Systematic computational identification of prognostic cytogenetic markers in neuroblastoma

Background: Neuroblastoma (NB) is the most common extracranial solid tumor found in children. The frequent gain/loss of many chromosome bands in tumor cells and absence of mutations found at diagnosis suggests that NB is a copy number-driven cancer. Despite the previous work, a systematic analysis that investigates the relationship between such frequent gain/loss of chromosome bands and patient prognosis has yet to be implemented. Methods: First, we analyzed two NB CNV datasets to select chromosomal bands with a high frequency of gain or loss. Second, we applied a computational approach to infer sample-specific CNVs for each chromosomal band selected in step 1 based on gene expression data. Third, we applied univariate Cox proportional hazards models to examine the association between the resulting inferred copy number values (iCNVs) and patient survival. Finally, we applied multivariate Cox proportional hazards models to select chromosomal bands that remained significantly associated with prognosis after adjusting for critical clinical variables, including age, stage, gender, and MYCN amplification status. Results: Here, we used a computational method to infer the copy number variations (CNVs) of sample-specific chromosome bands from NB patient gene expression profiles. The resulting inferred CNVs (iCNVs) were highly correlated with the experimentally determined CNVs, demonstrating CNVs can be accurately inferred from gene expression profiles. Using this iCNV metric, we identified 58 frequent gain/loss chromosome bands that were significantly associated with patient survival. Furthermore, we found that 7 chromosome bands were still significantly associated with patient survival even when clinical factors, such as MYCN status, were considered. Particularly, we found that the chromosome band chr11p14 has high potential as a novel candidate cytogenetic biomarker for clinical use. Conclusion: Our analysis resulted in a comprehensive list of prognostic chromosome bands supported by strong statistical evidence. In particular, the chr11p14 gain event provided additional prognostic value in addition to well-established clinical factors, including MYCN status, and thereby represents a novel candidate cytogenetic biomarker with high clinical potential. Additionally, this computational framework could be readily extended to other cancer types, such as leukemia

Connecting Multi-modal Contrastive Representations

Multi-modal Contrastive Representation learning aims to encode different modalities into a semantically aligned shared space. This paradigm shows remarkable generalization ability on numerous downstream tasks across various modalities. However, the reliance on massive high-quality data pairs limits its further development on more modalities. This paper proposes a novel training-efficient method for learning MCR without paired data called Connecting Multi-modal Contrastive Representations (C-MCR). Specifically, given two existing MCRs pre-trained on (A, B) and (B, C) modality pairs, we project them to a new space and use the data from the overlapping modality B to aligning the two MCRs in the new space. Meanwhile, since the modality pairs (A, B) and (B, C) are already aligned within each MCR, the connection learned by overlapping modality can also be transferred to non-overlapping modality pair (A, C). To unleash the potential of C-MCR, we further introduce a semantic-enhanced inter- and intra-MCR connection method. We first enhance the semantic consistency and completion of embeddings across different modalities for more robust alignment. Then we utilize the inter-MCR alignment to establish the connection, and employ the intra-MCR alignment to better maintain the connection for inputs from non-overlapping modalities. To demonstrate the effectiveness of C-MCR, we connect CLIP and CLAP via texts to derive audio-visual representations, and integrate CLIP and ULIP via images for 3D-language representations. Remarkably, without using any paired data, C-MCR for audio-visual achieves state-of-the-art performance on audio-image retrieval, audio-visual source localization, and counterfactual audio-image recognition tasks. Furthermore, C-MCR for 3D-language also attains advanced zero-shot 3D point cloud classification accuracy on ModelNet40.Comment: NeurIPS 202

Pien Tze Huang Alleviates Relapsing-Remitting Experimental Autoimmune Encephalomyelitis Mice by Regulating Th1 and Th17 Cells

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by infiltrating inflammatory cells and demyelinating lesions, and T helper (Th) cells play critical roles in the pathogenesis of MS. There is still lack of effective treatments currently. Pien Tze Huang (PZH), a traditional Chinese medicine formula, has been proved to have anti-inflammatory, neuroprotective, and immunoregulatory effects. However, whether PZH can be used to treat MS is still obscure. This study aimed to investigate the possible therapeutic effect and the underlying action mechanism of PZH in relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) mice. Female SJL/J mice were immunized with myelin proteolipid protein 139–151 (PLP139−151) and pertussis toxin to establish RR-EAE model. Mice were then randomly divided into normal group, model group, PZH group and positive control group (fingolimod, FTY-720), and drugs were orally administered for 60 days from the day 10 after immunization. Sera of mice were collected for ELISA detection. Tissues of CNS were harvested for hematoxylin-eosin (H-E) and luxol fast blue (LFB) staining. Furthermore, Th1, Th17 cells and their related cytokines in the CNS were detected by flow cytometry and quantitative real-time PCR, respectively. Proteins involved in STAT and NF-κB signaling pathways were detected by western blot. The results showed that PZH-treated mice displayed mild or moderate clinical symptoms compared with untreated EAE mice that exhibited severe clinical symptoms. PZH remarkably reduced inflammatory cell infiltration and myelin damage in the CNS of EAE mice. It markedly down-regulated the levels of IFN-γ and IL-17A in sera of EAE mice. Moreover, PZH could reduce the percentages of Th1 and Th17 cells. It also suppressed the production of transcription factors ROR-γt and T-bet as well as the mRNA levels of their downstream pro-inflammatory cytokines, such as IFN-γ and IL-17A. Furthermore, PZH could inhibit the phosphorylation of some key proteins in the STAT and NF-κB signaling pathways. In conclusion, the study demonstrated that PZH had a therapeutic effect on RR-EAE mice, which was associated with the modulation effect on Th1 and Th17 cells

Validation of the children international IgA nephropathy prediction tool based on data in Southwest China

BackgroundImmunoglobulin A nephropathy (IgAN) is one of the most common kidney diseases leading to renal injury. Of pediatric cases, 25%–30% progress into end-stage kidney disease (ESKD) in 20–25 years. Therefore, predicting and intervening in IgAN at an early stage is crucial. The purpose of this study was to validate the availability of an international predictive tool for childhood IgAN in a cohort of children with IgAN treated at a regional medical centre.MethodsAn external validation cohort of children with IgAN from medical centers in Southwest China was formed to validate the predictive performance of the two full models with and without race differences by comparing four measures: area under the curve (AUC), the regression coefficient of linear prediction (PI), survival analysis curves for different risk groups, and R2D.ResultsA total of 210 Chinese children, including 129 males, with an overall mean age of 9.43 ± 2.71 years, were incorporated from this regional medical center. In total, 11.43% (24/210) of patients achieved an outcome with a GFR decrease of more than 30% or reached ESKD. The AUC of the full model with race was 0.685 (95% CI: 0.570–0.800) and the AUC of the full model without race was 0.640 (95% CI: 0.517–0.764). The PI of the full model with race and without race was 0.816 (SE = 0.006, P < 0.001) and 0.751 (SE = 0.005, P < 0.001), respectively. The results of the survival curve analysis suggested the two models could not well distinguish between the low-risk and high-risk groups (P = 0.359 and P = 0.452), respectively, no matter the race difference. The evaluation of model fit for the full model with race was 66.5% and without race was 56.2%.ConclusionsThe international IgAN prediction tool has risk factors chosen based on adult data, and the validation cohort did not fully align with the derivation cohort in terms of demographic characteristics, clinical baseline levels, and pathological presentation, so the tool may not be highly applicable to children. We need to build IgAN prediction models that are more applicable to Chinese children based on their particular data

Investigation on viscosity and non-isothermal crystallization behavior of P-bearing steelmaking slags with varying TiO2 content

The viscous flow and crystallization behavior of CaO-SiO2-MgO-Al2O3-FetO-P2O5-TiO2 steelmaking slags have been investigated over a wide range of temperatures under Ar (High purity, >99.999 pct) atmosphere, and the relationship between viscosity and structure was determined. The results indicated that the viscosity of the slags slightly decreased with increasing TiO2 content. The constructed nonisothermal continuous cooling transformation (CCT) diagrams revealed that the addition of TiO2 lowered the crystallization temperature. This can mainly be ascribed to that addition of TiO2 promotes the formation of [TiO6]-octahedra units and, consequently, the formation of MgFe2O4-Mg2TiO4 solid solution. Moreover, the decreasing viscosity has a significant effect on enhancing the diffusion of ion units, such as Ca2+ and [TiO4]-tetrahedra, from bulk melts to the crystal–melt interface. The crystallization of CaTiO3 and CaSiTiO5 was consequently accelerated, which can improve the phosphorus content in P-enriched phase (n2CaO·SiO2-3CaO·P2O5). Finally, the nonisothermal crystallization kinetics was characterized and the activation energy for the primary crystal growth was derived such that the activation energy increases from −265.93 to −185.41 KJ·mol−1 with the addition of TiO2 content, suggesting that TiO2 lowered the tendency for the slags to crystallize

High mechanical advantage design of six-bar Stephenson mechanism for servo mechanical presses

This article proposed a two-phase design scheme of Stephenson six-bar working mechanisms for servo mechanical presses with high mechanical advantage. In the qualitative design phase, first, a Stephenson six-bar mechanism with a slide was derived from Stephenson six-bar kinematic chains. Second, based on the instant center analysis method, the relationship between mechanical advantage and some special instant centers was founded, and accordingly a primary mechanism configuration with high mechanical advantage was designed qualitatively. Then, a parameterized prototype model was established, and the influences of design parameters toward slide kinematical characteristics were analyzed. In the quantitative design phase, a multi-objective optimization model, aiming at high mechanical advantage and dwelling characteristics, was built, and a case design was done to find optimal dimensions. Finally, simulations based on the software ADAMS were conducted to compare the transmission characteristics of the optimized working mechanism with that of slide-crank mechanism and symmetrical toggle mechanism, and an experimental press was made to validate the design scheme. The simulation and experiment results show that, compared with general working mechanisms, the Stephenson six-bar working mechanism has higher mechanical advantage and better dwelling characteristics, reducing capacities and costs of servo motors effectively

Oxidation Behavior of (Mo,Hf)Si₂-Al₂O₃ Coating on Mo-Based Alloy at Elevated Temperature

To improve the oxidation resistance of Mo-based alloys, a novel (Mo,Hf)Si2-Al2O3 composite coating was fabricated on a Mo-based alloy by the method of slurry sintering. The isothermal oxidation behavior of the coating was evaluated at 1400 °C. The microstructure evolution and phase composition of the coating before and after oxidation exposure were characterized. The anti-oxidant mechanism for the good performance of the composite coating during high-temperature oxidation was discussed. The coating had a double-layer structure consisting of a MoSi2 inner layer and a (Mo,Hf)Si2-Al2O3 outer composite layer. The composite coating could offer more than 40 h of oxidation-resistant protection at 1400 °C for the Mo-based alloy, and the final weight gain rate was only 6.03 mg/cm2 after oxidation. A SiO2-based oxide scale embedded with Al2O3, HfO2, mullite, and HfSiO4 was formed on the surface of the composite coating during oxidation. The composite oxide scale exhibited high thermal stability, low oxygen permeability, and enhanced thermal mismatch between oxide and coating layers, thus improving the oxidation resistance of the coating