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Simple Summary: This study explores using engineered Myxoma virues (MyxV) encoding CD47 and IFN-γ to fight tumors and boost immune responses in the tumor environment. The findings show that the modified MyxV effectively infects and kills cancer cells, triggers immune responses, and reduces immune-suppressing cells. The dual-armed MyxV increases the presence and activity of T-cells in tumors. When combined with αPD-L1, a known immune therapy, MyxV effectively slows tumor growth and extends survival. These results highlight MyxV's potential as an oncolytic therapy. Further research to enhance its therapeutic efficacy and to determine anti-tumoral mechanisms, will offer a promising avenue for cancer treatment. Myxoma virus (MyxV) is a rabbit-specific poxvirus. However, its ability to selectively target tumor cells has established it as a safe and effective anticancer therapy. To strengthen its preclinical efficacy, transgenes that can prolong cancer cell infection and enhance anti-tumor effector functions are currently being investigated. We engineered MyxV armed with CD47, to turn on a 'do not eat me' signal within infected cells with actively replicating viruses, and with IFN-γ to further activate host immune anticancer responses. Tumor suppressive activities were significantly enhanced by the dual-armed MyxV_CD47/IFN-γ compared to parental MyxV or single-armed MyxV_CD47 or MyxV_IFN-γ. In addition, significant increases in IFN-γ+ CD8+T-cells and CD4+ T-cells populations within tumor-infiltrating lymphocytes (TIL) were observed after MyxV_CD47/IFN-γ treatment. Notably, all groups treated with MyxV showed a marked reduction in Foxp3+ CD4+ regulatory T-cells (Tregs) within TIL. We also show that MyxV infection induces PD-L1 up-regulation in cancer cells, and combinational treatment of MyxV with anti-mouse PD-L1 antibodies (αPD-L1) further controlled tumor burden and increased survival in the syngeneic melanoma model B16F10. Our data demonstrate that a CD47 and IFNγ dual-armed MyxV is an effective oncolytic viral immunotherapeutic. These findings strongly support further preclinical investigations to develop next-generation MyxV-based immunotherapy approaches. [ABSTRACT FROM AUTHOR]

This work aims to fabricate a large-area ceramic substrate for the application of probe cards. Mullite (M) and cordierite (C), which both have a low thermal expansion coefficient, excellent resistance to thermal shock, and high durability, were selected as starting powders. The mullite–cordierite composites were produced through different composition ratios of starting powders (M:C = 100:0, M:C = 90:10, M:C = 70:30, M:C = 50:50, M:C = 30:70, and M:C = 0:100). The effects of composition ratio and sintering temperature on the density, porosity, thermal expansion coefficient, and flexural strength of the mullite–cordierite composite pellets were investigated. The results showed that the mullite–cordierite composite pellet containing 70 wt% mullite and 30 wt% cordierite sintered at 1350 °C performed exceptionally well. Based on these findings, a large-area mullite–cordierite composite substrate with a diameter of 320 mm for use in semiconductor probe cards was successfully fabricated. Additionally, the changes in sheet resistance and flexural strength were measured to determine the effect of the environmental tests on the large-area substrate such as damp heat and thermal shock. The results indicated that the mullite–cordierite composite substrate was extremely reliable and durable. [ABSTRACT FROM AUTHOR]

The deposition behavior of copper particles during the aerosol deposition (AD) process was predicted according to the particle velocity via a numerical model. Plastic deformation of Cu particles was predicted by a cumulative effect among the injected carrier gas consumption, particle velocity, internal energy, compressive strain, and heat-induced thermal softening of the particle. Besides, there is possibility on oxidation of copper, which is influence on increase of electrical resistivity, caused by the induced heat. To compare the simulation results and understand the actual deposition behavior of Cu particles, Cu films were fabricated through AD using subdivided gas consumptions. The microstructure was confirmed by both the plastic strain through the Williamson–Hall plot and the strain results by the simulation. From the simulation and X-ray analysis, the characteristic of induced heat was analyzed to demonstrate the influence on oxidation, and to obtain suitable AD condition for low resistivity of Cu film. [ABSTRACT FROM AUTHOR]

Akt and p70 ribosomal S6 kinase (p70s6k) play a critical role in regulation of skeletal muscle mass in response to a variety of mechanical stimuli. However, the regulation of these molecules under decreased muscle usage has rarely been investigated according to skeletal muscle types that affect the rate of disuse muscle atrophy. This study was conducted in rats to elucidate the responses of Akt and p70s6k phosphorylation to ankle immobilization in different types of plantar flexors and its association with the muscle atrophy rate in the muscles. The results revealed that the rate of muscle atrophy in response to ten days of ankle immobilization was significantly less in the plantaris (PL) and gastrocnemius, which could not be completely immobilized with the ankle fixation, than in the soleus (SOL) (P<0.05). In accordance with these findings, the decrease in phosphorylation of p70s6k (T389) that was observed in SOL (P<0.001) was not observed in PL, and its level even increased in fast-twitch white gastrocnemius (WG) (P<0.05). However, phosphorylation of Akt (S473) was lower in all three muscles in response to immobilization treatment. The Akt-independent phosphorylations of p70s6k in PL and WG were further confirmed by the decreased phosphorylation of Akt (T308) and GSK3α. These results suggest that the skeletal muscle type-specific different rates of muscle atrophy that occur during ankle immobilization may be mediated by p70s6k, which responds differently in the distinct types of skeletal muscle. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) has been deeply associated with visceral adiposity, adipose tissue inflammation and a variety of adipocytokines. We reported previously that genistein inhibited NAFLD by enhancing fatty acid catabolism. However, this molecular approach focused on hepatic metabolism. Thus, we have attempted to determine whether this anti-steatotic effect of genistein is linked to visceral adipocyte metabolism. C57BL/6J mice were fed on normal-fat (NF) diet, high-fat (HF) diet and HF diet supplemented with genistein (1, 2 and 4 g/kg diet) for 12 weeks. Mice fed on the HF diet gained body weight, exhibited increased visceral fat mass and elevated levels of serum and liver lipids, and developed NAFLD, unlike what was observed in mice fed on the NF diet. However, genistein supplementation (2 and 4 g/kg diet) normalised these alternations. In the linear regression analysis, visceral fat (R 0·77) and TNFα (R 0·62) were strongly correlated with NAFLD among other NAFLD-related parameters. Genistein supplementation suppressed the hypertrophy of adipocytes via the up-regulation of genes involved in fatty acid β-oxidation, including PPARα, 5′-AMP-activated protein kinase and very long-chain acyl CoA dehydrogenase, as well as through the down-regulation of genes associated with adipogenesis or lipogenesis, including liver X receptor-α, sterol-regulatory element-binding protein-1c, PPARγ, retinoid X receptor-α and acetyl CoA carboxylase 2. Moreover, genistein supplementation augmented an anti-steatohepatitic adiponectin TNF and reduced a steatohepatitic TNFα. Collectively, these findings show that genistein may prevent NAFLD via the regulation of visceral adipocyte metabolism and adipocytokines. [ABSTRACT FROM PUBLISHER]

Abstract: AIMP1 (also known as p43) is a factor associated with a macromolecular aminoacyl-tRNA synthetase (ARS) complex but also plays diverse regulatory roles in various physiological processes. Here, we report that AIMP1 negatively regulates TGF-β signaling via stabilization of Smurf2. TGF-β-dependent phosphorylation and nuclear localization of R-Smads, induction of target genes, and growth arrest were increased in AIMP1-deficient or -suppressed cells. In AIMP1-deficient or suppressed cells, the Smurf2 level was decreased. Various binding assays demonstrated the direction interaction of the C-terminal region of AIMP1 directly with the Smad7-binding region of Smurf2. The association of Smurf2 with Smad7 and its ubiquitination were inhibited by AIMP1, thereby protecting its autocatalytic degradation stimulated by Smad7. Thus, this work suggests the novel activity of AIMP1 as a component of negative feedback loop of TGF-β signaling. [Copyright &y& Elsevier]

Abstract: We have performed virtual screening of a chemical database of 508,143 commercially available chemicals to search for new methionyl-tRNA synthetase (MetRS) inhibitors. In this study, potent lead compounds with a novel skeleton, including compound 27 with IC50 =237nM, were successfully identified as Escherichia coli MetRS inhibitors. [Copyright &y& Elsevier]

1. Semi-synthetic diets containing 200 g protein/kg were meal-fed for 1.5 h to groups of rats. The contents of the whole small intestinal tract were collected and the amount of soluble calcium was determined.2. In the rats given 200 g casein/kg diet, formation of a fraction containing macrophosphopeptide in the small intestine was confirmed by gelfiltration of the intestinal contents on Sephadex G-25. However, this macrophosphopeptide fraction was not found when casein alone was fed.3. In the intestinal contents at 2.5 h after ingestion, the amounts of both soluble Ca and phosphorus were significantly higher in rats fed the casein diet than in those fed diets containing egg albumin, isolated soyabean protein or an amino acid mixture. However, the amount of insoluble Ca was least in rats fed the casein diet. [ABSTRACT FROM PUBLISHER]

Abstract: We explored the association between the degree of adherence to recommendations and diabetes management in Korean adults who had type 2 diabetes for an average of 8 years. Subjects who met five or more lifestyle recommendations showed significantly lower blood lipid parameters and glycated hemoglobin than those who did not. [Copyright &y& Elsevier]

To understand the molecular mechanisms underlying alterations in the pathophysiologic status of dietary obesity, we examined hepatic genes differentially expressed in a long-term high-fat intake-induced obesity mouse model. C57BL/6J male mice were fed with two kinds of diets for 12 weeks; a low-fat diet (LFD), a high-fat diet (HFD; n=8), and the expression levels of ∼10,000 transcripts in liver tissues from the two groups were assessed using cDNA microarray analysis. Twelve-week feeding with the HFD resulted in significant increase in body weight, visceral fat accumulation and circulating cholesterol concentration, compared with the LFD group. The cDNA microarray analysis revealed marked differences in the expressions of 97 hepatic genes. These genes were categorized into seven groups:The expression of genes involved in fatty acid catabolism and ketone body synthesis, such as acyl–CoA oxidase1 (Acox1) and HMG–CoA lyase (Hmgcl), was significantly increased, and expression of genes involved in lipogenesis and cholesterol synthesis, such as acetyl–CoA synthetase2 (Acs2), fatty acid synthase (Fasn), and squalene epoxidase (Sqle), was drastically decreased in the HFD group. Interestingly, the genes implicated in defense and stress responses, such as glutathione S-transferases (GSTs) and heat shock proteins (Hsps), were also highly represented in the HFD group. Besides, a number of previously unappreciated regulatory molecules were changed by the HFD. These results revealed a transcriptional adaptation to long-term HFD and provided interesting information about the molecules involved in the development and maintenance of the obesity phenotype in vivo. [Copyright &y& Elsevier]

The Src homology 3 (SH3) domain plays a crucial role in protein–protein interactions during intracellular signal transduction. Blocking the SH3-mediated protein binding may inhibit the corresponding signal transduction, and thus, block the cellular functions. In this study, a peptide that specifically binds to SH3 domain could be introduced into the intracellular region when the peptides were conjugated with dipalmitic acid and appeared to disturb intracellular signaling. The dipalmitoyl peptide appeared to inhibit the phosphorylation of ZAP-70, Lck, and T-cell antigen receptor ζ in Jurkat. Mobilization of the intracellular free calcium induced by anti-CD3 antibody was reduced after treatment with the dipalmitoyl peptide. It was also observed that the dipalmitoyl peptide inhibited cancer cell growth both in vitro and in vivo. These results suggest that the dipalmitoyl peptide that presumably disturbs SH3-mediated signal transduction may have a potent anti-proliferative activity, which would be useful as a potential anti-tumor agent. [Copyright &y& Elsevier]