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Obesity predisposes to type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD), but underlying mechanisms are incompletely understood. Potassium channel tetramerization domain-containing protein 17 (Kctd17) levels are increased in livers from obese mice and humans. In this study, we investigated the mechanism of increased Kctd17 and whether it is causal to obesity-induced metabolic complications.We transduced Rosa26-LSL-Cas9 knockin mice with AAV8-TBG-Cre (Control), AAV8-U6-Kctd17 sgRNA-TBG-Cre (L-Kctd17), AAV8-U6-Oga sgRNA-TBG-Cre (L-Oga), or AAV8-U6-Kctd17/Oga sgRNA-TBG-Cre (DKO). We fed mice a high-fat diet (HFD) and assessed for hepatic glucose and lipid homeostasis. We generated Kctd17, O-GlcNAcase (Oga), or Kctd17/Oga-knockout hepatoma cells by CRISPR-Cas9, and Kctd17-directed antisense oligonucleotide to test therapeutic potential in vivo. We analyzed transcriptomic data from patients with NAFLD.Hepatocyte Kctd17 expression was increased in HFD-fed mice due to increased Srebp1c activity. HFD-fed L-Kctd17 or Kctd17 antisense oligonucleotide-treated mice show improved glucose tolerance and hepatic steatosis, whereas forced Kctd17 expression caused glucose intolerance and hepatic steatosis even in lean mice. Kctd17 induced Oga degradation, resulting in increasing carbohydrate response element-binding protein (Chrebp) protein, so concomitant Oga knockout negated metabolic benefits of hepatocyte Kctd17 deletion. In patients with NAFLD, KCTD17 messenger RNA was positively correlated with expression of Chrebp target and other lipogenic genes.Srebp1c-induced hepatocyte Kctd17 expression in obesity disrupted glucose and lipid metabolism by stabilizing Chrebp, and may represent a novel therapeutic target for obesity-induced T2D and NAFLD.

Supplementary Fig from Antimigratory effect of TK1-2 is mediated in part by interfering with integrin α2β1

The recombinant two kringle domain of human tissue-type plasminogen activator (TK1-2) has been shown to inhibit endothelial cell proliferation, angiogenesis, and tumor cell growth despite of sharing a low amino acid sequence homology with angiostatin. Here, we explored a possible inhibitory mechanism of action of TK1-2 by focusing on antimigratory effect. TK1-2 effectively inhibited endothelial cell migration induced by basic fibroblast growth factor or vascular endothelial growth factor in a dose-dependent manner and tube formation on Matrigel. It blocked basic fibroblast growth factor–induced or vascular endothelial growth factor–induced phosphorylation of extracellular signal-regulated kinase 1/2 and formation of actin stress fibers and focal adhesions. Interestingly, TK1-2 alone induced the weak phosphorylation of focal adhesion kinase, whereas it inhibited focal adhesion kinase phosphorylation induced by growth factors. When immobilized, TK1-2 promoted adhesion and spreading of endothelial cells compared with bovine serum albumin. However, treatment with anti-α2β1 blocking antibody markedly diminished endothelial cell adhesion to immobilized TK1-2 compared with anti-αvβ3 or anti-α5β1 antibody. Pretreatment of soluble TK1-2 also altered the binding level of anti-α2β1 antibody to endothelial cells in fluorescence-activated cell sorting analysis. Indeed, a blocking antibody against integrin α2β1 or knocking down of integrin α2 expression prevented the inhibitory effect of TK1-2 in cell migration. Therefore, these results suggest that TK1-2 inhibits endothelial cell migration through inhibition of signaling and cytoskeleton rearrangement in part by interfering with integrin α2β1. [Mol Cancer Ther 2008;7(7):2133–41]

Over the last decades, research has focused on the role of pleckstrin homology (PH) domain leucine-rich repeat protein phosphatases (PHLPPs) in regulating cellular signaling via PI3K/Akt inhibition. The PKB/Akt signaling imbalances are associated with a variety of illnesses, including various types of cancer, inflammatory response, insulin resistance, and diabetes, demonstrating the relevance of PHLPPs in the prevention of diseases. Furthermore, identification of novel substrates of PHLPPs unveils their role as a critical mediator in various cellular processes. Recently, researchers have explored the increasing complexity of signaling networks involving PHLPPs whereby relevant information of PHLPPs in metabolic diseases was obtained. In this review, we discuss the current knowledge of PHLPPs on the well-known substrates and metabolic regulation, especially in liver, pancreatic beta cell, adipose tissue, and skeletal muscle in relation with the stated diseases. Understanding the context-dependent functions of PHLPPs can lead to a promising treatment strategy for several kinds of metabolic diseases. [BMB Reports 2021; 54(9): 451-457].

Collagen type I is the most abundant form of collagen in human tissues, and is composed of two identical α-1 type I chains and an α-2 type I chain organized in a triple helical structure. A previous study has shown that human collagen α-2 type I (hCOL1A2) promotes collagen synthesis, wound healing, and elastin production in normal human dermal fibroblasts (HDFs). However, the biological effects of human collagen α-1 type I (hCOL1A1) on various skin properties have not been investigated. Here, we isolate and identify the hCOL1A1-collagen effective domain (CED) which promotes collagen type I synthesis. Recombinant hCOL1A1-CED effectively induces cell proliferation and collagen biosynthesis in HDFs, as well as increased cell migration and elastin production. Based on these results, hCOL1A1-CED may be explored further for its potential use as a preventative agent against skin aging. [BMB Reports 2021; 54(6): 329-334].

Increased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity., Obesity can be associated with an increased risk of metabolic complications. Here, the authors show that adipocyte-specific ablation of the phosphatase PHLPP2 improves glucose homeostasis in high-fat diet fed obese mice, and that this may be due at least in part to PHLPP2 dephosphorylation of HSL.

Skin aging appears to be the result of overlapping intrinsic (including genetic and hormonal factors) and extrinsic (external environment including chronic light exposure, chemicals, and toxins) processes. These factors cause decreases in the synthesis of collagen type I and elastin in fibroblasts and increases in the melanin in melanocytes. Collagen Type I is the most abundant type of collagen and is a major structural protein in human body tissues. In previous studies, many products containing collagen derived from land and marine animals as well as other sources have been used for a wide range of purposes in cosmetics and food. However, to our knowledge, the effects of human collagenderived peptides on improvements in skin condition have not been investigated. Here we isolate and identify the domain of a human COL1A2-derived protein which promotes fibroblast cell proliferation and collagen type I synthesis. This human COL 1A2-derived peptide enhances wound healing and elastin production. Finally, the human collagen alpha-2 type I-derived peptide (SMM) ameliorates collagen type I synthesis, cell proliferation, cell migration, and elastin synthesis, supporting a significant anti-wrinkle effect. Collectively, these results demonstrate that human collagen alpha-2 type I-derived peptides is practically accessible in both cosmetics and food, with the goal of improving skin condition. [BMB Reports 2020; 53(10): 539-544].

We demonstrate the enlargement of sensing range of Brillouin optical correlation domain analysis (BOCDA) system by introducing the first-order distributed Raman amplification. The time-domain data processing is adopted for the BOCDA system utilizing a gated Brillouin pump, and the Raman amplification is applied to compensate for the depletion of Brillouin pump induced by Rayleigh scattering and Brillouin interaction. The Raman pump is injected in the opposite direction to the propagation of Brillouin pump, where the pumping scheme is optimized by simulations. A differential measurement scheme is additionally introduced for improving spatial resolution and dynamic range. In experiments, we measure the strain distribution along a 52.1 km sensing fiber with 7 cm spatial resolution, where the number of resolving points of measurement is more than 744 000.

We propose a high resolution time-domain data processed BOCDA with more than 2 million sensing points by adopting Raman amplification, differential measurement scheme, and the injecting locking.

Changes in intraoral pH can cause changes in the chemical decomposition and surface properties of treated resin-based pits and fissure sealants (sealant). The purpose of this study is to evaluate the release of bisphenol A (BPA) from sealants under three different pH conditions over time. The test specimen was applied with 6 sealants 5 mg each on a glass plate (10 × 10 mm) and photopolymerized. The samples were immersed for 10 min, 1 h, and 24 h in solutions of pH 3.0, 6.5, and 10.0 at 37 °C. BPA release was measured using a gas chromatography-mass spectrometer. A statistical analysis was performed by two-way ANOVA and one-way ANOVA to verify the effect of pH conditions and time on BPA release. The BPA concentration in the pH 3.0 group was higher at all points than with pH 6.5 and pH 10.0 (p < 0.05), and gradually increased over time (p < 0.05). As a result, it was confirmed that low pH negatively influences BPA release. Therefore, frequent exposure to low pH due to the consumption of various beverages after sealant treatment can negatively affect the sealant’s chemical stability in the oral cavity.

We demonstrate a passively mode-locked fiber laser using aqueous DNA solution as a saturable absorber (SA), with broadband pulse laser emission from 1 to 1.5 µm. The mode-locked laser with erbium-doped fiber as the gain material has a center wavelength of 1563 nm, a 3 dB bandwidth of 3.9 nm, and a pulse width of 822 fs, whereas the laser with ytterbium-doped fiber as the gain material and an identical DNA aqueous SA has a center wavelength of 1037 nm, a 3 dB bandwidth of 5.04 nm, and a pulse width of 250 ps. The proposed laser, which is simple and cost effective to fabricate, exhibits excellent long-term stability as well as thermal stability during high-power operation. This mode-locked laser scheme with a liquid-phase DNA component has the potential to provide in-depth understanding of the optical nonlinearity and usefulness of DNA.

Akt signaling is an important regulator of neural development, but the distinctive function of Akt isoforms in brain development presents a challenge. Here we show Siah1 as an ubiquitin ligase that preferentially interacts with Akt3 and facilitates ubiquitination and degradation of Akt3. Akt3 is enriched in the axonal shaft and branches but not growth cone tips, where Siah1 is prominently present. Depletion of Siah1 enhanced Akt3 levels in the soma and axonal tips, eliciting multiple branching. Brain-specific somatic mutation in Akt3-E17K escapes from Siah1-mediated degradation and causes improper neural development with dysmorphic neurons. Remarkably, coexpression of Siah1 with Akt3-WT restricted disorganization of neural development is caused by Akt3 overexpression, whereas forced expression of Siah1 with the Akt3-E17K mutant fails to cope with malformation of neural development. These findings demonstrate that Siah1 limits Akt3 turnover during brain development and that this event is essential for normal organization of the neural network.

We propose a linearly configured Brillouin optical correlation domain analysis system incorporated with time domain data processing, where a fiber under test (FUT) is accessed from single end and multiple sensing points are simultaneously interrogated to extend the measurement range. In our scheme, correlation peaks (CPs) are sequentially generated by the interaction between a pump pulse outgoing from the system and a probe wave reflected from the end of an FUT, where the time-domain data processing is applied to obtain the Brillouin gain spectrum of each CP. In experiments, we demonstrate simultaneous acquisition of Brillouin gain spectra at 982 CPs with a spatial resolution of less than 5 cm and a sensing range extended from 10.3 m to 10.15 km. We also show that the amplitude of frequency modulation (Δ f ), which has been limited to the Brillouin frequency of an FUT in linear-configured BOCDA systems, can be enlarged without definite limitation by the time-domain data processing. In the experimental confirmation Δ f of 15.6 GHz, about 1.5 times of the Brillouin frequency of FUT, is successfully applied to simultaneous analysis of 98 CPs by the time-domain data processing.

BACKGROUND/AIMS The importance of α-cell dysfunction in the pathogenesis of type 2 diabetes has re-emerged recently. However, data on whether relative glucagon excess is present in clinical settings are scarce. We aimed to investigate associations between glucagon-to-insulin ratio and various metabolic parameters. METHODS A total of 451 patients with type 2 diabetes naive to insulin treatment were recruited. Using glucagon-to-insulin ratio, we divided subjects into quartiles according to both fasting and postprandial glucagon-to-insulin ratios. RESULTS The mean age of the subjects was 58 years, with a mean body mass index of 25 kg/m2 . The patients in the highest quartile of glucagon-to-insulin ratio had higher glycated hemoglobin (HbA1c) levels. HbA1c levels were positively correlated with both fasting and postprandial glucagon-to-insulin ratios. Subjects in the highest quartile of postprandial glucagon-to-insulin ratio were more likely to exhibit uncontrolled hyperglycemia, even after adjusting for confounding factors (odds ratio, 2.730; 95% confidence interval, 1.236 to 6.028; p for trend < 0.01). CONCLUSION Hyperglucagonemia relative to insulin could contribute to uncontrolled hyperglycemia in type 2 diabetes patients.

Aims/Introduction Natural killer (NK) cells are cytotoxic lymphocytes critical to human immunity. Previous studies showed correlations between NK cell function and blood glucose concentrations. The purpose of the present study was to assess the NK cell activity and various metabolic parameters in people with type 2 diabetes, prediabetes and normal glucose tolerance. Materials and Methods A total of 49 participants were enrolled in the study. Anthropometric and biochemical parameters including age, sex, body mass index, smoking status, blood pressure, fasting plasma glucose, C‐peptide, insulin, glycated hemoglobin, total cholesterol, triglyceride, high‐density lipoprotein cholesterol and low‐density lipoprotein cholesterol were assessed. The 75 g oral glucose tolerance test was carried out for 2‐h postload glucose level. Homeostatic model assessment was calculated for insulin resistance and β‐cell function. NK cell activity was measured by detecting the circulating interferon‐gamma level secreted from NK cells. Results NK cell activity was lower in patients with type 2 diabetes (768.01 ± 650.35) compared with those with prediabetes (2,396.08 ± 653.76, P

A theoretical model to describe in-band pumped holmium doped silica fiber lasers is presented. The model is established based upon theory and parameters obtained from published research works. Both core-pumped system and cladding-pumped system are simulated with the model. The simulation results agree well with most experimental results, and for the cases in which the simulation results show discrepancy with the experimental results the disagreement can be reasonably explained. Through numerical analysis it is found that besides common negative factors such as non-radiative decay, fiber loss, and non-optimized resonator configuration, energy transfer upconversion plays a deleterious role in the performance of in-band pumped holmium doped silica fiber lasers. In particular, inhomogeneous upconversion associated with ion clustering is found to cause significant degradation of slope efficiencies of lasers, a fact that is useful to understand the unsolved problem regarding the lower-than-expected slope efficiencies observed in previous studies of in-band pumped holmium doped fiber lasers.

We introduce the Raman amplification to increase the sensing range in the Brillouin optical correlation domain analysis (BOCDA). Compared to our previous report, the optimized Raman pumping scheme is numerically simulated and enhanced sensing length is experimentally demonstrated. The differential measurement method and time-domain data processing are further introduced in the backward distributed Raman pumped BOCDA system for the performance improvement. Strain changes of 1 mε over 7 cm have been measured at 52 km sensing fiber.

Frailty is defined as a reduced physiologic reserve vulnerable to external stressors. For older individuals, frailty plays a decisive role in increasing adverse health outcomes in most clinical situations. Many tools or criteria have been introduced to define frailty in recent years, and the definition of frailty has gradually converged into several consensuses. Frail older adults often have multi-domain risk factors in terms of physical, psychological, and social health. Comprehensive geriatric assessment (CGA) is the process of identifying and quantifying frailty by examining various risky domains and body functions, which is the basis for geriatric medicine and research. CGA provides physicians with information on the reversible area of frailty and the leading cause of deterioration in frail older adults. Therefore frailty assessment based on understanding CGA and its relationship with frailty, can help establish treatment strategies and intervention in frail older adults. This review article summarizes the recent consensus and evidence of frailty and CGA., Graphical Abstract

Although benign nerve sheath tumors have been described, primary tracheal schwannomas are extremely rare. We report a case of primary tracheal schwannoma, a rare benign nerve sheath tumor in a 58-year-old man with atypical symptoms of chronic cough, sputum and dyspnea for 2 months. Chest computerized tomography showed a 1.7 cm polypoid lesion in posterior wall of mid trachea. The results of bronchoscopic biopsy and immuno-histo-chemical studies were consistent with schwannoma. A surgical treatment of tumor resection and tracheal reconstruction by end-to-end anastomosis was performed.

We propose and experimentally demonstrate a Brillouin optical correlation domain analysis system adopting time-domain data processing and differential measurement for simultaneous interrogation of multiple sensing points. Continuous probe and pulsed pump waves are simultaneously frequency-modulated by a MHz-order sinusoidal RF wave so that multiple correlation peaks are sequentially generated according to the propagation of the pump along a fiber under test (FUT). The Brillouin gain spectrum of each correlation peak is obtained and interrogated by moving window averaging of the probe wave with a span of the period of the RF modulation, leading to the simultaneous monitoring of the multiple sensing points. In experiments, 148 correlation peaks are concurrently interrogated with a spatial resolution less than 3 cm along a 1530 m FUT.