During soldering and service, intermetallic compounds (IMCs) have an important impact on the performance and reliability of electronic products. A thin and continuous intermetallic layer facilitates ...the formation of reliable solder joints and improves the creep and fatigue resistance of solder joints. However, if the IMCs overgrow, the coarse IMC becomes brittle and tends to crack under stress, leading to a decrease in solder joint reliability. Based on the latest developments in the field of lead-free solders at home and abroad, this paper comprehensively reviews the interfacial reaction between SnAgCu Pb-free solders and different substrates and the growth behavior of IMCs and clarifies the growth mechanism of interfacial IMCs. The effects of the modification measures of lead-free solder on the IMCs and reliability of SnAgCu/substrate interface are analyzed, which provide a theoretical basis for the development and application of new lead-free solder.
With the development of lead-free solders in electronic packaging, Sn-Cu lead-free solder has attracted wide attention due to its excellent comprehensive performance and low cost. In this article, we ...present recent developments in Sn-Cu lead-free solder alloys. From the microstructure and interfacial structure, the evolution law of the internal structure of solder alloy/solder joint was analysed, and the model and theory describing the formation/growth mechanism of interfacial IMC were introduced. In addition, the effects of alloying, particle strengthening and process methods on the properties of Sn-Cu lead-free solders, including wettability, melting and mechanical properties, were described. Finally, we outline the issues that need to be resolved in the future research.
This figure presents the interface morphology of Sn-Cu-Ni-xPr joint. (a) x = 0, (b) x = 0.05wt%. It was clear that with the addition of 0.05% Pr, the thickness of IMC layer decreases significantly and the formation of voids at the interface is inhibited.
Electronic products are evolving towards miniaturization, high integration, and multi-function, which undoubtedly puts forward higher requirements for the reliability of solder joints in electronic ...packaging. Approximately 70% of failure in electronic devices originates during the packaging process, mostly due to the failure of solder joints. With the improvement of environmental protection awareness, lead-free solder joints have become a hot issue in recent years. This paper reviews the research progress on the reliability of lead-free solder joints and discusses the influence of temperature, vibration, tin whisker and electromigration on the reliability of solder joints. In addition, the measures to improve the reliability of solder joints are analyzed according to the problems of solder joints themselves, which provides a further theoretical basis for the study of the reliability of solder joints of electronic products in service.
Extensive studies during the past four decades have identified important roles for lysine acetylation in the regulation of nuclear transcription. Recent proteomic analyses on protein acetylation ...uncovered a large number of acetylated proteins in the cytoplasm and mitochondria, including most enzymes involved in intermediate metabolism. Acetylation regulates metabolic enzymes by multiple mechanisms, including via enzymatic activation or inhibition, and by influencing protein stability. Conversely, non-nuclear NAD
+-dependent sirtuin deacetylases can regulate cellular and organismal metabolism, possibly through direct deacetylation of metabolic enzymes. Furthermore, acetylation of metabolic enzymes is highly conserved from prokaryotes to eukaryotes. Given the frequent occurrence of metabolic dysregulation in diabetes, obesity and cancer, enzymes modulating acetylation could provide attractive targets for therapeutic intervention for these diseases.
Ultrasonic shot peening (USP) is a surface engineering technology used to enhance the mechanical properties of the components during manufacturing. M50 steel is one of the commonly used materials for ...aerospace bearings. In this study, surface nanocrystallization of the high-strength M50 bearing steel is performed at room temperature via USP technology. The materials characterizations show that the thickness of the lath martensite in the M50 bearing steel has been refined down to 10 nm. The extremely fine nanostructured M50 martensite increases the mechanical strength significantly at the nanoscale. Nanoindentation tests show that the nanohardness of the nanostructured M50 is 12.43 GPa, which is 38% higher than that of the as-received matrix materials with a value of 9.03 GPa. Additionally, the microstructure evolution of the M50 during the USP process is investigated and the grain refinement mechanism for M50 is revealed. EBSD characterization results confirm the transformation of the low angle grain boundaries to high angle grain boundaries and the formation of the equiaxed ultrafine grains. The decomposition of the carbides in the M50 during grain refinement is observed. This indicates that in addition to the diffusion of C, the decomposition of the carbides is also influenced by carbide-forming elements. This work deepens the current understanding of the grain refinement of the M50 bearing steel during the USP process and its mechanical strengthening at the nanoscale.
Background
NASH is one of the fastest growing liver diseases that leads to severe steatosis, inflammation and ultimately liver injury. However, the pathophysiological mechanisms of NASH remain ...unclear and pharmacological treatment against the disease is unavailable currently. Ferroptosis is a non‐apoptotic form of cell death induced by iron‐dependent lipid peroxidation. Since NASH progression is accompanied by massive lipid accumulation, which generates lipotoxic species, we investigated the role of ferroptosis in NASH progression.
Method
Mice were fed on MCD‐diet to mimic NASH progression and gene expression in liver was analysed by RNA‐seq. The occurrence of hepatic ferroptosis was measured by lipid ROS level, electron microscopy and in vivo PI staining. The beneficial effects of ferroptosis inhibitors on NASH was evaluated by liver pathology analysis. The mechanism of lipid ROS induced lipid droplets accumulation was investigated by in vitro cell culture.
Results
RNA‐seq analysis suggested that elevated arachidonic acid metabolism promotes ferroptosis in MCD‐diet fed mouse livers, which was further demonstrated by lipid ROS accumulation, morphological change of mitochondria and increased cell death. Iron accumulation was detected in the liver and the serum of MCD‐fed mice. Scavenging of ferroptosis‐linked lipid peroxides reduced lipid accumulation both in vivo and in vitro. Importantly, ferroptosis inhibitors alleviated MCD‐diet induced inflammation, fibrogenesis and liver injury. Finally, lipid ROS promotes liver steatosis by boosting lipid droplets formation.
Conclusion
Our results demonstrate an important role of ferroptosis in the progression of MCD‐diet induced NASH and suggest that ferroptosis may serve as a therapeutic target for NASH treatment.
Anaplastic lymphoma kinase (ALK) activation has been associated with many types of human cancer. Significant efforts have been devoted to the development of ALK inhibitors to antagonize the kinase ...activity of ALK. Four ALK inhibitors have been approved by the FDA to date for treating patients with ALK-positive non-small cell lung cancers (NSCLC). However, drug resistance has been observed in the majority of patients treated with these inhibitors. New therapeutic strategies (e.g., compounds with novel mechanisms of action) are needed to overcome the drug resistance issue. The emerging PROTAC (Proteolysis Targeting Chimera) technology has been successfully applied to selective degradation of multiple protein targets, but not ALK. Since ALK protein levels are not important for viability in mammals, ALK PROTACs could lead to novel therapeutics with minimal toxicity. Here we report the design, synthesis and biological evaluation of novel PROTACs (degraders) of ALK. MS4077 (5) and MS4078 (6) potently decreased cellular levels of oncogenic active ALK fusion proteins in a concentration- and time-dependent manner in SU-DHL-1 lymphoma and NCI-H2228 lung cancer cells. The ALK protein degradation induced by compounds 5 and 6 was cereblon and proteasome dependent. In addition, compounds 5 and 6 potently inhibited proliferation of SU-DHL-1 cells. Furthermore, compound 6 displayed good plasma exposure in a mouse pharmacokinetic study, thus is suitable for in vivo efficacy studies. We also developed MS4748 (7) and MS4740 (8), very close analogs of 5 and 6 respectively, which are incapable to degrade the ALK fusion proteins, as negative controls. Compounds 5–8 are valuable chemical tools for investigating effects of ALK pharmacological degradation. Our study paved the way for developing the next generation of ALK PROTACs.
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•We discovered novel ALK PROTACs (MS4077 and MS4078) and their close analogs as negative controls.•MS4077 and MS4078 potently reduced cellular ALK protein levels in a cereblon and proteasome dependent manner.•MS4077 and MS4078 potently inhibited cellular ALK signaling.•MS4077 and MS4078 effectively inhibited cancer cell proliferation.•MS4078 displayed good plasma exposure in mice, thus is suitable for in vivo efficacy studies.
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with onset in childhood. The mechanisms underlying ASD are unclear. In recent years, the role of microglia and astrocytes in ASD ...has received increasing attention. Microglia prune the synapses or respond to injury by sequestrating the injury site and expressing inflammatory cytokines. Astrocytes maintain homeostasis in the brain microenvironment through the uptake of ions and neurotransmitters. However, the molecular link between ASD and microglia and, or astrocytes remains unknown. Previous research has shown the significant role of microglia and astrocytes in ASD, with reports of increased numbers of reactive microglia and astrocytes in postmortem tissues and animal models of ASD. Therefore, an enhanced understanding of the roles of microglia and astrocytes in ASD is essential for developing effective therapies. This review aimed to summarize the functions of microglia and astrocytes and their contributions to ASD.
Isocitrate dehydrogenases (IDH1/2) are frequently mutated in multiple types of human cancer, resulting in neomorphic enzymes that convert α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). The ...current view on the mechanism of IDH mutation holds that 2-HG acts as an antagonist of α-KG to competitively inhibit the activity of α-KG-dependent dioxygenases, including those involved in histone and DNA demethylation. Recent studies have implicated 2-HG in activities beyond epigenetic modification. Multiple enzymes have been discovered that lack mutations but that can nevertheless produce 2-HG promiscuously under hypoxic or acidic conditions. Therapies are being developed to treat IDH-mutant cancers by targeting either the mutant IDH enzymes directly or the pathways sensitized by 2-HG.
Many enzymes can promiscuously produce 2-HG by side reactions, causing pathologically significant concentrations of 2-HG in cells lacking IDH mutations.
Metabolic and stress conditions such as T cell activation or hypoxia can promote enzyme promiscuity to produce 2-HG.
In addition to histone and DNA demethylases, 2-HG can impair the activity of other α-KG-dependent dioxygenases and their associated cellular pathways, such as DNA repair.
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