Paired Box Research Articles

Pax6 regulates neuronal migration and cell proliferation via interacting with Wnt3a during cortical development

The paired box 6 (Pax6) gene encodes a highly conserved transcription factor, involved in the development of eyes, brain, and endocrine glands. Homozygous loss of Pax6 resulted in neonatal death in mice, plus loss of eyes and malformation of cerebral cortex. In patients with heterozygous Pax6 mutations, a reduction in thickness of the frontoparietal cortex was detected, which was also observed in small eye mice. In this study, we found that Pax6 overexpression increased the cortical thickness, especially in the intermediate zone of the cortex, which conflicts with the report of Manuel et al. Pax6 overexpression appears to detain neurons in the intermediate zone while promoting cell proliferation. It is worth noting that the impact of Pax6 overexpression on cortical thickness and neuronal migration was temporal, explaining the differences with other reports. We postulated that the alteration of Pax6 isoform ratio by autoregulation might be responsible for this. JASPAR analysis together with the results of qPCR, Western blot, CUT&Tag, and rescue experiments revealed that Pax6 regulates neuronal migration and cell proliferation by indirectly mediating Wnt3a expression. Therefore, we propose that Pax6 participates in corticogenesis via interaction with Wnt3a in regulating neuronal migration and cell proliferation.

PAX2 induces endometrial cancer by inhibiting mitochondrial function via the CD133-AKT1 pathway.

Endometrial cancer (EC) is a malignancy of the endometrial epithelium. The prevalence and mortality rates associated with the disease are on the rise globally. A total of 20 cases of type I EC tissues were collected for transcriptomic sequencing, our findings indicate that PAX2 is highly expressed in EC tissues and is closely related to the pathogenesis of EC. PAX2 is a member of the paired homeobox domain family and has been linked to the development of a number of different tumours. In normal endometrial tissue, PAX2 is methylated; however, in EC, it is demethylated. Nevertheless, few studies have focused on its role in EC. A protein-protein interaction (PPI) analysis revealed a regulatory relationship between PAX2 and CD133, which in turn affects the activity of AKT1. CD133 is a well-known marker of tumor stem cells and is involved in tumor initiation, metastasis, recurrence, and drug resistance; AKT1 promotes cell survival by inhibiting apoptosis and is considered a major promoter of many types of cancer. Nevertheless, further investigation is required to ascertain whether PAX2 affects the progression of EC by regulating the CD133-AKT1 pathway. The present study demonstrated that PAX2 promoted cell proliferation, migration, invasion and adhesion, and inhibited apoptosis. Its mechanism of action was found to be the inhibition of mitochondrial oxidative phosphorylation, promotion of glycolysis, increase in mitochondrial copy number, and increase in the levels of reactive oxygen species (ROS) and hexokinase, as well as the concentration of mitochondrial calcium ions. This was achieved through the promotion of CD133 expression and the phosphorylation of AKT1. In conjunction with the aforementioned regulatory pathways, the progression of EC is facilitated.

Methylation of SOX1 and PAX1 Are Risk Factors and Potential Biomarkers for Cervical Lesions.

The correlation between methylation of paired box gene 1 (PAX1) and sex determining region Y-box 1 (SOX1) with human papillomavirus (HPV) infection and the progression of cervical lesions is not well understood. This study aims to explore the potential value of PAX1 and SOX1 as diagnostic biomarkers for cervical diseases. A total of 139 cervical biopsy tissue samples were obtained from the Department of Pathology, the Seventh Medical Center, Chinese PLA General Hospital from 2021 to 2023. The samples include 32 cases of chronic cervicitis (inflammation group), 30 cases of low-grade squamous intraepithelial lesions (LSIL group), 50 cases of high-grade squamous intraepithelial lesions (HSIL group), and 27 cases of cervical squamous cell carcinoma (CSCC group). DNA was extracted from paraffin-embedded tissues, and the levels of HPV infection and methylation of PAX1 and SOX1 were detected. The methylation index (M-index) of PAX1 and SOX1 in the HSIL and CSCC groups is significantly higher than in the inflammation group (both P < 0.0001), with no significant difference between the LSIL and inflammation groups. There is no significant difference in the positive PAX1 and SOX1 methylation rate with HPV infection and age. The positive rates of PAX1 methylation in the inflammation, LSIL, HSIL, and CSCC groups were 3.13%, 10.00%, 44.00%, and 88.89%, respectively. The positive rates of SOX1 methylation were 3.13%, 10.00%, 40.00%, and 77.78%, respectively, and increasing with the progression of cervical lesions (R2 = 0.9189/R2 = 0.9279, P < 0.0001/P < 0.0001). Comparing LSIL, HSIL, and CSCC with the inflammation group and using cervical biopsy pathology diagnosis as the gold standard, methylation of PAX1 and SOX1 is a risk factor for HSIL and CSCC, with odds ratio (OR) values significantly increasing as lesions progress. The sensitivity of PAX1 and SOX1 methylation to cervical lesions increases with the progression of the lesions. Methylation of SOX1 and PAX1 is not associated with HPV infection. The positive rate of methylation for SOX1 and PAX1 is positively correlated with cervical lesions, which can serve as potential biomarkers for HSIL and CSCC. They are risk factors and potential screening indicators for HSIL and above cervical lesions.

DNA methylation patterns are influenced by Pax3::Foxo1 expression and developmental lineage in rhabdomyosarcoma tumours forming in genetically engineered mouse models.

Rhabdomyosarcoma (RMS) is a family of phenotypically myogenic paediatric cancers consisting of two major subtypes: fusion-positive (FP) RMS, most commonly involving the PAX3::FOXO1 fusion gene, formed by the fusion of paired box 3 (PAX3) and forkhead box O1 (FOXO1) genes, and fusion-negative (FN) RMS, lacking these gene fusions. In humans, DNA methylation patterns distinguish these two subtypes as well as mutation-associated subsets within these subtypes. To investigate the biological factors responsible for these methylation differences, we profiled DNA methylation in RMS tumours derived from genetically engineered mouse models (GEMMs) in which various driver mutations were introduced into different myogenic lineages. Our unsupervised analyses of DNA methylation patterns in these GEMM tumours yielded two major clusters, corresponding to high and no/low expression of Pax3::Foxo1, which mirrored the results for human FP and FN RMS tumours. Two distinct methylation-defined subsets were found for GEMM RMS tumours with no/low Pax3::Foxo1 expression: one subset enriched in Pax7 lineage tumours and a second subset enriched in myogenic factor 5 (Myf5) lineage tumours. Integrative analysis of DNA methylation and transcriptomic data in mouse and human RMS revealed a common group of differentially methylated and differentially expressed genes, highlighting a conserved set of genes functioning in both human RMS models and GEMMs of RMS. In conclusion, these studies provide insight into the roles of oncogenic fusion proteins and developmental lineages in establishing DNA methylation patterns in FP and FN RMS respectively. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

A Comprehensive Analysis of the Role of PAX9 in Head and Neck Squamous Cell Carcinoma.

Paired box 9 (PAX9) has been linked to several human disorders; however, its relevance in Head And Neck Squamous Cell Carcinoma (HNSCC) remains unknown. The difference in PAX9 mRNA expression in pan-cancer was analyzed utilizing The Cancer Genome Atlas (TCGA), and the level of PAX9 protein expression across various types of cancer was assessed utilizing the Human Protein Atlas (HPA) and UALCAN databases, as well as the cellular localization of PAX9. UALCAN studied the methylation levels of PAX9 in pan-cancer. The predictive significance of PAX9 in pan-cancer was assessed utilizing the Kaplan-Meier Plotter website. Functional enrichment analysis was carried out with the "cluster Profiler" program. By employing CCK8 and colony formation methods, the influence of PAX9 on the growth of HNSCC cells was evaluated. By conducting a transwell experiment, we assessed the influence of PAX9 on the migration of HNSCC cells. Western blotting was used to determine the levels of Bax and Bcl-2, two proteins involved in the regulation of apoptosis. A nude mouse model was established to study the impact of PAX9 overexpression on the growth of subcutaneous HNSCC tumors. In HNSCC, the expression of PAX9 was found to be low, while levels of promoter methylation rose considerably. Low PAX9 expression has been linked to a decrease in overall survival (OS) rates among individuals with HNSCC. Furthermore, overexpressing the PAX9 gene decreased HNSCC cell proliferation, migration, and invasion while boosting apoptosis rates. The abnormal expression of PAX9 is linked to various cancers. In HNSCC, PAX9 is a potential tumor suppressor, inhibiting tumor invasion and migration. The results reveal a potentially significant new therapeutic target for HNSCC.

PAX6 enhances Nanog expression by inhibiting NOTCH signaling to promote malignant properties in small cell lung cancer cells.

Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer. The aberrant regulation of Paired box 6 (PAX6) expression has been proposed to play an important oncogenic role in several cancer types. Nevertheless, there is limited knowledge regarding its function in SCLC. Here, we find that PAX6 overexpression promotes SCLC cell proliferation and cell cycle progression, while downregulation of PAX6 expression suppresses SCLC cell proliferation and cell cycle progression. Moreover, PAX6 enhances the enrichment of the ALDEFLUOR+ and CD133+ population and promotes sphere formation in SCLC cells. Additionally, upregulation or downregulation of PAX6 expression does not induce apoptosis in SCLC cells. Upregulation of PAX6 expression alleviates cisplatin or etoposide-induced apoptosis in SCLC cells, while downregulation of PAX6 expression aggravates cisplatin or etoposide-induced apoptosis in SCLC cells. Furthermore, PAX6 promotes the expression of stem cell factor Nanog. Interestingly, the downregulation of Nanog expression abolishes PAX6 promoted cell proliferation and cell cycle progression. Moreover, the inhibition of Nanog expression results in the inability of PAX6 to promote the increase of the ALDEFLUOR+population, as well as the inability to mitigate apoptosis produced by cisplatin or etoposide in SCLC cells. Mechanically, PAX6 suppresses the activation of the NOTCH pathway to enhance Nanog expression. NOTCH pathway activation abolishes PAX6 promoted cell proliferation, cell cycle progression, ALDEFLUOR+population enrichment, and apoptosis protection effect in SCLC cells. Our data indicates that PAX6 could be a critical factor for controlling cell proliferation, cell cycle progression, cancer stem cell properties, and apoptosis in SCLC.

The Pax transcription factor EGL-38 links EGFR signaling to assembly of a cell-type specific apical extracellular matrix in the Caenorhabditis elegans vulva

The surface of epithelial tissues is covered by an apical extracellular matrix (aECM). The aECMs of different tissues have distinct compositions to serve distinct functions, yet how a particular cell type assembles the proper aECM is not well understood. We used the cell-type specific matrix of the C. elegans vulva to investigate the connection between cell identity and matrix assembly. The vulva is an epithelial tube composed of seven cell types descending from EGFR/Ras-dependent (1˚) and Notch-dependent (2˚) lineages. Vulva aECM contains multiple Zona Pellucida domain (ZP) proteins, which are a common component of aECMs across life. ZP proteins LET-653 and CUTL-18 assemble on 1˚ cell surfaces, while NOAH-1 assembles on a subset of 2˚ surfaces. All three ZP genes are broadly transcribed, indicating that cell-type specific ZP assembly must be determined by features of the destination cell surface. The paired box (Pax) transcription factor EGL-38 promotes assembly of 1˚ matrix and prevents inappropriate assembly of 2˚ matrix, suggesting that EGL-38 promotes expression of one or more ZP matrix organizers. Our results connect the known signaling pathways and various downstream effectors to EGL-38/Pax expression and the ZP matrix component of vulva cell fate execution. We propose that dedicated transcriptional networks may contribute to cell-appropriate assembly of aECM in many epithelial organs.

Resveratrol enhances post-injury muscle regeneration by regulating antioxidant and mitochondrial biogenesis.

Resveratrol (RES), a natural polyphenolic compound, has shown promise in enhancing skeletal muscle regeneration and metabolic function. This study aims to explore the impact of RES on muscle regeneration after injury through the regulation of antioxidant capacity and mitochondrial biogenesis. RES treatment significantly increased the ratio of tibialis anterior muscle mass to body weight, alongside reduced fasting glucose levels. Following cardiotoxin-induced injury, RES treatment improved muscle regeneration, characterized by greater formation of new fibers and better structural repair compared to the control. Notably, gene expression analyses demonstrated that RES-treated mice exhibited elevated levels of myogenic markers, such as paired box 7 (Pax7), myogenic factor 5 (Myf5), myoblast determination protein (MyoD), and Myogenin (MyoG). Concurrently, yes-associated protein (YAP) increased, underscoring its role in regulating satellite cell activity. Transcriptomic analysis identified enriched pathways related to muscle regeneration and mitochondrial biogenesis, with increased expression of mitochondrial transcription factors and higher mitochondrial DNA content in RES-treated mice. Furthermore, RES enhanced antioxidant capacity via the Kelch-like ECH-associated protein 1 (KEAP-1)/nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) signaling pathway, as indicated by elevated activities of total antioxidant capacity, Glutathione peroxidase (GSH-PX), and superoxidase dismutase (SOD). Collectively, these findings suggest that RES not only promotes muscle regeneration but also supports mitochondrial function and antioxidant defenses, positioning it as a food-derived pharmaceutical for targeting muscle repair after injury.

Melatonin supplementation to sows in mid to late gestation affects offspring circadian, myogenic, and growth factors in pre and postnatal skeletal muscle.

The neuroendocrine hormone melatonin is associated with circadian rhythms and has antioxidant and vasodilative properties. In cattle, melatonin rescues fetal growth during maternal nutrient restriction in a seasonally dependent manner, but melatonin research in swine is limited. The objective of this study was to evaluate effects of dietary melatonin supplementation during mid to late gestation on circadian rhythm and muscle growth and development of the longissimus dorsi in utero and postnatally. Sows received 20mg dietary melatonin daily (MEL) or no melatonin supplement (CON). Experiment 1 supplemented sows from gestational age (dGA) 38 ± 1 to 99 ± 1, experiment 2 supplemented sows from 41 to 106 ± 1 dGA, and experiment 3 supplemented sows from 60 dGA to farrowing. At harvest, morphometric measurements of all fetuses were taken, while the small (SM), medium (MED), and large (LG) piglet from each litter were used for further analysis. Prenatal data were analyzed using the MIXED procedure of SAS, and postnatal data were analyzed using the GLIMMIX procedure. Fetal morphometrics were analyzed for fixed effect of treatment, and transcript abundance was analyzed for treatment, time, and size. Postnatal parameters were analyzed for fixed effects of treatment, size, and production stage. In Exp. 1, MEL increased (P = 0.016) Period 1 (PER1) transcript abundance in the evening (PM) compared to the morning (AM). In Exp. 1, myogenin (MYOG) transcript abundance was increased (P = 0.033) in MEL fetuses in the AM compared to MEL in the PM. Myogenic factor 5 (MYF5) and paired box 7 (PAX7) were increased (P = 0.016) in the PM. Fetuses from MEL treated sows had increased (P < 0.05) BW, curve crown rump length, and head circumference in Exp. 2. In Exp. 2, MEL increased (P = 0.012) PER1 and Period 2 (PER2) transcript abundance in the PM. In Exp. 2, myoblast differentiation 1 (MYOD) was increased (P = 0.016) in SM and MED fetuses, while MYF5 and PAX7 were increased (P = 0.019) in SM fetuses. Postnatal BW was increased (P = 0.025) in MED and LG MEL treated offspring compared to CON. Insulin-like growth factor 1 (IGF1) was downregulated (P = 0.050) in MEL treated offspring, while insulin-like growth factor 1 receptor (IGF1R) was upregulated (P = 0.009) in MEL offspring. These results indicate that maternal melatonin supplementation during gestation modulates fetal circadian regulatory genes and alters myogenic genes during growth.

Exploring the transformational leadership capacities of nurse supervisors in Saudi Arabia

The COVID-19 pandemic posed a major challenge for healthcare systems worldwide. This study examined how hospital nurse supervisors in Saudi Arabia applied transformational leadership (TL) skills during the pandemic, as perceived by staff nurses. It also identified effective strategies and challenges nurse supervisors encountered during crises. Conducted across hospitals in Saudi Arabia, this quantitative cross-sectional study included 916 staff nurses. Data was collected from January to April 2023 through a 19-item survey questionnaire on TL. The six aspects of TL (Charisma, Social, Vision, Transactional, Delegation, and Execution) were consistently observed among nurse supervisors, with an average score of 2.99±1.014. All paired domains, except Charisma, showed strong positive correlations, indicating solid relationships within each pair. Identified best practices of nurse supervisors included shared goals, supervision, mentorship, and incentives. However, challenges included a sudden increase in patient numbers, limited resources, and nurses' concerns about health and safety. These findings can guide policymakers in developing leadership programs to strengthen nurses' leadership skills, particularly in crisis situations.

Promoter hypermethylation-mediated downregulation of PAX6 promotes tumor growth and metastasis during the progression of liver cancer

BackgroundThe progression of liver cancer is a complicated process that involves genetic and epigenetic changes. Paired box 6 (PAX6) is a critical transcription factor for embryonic development. PAX6 is abnormally methylated in human cancer. The role of the PAX6 gene in the pathogenesis of hepatocellular carcinoma (HCC) is still unclear.MethodsTranscriptional silencing of PAX6 mediated by promoter methylation was confirmed using quantitative methylation-specific polymerase chain reaction (PCR) and reverse-transcription (RT)-PCR. Then we conducted gain-and-loss of function approaches to evaluate the function of PAX6 in HCC progression in vitro. Moreover, we designed xenograft mouse models to assess the effect of PAX6 on tumor growth and metastasis. Finally, we used RNA sequencing (RNA-seq) strategy and phenotypic rescue experiments to identify potential targets of PAX6 performing tumor-suppressive function.ResultsConstitutive expression of PAX6 suppressed anchorage-independent growth and cell invasion in vitro as well as tumor growth and metastasis in xenograft mouse models. In contrast, the inhibition of PAX6 using knockout and knockdown strategies increased tumor growth both in vitro and in vivo. Downregulation of PAX6 by doxycycline depletion partially reversed the malignant phenotypes of HCC cells induced by PAX6. Moreover, we identified E-cadherin (CDH1) and thrombospondin-1 (THBS1) as targets of PAX6. Ultimately, we demonstrated that the knockdown of CDH1 and overexpression of THBS1 in PAX6-expressing HCC cells partly reversed the tumor-suppressive effect.ConclusionPAX6 functions as a tumor suppressor partly through upregulation of CDH1 and downregulation of THBS1. Promoter hypermethylation-mediated suppression of PAX6 reduces the tumor suppressor function in the progression of liver cancer.

Momordica charantia Extract Ameliorates Melanoma Cell Proliferation and Invasion into Mouse Lungs by Suppressing PAX3 Expression.

Melanomas, which develop on malignant transformations of melanocytes, are highly malignant and prone to metastasis; therefore, effective drugs are required. The Momordica charantia (MC) extract has been shown to suppress cancer cell proliferation and invasion; however, the effect of the MC extract on melanoma in living organisms remains unclear. In this study, we investigated the mechanism underlying the amelioration of melanoma cell extravasation into mouse lungs by the MC extract. Male C57BL/6j mice (aged 8 weeks) were injected with B16 melanoma cells (1 × 105 cells/mouse). Subsequently, they were orally administered the MC extract daily for 2 weeks; mouse lung samples were obtained on the final day and analyzed. The MC extract ameliorated melanoma proliferation and infiltration into the lungs caused by melanoma cell treatment. It also increased phosphatase and tensin homolog deletion from chromosome 10 and suppressed paired box gene 3 (PAX3) and the phosphatidylinositol trisphosphate/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin complex 1 signaling. Furthermore, it decreased microphthalmia-associated transcription factors and induced the suppression of cyclin-dependent kinase 2, hepatocyte growth factor receptor, B-cell/CLL lymphoma 2, and Ras-related proteins. Our findings suggest that the MC extract suppresses tumor survival genes by regulating PAX3, thereby ameliorating melanoma proliferation and invasion.

Shedding light on congenital aniridia: an in-depth study of two cases

Congenital aniridia is a rare ocular disorder characterized by the partial or complete absence of iris tissue. Although the classic form is associated with a range of ocular abnormalities, including foveal and optic nerve hypoplasia, nystagmus, and cataracts, it is the onset of glaucoma, cataracts, and keratopathy that most significantly impair vision in affected patients. Typically caused by mutations in the PAX6 gene, which encodes the paired box protein Pax-6, aniridia can also be associated with systemic conditions such as WAGR syndrome. This study emphasizes the importance of comprehensive ophthalmic examination and genetic testing in diagnosing and managing aniridia, particularly when associated with systemic conditions. Multidisciplinary management and regular follow-up are essential to monitor for potential complications, including Wilms' tumor, ensuring optimal care for affected patients.

Macromolecular crowding agent dependent extracellular matrix deposition and growth factor retention in human corneal fibroblast cultures

The major obstacle in the commercialisation and clinical translation of tissue engineered medicines is the required for the development of implantable tissue surrogates prolonged in vitro culture. Macromolecular crowding (MMC) enhances and accelerates extracellular matrix (ECM) deposition, thus offering an opportunity to bridge the gap between research and development in tissue engineered substitutes. However, the optimal MMC agent is still elusive. Herein, we first assessed the biophysical properties of the most widely used MMC agents [κλ carrageenan (κλ CR), λ carrageenan (λ CR) and Ficoll™ cocktail (FC)] and then assessed their effect in basic cell function, ECM deposition and growth factor retention in human corneal fibroblast (hCF) cultures. Dynamic light scattering analysis revealed that both CR macromolecules had significantly lower and higher zeta potential and hydrodynamic radius, respectively, than the FC. None of the MMC agents affected hCF morphology and all induced similar hCF viability, proliferation and metabolic activity. Electrophoresis and immunofluorescence analyses made apparent that at day 10 (longest time point assessed), the FC brought about the highest fibronectin and collagen types I, III, IV, V and VI deposition. Deposited ECM pattern analysis showed that at day 10, the FC induced the lowest lacunarity and normalised end points and the highest fractal dimension and % high density matrix. Further immunofluorescence analysis revealed no significant differences between the groups in vimentin, aldehyde dehydrogenase 3 family member A1, keratocan, paired box protein 6 and α-smooth muscle actin. Importantly, at day 10, the FC resulted in the highest growth factor retention (20 molecules). Our data clearly illustrate a MMC agent dependent cell response, with the FC having the highest positive effect in hCF cultures.

Clinicopathological features and outcomes of rare lung adenocarcinoma metastasis to the thyroid gland: A single-center, 11-year experience.

Metastasis to the thyroid gland from lung adenocarcinoma is rare and challenging to diagnose due to similar histopathological features. This study aimed to analyze the clinicopathological characteristics of and treatment strategies for lung adenocarcinoma metastasis to the thyroid based on 11 years of institutional experience. A retrospective study included patients with lung adenocarcinoma metastasis to the thyroid at our center from 2010 to 2023. Clinicopathological features and clinical outcomes were analyzed. Among 9714 lung adenocarcinoma patients, nine patients (five females, 55.6%) were diagnosed with thyroid metastasis, presenting primarily with cough symptoms. Most patients (88.9%) had synchronous tumors, whereas a minority (11.1%) had metachronous tumors. The median time from primary tumor diagnosis to metastasis was 4.8 months. Most patients developed bilateral thyroid metastases (88.9%). Diagnosis of thyroid metastasis was primarily through fine-needle aspiration (FNA), with one case misdiagnosed as papillary thyroid carcinoma. Immunohistochemical staining revealed thyroid transcription factor-1 (TTF-1) and novel aspartic proteinase of pepsin family A (Napsin-A) positivity and paired box 8 (PAX8) negativity. Genetic testing found epidermal growth factor receptor mutations in 71.4% of patients. The individualized comprehensive therapy included surgery, chemotherapy, immunotherapy, and targeted and supportive therapy. The median overall survival was 56.0 months, with a progression-free survival of 12.7 months. Kaplan-Meier (K-M) analysis suggested improved survival with no advanced symptoms (p = 0.03) and targeted therapies (p = 0.05). Lung adenocarcinoma metastasis to the thyroid is a rare disease, with an incidence of 0.1% among lung adenocarcinoma patients. Early treatment after symptom onset and personalized targeted therapies may improve prognosis. Despite rapid disease progression, favorable outcomes can be achieved with comprehensive treatment.

Efficient Cross-Domain Fault Diagnosis via Distributed Multi-Source Domain Deep Transfer Learning

Abstract In the actual industrial production, the working conditions of rotating machinery are complex and changeable, and the health-state monitoring data are increasingly large and difficult to be labeled, which will seriously restrict the accuracy and efficiency of cross-domain fault diagnosis (CDFD) of rotating machinery. Therefore, an efficient multi-source domain deep transfer learning (MDDTL) method for CDFD of rotating machinery is proposed. Firstly, a MDDTL model is constructed to improve the accuracy of CDFD. In the model, a dual-phase domain alignment strategy is designed, which considers the alignment of feature distributions between each source and target domain pair in the feature space and that of prediction probabilities between domain-specific fault classifiers in the output space. The fault prediction results from multiple different fault classifiers are merged dynamically by the proposed imbalanced adaptive prediction strategy. Secondly, a data-parallel distributed training scheme for MDDTL model is proposed. Based on the idea of data parallelism, the distributed parallel training of MDDTL model is performed with Horovod-GPU platform, and the parameters are synchronously updated with the bandwidth-optimal Ring-AllReduce architecture. Under the premise of ensuring the accuracy of fault diagnosis (FD), the training time of MDDTL model is significantly reduced. Finally, extensive experiments are conducted to verify the effectiveness of the proposed MDDTL method. The results demonstrate that the proposed method not only effectively improves the accuracy of CDFD of rotating machinery, but also significantly improves the training efficiency of MDDTL model. After adopting the proposed method, the diagnosis accuracies achieved under two different cross-working condition scenarios reach 97.09% and 97.87% respectively, and the model training time is reduced by 73.62% when facing a large-scale rotating machinery training set.

The trans-differentiation promotion of parietal epithelial cells by magnesium isoglycyrrhizinate to improve podocyte injury induced by high fructose consumption

BackgroundPodocytes have limited proliferative capacity, which leads to irreversible glomerular injury in diverse kidney diseases. Magnesium isoglycyrrhizinate (MgIG), a hepatoprotective agent in clinic, has been reported to improve glomerular podocyte injury. However, the underlying mechanism of MgIG in ameliorating podocyte injury remains unclear. PurposeGlomerular parietal epithelial cells (PECs) are recognized as podocyte progenitors and play a pivotal role in the recovery following glomerular injury. This work aims to investigate the protective mechanisms of MgIG in mitigating glomerular injury by promoting PEC trans-differentiation. Study DesignA rat model of progressive glomerular podocyte injury, and in vitro models using the primary podocytes and primary PECs, were established to further explore the pharmacological mechanism of MgIG. MethodsFour-week-old male Sprague-Dawley (SD) rats were fed a 10 % fructose solution for 3, 6, 9 and 12 weeks to induce glomerular injury. The effects of MgIG on the progressive changes in podocytes and PECs, and the correlation between PEC density and podocyte loss, were analyzed. The mechanism of MgIG in triggering PEC trans-differentiation was investigated, by examining adenosine secretion in injured podocytes, as well as the expression of cluster of differentiation 44 (CD44), nephrin, adenosine receptor A2B (ARA2B) and glucocorticoid receptor (GR) in PECs both in vivo and in vitro. ResultsRats fed a high fructose diet exhibited progressive changes in glomerular PECs, including increased cell density and a preference for trans-differentiation. A positive correlation was observed between PEC density and podocyte loss. Co-culture experiments demonstrated that extracellular adenosine accumulation from injured podocytes induced by high fructose exposure promoted PEC trans-differentiation via ARA2B. MgIG significantly improved podocyte injury and exhibited effects similar to dexamethasone on nephrin upregulation and CD44 inhibition. Moreover, the effect of MgIG on PEC ARA2B activation was more effective than that of dexamethasone. The co-expression of paired box 2 (PAX2)+-Nephrin+ in glomeruli indicated that MgIG induced PEC trans-differentiation and podocyte regeneration in model rats. Accordingly, podocyte loss and increased urine albumin-to-creatinine ratio (UACR) were also alleviated. Moreover, MgIG, which acts as a GR agonist to activate GR, reversed the upregulation of CD44 and decreased ARA2B induced by tumor necrosis factor-α (TNF-α) in primary PECs. The siRNA interference experiment manifested that MgIG exhibited a more pronounced enhancement of GR upregulation, in contrast to ARA2B activation, to promote PEC trans-differentiation. ConclusionThis work reports for the first time that PECs respond to the accumulation of extracellular adenosine from injured podocytes via activating ARA2B and focuses on the role of adenosine and adenosine receptors in the trans-differentiation of PECs. Furthermore, this study provides the first evidence that MgIG may promote podocyte regeneration by enhancing PEC trans-differentiation through GR activation, providing a research basis for investigating the glucocorticoid-like activity of MgIG in ameliorating glomerular podocyte injury.

Enhanced activity of split trehalase biosensors by interspecies domain combineering.

The split trehalase biosensor has potential as a versatile diagnostic technology. Split enzymes are engineered proteins, divided into inactive fragments, which can reassemble and regain activity when brought together by an analyte. The split TreA biosensor requires no sample processing and produces stable signals (in the form of glucose). Split trehalase reagents can function in blood, but periplasmic trehalase of E.coli requires blood acidification for maximal activity. The objective of this study was to obtain split trehalase with near physiological pH optimum. For this purpose, periplasmic trehalases of Cellvibrio spp. with higher activity at neutral pH, were split in analogy with the E. coli TreA into hood and catalytic domains. However, these split trehalases displayed self-complementation due to spontaneous reassembly. In contrast, when catalytic domains of Cellvibrio trehalases were combined with E.coli hood domains, these hybrids displayed conditional complementation capacity when split trehalase fragments fused to immunoglobulin-binding protein G (STIGA) were used to quantify immunoglobulin concentrations. Other hybrid combinations of Cellvibrio spp. had increased activity compared to the cognate pairs, albeit with strong self-complementation. A mutagenesis analysis of residues responsible for self-complementation led to uncoupling of self-complementation from allostery. The Michaelis-Menten kinetics of Cellvibrio enzymes and fragment pairs confirmed improved activity of a mutated hybrid pair of Cellvibrio hood and catalytic domains at physiological pH. In conclusion, the improvements in pH optimum and activity, demonstrated with STIGA, can now be leveraged to enhance other variations of the split trehalase biosensor platform, broadening its utility for testing clinical samples.

The Cancer-Specific Health Economic Measure QLU-C10D is Valid and Responsive for Assessing Health Utility in Patients with Thyroid Cancer.

Background: Health economic appraisals often rely on the assessment of health utilities using preference-based measures (PBM). The cancer-specific PBM, European Organisation for Research and Treatment of Cancer Quality of Life Utility - Core 10 Dimensions (EORTC QLU-C10D), was developed recently, and now needs to be validated in various clinical populations. Methods: In a multicenter, multinational prospective cohort study, we longitudinally collected EORTC QLQ-C30 and EQ-5D-5L data from patients with thyroid cancer. We applied seven country-specific value sets to the QLQ-C30 data to derive country-specific utility values and used the EQ-5D-5L as a comparator PBM. Criterion validity was assessed by correlating index scores and Bland-Altman plots. Construct validity was investigated by correlating domain scores. Known-group comparisons and responsiveness were assessed using external clinical criteria. Results: A total of 181 patients with thyroid cancer from nine countries (three continents) provided analyzable data. Patients were included if they had differentiated, medullary, or anaplastic thyroid cancer. Mean utility values of both instruments were generally lower compared to general population norms. No floor or ceiling effects were present for the QLU-C10D. The intra-class correlation for EQ-5D-5L and QLU-C10D index values ranged from 0.761 to 0.901 across the measurement timepoints, supporting criterion validity. Spearman's correlation coefficients ranged from 0.289 to 0.716 for theoretically corresponding domain pairs. The QLU-C10D detected differences in 9 of 15 known-group comparisons, supporting sensitivity. Clinically important changes were detected by all QLU-C10D country specific value sets, supporting responsiveness. Further, the QLU-C10D had higher statistical efficiency than the EQ-5D-5L in 74.7% of comparisons. Conclusions: The QLU-C10D is a valid PBM for health economic evaluations in thyroid cancer studies. We recommend its use to estimate health utilities in economic evaluations of thyroid cancer therapies.

Effect of Porphyromonas gingivalis Infection on Healing of Skeletal Muscle Injury: An In Vivo Study.

Background/Objectives:Porphyromonas gingivalis infection has been associated with various systemic diseases and may cause delayed healing of muscle injury. However, the relationship between muscle injury healing and P. gingivalis infection remains unclear. Our hypothesis was that P. gingivalis infection delays the healing of muscle injuries. Methods: Fifty-six 8-week-old male Wistar rats were randomly divided into two groups: sonicated P. gingivalis was intraperitoneally administered in one group (PG group), whereas saline was administered in the other group (CO group). Skeletal muscle injury was induced via cardiotoxin injections in all animals. The cross-sectional area of regenerating muscle cells was evaluated by haematoxylin-eosin staining, and the degree of muscle fibrosis was evaluated by Masson's trichrome staining. The expression of paired box protein (Pax7) and myoblast determination protein (MyoD) and the identified stages of myocyte regeneration were analysed by immunohistochemical staining. Motion analysis was performed during walking. Results: The cross-sectional area of muscle cells was significantly smaller in the PG group on days 7 and 14 post-injury than in the CO group. The Pax7+/MyoD- ratio was significantly lower in the PG group on day 1 post-injury than in the CO group. Motion analysis of treadmill walking showed that the PG group had a lower minimum calcaneal height on days 3 and 7 post-injury than the CO group. Conclusions: This study suggests that administration of sonicated P. gingivalis in rats can delay the healing process of muscle injury. Further research is needed to understand this mechanism of delay of P. gingivalis.