CIRCULATING ADIPOCYTE-DERIVED EXOSOMAL MICRORNAs ASSOCIATED WITH DECREASED INSULIN RESISTANCE AFTER GASTRIC BYPASS

OBJECTIVE: Exosomes from obese adipose contain dysregulated microRNAs linked to insulin signaling, as compared to lean controls, providing a direct connection between adiposity and insulin resistance. The current study tested the hypotheses that gastric bypass surgery and its subsequent weight loss would normalize adipocyte-derived-exosomal microRNAs associated with insulin signaling and the associated metabolome related to glucose homeostasis. METHODS: African-American female subjects with obesity (N=6; age: 38.5±6.8 years; BMI: 51.2±8.8 kg/m(2)) were tested before and one year after surgery. Insulin resistance (HOMA), serum metabolomics and global microRNA profiles of circulating adipocyte-derived exosomes were evaluated via ANCOVA and correlational analyses. RESULTS: One-year post-surgery, patients showed decreased BMI (−18.6±5.1 kg/m(2); p<0.001), ameliorated insulin resistance (HOMA: 1.94±0.6 pre-surgery, 0.49±0.1 post-surgery; p<0.001), and altered metabolites including branched chain amino acids. Biological pathways analysis of predicted mRNA targets of 168 surgery-responsive microRNAs (p<0.05) identified the insulin signaling pathway (p=1.27E-10; 52/138 elements), among others, in our dataset. The insulin signaling pathway was also a target of 10 microRNAs correlated to changes in HOMA (p<0.05; r>0.4), and 48 microRNAs correlated to changes in BCAA levels. CONCLUSIONS: These data indicate that circulating adipocyte-derived exosomes are modified following gastric bypass surgery and correlate to improved post-surgery insulin resistance

Phospholipase C–mediated hydrolysis of PIP2 releases ERM proteins from lymphocyte membrane

Mechanisms controlling the disassembly of ezrin/radixin/moesin (ERM) proteins, which link the cytoskeleton to the plasma membrane, are incompletely understood. In lymphocytes, chemokine (e.g., SDF-1) stimulation inactivates ERM proteins, causing their release from the plasma membrane and dephosphorylation. SDF-1–mediated inactivation of ERM proteins is blocked by phospholipase C (PLC) inhibitors. Conversely, reduction of phosphatidylinositol 4,5-bisphosphate (PIP2) levels by activation of PLC, expression of active PLC mutants, or acute targeting of phosphoinositide 5-phosphatase to the plasma membrane promotes release and dephosphorylation of moesin and ezrin. Although expression of phosphomimetic moesin (T558D) or ezrin (T567D) mutants enhances membrane association, activation of PLC still relocalizes them to the cytosol. Similarly, in vitro binding of ERM proteins to the cytoplasmic tail of CD44 is also dependent on PIP2. These results demonstrate a new role of PLCs in rapid cytoskeletal remodeling and an additional key role of PIP2 in ERM protein biology, namely hydrolysis-mediated ERM inactivation

Overexpression of Akt1 Enhances Adipogenesis and Leads to Lipoma Formation in Zebrafish

<div><h3>Background</h3><p>Obesity is a complex, multifactorial disorder influenced by the interaction of genetic, epigenetic, and environmental factors. Obesity increases the risk of contracting many chronic diseases or metabolic syndrome. Researchers have established several mammalian models of obesity to study its underlying mechanism. However, a lower vertebrate model for conveniently performing drug screening against obesity remains elusive. The specific aim of this study was to create a zebrafish obesity model by over expressing the insulin signaling hub of the <em>Akt1</em> gene.</p> <h3>Methodology/Principal Findings</h3><p><em>Skin oncogenic transformation screening shows that a stable zebrafish transgenic of Tg(krt4Hsa.myrAkt1</em>)^cy18 displays severely obese phenotypes at the adult stage. In Tg(<em>krt4:Hsa.myrAkt1</em>)^cy18, the expression of exogenous human constitutively active Akt1 (myrAkt1) can activate endogenous downstream targets of mTOR, GSK-3α/β, and 70S6K. During the embryonic to larval transitory phase, the specific over expression of myrAkt1 in skin can promote hypertrophic and hyperplastic growth. From 21 hour post-fertilization (hpf) onwards, myrAkt1 transgene was ectopically expressed in several mesenchymal derived tissues. This may be the result of the integration position effect. Tg(<em>krt4:Hsa.myrAkt1</em>)^cy18 caused a rapid increase of body weight, hyperplastic growth of adipocytes, abnormal accumulation of fat tissues, and blood glucose intolerance at the adult stage. Real-time RT-PCR analysis showed the majority of key genes on regulating adipogenesis, adipocytokine, and inflammation are highly upregulated in Tg(<em>krt4:Hsa.myrAkt1</em>)^cy18. In contrast, the myogenesis- and skeletogenesis-related gene transcripts are significantly downregulated in Tg(<em>krt4:Hsa.myrAkt1</em>)^cy18, suggesting that excess adipocyte differentiation occurs at the expense of other mesenchymal derived tissues.</p> <h3>Conclusion/Significance</h3><p>Collectively, the findings of this study provide direct evidence that Akt1 signaling plays an important role in balancing normal levels of fat tissue in vivo. The obese zebrafish examined in this study could be a new powerful model to screen novel drugs for the treatment of human obesity.</p> </div

Minimizing the total completion time in single-machine scheduling with aging/deteriorating effects and deteriorating maintenance activities

AbstractIn a real manufacturing system, a machine may need multiple maintenance activities to improve its production efficiency due to the effects of aging or deteriorating. This paper considers scheduling with aging or deteriorating effects and deteriorating maintenance activities simultaneously on a single machine. We assume that the machine may be subject to several maintenance activities during the planning horizon. However, due to the restriction of budget of maintenance, the upper bound of the maintenance frequency on the machine is assumed to be known in advance. Moreover, we assume that the duration of each maintenance activity depends on the running time of the machine. The objective is to find jointly the optimal maintenance frequencies, the optimal maintenance positions, and the optimal job sequence for minimizing the total completion time. We show that all the problems studied are polynomially solvable

Minimizing the makespan on single-machine scheduling with aging effect and variable maintenance activities

This paper considers a single-machine scheduling with a position-dependent aging effect described by a power function under maintenance activities and variable maintenance duration considerations simultaneously. We examine two models of the maintenance duration in this study. The objective is to find jointly the optimal maintenance frequency, the optimal maintenance positions, and the optimal job sequences to minimize the makespan of all jobs. We provided polynomial time solution algorithms for all the studied problems.Scheduling Aging effect Maintenance activities Variable maintenance duration Makespan

Prior-guided image reconstruction for accelerated multi-contrast MRI via generative adversarial networks

Multi-contrast MRI acquisitions of an anatomy enrich the magnitude of information available for diagnosis. Yet, excessive scan times associated with additional contrasts may be a limiting factor. Two mainstream frameworks for enhanced scan efficiency are reconstruction of undersampled acquisitions and synthesis of missing acquisitions. Recently, deep learning methods have enabled significant performance improvements in both frameworks. Yet, reconstruction performance decreases towards higher acceleration factors with diminished sampling density at high-spatial-frequencies, whereas synthesis can manifest artefactual sensitivity or insensitivity to image features due to the absence of data samples from the target contrast. Here we propose a new approach for synergistic recovery of undersampled multi-contrast acquisitions based on conditional generative adversarial networks. The proposed method mitigates the limitations of pure learning-based reconstruction or synthesis by utilizing three priors: shared high-frequency prior available in the source contrast to preserve high-spatial-frequency details, low-frequency prior available in the undersampled target contrast to prevent feature leakage/loss, and perceptual prior to improve recovery of high-level features. Demonstrations on brain MRI datasets from healthy subjects and patients indicate the superior performance of the proposed method compared to pure reconstruction and synthesis methods. The proposed method can help improve the quality and scan efficiency of multi-contrast MRI exams

Hemoglobin adducts as biomarkers of estrogen homeostasis: Elevation of estrogenquinones as a risk factor for developing breast cancer in Taiwanese Women

The aim of this study was to establish a methodology to analyze estrogen quinone-derived adducts, including 17β-estradiol-2,3-quinone (E2-2,3-Q) and 17β-estradiol-3,4-quinone (E2-3,4-Q), in human hemoglobin (Hb). The methodology was then used to measure the levels of these adducts in Hb derived from female breast cancer patients (n=143) as well as controls (n=147) in Taiwan. Our result confirmed that both E2-2,3-Q- and E2-3,4-Q-derived adducts, including E2-2,3-Q-4-S-Hb and E2-3,4-Q-2-S-Hb, were detected in all breast cancer patients with median levels at 434 (215-1472) and 913 (559-2384) (pmol/g), respectively. Levels of E2-2,3-Q-4-S-Hb correlated significantly with those of E2-3,4-Q-2-S-Hb (r=0.622-0.628, p<0.001). By contrast, median levels of these same estrogen quinone-derived adducts in healthy controls were 71.8 (35.7-292) and 139 (69.1-453) (pmol/g). This translated to ~6-fold increase in mean values of E2-2,3-Q-4-S-Hb and E2-3,4-Q-2-S-Hb in breast cancer patients compared to those in the controls (p<0.001). Our findings add further support to the theme that cumulative body burden of estrogen quinones is an important indicator of breast cancer risk. We hypothesize that combination of genetic events and environmental factors may modulate estrogen homeostasis and enhance the production of estrogen quinones which lead to subsequent generation of pro-mutagenic DNA lesions in breast cancer patients

Hemoglobin adducts as biomarkers of estrogen homeostasis:Elevation of estrogenquinones as a risk factor for developingbreast cancer in Taiwanese Women

The aim of this study was to establish a methodology to analyze estrogen quinone-derived adducts,including 17 -estradiol-2,3-quinone (E2-2,3-Q) and 17 -estradiol-3,4-quinone (E2-3,4-Q), in humanhemoglobin (Hb). The methodology was then used to measure the levels of these adducts in Hb derivedfrom female breast cancer patients (n = 143) as well as controls (n = 147) in Taiwan. Our result confirmedthat both E2-2,3-Q- and E2-3,4-Q-derived adducts, including E2-2,3-Q-4-S-Hb and E2-3,4-Q-2-S-Hb,were detected in all breast cancer patients with median levels at 434 (215–1472) and 913 (559–2384)(pmol/g), respectively. Levels of E2-2,3-Q-4-S-Hb correlated significantly with those of E2-3,4-Q-2-S-Hb(r = 0.622–0.628, p < 0.001). By contrast, median levels of these same estrogen quinone-derived adducts inhealthy controls were 71.8 (35.7–292) and 139 (69.1–453) (pmol/g). This translated to ∼6-fold increasein mean values of E2-2,3-Q-4-S-Hb and E2-3,4-Q-2-S-Hb in breast cancer patients compared to those inthe controls (p < 0.001). Our findings add further support to the theme that cumulative body burden of estrogen quinones is an important indicator of breast cancer risk. We hypothesize that combination ofgenetic events and environmental factors may modulate estrogen homeostasis and enhance the produc-tion of estrogen quinones which lead to subsequent generation of pro-mutagenic DNA lesions in breastcancer patients