underlying mechanisms remain unclear. Accumulating evidence suggests that gut microbiota (GM) have the potential to affect bone development, and the GM signatures are altered in AIS patients. However, the effect of GM alterations on aberrant bone homeostasis in AIS remains unclear. This study aims to investigate the GM profile in AIS patients with different bone mineral density (BMD) and explore the association between GM, osteopenia, and aberrant bone turnover. METHODS: A total of 126 patients with AIS who received surgical treatment were retrospectively included in this study. We analyzed the composition of the GM by 16S rRNA sequencing and BMD by dual X-ray absorptiometry. Based on the BMD of the femur neck, the patients were divided into the osteopenia group (OPN) if the Z score < -1, and the normal (NOR) group if the Z score ≥ -1 SD compared to the healthy control. For the 16S rRNA sequencing, the raw reads were filtered to remove low-quality reads, and operational taxonomic units were identified with the Uparse program. Weighted UniFrac distance matrix for the beta-diversity metrics and principal coordinate analysis (PCoA) was performed, and the statistical comparisons were made with permutational multivariate analysis of variance (PERMANOVA) and analysis of similarity (ANONISM). Linear discriminant analysis effect size (LEfSe) was used to identify the enriched species in two groups. The "Random forest" was applied to determine the optimal biomarker for OPN according to the mean decrease in Gini value. The metabolic function was predicted by the Tax4Fun analysis. The Pearson correlation coefficient was used to evaluate the associations between GM species, bone turnover markers, and BMD. RESULTS: The serum ß-CTX was increased in the OPN group (n = 67) compared to the NOR group (n = 59). Patients in OPN groups showed significantly decreased α diversity indicated by the Shannon index. Principal coordinate analysis (PCoA) analysis showed significant clustering of GM between OPN and NOR groups. At genus level, the Escherichia-Shigella and Faecalibacterium were significantly enriched in the OPN group compared to that in the NOR group (p < 0.05), whereas the abundance of Prevotella was significantly decreased (p = 0.0012). The relative abundance of Megamonas and Prevotella was positively correlated with the femur BMD. The abundance of Escherichia-Shigella was negatively correlated with femur BMD and positively correlated with serum ß-CTX levels. Functional analysis revealed significant differences in starch and sucrose metabolism, pyruvate and cysteine, and methionine metabolism between NOR and OPN groups. CONCLUSION: The alterations of GM in AIS patients are correlated with osteopenia. The association between enriched species, BMD, and bone turnover markers provides novel diagnostic and therapeutic targets for the clinical management of AIS.