Delamination of Plasticized Devices in Dynamic Service Environments.

With the continuous development of advanced packaging technology in heterogeneous semiconductor integration, the delamination failure problem in a dynamic service environment has gradually become a key factor limiting the reliability of packaging devices. In this paper, the delamination failure mechanism of polymer-based packaging devices is clarified by summarizing the relevant literature and the latest research solutions are proposed. The results show that, at the microscopic scale, thermal stress and moisture damage are still the two main mechanisms of two-phase interface failure of encapsulation devices. Additionally, the application of emerging technologies such as RDL structure modification and self-healing polymers can significantly improve the thermal stress state of encapsulation devices and enhance their moisture resistance, which can improve the anti-delamination reliability of polymer-based encapsulation devices. In addition, this paper provides theoretical support for subsequent research and optimization of polymer-based packages by summarizing the microscopic failure mechanism of delamination at the two-phase interface and introducing the latest solutions.

Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells.

Chimeric antigen receptor (CAR)-T therapy requires autologous T lymphocytes from cancer patients, a process that is both costly and complex. Universal CAR-T cell treatment from allogeneic sources can overcome this limitation but is impeded by graft-versus-host disease (GvHD) and host versus-graft rejection (HvGR). Here, we introduce a mutated calcineurin subunit A (CNA) and a CD19-specific CAR into the T cell receptor α constant (TRAC) locus to generate cells that are resistant to the widely used immunosuppressant, cyclosporine A (CsA). These immunosuppressant-resistant universal (IRU) CAR-T cells display improved effector function in vitro and anti-tumour efficacy in a leukemia xenograft mouse model in the presence of CsA, compared with CAR-T cells carrying wild-type CNA. Moreover, IRU CAR-T cells retain effector function in vitro and in vivo in the presence of both allogeneic T cells and CsA. Lastly, CsA withdrawal restores HvGR, acting as a safety switch that can eliminate IRU CAR-T cells. These findings demonstrate the efficacy of CsA-resistant CAR-T cells as a universal, 'off-the-shelf' treatment option.

Single-cell analysis reveals HBV-specific PD-1+CD8+ TRM cells in tumor borders are associated with HBV-related hepatic damage and fibrosis in HCC patients.

Immune checkpoint blockade (ICB) treatment of hepatocellular carcinoma (HCC) patients with hepatitis B virus (HBV) infection may activate viral-specific T cells to attack HBV infected hepatocytes and thus induce immune-related liver injury. Therefore, it is important to deeply understand the impacts of HBV infection on HCC immune microenvironment in order to better design effective immunotherapies for HBV+ (HBV infected) HCC patients. Here, We performed cytometry by time-of-flight (CyTOF) analyses to characterize the distinct immune compositions of HCC tumors, tumor borders, and their associations with HCC/HBV related clinical characteristics. We identified 31 distinct immune clusters and found significant associations between immune signatures with clinicopathological features of HCC. We further revealed the HBV infection had more effects on shaping immune compositions in tumor borders than in tumors, with the significant enrichment of HBV-specific PD-1+CD8+ tissue-resident memory T (TRM) cells in tumor borders of HBV+ patients. We confirmed this subset with a more exhausted phenotype and respond more actively under anti-PD-L1 treatment, suggesting its involvement in immune-related liver injury induced by ICB treatment to HBV+ HCC patients. Our study shows it may be necessary to consider antiviral prophylaxis for HBV+ HCC patients receiving ICB treatment.

Intermediate occupation numbers for 5f electrons in a Pu and U mixed oxide.

In order to reveal the correlation effect on the electronic properties in particular 5f electron occupation numbers of Pu/U ions in a (Pu,U) mixed oxide-PuUO4, a first principles calculation is performed by using density functional theory (DFT) plus a dynamical mean field theory (DMFT) scheme with the spin-orbit coupling (SOC) and on-site Coulomb repulsion for correlation effect due to localized Pu/U 5f orbitals. Results demonstrate that Pu/U 5f electron occupation numbers in the ground state of PuUO4 are mainly composed of 5f4/5f5 and 5f2/5f3 configurations, and exhibiting the intermediate occupation (IO) numbers with average 5f occupation numbers of about nf = 4.879 and 2.423 for Pu and U ions, respectively, irrespective of different Pu and U lattice sites in PuUO4. Pu 5f j = 5/2 and j = 7/2 components are in moderately and weakly correlated states, respectively, while U 5f j = 5/2 and j = 7/2 manifolds are both in weakly correlated states. jj and LS coupling schemes are feasible for Pu and U 5f electrons, respectively. In order to directly compare with the experimental angle-resolved photoemission spectrum (ARPES), we also estimate the momentum-resolved electronic spectrum function for this system.

Effects of chronic HBV infection on lipid metabolism in non-alcoholic fatty liver disease: A lipidomic analysis.

INTRODUCTION AND OBJECTIVES: Chronic hepatitis B virus (HBV) infection exerts an impact on lipid metabolism, but its interaction with dysmetabolism-based non-alcoholic fatty liver disease (NAFLD) remains uncertain. The purpose of the study was to investigate the effects of HBV infection on lipid metabolism, hepatic steatosis and related impairments of NAFLD patients. METHODS: Biopsy-proven Chinese NAFLD patients with (NAFLD-HBV group, n = 21) or without chronic HBV infection (NAFLD group, n = 41) were enrolled in the case-control study. Their serum lipidomics was subjected to individual investigation by ultra-performance liquid chromatography-tandem mass spectrometry. Steatosis, activity, and fibrosis (SAF) scoring revealed the NAFLD-specific pathological characteristics. RESULTS: Chronic HBV infection was associated with global alteration of serum lipidomics in NAFLD patients. Upregulation of phosphatidylcholine (PCs), choline plasmalogen (PC-Os) and downregulation of free fatty acids (FFAs), lysophosphatidylcholine (LPCs) dominated the HBV-related lipidomic characteristics. Compared to those of NAFLD group, the levels of serum hepatoxic lipids (FFA16:0, FFA16: 1, FFA18:1, FFA18:2) were significantly lowered in the NAFLD-HBV group. These low-level FFAs demonstrated correlation to statistical improvements in aspartate aminotransferase activity (FFA16:0, r = 0.33; FFA16:1, r = 0.37; FFA18:1, r = 0.32; FFA18:2, r = 0.42), hepatocyte steatosis (FFA16: 1, r = 0.39; FFA18:1, r = 0.39; FFA18:2, r = 0.32), and ballooning (FFA16:0, r = 0.30; FFA16:1, r = 0.45; FFA18:1, r = 0.36; FFA18:2, r = 0.30) (all P < 0.05). CONCLUSION: Chronic HBV infection may impact on the serum lipidomics and steatosis-related pathological characteristics of NAFLD.

PNPLA3 rs139051 is associated with phospholipid metabolite profile and hepatic inflammation in nonalcoholic fatty liver disease.

AIM: To investigate the effect of PNPLA3 polymorphisms on serum lipidomics and pathological characteristics in nonalcoholic fatty liver disease (NAFLD). METHODS: Thirty-four biopsy-proven NAFLD patients from Northern, Central, and Southern China were subjected to stratification by genotyping their single nucleotide polymorphisms (SNPs) in PNPLA3. Ultra performance liquid chromatographytandem mass spectrometry was then employed to characterize the effects of PNPLA3 SNPs on serum lipidomics. In succession, correlation analysis revealed the association of PNPLA3-related lipid profile and hepatic pathological characteristics on a basis of steatosis, activity, and fibrosis assessment. The variant-based scoring of hepatocyte steatosis, ballooning, lobular inflammation, and liver fibrosis was finally performed so as to uncover the actions of lipidomics-affecting PNPLA3 SNPs in NAFLD-specific pathological alterations. RESULTS: PNPLA3 SNPs (rs139051, rs738408, rs738409, rs 2072906, rs2294918, rs2294919, and rs4823173) demonstrated extensive association with the serum lipidomics, especially phospholipid metabolites [lysophosphatidylcholine (LPC), lysophosphatidylcholine plasmalogen (LPCO), lysophosphatdylethanolamine (LPE), phosphatidylcholine (PC), choline plasmalogen (PCO), phosphatidylethanolamine (PE), ethanolamine plasmalogen (PEO)], of NAFLD patients. PNPLA3 rs139051 (A/A genotype) and rs2294918 (G/G genotype) dominated the up-regulatory effect on phospholipids of LPCs (LPC 17:0, LPC 18:0, LPC 20:0, LPC 20:1, LPC 20:2) and LPCOs (LPC O-16:1, LPC O-18:1). Moreover, subjects with high-level LPCs/LPCOs were predisposed to low-grade lobular inflammation of NAFLD (rho: -0.407 to -0.585, P < 0.05-0.001). The significant correlation of PNPLA3 rs139051 and inflammation grading [A/A vs A/G + G/G: 0.50 (0.00, 1.75) vs 1.50 (1.00, 2.00), P < 0.05] further demonstrated its pathological role based on the modulation of phospholipid metabolite profile. CONCLUSION: The A/A genotype at PNPLA3 rs139051 exerts an up-regulatory effect on serum phospholipids of LPCs and LPCOs, which are associated with low-grade lobular inflammation of NAFLD.

Exosomes in the Oncobiology, Diagnosis, and Therapy of Hepatic Carcinoma: A New Player of an Old Game.

Exosomes are emerging as essential vehicles mediated cross-talk between different types of cells in tumor microenvironment. The extensive exploration of exosomes in hepatocellular carcinoma (HCC) enhances our comprehension of cancer biology referring to tumor growth, metastasis, immune evasion, and chemoresistance. Besides, the versatile roles of exosomes provide reasonable explanations for the propensity for liver metastasis of gastric cancer, pancreatic ductal adenocarcinoma, breast cancer, and colorectal cancer. The selective-enriched components, especially some specific proteins and noncoding RNAs in exosomes, have great potential as noninvasive biomarkers of HCC with high sensitivity and specificity. The characteristics of exosomes further inspire frontier research to interrupt intercellular malignant signals by controlling the biogenesis, release, or contents of exosomes.