The Effect of MyD88 Deficiency During Graft-Versus-Host Disease

Graft-versus-host disease is the onset of an un- wanted immune response in patients who have undergone bone marrow transplantation [1]. The effect of this unwanted immune response is lethal in many cases. The goal of this research is to reduce the effect of graft-versus-host disease which can possibly reduce the waiting time for an eligible bone marrow donor to appear. This paper focused on the MyD88 adaptor protein, which triggers biochemical signals that can initiate, maintain, expand, or terminate inflammatory sites [2]. Inflammatory sites are the areas where the immune cells are gathered to fight foreign pathogens [1]. Experiments were carried out wherein stem cells were extracted from C57BL/6 mice and injected into BALB.B mice. This experiment design establishes the allogeneic bone marrow transplantation because the minor histocompatibility complex gene is un-matched between the two strains of mice while the major histocompatibility complex gene is matched. We focused on the effect of MyD88 protein deficiency in transplan- tation recipient. The positive/negative controls for the allogeneic bone marrow transplantation and MyD88 knockout allogeneic bone marrow transplantation group were carefully observed for 28 days and assessed for survival, weight, and immune cell fraction changes. We found that MyD88 protein deficiency yields prolonged survival in graft-versus-host disease. Data also suggests that innate immunity is the dominant factor in graft-versus- host disease, not adaptive immunity. Future experiments with cytokine analysis in a similar experiment design will provide more information about the relationship between the innate immunity and the severity of graft versus host disease

Heat conduction in graphite-nanoplatelet-reinforced polymer nanocomposites

Heat transport in polymer nanocomposites reinforced with graphite nanoplatelets (GNPs) is studied using high-precision thermal conductivity measurements. The resistance to heat conduction across interfaces between GNPs and the polymer matrix has a strong effect on energy transport in the nanocomposites. The thermal conductivity is observed to increase when GNPs are pretreated with nitric acid to improve interfacial bonding. The improvement in the thermal conductivity, however, is much smaller than the corresponding improvement in mechanical properties. The thermal interface resistance extracted from the present thermal conductivity data is comparable to that obtained from the previously reported data on carbon nanotube suspensions. (c)2006 American Institute of Physics

Production and optical properties of liquid scintillator for the JSNS2^{2} experiment

The JSNS$^{2}$ (J-PARC Sterile Neutrino Search at J-PARC Spallation Neutron Source) experiment will search for neutrino oscillations over a 24 m short baseline at J-PARC. The JSNS$^{2}$ inner detector will be filled with 17 tons of gadolinium-loaded liquid scintillator (LS) with an additional 31 tons of unloaded LS in the intermediate $\gamma$-catcher and outer veto volumes. JSNS$^{2}$ has chosen Linear Alkyl Benzene (LAB) as an organic solvent because of its chemical properties. The unloaded LS was produced at a refurbished facility, originally used for scintillator production by the RENO experiment. JSNS$^{2}$ plans to use ISO tanks for the storage and transportation of the LS. In this paper, we describe the LS production, and present measurements of its optical properties and long term stability. Our measurements show that storing the LS in ISO tanks does not result in degradation of its optical properties.Comment: 7 pages, 4 figures

Mid-JJ CO Line Observations of Protostellar Outflows in the Orion Molecular Clouds

Ten protostellar outflows in the Orion molecular clouds were mapped in the $^{12}$CO/$^{13}$CO ${J=6\rightarrow5}$ and $^{12}$CO ${J=7\rightarrow6}$ lines. The maps of these mid-$J$ CO lines have an angular resolution of about 10$''$ and a typical field size of about 100$''$. Physical parameters of the molecular outflows were derived, including mass transfer rates, kinetic luminosities, and outflow forces. The outflow sample was expanded by re-analyzing archival data of nearby low-luminosity protostars, to cover a wide range of bolometric luminosities. Outflow parameters derived from other transitions of CO were compared. The mid-$J$ ($J_{\rm up} \approx 6$) and low-$J$ ($J_{\rm up} \leq 3$) CO line wings trace essentially the same outflow component. By contrast, the high-$J$ (up to $J_{\rm up} \approx 50$) line-emission luminosity of CO shows little correlation with the kinetic luminosity from the ${J=6\rightarrow5}$ line, which suggests that they trace distinct components. The low/mid-$J$ CO line wings trace long-term outflow behaviors while the high-$J$ CO lines are sensitive to short-term activities. The correlations between the outflow parameters and protostellar properties are presented, which shows that the strengths of molecular outflows increase with bolometric luminosity and envelope mass.Comment: 31 pages, 16 figures, Accepted for publication in ApJ

A transcriptomic analysis of serial-cultured, tonsil-derived mesenchymal stem cells reveals decreased integrin α3 protein as a potential biomarker of senescent cells

Abstract Background Mesenchymal stem cells (MSCs) have been widely used for stem cell therapy, and serial passage of stem cells is often required to obtain sufficient cell numbers for practical applications in regenerative medicine. A long-term serial cell expansion can potentially induce replicative senescence, which leads to a progressive decline in stem cell function and stemness, losing multipotent characteristics. To improve the therapeutic efficiency of stem cell therapy, it would be important to identify specific biomarkers for senescent cells. Methods Tonsil-derived mesenchymal stem cells (TMSCs) with 20–25 passages were designated as culture-aged TMSCs, and their mesodermal differentiation potentials as well as markers of senescence and stemness were compared with the control TMSCs passaged up to 8 times at the most (designated as young). A whole-genome analysis was used to identify novel regulatory factors that distinguish between the culture-aged and control TMSCs. The identified markers of replicative senescence were validated using Western blot analyses. Results The culture-aged TMSCs showed longer doubling time compared to control TMSCs and had higher expression of senescence-associated (SA)-β-gal staining but lower expression of the stemness protein markers, including Nanog, Oct4, and Sox2 with decreased adipogenic, osteogenic, and chondrogenic differentiation potentials. Microarray analyses identified a total of 18,614 differentially expressed genes between the culture-aged and control TMSCs. The differentially expressed genes were classified into the Gene Ontology categories of cellular component (CC), functional component (FC), and biological process (BP) using KEGG (Kyoto encyclopedia of genes and genomes) pathway analysis. This analysis revealed that those genes associated with CC and BP showed the most significant difference between the culture-aged and control TMSCs. The genes related to extracellular matrix-receptor interactions were also shown to be significantly different (p < 0.001). We also found that culture-aged TMSCs had decreased expressions of integrin α3 (ITGA3) and phosphorylated AKT protein (p-AKT-Ser473) compared to the control TMSCs. Conclusions Our data suggest that activation of ECM-receptor signaling, specifically involved with integrin family-mediated activation of the intracellular cell survival-signaling molecule AKT, can regulate stem cell senescence in TMSCs. Among these identified factors, ITGA3 was found to be a representative biomarker of the senescent TMSCs. Exclusion of the TMSCs with the senescent TMSC markers in this study could potentially increase the therapeutic efficacy of TMSCs in clinical applications

Enhanced cardiac expression of two isoforms of matrix metalloproteinase-2 in experimental diabetes mellitus.

BackgroundDiabetic cardiomyopathy (DM CMP) is defined as cardiomyocyte damage and ventricular dysfunction directly associated with diabetes independent of concomitant coronary artery disease or hypertension. Matrix metalloproteinases (MMPs), especially MMP-2, have been reported to underlie the pathogenesis of DM CMP by increasing extracellular collagen content.PurposeWe hypothesized that two discrete MMP-2 isoforms (full length MMP-2, FL-MMP-2; N-terminal truncated MMP-2, NTT-MMP-2) are induced by high glucose stimulation in vitro and in an experimental diabetic heart model.MethodsRat cardiomyoblasts (H9C2 cells) were examined to determine whether high glucose can induce the expression of the two isoforms of MMP-2. For the in vivo study, we used the streptozotocin-induced DM mouse heart model and age-matched controls. The changes of each MMP-2 isoform expression in the diabetic mice hearts were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical stains were conducted to identify the location and patterns of MMP-2 isoform expression. Echocardiography was performed to compare and analyze the changes in cardiac function induced by diabetes.ResultsQuantitative RT-PCR and immunofluorescence staining showed that the two MMP-2 isoforms were strongly induced by high glucose stimulation in H9C2 cells. Although no definite histologic features of diabetic cardiomyopathy were observed in diabetic mice hearts, left ventricular systolic dysfunction was determined by echocardiography. Quantitative RT-PCR and IHC staining showed this abnormal cardiac function was accompanied with the increases in the mRNA levels of the two isoforms of MMP-2 and related to intracellular localization.ConclusionTwo isoforms of MMP-2 were induced by high glucose stimulation in vitro and in a Type 1 DM mouse heart model. Further study is required to examine the role of these isoforms in DM CMP

Risk of Dementia After Smoking Cessation in Patients With Newly Diagnosed Atrial Fibrillation

IMPORTANCE: Incident atrial fibrillation (AF) is associated with an increased risk of dementia. However, data on the association between smoking cessation after AF diagnosis and dementia risk are limited. OBJECTIVE: To evaluate the association between changes in smoking status after AF diagnosis and dementia risk. DESIGN, SETTING, AND PARTICIPANTS: This nationwide cohort study with 126 252 patients used data from the Korean National Health Insurance Service database, including patients who had a national health checkup examination within 2 years before and after AF diagnosis between January 1, 2010, and December 31, 2016. Based on their smoking status, participants were classified as never smokers, ex-smokers, quit smokers, and current smokers. Ex-smokers were defined as those who had quit smoking before the first examination and remained quit until the second examination. Patients who were current smokers at the first health examination but had quit smoking before the second examination were classed as quit smokers. The index date was the second health examination. Patients were followed up until dementia, death, or the study period ended (December 31, 2017), whichever occurred first. Data were analyzed from January 13, 2020, to March 29, 2022. EXPOSURES: Smoking cessation after newly diagnosed AF. MAIN OUTCOMES AND MEASURES: Dementia, including Alzheimer disease and vascular dementia, was the primary outcome. Cox proportional hazards regression model was used to estimate hazard ratios. RESULTS: A total of 126 252 patients (mean [SD] age, 62.6 [12.0] years; 61.9% men) were included in the analysis. The mean (SD) CHA(2)DS(2)-VASc score, which measures the risk of ischemic stroke, was 2.7 (1.7). Smoking status of the total study population was as follows: 65 579 never smokers (51.9%), 34 670 ex-smokers (27.5%), 8919 quit smokers (7.1%), and 17 084 current smokers (13.5%). During a median of 3 years of follow-up, dementia occurred in 5925 patients (1.11 per 1000 person-years). After multivariable adjustment, the risk of quit smokers was significantly lower than that of current smokers (hazard ratio, 0.83 [95% CI, 0.72-0.95]). CONCLUSIONS AND RELEVANCE: The findings of this cohort study suggest that all types of smoking were associated with a significantly higher risk of dementia in patients with new-onset AF. Smoking cessation after AF diagnosis was associated with a lower risk of dementia than among current smokers. These findings may support promoting smoking cessation to reduce dementia risk in patients with new-onset AF

A Polytherapy Strategy Using Vincristine and ALK Inhibitors to Sensitise EML4-ALK-Positive NSCLC

The oncogenic fusion of EML4-ALK is present in about 4–6% of non-small cell lung cancer (NSCLC). A targeted approach with ALK tyrosine kinase inhibitors (TKIs) has been proven highly effective in ALK-positive NSCLC patients. However, despite the initial responses, the outcome of the treatment is variable. Previous studies have shown that the differential response depends in part on the type of EML4-ALK variant. Here, we examined the combination of ALK inhibitors and microtubule poison, vincristine, in cells expressing EML4-ALK V1 and V3, the two most common variants in NSCLC. We showed that combination therapy of ALK-TKIs with vincristine had anti-proliferative effects and blocked RAS/MAPK, PI3K/AKT and JAK/STAT3 signalling pathways in EML4-ALK V1 but not V3 cells. Our results demonstrate that high levels of tubulin acetylation are associated with poor response to vincristine in EML4-ALK V3 cells. Additionally, we demonstrated differences in microtubule stability between the two EML4-ALK fusions. EML4-ALK V3 cells exhibited dynamic microtubules that confer poor response to vincristine compared to V1 cells. Hence, we suggested that the portion of EML4 in the fusion has an important role for the outcome of the combination treatment