Uncovering novel drug targets for bipolar disorder: a Mendelian randomization analysis of brain, cerebrospinal fluid, and plasma proteomes.

BACKGROUND: There is a clear demand for innovative therapeutics for bipolar disorder (BD). METHODS: We integrated the largest BD genome-wide association study (GWAS) dataset (NCase = 41 917, NControl = 371 549) with protein quantitative trait loci from brain, cerebrospinal fluid, and plasma. Using a range of integrative analyses, including Mendelian randomization (MR), Steiger filter analysis, Bayesian colocalization, and phenome-wide MR analysis, we prioritized novel drug targets for BD. Additionally, we incorporated data from the UK Biobank (NCase = 1064, NControl = 365 476) and the FinnGen study (NCase = 7006, NControl = 329 192) for robust biological validation. RESULTS: Through MR analysis, we found that in the brain, downregulation of DNM3, MCTP1, ABCB8 and elevation of DFNA5 and PDF were risk factors for BD. In cerebrospinal fluid, increased BD risk was associated with increased levels of FRZB, AGRP, and IL36A and decreased CTSF and LRP8. Plasma analysis revealed that decreased LMAN2L, CX3CL1, PI3, NCAM1, and TIMP4 correlated with increased BD risk, but ITIH1 did not. All these proteins passed Steiger filtering, and Bayesian colocalization confirmed that 12 proteins were colocalized with BD. Phenome-wide MR analysis revealed no significant side effects for potential drug targets, except for LRP8. External validation further underscored the concordance between the primary and validation cohorts, confirming MCTP1, DNM3, PDF, CTSF, AGRP, FRZB, LMAN2L, NCAM1, and TIMP4 are intriguing targets for BD. CONCLUSIONS: Our study identified druggable proteins for BD, including MCTP1, DNM3, and PDF in the brain; CTSF, AGRP, and FRZB in cerebrospinal fluid; and LMAN2L, NCAM1, and TIMP4 in plasma, delineating promising avenues to development of novel therapies.

Cotton BLH1 and KNOX6 antagonistically modulate fiber elongation via regulation of linolenic acid biosynthesis.

BEL1-LIKE HOMEODOMAIN (BLH) proteins are known to function in various plant developmental processes. However, the role of BLHs in regulating plant cell elongation is still unknown. Here, we identify a BLH gene, GhBLH1, that positively regulates fiber cell elongation. Combined transcriptomic and biochemical analyses reveal that GhBLH1 enhances linolenic acid accumulation to promote cotton fiber cell elongation by activating the transcription of GhFAD7A-1 via binding of the POX domain of GhBLH1 to the TGGA cis-element in the GhFAD7A-1 promoter. Knockout of GhFAD7A-1 in cotton significantly reduces fiber length, whereas overexpression of GhFAD7A-1 results in longer fibers. The K2 domain of GhKNOX6 directly interacts with the POX domain of GhBLH1 to form a functional heterodimer, which interferes with the transcriptional activation of GhFAD7A-1 via the POX domain of GhBLH1. Overexpression of GhKNOX6 leads to a significant reduction in cotton fiber length, whereas knockout of GhKNOX6 results in longer cotton fibers. An examination of the hybrid progeny of GhBLH1 and GhKNOX6 transgenic cotton lines provides evidence that GhKNOX6 negatively regulates GhBLH1-mediated cotton fiber elongation. Our results show that the interplay between GhBLH1 and GhKNOX6 modulates regulation of linolenic acid synthesis and thus contributes to plant cell elongation.

Lanthanum Significantly Contributes to the Growth of the Fine Roots' Morphology and Phosphorus Uptake Efficiency by Increasing the Yield and Quality of Glycyrrhiza uralensis Taproots.

The occurrence of different degrees of phosphorus deficiency in the vast majority of G. uralensis cultivation regions worldwide is common. There is a pressing need within the cultivated G. uralensis industry to identify appropriate exogenous substances that can enhance the uptake of phosphorus and improve both the yield and quality of the taproots of G. uralensis. This study was conducted to investigate the fine root and taproot morphology, physiological characteristics, and secondary metabolite accumulation in response to the supply of varying concentrations of LaCl3 to G. uralensis, to determine the optimal concentration of LaCl3 that can effectively enhance the yield and quality of G. uralensis's taproots, while also alleviating its reliance on soil phosphate fertilizer. The findings indicate that the foliar application of lanthanum enhanced root activity and increased APase activity, eliciting alterations in the fine root morphology, leading to promoting the accumulation of biomass in grown G. uralensis when subjected to P-deficient conditions. Furthermore, it was observed that the nutrient uptake of G. uralensis was significantly improved when subjected to P-deficient conditions but treated with LaCl3. Additionally, the yield and quality of the medicinal organs of G. uralensis were significantly enhanced.

Prognostic models for patients suffering a heart failure with a preserved ejection fraction: a systematic review.

The purpose of this study was to systematically review the development, performance, and applicability of prognostic models developed for predicting poor events in patients with heart failure with preserved ejection fraction (HFpEF). Databases including Embase, PubMed, Web of Science Core Collection, the Cochrane Library, China National Knowledge Infrastructure, Wan Fang, Wei Pu, and China Biological Medicine were queried from their respective dates of inception to 1 June 2023, to examine multivariate models for prognostic prediction in HFpEF. Both forward and backward citations of all studies were included in our analysis. Two researchers individually used the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS) checklist to extract data and assess the quality of the models using the Predictive Mode Bias Risk Assessment Tool (PROBAST). Among the 6897 studies screened, 16 studies derived and/or validated a total of 39 prognostic models. The sample size ranges for model development, internal validation, and external validation are 119 to 5988, 152 to 1000, and 30 to 5957, respectively. The most frequently employed modelling technique was Cox proportional hazards regression. Six studies (37.50%) conducted internal validation of models; bootstrap and k-fold cross-validation were the commonly used methods for internal validation of models. Ten of these models (25.64%) were validated externally, with reported the c-statistic in the external validation set ranging from 0.70 to 0.96, while the remaining models await external validation. The MEDIA echo score and I-PRESERVE-sudden cardiac death prediction mode have been externally validated using multiple cohorts, and the results consistently show good predictive performance. The most frequently used predictors identified among the models were age, n-terminal pro-brain natriuretic peptide, ejection fraction, albumin, and hospital stay in the last 5 months owing to heart failure. All study predictor domains and outcome domains were at low risk of bias, high or unclear risk of bias of all prognostic models due to underreporting in the area of analysis. All studies did not evaluate the clinical utility of the prognostic models. Predictive models for predicting prognostic outcomes in patients with HFpEF showed good discriminatory ability but their utility and generalization remain uncertain due to the risk of bias, differences in predictors between models, and the lack of clinical application studies. Future studies should improve the methodological quality of model development and conduct external validation of models.

The bacterial pathogen Pseudomonas plecoglossicida, its epidemiology, virulence factors, vaccine development, and host-pathogen interactions.

OBJECTIVE: Pseudomoans plecoglossicida has been identified as a fish pathogen since 2000 and has caused serious infections in cultured Large Yellow Croakers Larimiththys crocea in coastal eastern China during recent years. METHODS: Published literatures of this pathogen have been reviewed. RESULT: Several strains with high genomic similarity have been isolated and identified; the bacteria induce natural infection at lower water temperatures (12.0-25.5°C) and induce numerous granulomas and nodules in the visceral organs of croakers. Researchers have investigated the epidemiology of P. plecoglossicida infection, identified major virulence factors, searched for pathogenic genes, analyzed host-pathogen interactions, and endeavored to develop efficient vaccines. CONCLUSION: This paper provides an overview of these research advances to elucidate the virulence mechanisms of the pathogen and to promote vaccine development against infection.

Measurement properties of assessment tools of Kinesophobia in patients with cardiovascular disease: A systematic review.

Objectives: This study aimed to evaluate the measurement properties and methodological quality of assessment tools for Kinesophobia among patients with cardiovascular disease and provide a reference for healthcare professionals in selecting high-quality assessment tools. Methods: A systematic search was performed on specific databases: Embase, the Cochrane Library, PubMed, Web of Science, China National Knowledge Infrastructure, Wanfang database, China Biological Medicine disc, CINAHL, and China Science and Technology Journal Database, from inception to April 1, 2023. The researchers retrieved studies on the measurement attributes of the exercise fear scale in patients with cardiovascular diseases. They also traced back the references of the included studies to supplement relevant literature. According to the inclusion and exclusion criteria, screening and data extraction were independently undertaken by two reviewers. Two researchers individually used the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) Risk of Bias Checklist to assess the methodological quality of the scale, applied the COSMIN criteria to evaluate the measurement properties of the scale, and used a modified Grading, Recommendations, Assessment, Development, and Evaluation system to assess the certainty of evidence. Results: Seventeen studies were identified that reported the psychometric properties of six patient reported outcome measurement tools (included different languages version) The methodological quality of content validity was adequate in only two studies, the remaining patient-reported outcome measures demonstrated doubtful content validity. Limited information on cross-cultural validity/measurement invariance, measurement error, and responsiveness was retrieved. The Swedish version and the Chinese version of the Tampa Scale for Kinesiophobia Heart were graded "A." The remaining instruments were graded "B." Conclusions: The methodological and measurement attributes of the Swedish and Chinese versions of the Tampa Scale for Kinesiophobia Heart are relatively high quality and can be tentatively recommended. The measurement properties of the remaining scales remain to be verified.

Abnormal Brain Protein Abundance and Cross-tissue mRNA Expression in Amyotrophic Lateral Sclerosis.

Due to the limitations of the present risk genes in understanding the etiology of amyotrophic lateral sclerosis (ALS), it is necessary to find additional causative genes utilizing novel approaches. In this study, we conducted a two-stage proteome-wide association study (PWAS) using ALS genome-wide association study (GWAS) data (N = 152,268) and two distinct human brain protein quantitative trait loci (pQTL) datasets (ROSMAP N = 376 and Banner N = 152) to identify ALS risk genes and prioritized candidate genes with Mendelian randomization (MR) and Bayesian colocalization analysis. Next, we verified the aberrant expression of risk genes in multiple tissues, including lower motor neurons, skeletal muscle, and whole blood. Six ALS risk genes (SCFD1, SARM1, TMEM175, BCS1L, WIPI2, and DHRS11) were found during the PWAS discovery phase, and SARM1 and BCS1L were confirmed during the validation phase. The following MR (p = 2.10 × 10-7) and Bayesian colocalization analysis (ROSMAP PP4 = 0.999, Banner PP4 = 0.999) confirmed the causal association between SARM1 and ALS. Further differential expression analysis revealed that SARM1 was markedly downregulated in lower motor neurons (p = 7.64 × 10-3), skeletal muscle (p = 9.34 × 10-3), and whole blood (p = 1.94 × 10-3). Our findings identified some promising protein candidates for future investigation as therapeutic targets. The dysregulation of SARM1 in multiple tissues provides a new way to explain ALS pathology.

miR-186 regulates epithelial-mesenchymal transformation to promote nasopharyngeal carcinoma metastasis by targeting ZEB1.

OBJECTIVES: Nasopharyngeal carcinoma (NPC) is an aggressive epithelial cancer. The expression of miR-186 is decreased in a variety of malignancies and can promote the invasion and metastasis of cancer cells. This study aimed to explore the role and possible mechanism of miR-186 in the metastasis and epithelial-mesenchymal transformation (EMT) of NPC. METHODS: The expression of miR-186 in NPC tissues and cells was detected by RT-PCR. Then, miR-186 mimic was used to transfect NPC cell lines C666-1 and CNE-2, and cell activity, invasion and migration were detected by CCK8, transwell and scratch assay, respectively. The expression of EMT-related proteins was analyzed by western blotting analysis. The binding relationship between miR-186 and target gene Zinc Finger E-Box Binding Homeobox 1 (ZEB1) was confirmed by double luciferase assay. RESULTS: The expression of miR-186 in NPC was significantly decreased, and transfection of miR-186 mimic could significantly inhibit the cell activity, invasion, and migration, and regulate the protein expressions of E-cadherin, N-cadherin and vimentin in C666-1 and CNE-2 cells. Further experiments confirmed that miR-186 could directly target ZEB1 and negatively regulate its expression. In addition, ZEB1 has been confirmed to be highly expressed in NPC, and inhibition of ZEB1 could inhibit the activity, invasion, metastasis and EMT of NPC cells. And co-transfection of miR-186 mimic and si-ZEB1 could further inhibit the proliferation and metastasis of NPC. CONCLUSION: miR-186 may inhibit the proliferation, metastasis and EMT of NPC by targeting ZEB1, and the miR-186/ZEB1 axis plays an important role in NPC.

Knockdown of BACE1 by a multistage brain-targeting polyion complex improved memory and learning behaviors in APP/PS1 transgenic mouse model.

Cleavage of Amyloid precursor protein (APP) by the ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting step in the production of amyloid-ß (Aß) synaptotoxins. The siRNA-mediated silencing to attenuate the expression of BACE1 to ameliorate cognitive dysfunction in mice had been investigated. To improve therapeutic gene delivery to the central nervous system, cationic copolymer poly(ethylene glycol)-b-poly[N-(N'-{N''-[N'''-(2-aminoethyl)-2-aminoethyl]-2-aminoethyl}-2-aminoethyl)aspartamide]-cholesterol was synthesized, then RVG29 and Tet1 peptides were exploited as ligands to construct a dual-targeting brain gene delivery polyion complex (Tet1/RVG29-PIC). The cell uptake of a coculture cell model showed that the Tet1/RVG29-PIC exhibited notable transport characteristics and possessed affinity towards nerve cells. In vivo transfection, Tet1/RVG29-PIC possessed the highest expression of luciferase in brain compared with that of RVG29-PIC or Tet1-PIC, which were 1.25 and 1.22 times respectively. Silence BACE1 expression using siRNA-expressing plasmid loaded Tet1/RVG29-PIC that improved behavioral deficits in the APP/PS1 mouse model, demonstrating the favorable brain delivery properties of Tet1/RVG29-PIC by synergistical engagement of GT1B and nicotinic acetylcholine receptors. Our results suggested that the nanoformulation has the potential to be exploited as a multistage-targeting gene vector for the CNS disease therapy.

miR-186 regulates epithelial-mesenchymal transformation to promote nasopharyngeal carcinoma metastasis by targeting ZEB1

Abstract Objectives Nasopharyngeal carcinoma (NPC) is an aggressive epithelial cancer. The expression of miR-186 is decreased in a variety of malignancies and can promote the invasion and metastasis of cancer cells. This study aimed to explore the role and possible mechanism of miR-186 in the metastasis and epithelial-mesenchymal transformation (EMT) of NPC. Methods The expression of miR-186 in NPC tissues and cells was detected by RT-PCR. Then, miR-186 mimic was used to transfect NPC cell lines C666-1 and CNE-2, and cell activity, invasion and migration were detected by CCK8, transwell and scratch assay, respectively. The expression of EMT-related proteins was analyzed by western blotting analysis. The binding relationship between miR-186 and target gene Zinc Finger E-Box Binding Homeobox 1 (ZEB1) was confirmed by double luciferase assay. Results The expression of miR-186 in NPC was significantly decreased, and transfection of miR-186 mimic could significantly inhibit the cell activity, invasion, and migration, and regulate the protein expressions of E-cadherin, N-cadherin and vimentin in C666-1 and CNE-2 cells. Further experiments confirmed that miR-186 could directly target ZEB1 and negatively regulate its expression. In addition, ZEB1 has been confirmed to be highly expressed in NPC, and inhibition of ZEB1 could inhibit the activity, invasion, metastasis and EMT of NPC cells. And co-transfection of miR-186 mimic and si-ZEB1 could further inhibit the proliferation and metastasis of NPC. Conclusion miR-186 may inhibit the proliferation, metastasis and EMT of NPC by targeting ZEB1, and the miR-186/ZEB1 axis plays an important role in NPC.

Multiple enzymatic activities of a Sir2-HerA system cooperate for anti-phage defense.

In response to the persistent exposure to phage infection, bacteria have evolved diverse antiviral defense mechanisms. In this study, we report a bacterial two-component defense system consisting of a Sir2 NADase and a HerA helicase. Cryo-electron microscopy reveals that Sir2 and HerA assemble into a ∼1 MDa supramolecular octadecamer. Unexpectedly, this complex exhibits various enzymatic activities, including ATPase, NADase, helicase, and nuclease, which work together in a sophisticated manner to fulfill the antiphage function. Therefore, we name this defense system "Nezha" after a divine warrior in Chinese mythology who employs multiple weapons to defeat enemies. Our findings demonstrate that Nezha could sense phage infections, self-activate to arrest cell growth, eliminate phage genomes, and subsequently deactivate to allow for cell recovery. Collectively, Nezha represents a paradigm of sophisticated and multifaceted strategies bacteria use to defend against viral infections.

DnaQ mediates directional spacer acquisition in the CRISPR-Cas system by a time-dependent mechanism.

In the spacer acquisition stage of CRISPR-Cas immunity, spacer orientation and protospacer adjacent motif (PAM) removal are two prerequisites for functional spacer integration. Cas4 has been implicated in both processing the prespacer and determining the spacer orientation. In Cas4-lacking systems, host 3'-5' DnaQ family exonucleases were recently reported to play a Cas4-like role. However, the molecular details of DnaQ functions remain elusive. Here, we characterized the spacer acquisition of the adaptation module of the Streptococcus thermophilus type I-E system, in which a DnaQ domain naturally fuses with Cas2. We presented X-ray crystal structures and cryo-electron microscopy structures of this adaptation module. Our biochemical data showed that DnaQ trimmed PAM-containing and PAM-deficient overhangs with different efficiencies. Based on these results, we proposed a time-dependent model for DnaQ-mediated spacer acquisition to elucidate PAM removal and spacer orientation determination in Cas4-lacking CRISPR-Cas systems.

Piezoelectricity of Bi2Se3 Nanosheet.

Bi2Se3, one of the most extensively studied topological insulators, has received significant attention, and abundant research has been dedicated to exploring its surface electronic properties. However, little attention has been given to its piezoelectric properties. Herein, we investigate the piezoelectric response in a five-layer Bi2Se3 nanosheet using scanning probe microscopy (SPM) techniques. The piezoelectricity of Bi2Se3 is characterized using both conventional piezoresponse force microscopy (PFM) and a sequential excitation scanning probe microscopy (SE-SPM) technique. To confirm the linear piezoelectricity of Bi2Se3 two-dimensional materials, measurements of point-wise linear and quadratic electromechanical responses are carried out. Furthermore, the presence of polarization and relaxation is confirmed through hysteresis loops. As expected, the Bi2Se3 nanosheet exhibits an electromechanical solid response. Due to the inevitable loss of translational symmetry at the crystal edge, the lattice of the odd-layer Bi2Se3 nanosheet is noncentrosymmetric, indicating its potential for linear piezoelectricity. This research holds promise for nanoelectromechanical systems (NEMS) applications and future nanogenerators.

Comparative analysis of anchorage strength and histomorphometric changes after implantation of miniscrews in adults and adolescents: an experimental study in Beagles.

OBJECTIVES: This study aimed to explore the differences in anchorage strength and histomorphometric changes in orthodontic miniscrews between adult and adolescent beagles. MATERIAL AND METHOD: Six adult beagles and six young beagles were used as experimental subjects, and eight miniscrews were symmetrically placed in the posterior mandible of each dog. Measurement of the displacement (mm) of two adjacent miniscrews after load application was performed to compare the anchorage strength between the adult and adolescent groups. Three intravital bone fluorochromes (oxytetracycline, calcein green, xylenol orange) were administered postoperatively to mark the active bone-forming surface. Subsequently, the mineral apposition rate and bone-implant contact ratio were measured for dynamic and static histomorphometry. Finally, the expression levels of the RANKL/OPG ratio were evaluated by immunohistochemistry. RESULTS: The average displacement of miniscrews in the adult group was significantly less than that in the adolescent group after load application. For histomorphometry analysis, the mineral exposure rate in the adolescent group was higher than that in the adult group with or without force application. In addition, more fractures and new bone formation but deceased bone-implant contact ratios were observed in the adolescent group than in the adult group. The ratio of RANKL/OPG expression increased more in the adolescent group than in the adult group. CONCLUSION: Miniscrews do not remain in the same position as skeletal anchors, and the amount of displacement was higher in adolescent group than that in adult group, reflecting the weaker anchorage strength of miniscrews in adolescents due to the higher bone turnover rate and active bone remodelling. Therefore, it is feasible to apply orthodontic loading to the miniscrews in adult patients earlier, even immediately, but it is recommended to wait a period for the adolescents.

CRISPR/Cas13d targeting GZMA in PARs pathway regulates the function of osteoclasts in chronic apical periodontitis.

Chronic apical periodontitis is a prevalent oral disease characterized by bone loss, and its underlying mechanisms remain unclear. This study aimed to investigate the role and mechanism of the serine protease GZMA in osteoclasts during chronic apical periodontitis. To address this, we employed crRNA/Cas13d to inhibit GZMA expression and examined its impact on osteoclast behavior. Our findings revealed that GZMA plays a significant role in promoting osteoclast cell proliferation while inhibiting cell apoptosis. Additionally, the inhibition of GZMA led to a notable increase in miR-25-3p expression, which, in turn, downregulated the expression of TGF-ß. Consequently, the reduction in TGF-ß expression led to a decrease in PAR1 expression within the PARs pathway. These results suggest that GZMA might serve as a promising therapeutic target for the treatment of chronic apical periodontitis. Furthermore, our study highlights the potential of targeting GZMA using crRNA/Cas13d as a valuable approach for future therapeutic interventions.

Effect and mechanism of fluctuant glucose on restraining implant osseointegration in diabetes.

OBJECTIVES: The objectives of the study was to discuss the effect and mechanism of fluctuant glucose (FG) on implant osseointegration in type 2 diabetic mellitus (T2DM). MATERIALS AND METHODS: Rats were divided into control, T2DM and FG group, and the implants were inserted into their femurs. Micro-CT and histological analysis were used to evaluate the effect on osseointegration in vivo. And we investigated the effect of different conditions (normal, control, high glucose, and FG medium) on rat osteoblast in vitro. Then transmission electron microscope (TEM) and Western blot were used to evaluate the endoplasmic reticulum stress (ERS) response. Finally, 4-PBA, an inhibitor of ERS, was added into different conditions to observe the functions of osteoblast. RESULTS: In vivo, Micro-CT and histological analysis showed that the percentage of osseointegration in FG rats were lower than other two group. In vitro, the results demonstrated that the adhesion of the cells becomes worst, and osteogenic ability was also severely impaired in FG group. In addition, FG could induce more serious ERS and 4-PBA could improve the dysfunction of osteoblasts induced by FG. CONCLUSION: Fluctuant glucose could restrain the implant osseointegration in T2DM, and the effect was more obvious than consistent high glucose by a possible mechanism of activation ERS pathway.

Discovery of novel hypoxia-activated, nitroimidazole constructed multi-target kinase inhibitors on the basis of AZD9291 for the treatment of human lung cancer.

A group of 4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine derivatives containing a hypoxia-activated nitroimidazole group were designed as EGFR inhibitors. Among this series, A14 was identified as the optimal compound, exhibiting potent anti-proliferative activities against H1975 and HCC827 cells. Under hypoxic condition, the anti-proliferative activities of A14 improved by 4-6-fold (IC50 < 10 nM), indicating its hypoxia-selectivity. A14's high potency may be attributed to its inhibition against multiple kinases, including EGFR, JAK2, ROS1, FLT3, FLT4 and PDGFRα, which was confirmed by binding assays on a panel of 30 kinases. Furthermore, A14 exhibited good bio-reductive property and could bind with nucleophilic amino acids after being activated under hypoxic conditions. With its anti-proliferative activities and selectivity for hypoxia and oncogenic kinases, A14 shows promise as a multi-target kinase inhibitor for cancer therapy.

Network pharmacological analysis of corosolic acid reveals P4HA2 inhibits hepatocellular carcinoma progression.

BACKGROUND: Corosolic acid is a pentacyclic triterpene acid with hypoglycemic, anti-inflammatory, and anti-cancer effects. However, its potential targets in hepatocellular carcinoma (HCC) are unknown, hindering clinical utilization. METHODS: Differentially expressed proteins of the Bel-7404 cell line were identified with tandem mass tag analysis and differentially expressed genes (DEGs) of an HCC TCGA dataset using bioinformatics. Gene functions and pathways were inferred using the DAVID database. Online databases were used to establish P4HA2 expression in HCC (GEPIA2) and its relationship with patient survival (UALCAN and The Human Protein Atlas), the association between P4HA2 expression and immune cell infiltration (TIMER2), and DNA methylation of the P4HA2 gene (MethSurv). Cell proliferation, cell cycle, and cell death were assessed with PI and SYTOX-Green staining, CCK-8, and colony formation assays. Protein expression levels were detected by Western blotting. RESULTS: A total of 44 differentially expressed proteins and 4498 DEGs were identified. Four genes whose proteins were also found in the differential protein profile but with opposing expressions were selected as candidate targets. The candidate gene prolyl 4-hydroxylase subunit alpha 2 (P4HA2) was recognized as the only potential target due to its high expression in public datasets, association with poor patient survival, and relation to immune cell infiltration in HCC tissues. Moreover, the DNA methylation status in 4 CpG islands of the P4HA2 gene correlated with a poor prognosis. Furthermore, corosolic acid treatment inhibited the proliferation of HCC cell lines Bel-7404 and HepG2 in a dose-dependent manner, caused G2/M phase cell cycle arrest, and promoted cell death. In addition, the treatment reduced P4HA2 protein levels. CONCLUSION: Our results indicate that P4HA2 is a potential target of corosolic acid. Thus, they contribute to understanding molecular changes in HCC after corosolic acid treatment and facilitate finding new treatment regimens.

Density-adaptive registration of pointclouds based on Dirichlet Process Gaussian Mixture Models.

We propose an algorithm for rigid registration of pre- and intra-operative patient anatomy, represented as pointclouds, during minimally invasive surgery. This capability is essential for development of augmented reality systems for guiding such interventions. Key challenges in this context are differences in the point density in the pre- and intra-operative pointclouds, and potentially low spatial overlap between the two. Solutions, correspondingly, must be robust to both of these phenomena. We formulated a pointclouds registration approach which considers the pointclouds after rigid transformation to be observations of a global non-parametric probabilistic model named Dirichlet Process Gaussian Mixture Model. The registration problem is solved by minimizing the Kullback-Leibler divergence in a variational Bayesian inference framework. By this means, all unknown parameters are recursively inferred, including, importantly, the optimal number of mixture model components, which ensures the model complexity efficiently matches that of the observed data. By presenting the pointclouds as KDTrees, both the data and model are expanded in a coarse-to-fine style. The scanning weight of each point is estimated by its neighborhood, imparting the algorithm with robustness to point density variations. Experiments on several datasets with different levels of noise, outliers and pointcloud overlap show that our method has a comparable accuracy, but higher efficiency than existing Gaussian Mixture Model methods, whose performance is sensitive to the number of model components.

Bufalin reverses ABCB1-mediated resistance to docetaxel in breast cancer.

Background: Docetaxel (DCT) is widely used in clinical practice, but the drug resistance of breast cancer patients has become an important reason to limit its clinical efficacy. Chan'su is a commonly used traditional Chinese medicine for the treatment of breast cancer. Bufalin (BUF) is a bioactive polyhydroxy steroid extracted from chan'su and has strong antitumor activity, but there are few studies on reversing drug resistance in breast cancer. The aim of this study is to determine whether BUF can reverse the drug resistance to DCT and restore efficacy in breast cancer. Methodology: The reversal index of BUF was detected by Cell Counting Kit-8 (CCK-8) assays. The effects of BUF on enhancing the apoptosis of DCT were detected by flow cytometry and Western Blot (WB), and the main differential expression levels of sensitive and resistant strains were detected by high-throughput sequencing. Rhodamine 123 assay, WB and ATP Binding Cassette Subfamily B Member 1 (ABCB1) ATPase activity experiments were used to detect the effect of BUF on ABCB1. The nude mouse orthotopic model was constructed to investigate the reversal effect of BUF on DCT resistance in vivo. Results: With BUF intervention, the sensitivity of drug-resistant cell lines to DCT was increased. BUF can inhibit the expression of ABCB1 protein, increase the drug accumulation of DCT in drug-resistant strains, and reduce the ATPase activity of ABCB1. Animal experiments show that BUF can inhibit the growth of drug-resistant tumors in an orthotopic model of breast cancer and decrease the expression of ABCB1. Conclusion: BUF can reverse ABCB1-mediated docetaxel resistance in breast cancer.