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Abstract: A double-variable decoupling control scheme was proposed for GMAW-P process of aluminum helping to efficiently develop welding procedure. Weld pool width and arc length were both measured through vision sensing in welding process. Weld bead shape was improved by changing the current waveforms to adjust the heat input while the arc length was controlled to stabilize the welding process. An experimental system was developed to sense, observe and control the welding process real-timely. Experiments were conducted to verify the effectiveness of the scheme. The results show that good weld bead shape and stable welding process can be obtained through the double-variable decoupling control scheme without complex metal transfer control and considerable trial and error to identify suitable combinations of welding parameters in GMAW-P. This control scheme provides an alternative to obtain proper weld quality for GMAW-P. [Copyright &y& Elsevier]

B-cell acute lymphoblastic leukemia (B-ALL) is the most prevalent malignant tumor affecting children. While the majority of B-ALL patients (90%) experience successful recovery, early relapse cases of B-ALL continue to exhibit high mortality rates. MZ1, a novel inhibitor of Bromodomains and extra-terminal (BET) proteins, has demonstrated potent antitumor activity against hematological malignancies. The objective of this study was to examine the role and therapeutic potential of MZ1 in the treatment of B-ALL. In order to ascertain the fundamental mechanism of MZ1, a sequence of in vitro assays was conducted on B-ALL cell lines, encompassing Cell Counting Kit 8 (CCK8) assay, Propidium iodide (PI) staining, and Annexin V/PI staining. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to examine protein and mRNA expression levels. Transcriptomic RNA sequencing (RNA-seq) was utilized to screen the target genes of MZ1, and lentiviral transfection was employed to establish stably-expressing/knockdown cell lines. MZ1 has been observed to induce the degradation of Bromodomain Containing 4 (BRD4), Bromodomain Containing 3 (BRD3), and Bromodomain Containing 2 (BRD2) in B-ALL cell strains, leading to inhibited cell growth and induction of cell apoptosis and cycle arrest in vitro. These findings suggest that MZ1 exhibits cytotoxic effects on two distinct molecular subtypes of B-ALL, namely 697 (TCF3/PBX1) and RS4;11 (MLL-AF4) B-ALL cell lines. Additionally, RNA-sequencing analysis revealed that MZ1 significantly downregulated the expression of Cyclin D3 (CCND3) gene in B-ALL cell lines, which in turn promoted cell apoptosis, blocked cell cycle, and caused cell proliferation inhibition. Our results suggest that MZ1 has potential anti-B-ALL effects and might be a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Background. Arising from T progenitor cells, T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignant tumor, accounting for 15% of childhood ALL and 25% of adult ALL. Composing of putative enhancers in close genomic proximity, super enhancer (SE) is critical for cell identity and the pathogenesis of multiple cancers. Belonging to the cytosolute linker protein group, FYB1 is essential for TCR signaling and extensively studied in terms of tumor pathogenesis and metastasis. Dissecting the role of FYN binding protein 1 (FYB1) in T-ALL holds the potential to improve the treatment outcome and prognosis of T-ALL. Methods. In this study, SEs were explored using public H3K27ac ChIP-seq data derived from T-ALL cell lines, AML cell lines and hematopoietic stem and progenitor cells (HSPCs). Downstream target of FYB1 gene was identified by RNA-seq. Effects of shRNA-mediated downregulation of FYB1 and immunoglobulin lambda-like polypeptide 1 (IGLL1) on self-renewal of T-ALL cells were evaluated in vitro and/or in vivo. Results. As an SE-driven gene, overexpression of FYB1 was observed in T-ALL, according to the Cancer Cell Line Encyclopedia database. In vitro, knocking down FYB1 led to comprised growth and enhanced apoptosis of T-ALL cells. In vivo, downregulation of FYB1 significantly decreased the disease burden by suppressing tumor growth and improved survival rate. Knocking down FYB1 resulted in significantly decreased expression of IGLL1 that was also an SE-driven gene in T-ALL. As a downstream target of FYB1, IGLL1 exerted similar role as FYB1 in inhibiting growth of T-ALL cells. Conclusion. Our results suggested that FYB1 gene played important role in regulating self-renewal of T-ALL cells by activating IGLL1, representing a promising therapeutic target for T-ALL patients. [ABSTRACT FROM AUTHOR]

Background: AML (acute myeloid leukemia) is a common hematological malignancy in children with poor treatment effects and poor prognosis. Recent studies have shown that as a novel BRD4 (bromodomain containing 4) PROTACs (proteolysis targeting chimeras) degrader, GNE-987 can slow down the growth of various tumors and increase apoptosis, with promising clinical prospects. However, the function and molecular mechanism of GNE-987 in AML remain unclear. This study is aimed at investigating the therapeutic effect of GNE-987 on AML and its underlying mechanism.Methods: The association between BRD4 and AML was assessed by studying public databases. After GNE-987 was added to AML cells, cell proliferation slowed down, the cycle was disturbed, and apoptosis increased. Western blotting was used to detect BRD2 (bromodomain containing 2), BRD3 (bromodomain containing 3), BRD4, and PARP (poly ADP-ribose polymerase) proteins. The effect of GNE-987 on AML cells was analyzed in vivo. RNA-seq (RNA sequencing) and ChIP-seq (chromatin immunoprecipitation sequencing) validated the function and molecular pathways of GNE-987 in processing AML.Results: BRD4 expression was significantly elevated in pediatric AML samples compared with healthy donors. GNE-987 inhibited AML cell proliferation by inhibiting the cell cycle and inducing apoptosis. BRD2, BRD3, and BRD4 were consistent with decreased VHL (Von Hippel Lindau) expression in AML cells. In an AML xenograft model, GNE-987 significantly reduced the hepatosplenic infiltration of leukemia cells and increased the mouse survival time. Based on analysis of RNA-seq and ChIP-seq analyses, GNE-987 could target multiple SE- (super-enhancer-) related genes, including LYL1 (lymphoblastic leukemia 1), to inhibit AML.Conclusions: GNE-987 had strong antitumor activity in AML. GNE-987 could effectively inhibit the expression of SE-related oncogenes including LYL1 in AML. Our results suggested that GNE-987 had broad prospects in the treatment of AML. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a highly cancerous and aggressive hematologic disease with elevated levels of drug resistance and relapse resulting in high mortality. Recently, bromodomains and extra-terminal (BET) protein inhibitors have been extensively researched in hematological tumors as potential anticancer agents. MZ1 is a novel BET inhibitor that mediates selective proteins degradation and suppression of tumor growth through proteolysis-targeting chimeras (PROTAC) technology. Accordingly, this study aimed to investigate the role and therapeutic potential of MZ1 in AML. In this study, we first identified that AML patients with high BRD4 expression had poor overall survival than those with low expression group. MZ1 inhibited AML cell growth and induced apoptosis and cycle arrest in vitro. MZ1 induced degradation of BRD4, BRD3 and BRD2 in AML cell strains. Additionally, MZ1 also initiated the cleavage of poly-ADP-ribose polymerase (PARP), which showed cytotoxic effects on NB4 (PML-RARa), K562 (BCR-ABL), Kasumi-1 (AML1-ETO), and MV4-11 (MLL-AF4) cell lines representing different molecular subtypes of AML. In AML mouse leukemia model, MZ1 significantly decreased leukemia cell growth and increased the mouse survival time. According to the RNA-sequencing analysis, MZ1 led to c-Myc and ANP32B genes significant downregulation in AML cell lines. Knockdown of ANP32B promoted AML cell apoptosis and inhibited cell growth. Overall, our data indicated that MZ1 had broad anti-cancer effects on AML cell lines with different molecular lesions, which might be exploited as a novel therapeutic strategy for AML patients. [ABSTRACT FROM AUTHOR]

An integrated study using cathodoluminescence (CL) images, U–Pb geochronology, and Hf isotopic characterization of zircons was performed on migmatites from the Yuka terrane to provide insights into the timing and nature of the protoliths, metamorphism, and partial melting of these rocks. Zircon grains separated from the migmatites have three distinct domains. Residual zircon cores in samples YKT01 and YKT02 exhibit oscillatory zoning, high Th/U ratios (0.10–0.79), steep heavy rare earth element (HREE) patterns, and mean ages of 936 ± 5 Ma and 927 ± 11 Ma, respectively, indicating that they are igneous in origin and record Neoproterozoic magmatism during the Grenvillian Orogeny. CL‐grey cores record an ultrahigh‐pressure (UHP) peak metamorphism age of 435 ± 5 Ma and have low Th/U and 176Lu/177Hf ratios, weak negative Eu anomalies, and relatively flat HREE patterns. The CL‐bright rims have steep HREE patterns with lower middle rare earth element (MREE) concentrations but higher HREE concentrations compared with the metamorphic cores and a weighted average age of 422 ± 4 Ma, which records the timing of melt crystallization. The migmatites incorporate garnet relicts coexisting with fluid inclusions and hydrous minerals like peritectic phengite and peritectic large anhedral poikilitic tourmaline in the leucosomes. Peak temperatures are less than 750°C, suggesting that the anatectic melts may be derived from melting of felsic gneiss in the presence of water. The timing of melt crystallization is ca. 13 Ma later than UHP metamorphism, indicating that the partial melting took place during the exhumation stage. The metamorphic zircon cores have higher 176Hf/177Hf(t) ratios than the residual magmatic cores, which provides powerful evidence for the generation of the metamorphic zircons through the incorporation of internal high Hf minerals other than zircon in a closed system. Anatectic rims with lower 176Hf/177Hf(t) ratios but higher 176Lu/177Hf ratios than metamorphic cores suggest that the main formation mechanism is dissolution‐reprecipitation of pre‐existing zircons. In conclusion, the elevated 176Hf/177Hf(t), TDM2 age and decreasing 176Lu/177Hf(t) ratios in the metamorphic and anatectic domains imply that the new zircons in some migmatites and granites may not reflect the Hf isotope compositions of their source rocks, accounting for the variable Hf isotope compositions in S‐type granites. [ABSTRACT FROM AUTHOR]