Deubiquitinase USP47/UBP64E Regulates β-Catenin Ubiquitination and Degradation and Plays a Positive Role in Wnt Signaling

Wnt signaling plays important roles in development and tumorigenesis. A central question about the Wnt pathway is the regulation of β-catenin. Phosphorylation of β-catenin by CK1α and GSK3 promotes β-catenin binding to β-TrCP, leading to β-catenin degradation through the proteasome. The phosphorylation and ubiquitination of β-catenin have been well characterized; however, it is unknown whether and how a deubiquitinase is involved. In this study, by screening RNA interference (RNAi) libraries, we identified USP47 as a deubiquitinase that prevents β-catenin ubiquitination. Inactivation of USP47 by RNAi increased β-catenin ubiquitination, attenuated Wnt signaling, and repressed cancer cell growth. Furthermore, USP47 deubiquitinates itself, whereas β-TrCP promotes USP47 ubiquitination through interaction with an atypical motif in USP47. Finally, in vivo studies in the Drosophila wing suggest that UBP64E, the USP47 counterpart in Drosophila, is required for Armadillo stabilization and plays a positive role in regulating Wnt target gene expression

Parallel Prediction Method of Knowledge Proficiency Based on Bloom’s Cognitive Theory

Knowledge proficiency refers to the extent to which students master knowledge and reflects their cognitive status. To accurately assess knowledge proficiency, various pedagogical theories have emerged. Bloom’s cognitive theory, proposed in 1956 as one of the classic theories, follows the cognitive progression from foundational to advanced levels, categorizing cognition into multiple tiers including “knowing”, “understanding”, and “application”, thereby constructing a hierarchical cognitive structure. This theory is predominantly employed to frame the design of teaching objectives and guide the implementation of teaching activities. Additionally, due to the large number of students in real-world online education systems, the time required to calculate knowledge proficiency is significantly high and unacceptable. To ensure the applicability of this method in large-scale systems, there is a substantial demand for the design of a parallel prediction model to assess knowledge proficiency. The research in this paper is grounded in Bloom’s Cognitive theory, and a Bloom Cognitive Diagnosis Parallel Model (BloomCDM) for calculating knowledge proficiency is designed based on this theory. The model is founded on the concept of matrix decomposition. In the theoretical modeling phase, hierarchical and inter-hierarchical assumptions are initially established, leading to the abstraction of the mathematical model. Subsequently, subject features are mapped onto the three-tier cognitive space of “knowing”, “understanding”, and “applying” to derive the posterior distribution of the target parameters. Upon determining the objective function of the model, both student and topic characteristic parameters are computed to ascertain students’ knowledge proficiency. During the modeling process, in order to formalize the mathematical expressions of “understanding” and “application”, the notions of “knowledge group” and “higher-order knowledge group” are introduced, along with a parallel method for identifying the structure of higher-order knowledge groups. Finally, the experiments in this paper validate that the model can accurately diagnose students’ knowledge proficiency, affirming the scientific and meaningful integration of Bloom’s cognitive hierarchy in knowledge proficiency assessment

Dub3 Inhibition Suppresses Breast Cancer Invasion and Metastasis by Promoting Snail1 Degradation

Snail1, a key transcription factor of epithelial–mesenchymal transition (EMT), is subjected to ubiquitination and degradation, but the mechanism by which Snail1 is stabilized in tumours remains unclear. We identify Dub3 as a bona fide Snail1 deubiquitinase, which interacts with and stabilizes Snail1. Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis. These effects are rescued by ectopic Snail1 expression. IL-6 also stabilizes Snail1 by inducing Dub3 expression, the specific inhibitor WP1130 binds to Dub3 and inhibits the Dub3-mediating Snail1 stabilization in vitroand in vivo. Our study reveals a critical Dub3–Snail1 signalling axis in EMT and metastasis, and provides an effective therapeutic approach against breast cancer

Clinical presentation, management, and research progress of adrenal schwannoma

ObjectiveThis study shares our experience in managing adrenal schwannoma (AS).MethodsThe clinical data of eight patients with AS in our hospital from April 2007 to April 2022 were analyzed retrospectively.ResultsA total of 1309 patients with adrenal lesions were treated in the affiliated hospital of Guizhou Medical University for 15 years, of which only 8 cases were diagnosed as AS, accounting for 0.61%. Among the eight patients with AS, there were five females and three males, with an average age of 48.63 ± 12.05 years, and the average maximum diameter of the tumor was 6.96 ± 1.83 cm. All patients underwent adrenalectomy and were pathologically diagnosed as AS after the operation. The average follow-up time of eight patients with AS was 60.13 ± 22.33 months, and there was no recurrence or metastasis.ConclusionThe retroperitoneum is an uncommon site for schwannoma tumors, and among adrenal incidentalomas, the schwannoma is rare. The disease lacks specific clinical and imaging features, but correct diagnosis before the pathological examination is very important for clinical management and surgical decision. When imaging examination indicates a slow-growing retroperitoneal mass, schwannoma should be considered. Surgical resection is the main treatment. Pathology is the gold standard for diagnosis. Most of the tumors are benign and have a good prognosis. There is a risk of recurrence after the operation, and it should be monitored actively

Sublytic C5b-9 Induces Glomerular Mesangial Cell Apoptosis Through miR-3546/SOX4/Survivin Axis in Rat Thy-1 Nephritis

Background/Aims: The activation of complement system and the formation of C5b-9 complex have been confirmed in the glomeruli of patients with mesangioproliferative glomerulonephritis (MsPGN). However, the role and mechanism of C5b-9-induced injury in glomerular mesangial cell (GMC) are poorly understood. Rat Thy-1N is an animal model for studying MsPGN. It has been revealed that the attack of C5b-9 to the GMC in rat Thy-1N is sublytic, and sublytic C5b-9 can cause GMC apoptosis, but the underlying mechanism is not fully elucidated. To explore the role and regulatory mechanism of C5b-9 in MsPGN lesion, we used rat Thy-1N model and first detected the change of microRNA (miRNA) profiles both in Thy-1N rat renal tissues (in vivo) and in the cultured GMCs with sublytic C5b-9 stimulation (in vitro). Then we determined the effect of miR-3546, which increased both in vivo and in vitro, on GMC apoptosis upon sublytic C5b-9 as well as the involved mechanism. Methods: Rat Thy-1N model was established and GMCs were treated with sublytic C5b-9. The rat renal cortex and the stimulated GMCs were obtained for miRNA microarray detection. Subsequently, the increased miRNAs were verified by real-time PCR. Meanwhile, to ascertain the ability of some miRNAs to upregulate cleaved caspase 3 and induce GMC apoptosis, the corresponding miRNA mimics were transfected into GMCs, followed by western blotting (WB) and flow cytometry mesurement. Thereafter, the miR-3546-targeted gene (SOX4) was predicted using bioinformatics approaches, and SOX4 expression in Thy-1N tissues and in the GMCs upon sublytic C5b-9 stimulation or miR-3546 mimic/inhibitor transfection were detected using real-time PCR and WB. To prove that miR-3546 can affect SOX4 gene transcription and SOX4 can regulate survivin expression, dual luciferase reporter assay, real-time PCR, WB and chromatin immunoprecipitation (ChIP) assays were performed. Furthermore, the role of miR-3546/SOX4/survivin axis in the GMC apoptosis induced by sublytic C5b-9 was examined using WB and flow cytometry. Results: Compared with normal renal tissues and untreated GMCs, there were 43 and 62 upregulated miRNAs (> 2-fold) in Thy-1N tissues and sublytic C5b-9-stimulated GMCs respectively. A total of 17 miRNAs were increased both in vivo and in vitro, 11 of which were validated by real-time PCR. Among them, miR-3546 could markedly promote GMC apoptosis and inhibit SOX4 or survivin expression in response to sublytic C5b-9, and either SOX4 or survivin overexpression markedly rescued the GMC apoptosis mediated by miR-3546 mimic. Additionally, SOX4 overexpression could reverse the survivin suppression by miR-3546 mimic, and SOX4 could bind to survivin promoter (-1,278 to -853 nt) and activate survivin gene transcription. Conclusion: MiR-3546/ SOX4/survivin axis has a promoting role in the GMC apoptosis triggered by sublytic C5b-9, and our findings may provide a new insight into the pathogenesis of rat Thy-1N and human MsPGN

Increased Mortality Associated with Well-Water Arsenic Exposure in Inner Mongolia, China

We conducted a retrospective mortality study in an Inner Mongolian village exposed to well water contaminated by arsenic since the 1980s. Deaths occurring between January 1, 1997 and December 1, 2004 were classified according to underlying cause and water samples from household wells were tested for total arsenic. Heart disease mortality was associated with arsenic exposure, and the association strengthened with time exposed to the water source. Cancer mortality and all-cause mortality were associated with well-water arsenic exposure among those exposed 10–20 years. This is the first study to document increased arsenic-associated mortality in the Bayingnormen region of Inner Mongolia

Well Water Arsenic Exposure, Arsenic Induced Skin-Lesions and Self-Reported Morbidity in Inner Mongolia

Residents of the Bayingnormen region of Inner Mongolia have been exposed to arsenic-contaminated well water for over 20 years, but relatively few studies have investigated health effects in this region. We surveyed one village to document exposure to arsenic and assess the prevalence of arsenic-associated skin lesions and self-reported morbidity. Five-percent (632) of the 12,334 residents surveyed had skin lesions characteristics of arsenic exposure. Skin lesions were strongly associated with well water arsenic and there was an elevated prevalence among residents with water arsenic exposures as low as 5 μg/L-10 μg/L. The presence of skin lesions was also associated with self-reported cardiovascular disease

Associations of Educational Attainment, Occupation, Social Class and Major Depressive Disorder among Han Chinese Women

Background The prevalence of major depressive disorder (MDD) is higher in those with low levels of educational attainment, the unemployed and those with low social status. However the extent to which these factors cause MDD is unclear. Most of the available data comes from studies in developed countries, and these findings may not extrapolate to developing countries. Examining the relationship between MDD and socio economic status in China is likely to add to the debate because of the radical economic and social changes occurring in China over the last 30 years. Principal findings We report results from 3,639 Chinese women with recurrent MDD and 3,800 controls. Highly significant odds ratios (ORs) were observed between MDD and full time employment (OR = 0.36, 95% CI = 0.25–0.46, logP = 78), social status (OR = 0.83, 95% CI = 0.77–0.87, logP = 13.3) and education attainment (OR = 0.90, 95% CI = 0.86–0.90, logP = 6.8). We found a monotonic relationship between increasing age and increasing levels of educational attainment. Those with only primary school education have significantly more episodes of MDD (mean 6.5, P-value = 0.009) and have a clinically more severe disorder, while those with higher educational attainment are likely to manifest more comorbid anxiety disorders. Conclusions In China lower socioeconomic position is associated with increased rates of MDD, as it is elsewhere in the world. Significantly more episodes of MDD occur among those with lower educational attainment (rather than longer episodes of disease), consistent with the hypothesis that the lower socioeconomic position increases the likelihood of developing MDD. The phenomenology of MDD varies according to the degree of educational attainment: higher educational attainment not only appears to protect against MDD but alters its presentation, to a more anxious phenotype

Aegilops sharonensis genome-assisted identification of stem rust resistance gene Sr62

The wild relatives and progenitors of wheat have been widely used as sources of disease resistance (R) genes. Molecular identification and characterization of these R genes facilitates their manipulation and tracking in breeding programmes. Here, we develop a reference-quality genome assembly of the wild diploid wheat relative Aegilops sharonensis and use positional mapping, mutagenesis, RNA-Seq and transgenesis to identify the stem rust resistance gene Sr62, which has also been transferred to common wheat. This gene encodes a tandem kinase, homologues of which exist across multiple taxa in the plant kingdom. Stable Sr62 transgenic wheat lines show high levels of resistance against diverse isolates of the stem rust pathogen, highlighting the utility of Sr62 for deployment as part of a polygenic stack to maximize the durability of stem rust resistance