CDK12 Loss Promotes Prostate Cancer Development While Exposing Vulnerabilities to Paralog-Based Synthetic Lethality.

Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration-resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development-either alone, or in the context of other genetic alterations-and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions and robust T cell infiltration in the mouse prostate. Allograft-based CRISPR screening demonstrated that Cdk12 loss is positively associated with Trp53 inactivation but negatively associated with Pten inactivation-akin to what is observed in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent Trp53 loss promotes their proliferation and ability to form tumors in mice, while Cdk12 knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic Cdk12 and Trp53 loss allografts represent a new syngeneic model for the study of androgen receptor (AR)-positive, luminal prostate cancer. Notably, Cdk12/Trp53 loss prostate tumors are sensitive to immune checkpoint blockade. Cdk12-null organoids (either with or without Trp53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fide tumor suppressor gene with impact on tumor progression and lends support to paralog-based synthetic lethality as a promising strategy for treating CDK12-mutant mCRPC.

Evaluation of TRIM63 RNA in situ hybridization (RNA-ISH) as a potential biomarker for alveolar soft-part sarcoma (ASPS).

Alveolar soft-part sarcoma (ASPS) is a rare soft tissue tumor with a broad morphologic differential diagnosis. While histology and immunohistochemistry can be suggestive, diagnosis often requires exclusion of other entities followed by confirmatory molecular analysis for its characteristic ASPSCR1-TFE3 fusion. Current stain-based biomarkers (such as immunohistochemistry for cathepsin K and TFE3) show relatively high sensitivity but may lack specificity, often showing staining in multiple other entities under diagnostic consideration. Given the discovery of RNA in situ hybridization (RNA-ISH) for TRIM63 as a sensitive and specific marker of MiTF-family aberration renal cell carcinomas, we sought to evaluate its utility in the workup of ASPS. TRIM63 RNA-ISH demonstrated high levels (H-score greater than 200) of expression in 19/20 (95%) cases of ASPS (average H-score 330) and was weak or negative in cases of paraganglioma, clear cell sarcoma, rhabdomyosarcoma, malignant epithelioid hemangioendothelioma, as well as hepatocellular and adrenal cortical carcinomas. Staining was also identified in tumors with known subsets characterized by TFE3 alterations such as perivascular epithelioid cell neoplasm (PEComa, average H-score 228), while tumors known to exhibit overexpression of TFE3 protein without cytogenetic alterations, such as melanoma and granular cell tumor, generally showed less TRIM63 ISH staining (average H-scores 147 and 96, respectively). Quantitative assessment of TRIM63 staining by RNA-ISH is potentially a helpful biomarker for tumors with molecular TFE3 alterations such as ASPS.

Mycolicibacterium arseniciresistens sp. nov., isolated from lead-zinc mine tailing, and reclassification of two Mycobacterium species as Mycolicibacterium palauense comb. nov. and Mycolicibacterium grossiae comb. nov.

A Gram-positive, acid-fast, aerobic, rapidly growing and non-motile strain was isolated from lead-zinc mine tailing sampled in Lanping, Yunnan province, Southwest China. 16S rRNA gene sequence analysis showed that the most closely related species of strain KC 300T was Mycolicibacterium litorale CGMCC 4.5724T (98.47 %). Additionally, phylogenomic and specific conserved signature indel analysis revealed that strain KC 300T should be a member of genus Mycolicibacterium, and Mycobacterium palauense CECT 8779T and Mycobacterium grossiae DSM 104744T should also members of genus Mycolicibacterium. The genome size of strain KC 300T was 6.2 Mb with an in silico DNA G+C content of 69.2 mol%. Chemotaxonomic characteristics of strain KC 300T were also consistent with the genus Mycolicibacterium. The average nucleotide identity, digital DNA-DNA hybridization and average amino acid identity values, as well as phenotypic, physiological and biochemical characteristics, support that strain KC 300T represents a new species within the genus Mycolicibacterium, for which the name Mycolicibacterium arseniciresistens sp. nov. is proposed, with the type strain KC 300T (=CGMCC 1.19494T=JCM 35915T). In addition, we reclassified Mycobacterium palauense and Mycobacterium grossiae as Mycolicibacterium palauense comb. nov. and Mycolicibacterium grossiae comb. nov., respectively.

Hybrid Oncocytic Tumors (HOTs) in Birt-Hogg-Dubé Syndrome Patients-A Tale of Two Cities: Sequencing Analysis Reveals Dual Lineage Markers Capturing the 2 Cellular Populations of HOT.

Birt-Hogg-Dubé (BHD) syndrome is associated with an increased risk of multifocal renal tumors, including hybrid oncocytic tumor (HOT) and chromophobe renal cell carcinoma (chRCC). HOT exhibits heterogenous histologic features overlapping with chRCC and benign renal oncocytoma, posing challenges in diagnosis of HOT and renal tumor entities resembling HOT. In this study, we performed integrative analysis of bulk and single-cell RNA sequencing data from renal tumors and normal kidney tissues, and nominated candidate biomarkers of HOT, L1CAM, and LINC01187 , which are also lineage-specific markers labeling the principal cell and intercalated cell lineages of the distal nephron, respectively. Our findings indicate the principal cell lineage marker L1CAM and intercalated cell lineage marker LINC01187 to be expressed mutually exclusively in a unique checkered pattern in BHD-associated HOTs, and these 2 lineage markers collectively capture the 2 distinct tumor epithelial populations seen to co-exist morphologically in HOTs. We further confirmed that the unique checkered expression pattern of L1CAM and LINC01187 distinguished HOT from chRCC, renal oncocytoma, and other major and rare renal cell carcinoma subtypes. We also characterized the histopathologic features and immunophenotypic features of oncocytosis in the background kidney of patients with BHD, as well as the intertumor and intratumor heterogeneity seen within HOT. We suggest that L1CAM and LINC01187 can serve as stand-alone diagnostic markers or as a panel for the diagnosis of HOT. These lineage markers will inform future studies on the evolution and interaction between the 2 transcriptionally distinct tumor epithelial populations in such tumors.

Gut microbiota influence frailty syndrome in older adults: mechanisms and therapeutic strategies.

Frailty syndrome denotes a decreased capacity of the body to maintain the homeostasis and stress of the internal environment, which simultaneously increases the risk of adverse health outcomes in older adults, including disability, hospitalization, falls, and death. To promote healthy aging, we should find strategies to cope with frailty. However, the pathogenesis of frailty syndrome is not yet clear. Recent studies have shown that the diversity, composition, and metabolites of gut microbiota significantly changed in older adults with frailty. In addition, several frailty symptoms were alleviated by adjusting gut microbiota with prebiotics, probiotics, and symbiosis. Therefore, we attempt to explore the pathogenesis of frailty syndrome in older people from gut microbiota and summarize the existing interventions for frailty syndrome targeting gut microbiota, with the aim of providing timely and necessary interventions and assistance for older adults with frailty.

Correlation analysis and clinical significance of Musculoskeletal Ultrasound semi-quantitative grading with bone salt metabolism, Rheumatoid factor and Erythrocyte Sedimentation rate in patients with Rheumatoid Arthritis.

Objective: To determine the correlation and clinical significance of musculoskeletal ultrasound semi-quantitative grading with bone salt metabolism, rheumatoid factor and erythrocyte sedimentation rate (ESR) in patients with rheumatoid arthritis. Methods: This is a clinical comparative study. A total of 240 patients with rheumatoid arthritis admitted to Baoding NO.1 Central Hospital were selected according to the DAS28 score of rheumatoid arthritis, and were divided into four groups, with 60 cases in each group from May 2020 to May 2022. The differences and correlation of musculoskeletal ultrasound semi-quantitative grading, bone metabolism indicators, erythrocyte sedimentation rate and rheumatoid factor among the four groups were statistically analyzed. Results: The scores of bone erosion, synovial hyperplasia, joint effusion and intrasynovial blood flow in Group-H were significantly higher than those in Group-R, L and M, with statistically significant differences(p=0.00). The procollagen Type-1 N-terminal propeptide(P1NP), bone-specific alkaline phosphatase(BALP) and osteoprotegerin(OPG) in Group-H were significantly lower than those in Group-R, L and M, with statistically significant differences(p=0.00); The tartrate-resistant acid phosphatase(TRAC) in Group-H was significantly higher than that in Group-R, L and M, with a statistically significant difference(p=0.00). The levels of RF and ESR in Group-H were significantly higher than those in Group-R, L and M, with statistically significant differences(p=0.00). Conclusion: Musculoskeletal ultrasound semi-quantitative grading is correlated with the level of bone salt metabolism, rheumatoid factor and ESR in patients with rheumatoid arthritis. It can be combined with laboratory examination to objectively judge the severity of the course of rheumatoid arthritis.

Zeolite-like Topology Oxonitridosilicate La3.6Ba1.7Si5N10O2.1 with Potential Applications in Nonlinear Optical Materials.

A novel zeolite-like topology oxonitridosilicate La3.6Ba1.7Si5N10O2.1 with the space group Amm2 (no. 38) and lattice parameters a = 9.5193 (3) Å, b = 16.7011 (5) Å, c = 26.0279 (8) Å, and Z = 12 has been synthesized by a high-temperature solid-state reaction. The crystal structure of La3.6Ba1.7Si5N10O2.1 has four different kinds of tiling, and the cages in the structure are filled with La, Ba, and O atoms. The presence of a noncentrosymmetric space group further suggests its potential for nonlinear optical (NLO) applications, and La3.6Ba1.7Si5N10O2.1 demonstrated a stronger second-harmonic generation (SHG) response than that of SiO2.

Retinoic acid delays murine palatal shelf elevation by inhibiting Wnt5a-mediated noncanonical Wnt signaling and downstream Cdc-42/F-actin remodeling in mesenchymal cells.

BACKGROUND: Mammalian palatal shelves erupted from maxillary prominences undergo vertical extention, transient elevation, and horizontal growth to fuse. Previous studies in mice reported that the retinoic acid (RA) contributed to cleft palate in high incidence by delaying the elevating procedure, but little was known about the underlying biological mechanisms. METHODS: In this study, hematoxylin-eosin and immunofluorescence staining were employed to evaluate the phenotypes and the expression of related markers in the RA-treated mice model. In situ hybridization and RT-qPCR were used to detect the expression of genes involved in Wnt signaling pathway. The palatal mesenchymal cells were cultured in vitro, and stimulated with RA or CASIN, and co-treated with Foxy5. Wnt5a and Ccd42 expression were evaluated by immunofluorescence staining. Phalloidin was used to label the microfilament cytoskeleton (F-actin) in cultured cells. RESULTS: We revealed that RA resulted in 100% incidence of cleft palate in mouse embryos, and the expression of genes responsible for Wnt5a-mediated noncanonical Wnt signal transduction were specifically downregulated in mesenchymal palatal shelves. The in vitro study of palatal mesenchymal cells indicated that RA treatment disrupted the organized remodeling of cytoskeleton, an indicative structure of cell migration regulated by the small Rho GTPase Cdc42. Moreover, we showed that the suppression of cytoskeleton and cell migration induced by RA was partially restored using the small molecule Foxy-5-mediated activation of Wnt5A, and this restoration was attenuated by CASIN (a selective GTPase Cdc42 inhibitor) again. CONCLUSIONS: These data identified a crucial mechanism for Wnt5a-mediated noncanonical Wnt signaling in acting downstream of Rho GTPase Cdc42 to regulate cytoskeletal remodeling and cell migration during the process of palate elevation. Our study provided a new explanation for the cause of cleft palate induced by RA.

BaLa5V2O3N7: a novel anti-perovskite oxynitride for electrode applications.

The exploration of transition metal oxynitrides has garnered significant interest due to their intriguing property diversity. Herein, we present a promising new transition metal oxynitride BaLa5V2O3N7, which features an anti-perovskite structure type. This unique structural configuration endows the material with remarkable conductivity, particularly at low temperatures, paving the way for the material to be used in a wide range of technological applications.

Risk factors related with avascular necrosis after internal fixation of femoral neck fractures in children: a systematic review and meta-analysis.

Background: Less than 1% of children develop femoral neck fractures (FNF), making them uncommon. However, they may have dangerous side effects, like avascular necrosis. Even though several risk factors for postoperative avascular necrosis have been identified, there is still debate regarding them. In this investigation, a meta-analysis was performed to examine the potential causes of postoperative avascular necrosis in children with FNF. Methods: We conducted a thorough literature search to find risk factors for avascular necrosis (AVN) after internal fixation of pediatric FNF. Until December 2022, we searched several databases, including PubMed, Embase, Cochrane Library, Web of Science, CNKI, Orthosearch, and Sinomed. Software Zotero 6.0 and Stata 17.0 were used to organise and synthesise the data. Finally, a sensitivity and publication bias test was carried out. Results: Our study includes a total of 15 case-control studies involving 814 patients. The risk of postoperative AVN increased with age at fracture encounter (95% CI: 0.64-1.88, P = 0.0003), initial fracture displacement (95% CI: 1.87-9.54, P = 0.0005), and poor fracture reduction (95% CI:1.95-22.34, P = 0.0024) were risk factors for postoperative AVN. There was no significant relationship between gender and postoperative AVN (95% CI: 0.52-1.31, P = 0.41). Conversely, Postoperative AVN and reduction methods have no connection with each other (95% CI: 0.77-2.66, P = 0.25), procedure time (95% CI: 0.43-2.99, P = 0.16), or injury mechanism (95% CI: 0.32-2.26, P = 0.75). The incidence of post-operative AVN varies between Delbet fracture types (95% CI: 0.15-0.31, P < 0.0001), with the overall trend being that the incidence of post-operative AVN is highest for type II, lowest for type IV, and close for types I and III, but it is not clear which type of fracture is the independent risk factor. Funnel plots indicate no significant publication bias. Conclusions: In line with this study, About 26% of children who underwent surgery for a femoral neck fracture suffered postoperative AVN. The main risk factors for AVN were the child's age, the initial displacement of the fractures, and poorly reduced fractures. The risk of AVN did not significantly correlate with gender, the time of the procedure, reduction methods or the mechanism of injury. The overall trend in the incidence of postoperative AVN for the different Delbet types of fracture is that the incidence of postoperative AVN is highest for type II, lowest for type IV, and close for types I and III, but it is not clear which type of fracture is the independent risk factor.

Is Toxoplasma gondii infection a concern in individuals with rheumatic diseases? Evidence from a case-control study based on serological diagnosis.

Toxoplasma gondii infection in clinical cases of rheumatic diseases is increasing, whereas, the relationship between T. gondii infection and rheumatic diseases is still ambiguous and contradictory. Thus, the present case-control study based on serological diagnosis was carried out to identify the underlying relationship between T. gondii infection and rheumatic diseases in China. Serological results showed that rheumatic patients (17.25%, 79/458) had a significantly higher T. gondii seroprevalence than control subjects (10.70%, 49/458) (p = 0.004). However, the difference in T. gondii seroprevalence among clinical rheumatic disease forms was insignificant. Moreover, disease duration not effect the T. gondii seroprevalence in the included clinical rheumatic patients. Three risk factors (presence of cats at home, blood transfusion history, and consumption of raw shellfish) were identified through multivariate analysis to affect the T. gondii seroprevalence in the included clinical rheumatic patients. In conclusion, these results indicate that the latent T. gondii infection in clinical rheumatic patients should cause alarm and attention in the course of future scientific research or clinical treatment.

LSD1 promotes prostate cancer reprogramming by repressing TP53 signaling independently of its demethylase function.

Lysine-specific demethylase 1 (LSD1) is a histone demethylase that promotes stemness and cell survival in cancers such as prostate cancer. Most prostate malignancies are adenocarcinomas with luminal differentiation. However, some tumors undergo cellular reprogramming to a more lethal subset termed neuroendocrine prostate cancer (NEPC) with neuronal differentiation. The frequency of NEPC is increasing since the widespread use of potent androgen receptor signaling inhibitors. Currently, there are no effective treatments for NEPC. We previously determined that LSD1 promotes survival of prostate adenocarcinoma tumors. However, the role of LSD1 in NEPC is unknown. Here, we determined that LSD1 is highly upregulated in NEPC versus adenocarcinoma patient tumors. LSD1 suppression with RNAi or allosteric LSD1 inhibitors - but not catalytic inhibitors - reduced NEPC cell survival. RNA-Seq analysis revealed that LSD1 represses pathways linked to luminal differentiation, and TP53 was the top reactivated pathway. We confirmed that LSD1 suppressed the TP53 pathway by reducing TP53 occupancy at target genes while LSD1's catalytic function was dispensable for this effect. Mechanistically, LSD1 inhibition disrupted LSD1-HDAC interactions, increasing histone acetylation at TP53 targets. Finally, LSD1 inhibition suppressed NEPC tumor growth in vivo. These findings suggest that blocking LSD1's noncatalytic function may be a promising treatment strategy for NEPC.

Lessons from 801 clinical TFE3/TFEB fluorescence in situ hybridization assays performed on renal cell carcinoma suspicious for MiTF family aberrations.

OBJECTIVES: Fluorescence in situ hybridization (FISH) assays for the detection of chromosomal rearrangements involving TFE3 and TFEB are considered the gold standard for the diagnosis of MiTF family altered renal cell carcinoma (MiTF-RCC). We reviewed 801 clinical TFE3/TFEB FISH assays performed at our tertiary-level institution between 2014 and 2023 on kidney tumors suspicious at the morphologic or biomarker level for MiTF aberrations. METHODS: We summarized and analyzed clinical information, TFE3/TFEB FISH results, and available biomarker staining results in a cohort of 453 consecutive kidney tumor cases suspicious for MiTF-RCC. RESULTS: In total, 61 of 434 (14%) kidney tumors were confirmed for TFE3 translocation; 10 of 367 cases (2.7%) were confirmed for TFEB translocation. Since TFEB amplification interpretation was implemented in our service line, 20 of 306 cases (6.5%) were diagnosed with TFEB amplification. Importantly, TFE3 and TFEB rearrangements were never co-detected within the same kidney tumor. Patients with TFEB amplification were significantly older (P < .001) than patients with TFE3 or TFEB translocation. Kidney tumors with TFEB amplification were seen to be at least 3 times as common as those with TFEB translocation. CONCLUSIONS: Clinical TFE3/TFEB FISH assays successfully identified and confirmed rare MiTF-RCC with TFE3 and TFEB rearrangements. Although morphologic and biomarker features associated with a kidney tumor may be suggestive of MiTF-RCC, clinical TFE3/TFEB FISH assays are crucial for a confirmation and definitive subclassification of patients with MiTF-RCC.

High expression of peroxisomal D-bifunctional protein in cytosol regulates apoptosis and energy metabolism of hepatocellular carcinoma cells via PI3K/AKT pathway.

Peroxisomal D-bifunctional protein (DBP) is an indispensable enzyme of the fatty acid ß-oxidation in the peroxisome of humans. However, the role of DBP in oncogenesis is poorly understood. Our previous studies have demonstrated that DBP overexpression promotes hepatocellular carcinoma (HCC) cell proliferation. In this study, we evaluated the expression of DBP in 75 primary HCC samples using RT-qPCR, immunohistochemistry, and Western blot, as well as its correlation with the prognosis of HCC. In addition, we explored the mechanisms by which DBP promotes HCC cell proliferation. We found that DBP expression was upregulated in HCC tumor tissues, and higher DBP expression was positively correlated with tumor size and TNM stage. Multinomial ordinal logistic regression analysis indicated that lower DBP mRNA level was an independent protective factor of HCC. Notably, DBP was overexpressed in the peroxisome and cytosol and mitochondria of tumor tissue cells. Xenograft tumor growth was promoted by overexpressing DBP outside peroxisome in vivo. Mechanistically, DBP overexpression in cytosol activated the PI3K/AKT signaling axis and promoted HCC cell proliferation by downregulating apoptosis via AKT/FOXO3a/Bim axis. In addition, overexpression of DBP increased glucose uptake and glycogen content via AKT/GSK3ß axis, as well as elevated the activity of mitochondrial respiratory chain complex III to increase ATP content via the mitochondrial translocation of p-GSK3ß in an AKT-dependent manner. Taken together, this study was the first to report the expression of DBP in peroxisome and cytosol, and that the cytosolic DBP has a critical role in the metabolic reprogramming and adaptation of HCC cells, which provides a valuable reference for instituting an HCC treatment plan.

PRDX1 negatively regulates bleomycin-induced pulmonary fibrosis via inhibiting the epithelial-mesenchymal transition and lung fibroblast proliferation in vitro and in vivo.

BACKGROUND: Pulmonary fibrosis is a major category of end-stage changes in lung diseases, characterized by lung epithelial cell damage, proliferation of fibroblasts, and accumulation of extracellular matrix. Peroxiredoxin 1 (PRDX1), a member of the peroxiredoxin protein family, participates in the regulation of the levels of reactive oxygen species in cells and various other physiological activities, as well as the occurrence and development of diseases by functioning as a chaperonin. METHODS: Experimental methods including MTT assay, morphological observation of fibrosis, wound healing assay, fluorescence microscopy, flow cytometry, ELISA, western blot, transcriptome sequencing, and histopathological analysis were used in this study. RESULTS: PRDX1 knockdown increased ROS levels in lung epithelial cells and promoted epithelial-mesenchymal transition (EMT) through the PI3K/Akt and JNK/Smad signalling pathways. PRDX1 knockout significantly increased TGF-ß secretion, ROS production, and cell migration in primary lung fibroblasts. PRDX1 deficiency also increased cell proliferation, cell cycle circulation, and fibrosis progression through the PI3K/Akt and JNK/Smad signalling pathways. BLM treatment induced more severe pulmonary fibrosis in PRDX1-knockout mice, mainly through the PI3K/Akt and JNK/Smad signalling pathways. CONCLUSIONS: Our findings strongly suggest that PRDX1 is a key molecule in BLM-induced lung fibrosis progression and acts through modulating EMT and lung fibroblast proliferation; therefore, it may be a therapeutic target for the treatment of BLM-induced lung fibrosis.

Network-based analysis identifies key regulatory transcription factors involved in skin aging.

Skin aging is a complex process involving intricate genetic and environmental factors. In this study, we performed a comprehensive analysis of the transcriptional regulatory landscape of skin aging in canines. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to identify aging-related gene modules. We subsequently validated the expression changes of these module genes in single-cell RNA sequencing (scRNA-seq) data of human aging skin. Notably, basal cell (BC), spinous cell (SC), mitotic cell (MC), and fibroblast (FB) were identified as the cell types with the most significant gene expression changes during aging. By integrating GENIE3 and RcisTarget, we constructed gene regulation networks (GRNs) for aging-related modules and identified core transcription factors (TFs) by intersecting significantly enriched TFs within the GRNs with hub TFs from WGCNA analysis, revealing key regulators of skin aging. Furthermore, we demonstrated the conserved role of CTCF and RAD21 in skin aging using an H2O2-stimulated cell aging model in HaCaT cells. Our findings provide new insights into the transcriptional regulatory landscape of skin aging and unveil potential targets for future intervention strategies against age-related skin disorders in both canines and humans.

Targeting peroxisome proliferator-activated receptor γ proteasomal degradation by magnolol is a potential avenue for adipogenesis-mediated metabolic homeostasis.

OBJECTIVE: Adipogenesis has been recognized as an attractive avenue for maintaining systemic homeostasis, with peroxisome proliferator-activated receptor γ (PPARγ) showing predominant roles in this process. This study aims to identify promising drug candidates by targeting PPARγ for adipogenesis-based metabolic homeostasis and to clarify the detailed mechanisms. METHODS: Molecular events contributing to adipogenesis were screened, which identified PPARγ as having the predominant role. Promising agents of adipogenesis agonism were screened using a PPARγ-based luciferase reporter assay. The functional capacity and molecular mechanisms of magnolol were intensively examined using 3T3-L1 preadipocytes and dietary models. RESULTS: This study found that F-box only protein 9 (FBXO9)-mediated lysine 11 (K11)-linked ubiquitination and proteasomal degradation of PPARγ are critically required during adipogenesis and systemic homeostasis. Notably, magnolol was identified as a potent adipogenesis activator by stabilizing PPARγ. The pharmacological mechanisms investigations clarified that magnolol directly binds to PPARγ and markedly interrupts its interaction with FBXO9, leading to a decline in K11-linked ubiquitination and proteasomal degradation of PPARγ. Clinically important, magnolol treatment significantly facilitates adipogenesis in vitro and in vivo. CONCLUSIONS: The downregulation of K11-linked ubiquitination of PPARγ caused by FBOX9 is essentially required for adipogenesis, while targeting PPARγ-FBXO9 interaction provides a new avenue for the therapy of adipogenesis-related metabolic disorder.

Metabolic dysfunction-associated fatty liver disease increased the risk of subclinical carotid atherosclerosis in China.

Background and aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to substitute NAFLD in 2020. This new term highlights the systematic metabolic disturbances that accompany fatty liver. We evaluated the correlations between MAFLD and subclinical carotid atherosclerosis (SCA) based on a nationwide health examination population in China. Methods: We performed a nationwide cross-sectional population and a Beijing retrospective cohort from 2009 to 2017. SCA was defined as elevated carotid intima-media thickness. The multivariable logistic and Cox models were used to analyze the association between MAFLD and SCA. Results: 153,482 participants were included in the cross-sectional study. MAFLD was significantly associated with SCA in fully adjusted models, with an odds ratio of 1.66; 95% confidence interval (CI): 1.62-1.70. This association was consistent in the cohort, with a hazard ratio (HR) of 1.31. The association between baseline MAFLD and incident SCA increased with hepatic steatosis severity. Subgroup analysis showed an interaction between age and MAFLD, with a higher risk in younger groups (HR:1.67, 95% CI: 1.17-2.40). Conclusion: In this large cross-section and cohort study, MAFLD was significantly associated with the presence and development of SCA. Further, the risk was higher among MAFLD individuals with high hepatic steatosis index and young adults.

Accuracy and eligibility of Bonwill⁃Hawley arch form established by CBCT image for dental crowding measurement: a comparative study with the conventional brass wire and caliper methods.

OBJECTIVES: The purpose of this study was to develop a novel Bonwill⁃Hawley method (Bonwill⁃Hawley arch form based on CBCT image) for the assessment of dental crowding, and to investigate and compare the accuracy and eligibility with the conventional brass wire and caliper methods under different crowding conditions. MATERIAL AND METHODS: Sixty patients with the pair of plaster casts and CBCT data were collected. All the casts were marked and transformed into digital models using iTero scanner, and imported into OrthoCAD software to measure the required space. Using the conventional brass wire (M1) and caliper methods (M2), the available space and dental crowding were measured and calculated basing on digital models, respectively. Correspondingly, the axial planes in the level of dental arches were oriented and captured from the CBCT images to draw the Bonwill⁃Hawley arch forms (M3), which were used to measure and calculate the available space and dental crowding. For each method, intra and inter-examiner reliabilities were evaluated with intra-class correlation coefficients (ICCs). Wilcoxon test and Kruskal-Wallis test were performed for statistically analyzing the discrepancy among different groups. RESULTS: Both intra- and inter-examiner reliability were generally excellent for all parameters obtained by the three methods, except for the dental crowding measured using M1(ICC: 0.473/0.261). The dental crowding measured using M2 were significantly increased in mild, moderate and severe-crowding groups compared with M1. However, no significant difference was detected between M1 and M3 in severe-crowding group (maxilla, p = 0.108 > 0.05; mandible, p = 0.074 > 0.05). With the deterioration of crowding condition, the discrepancy of dental crowding between M1 and M2, or M1 and M3 were significantly decreased (maxilla, M2-M1, mild VS serve, p = 0.003 < 0.05; maxilla, M3-M1, mild VS serve, p = 0.003 < 0.05; mandible, M2-M1, mild VS serve, p = 0.000 < 0.001; mandible, M3-M1, mild VS serve, p = 0.043 < 0.05). CONCLUSION: Dental crowding measured using the novel Bonwill⁃Hawley method was relatively greater than the caliper method, but not exceeding the brass wire method, which wound gradually come close to the brass wire method with the deterioration of crowding condition. CLINICAL RELEVANCE: The Bonwill⁃Hawley method basing on CBCT image proved to be a reliable and acceptable choice for orthodontists to analyze the dental crowding.