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Hanyu Liang,1 Huaibin Jiang,2 Chengmian Zhang,2 Huiling Zhou,1 Bin Zhang,3 Anxie Tuo1 1Department Medical Humanities, Guizhou Medical University, Guiyang, People’s Republic of China; 2Department of Education, Fujian Normal University of Technology, Fuqing, People’s Republic of China; 3Department of Applied Psychology, Hunan University of Chinese Medicine, Changsha, People’s Republic of ChinaCorrespondence: Anxie Tuo, Email 1298253638@qq.comPurpose: With the widespread use of the Internet and mobile phone, cyberbullying has become a new type of bullying among adolescents. It is of great practical significance to explore the relevant factors affecting cyberbullying for prevention and intervention of adolescents’ cyberbullying. However, few studies have considered the effect of both the family and social factors on cyberbullying. Therefore, the current study examines whether the parent-adolescent conflict as a family factor and deviant peer affiliation as a social factor have an effect on adolescents’ cyberbullying, as well as the role of moral disengagement and gender.Methods: A total of 777 middle school students (females = 336; mean age = 13.57; SD = 0.98) were surveyed by using the Parent-child Relationship Questionnaire, Deviant Peer Affiliation Questionnaire, Moral Disengagement Questionnaire and Cyber Bullying Behavior Questionnaire. SPSS21.0 was used to conduct descriptive statistics, Pearson correlation analysis and T-test, PROCESS were used to conduct significance test of moderated mediation effect on the data.Results: Parent-adolescent conflict does not directly predict cyberbullying. Moral disengagement played a complete mediating role between parent-adolescent conflict and cyberbullying, and gender played a moderating role between moral disengagement and cyberbullying. Deviant peer affiliation directly predict cyberbullying. Moral disengagement played a partially mediating role between parent-adolescent conflict and cyberbullying, and gender played a moderating role between moral disengagement and cyberbullying.Conclusion: Attention should be paid to the effect of moral disengagement on cyberbullying in family and social factors, as well as the role of gender.Keywords: parent-adolescent conflict, deviant peer affiliation, moral disengagement, cyberbullying, gender

The task of image difference captioning aims at locating changed objects in similar image pairs and describing the difference with natural language. The key challenges of this task are to comprehend the context of image pairs sufficiently and locate the changed objects accurately in the presence of viewpoint change. Previous studies focus on pixel-level image features, neglecting rich explicit features of objects in an image pair which are beneficial to generate a fine-grained difference caption. Additionally, existing generative models suffer from accurately locate the differences in the interference of viewpoint change. To address these issues, we propose an Instance-Level Fine-Grained Difference Captioning (IFDC) model, which consists of a fine-grained feature extraction module, a multi-round feature fusion module, a similarity-based difference finding module, and a difference captioning module. To describe the changed objects comprehensively, we extract the fine-grained features, i.e., visual features, semantic features, and positional features at instance-level, as the objects representation. To enhance the model's immunity to viewpoint change, we design a similarity-based difference finding module to locate the changed objects accurately. Extensive experiments show that our IFDC model achieves comparable performance with the state-of-the-art models on the datasets of CLEVR-Change and Spot-the-Diff, thus verifying the effectiveness of our proposed model.

Cell temperature monitoring is of great importance to uncover temperature-dependent intracellular events and regulate cellular functions. However, it remains a great challenge to precisely probe the localized temperature status in living cells. Herein, we report a strategy for in situ temperature mapping on an immune cell membrane for the first time, which was achieved by using the lanthanide-doped upconversion nanoparticles. The nanothermometer was designed to label the cell membrane by combining metabolic labeling and click chemistry and can leverage ratiometric upconversion luminescence signals to in situ sensitively monitor temperature variation (1.4% K

Adolescence is a high-risk age for exposure to violent media (EVM) and bullying. Some previous theories and empirical studies have highlighted a moderated mediating model that normative beliefs about aggression (NBA) as a mediator and self-control (SC) as a moderator for the link between EVM and aggressive behaviors (including bullying behaviors). However, most previous studies analyzed traditional bullying (TB) and cyberbullying (CB) separately, which is not conducive to finding the differences between the two bullying behaviors. Therefore, this study aims to compare the differences between risk prediction models of TB and CB among adolescents. A total of 777 Chinese adolescent students (336 girls; M

The development of multimodal molecular imaging contrast agents based on versatile nanomaterials has recently attracted much attention in disease diagnosis and therapeutic delivery. Contrast agents made from nanoparticles and used for multimodal imaging in vivo provide a multidimensional pathophysiological overview of diseases. This review summarizes recently developed advanced nanomaterials for multimodal molecular imaging. We comprehensively discuss these nanoparticle contrast agents in terms of their targeting modalities, limitations in clinical translation and future directions.

INTRODUCTION The pneumatic tube system (PTS) is widely used for sample delivery. We aimed to investigate the impacts of PTS on hemostasis assays. METHODS Triplicate samples from 30 healthy volunteers were delivered to the core laboratory manually by human courier or via the 500 m long-distance PTS or via the 1000 m long-distance PTS. Comparisons of 19 hemostasis tests were conducted. RESULTS Although PT, INR, APTT, FII, FV, FVII FIX, FX, FXII, DD, α2-PI, and PC had statistical significance (all P

Background Urinalysis is one of the most commonly performed tests in clinical practice and supplies important information for a series of clinical conditions, including renal and urinary tract diseases. The clinical laboratory often completes urinalysis through the combined use of urinary dry-chemistry and formed-element analyzers. Urine red blood cell (RBC) morphology test is often used to discriminate the source of hematuria by manual microscopy. Case presentation In this case report, we describe a 39-year-old woman with chronic glomerulonephritis (CGN) who underwent both urine routine test and RBC morphology test. Her RBC count was in the normal range and the occult blood test was negative in routine test, while the RBC morphology test indicated the presence of non-homogeneous hematuria. Conclusions Therefore, we analyzed the causes of false-negative result on the urine chemical analyzer and the automatic microscope system, respectively.

Discrimination of nucleotides serves as the basis for DNA sequencing using solid-state nanopores. However, the translocation of DNA is usually too fast to be detected, not to mention nucleotide discrimination. Here, we utilized polyphenolic TA and Fe

Intravesical instillation therapy is increasingly recognized as one of the most common clinical treatment strategies for bladder cancer. However, the antitumor efficacy of chemotherapy drugs is still limited due to their rapid clearance by periodic urination. To circumvent this issue, a drug-loaded thin film comprising the self-assembly of tannic acid (TA) and ferric ions (Fe

Hispanic family caregivers of people with dementia experience higher levels of stress compared to non-Hispanic white caregivers. Long-term stress causes depression, caregiver burden, cellular aging, and dysregulation of the immune, nervous, and endocrine systems. The purpose of this study was to determine the validity of the Spanish version of the English Stress-Busting Program (SBP) for Family Caregivers by determining changes in quality-of-life measures and biomarkers. Thirty-six caregivers completed the SBP in the language of their choice (14 Spanish-speaking Hispanics [HS], 8 English-speaking Hispanics [HE], and 14 non-Hispanic English [NHE] speakers). Quality-of-life measures included the Perceived Stress Scale, the Screen for Caregiver Burden, and the Center for Epidemiologic Studies Depression Scale. Assessment of oral health and immunity included salivary flow rate, pH, buffer capacity, total protein, and secretory immunoglobulin A (sIgA). Indicators of stress (salivary cortisol), inflammation (C-reactive protein), and cellular aging (leukocyte telomere length) were assessed. Following completion of the SBP, the Spanish-speaking group had less depression and caregiver burden along with improved oral health and reduced cellular aging. When comparing baseline values to post-intervention, all three groups showed significant improvement in subjective caregiver burden. When the data from all three groups were combined, biomarkers that showed improvement after nine weeks of SBP included the stress hormone cortisol, salivary pH, and leukocyte telomere length. The results indicate that the Spanish SBP reduces caregiver stress as assessed by quality-of-life indicators and biomarkers. The Spanish SBP can help to mitigate health disparities in Hispanic Spanish-speaking caregivers.

Using single metal salts of zirconium, lanthanum, and iron as raw materials and sodium alginate as a cross-linking agent, a new composite adsorbent was prepared via the co-precipitation method and embedding immobilization technology, and its phosphorus adsorption performance in wastewater was evaluated. Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) were used for characterization, and a 0.5 mol·L−1 sodium hydroxide solution was used to regenerate the adsorbent. The experimental results demonstrated that the adsorption rate reached 99.88% when the wastewater volume was 50 mL, the initial concentration of phosphorus-containing wastewater was 5 mg·L−1, the pH was 5, the dosage of composite adsorbent was 0.2 g, and the adsorption time was 200 min. The prepared adsorbent could reduce the initial phosphorus concentration of 5 mg·L−1 to 0.006 mg·L−1 in simulated wastewater, and from 4.17 mg·L−1 in urban sewage to undetected (

Fault diagnosis of satellite attitude control system is an important task to ensure the safe and reliable operation of on-orbit satellites. At present, most fault diagnosis methods are to diagnose independent identically distributed(i.i.d) task objects. However, even if the same device works under different working conditions, the distribution domain of the collected data almost always changes. At the same time, the training of fault diagnosis model under full working conditions can increase the model complexity and training time, and there may unknown working conditions. In view of the above situation, this paper proposed a domain adaptive adversarial deep neural network based fault diagnosis method. By combining the feature extractor, label classifier and domain classifier with the convolutional neural network and gradient inversion layer (GRL), the effective label classification can be achieved while the resolution of different domains can be reduced. We achieved feature extraction of the classification learning task in the source domain and transfer of the classification task between the two domains. The effectiveness of the diagnosis model is verified in the ground simulation data of a certain satellite under different conditions.

The design and development of contrast agents for magnetic resonance imaging (MRI) with improved chemical stability and higher contrasting capability for clinical translation compared to conventional contrast agents are still of great interest. In this study, a facile and universal approach was explored for controllable functionalization of red-emissive carbon nanodots (RCNDs) with diethylenetriaminepentaacetic anhydride (DTPA) for chelation of gadolinium. A series of accurate characterizations were used to control each step of the synthesis. The functionalization did not alter the band gap of the carbon nanodots, preserving their inherent far-red fluorescence. The as-prepared RCND-DTPA-Gd displayed a high colloidal stability with negligible Gd leakage. The nanodots also showed a better magnetic resonance relaxivity than commercial MRI agents. RCND-DTPA-Gd had good biocompatibility in vivo even at high doses. The systemically injected RCND-DTPA-Gd were found to be efficiently excreted through the renal route, a feature that further minimizes the potential toxicity risks. All these properties suggest that carbon nanodots can be well designed as efficient carriers of Gd, resulting in potential clinical tools as dual MRI/fluorescence functional probes for imaging applications. The approach described here could pave the pathway to a flexible strategy for the controllable functionalization of small-sized nanoparticles including carbon dots, rendering them more versatile. This work is expected to promote the future translation of carbon nanodots into clinical trials., We gratefully acknowledge the Centre National de la Recherche Scientifique (CNRS) and International Center for Frontier Research in Chemistry (icFRC), and financial support from the Agence Nationale de la Recherche (ANR) through the LabEx project Chemistry of Complex Systems (ANR-10-LABX-0026_CSC) within the Investissement d’Avenir program (ANR-10-120 IDEX-0002-02). We wish to thank D. Lamon for injecting the mice and collecting the samples for the biochemical analyses, C. Royer and V. Demais for help with TEM analyses at the “Plateforme Imagerie in vitro” at the Center of Neurochemistry (INCI, Strasbourg, France), D. Ihiawakrim for HRTEM measurements, and S. Guo for his help in the XPS analyses. ICN2 acknowledges the financial support from the Spanish Ministry of Economy and Competitiveness through the “Severo Ochoa” Programme for Centres of Excellence in R&D (SEV-2017-0706). B.B. acknowledges funding from Generalitat de Catalunya 2017 SGR 327. We wish to thank the Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fujian Key Laboratory of Integrative Medicine on Geriatrics, and Prof. Jun Peng for the use of 7 T small-animal MRI scanner.

Visual Question Answering (VQA) requires a fine-grained and simultaneous understanding of both the visual content of images and the textual content of questions. Recent research works mainly focus on the bilinear fusion methods and attention mechanism methods to explore the global features and local features, respectively. When an image exists multiple objects, the fine-grained question features can effectively identify the relationship between objects in an image. Therefore we propose a graph convolutional network based on fine-grained question representation (FQ-GCN). The object relation graph is firstly constructed. The fine-grained question features are used to explore the relations between objects in an image and prune unrelated edges between object nodes. Graph convolutional network is used to aggregate all neighborhood information of each object in an object graph. Experiments on the VQA 2.0 dataset show that the performance of our FQ-GCN model improves 2%$\sim 3$% than the classical methods.

Obese subjects have increased levels of free fatty acids (FFA) in plasma that may mediate the inflammation and insulin resistance seen in these individuals. Data generated mostly in cells and rodents suggest that toll like receptor 4 (TLR4) mediates the inflammatory and insulin resistant states induced by FFA. In the present study, we tested the hypothesis that pharmacologic blockade of TLR4 with eritoran would prevent lipid-induced insulin resistance. We recruited 10 lean, healthy subjects (Age: 51 ± 1 y, Sex: 6M/4F, BMI: 23.8 ± 0.7 kg/m2, Fasting plasma glucose (FPG): 5.5 ± 0.1 mmol/l). They were randomized to receive the following 72 h long i.v. treatments on separate occasions: saline (30 ml/h)+vehicle (12 mg every 12 h); Intralipid (30 ml/h)+vehicle; Intralipid (30 ml/h)+eritoran (12 mg every 12 h). After these infusions, insulin sensitivity was measured with an hyperinsulinemic clamp. Infusion of Intralipid significantly decreased insulin sensitivity (M value) by 14%. FPG and fasting plasma insulin concentrations increased with Intralipid infusion by 7% and 22%, respectively. Intralipid also caused a low-grade inflammatory state, evidenced by increases in plasma levels of TNFa (32%), lipopolysaccharide (14%), LPS binding protein (21%), and blood monocytes counts (15%). However, metabolic and inflammatory outcomes were not different between the Intralipid+vehicle and the Intralipid+eritoran groups. We conclude that short-term TLR4 inhibition with eritoran fails to prevent lipid-induced inflammation and insulin resistance. Studies with longer acting TLR4 inhibitors may be needed to clarify the role of TLR4 on the pro-inflammatory and insulin resistant states seen obesity and type 2 diabetes. Disclosure H. Liang: None. N. Sathavarodom: None. C.V. Colmenares: None. V. Ganapathy: None. N. Musi: None. Funding American Diabetes Association (7-13-GSK-01 to N.M.); National Institutes of Health (R01DK080157)

The human gut and its microbial content (microbiome) may contribute to the pathogenesis of obesity, insulin resistance and type 2 diabetes. Possible mechanisms include altered bacterial profile, increased intestinal permeability, and elevated bacterial lipopolysaccharide (LPS) leading to low-grade systemic inflammation termed metabolic endotoxemia. We hypothesized that two interventions with putative LPS-lowering effects, sevelamer and a synbiotic (combination pre- and probiotic), would improve peripheral insulin sensitivity in obese subjects. Based upon pre-clinical studies, sevelamer is reported to sequester LPS in the GI tract, whereas a synbiotic of Bifidobacterium longum plus oligofructose can improve intestinal barrier integrity. We randomized 22, normal glucose tolerant (NGT), lean (15F/7M, BMI=23.0, age=45.4yr, A1c=5.3%) and 28 NGT, obese subjects (20F/8M, BMI=32.7, age=51.9yr, A1c=5.5%) to receive oral sevelamer, synbiotic or placebo daily for 28 days. Insulin sensitivity (euglycemic clamp), cholesterol, endotoxemia (LPS, LBP, CD14), and intestinal permeability (lactulose/mannitol ratio, zonulin) were assessed before and after intervention. Obese subjects had reduced baseline insulin sensitivity compared to lean subjects (M value, -28.6%, p=0.0001 based on 2-sample t-test). Generalized estimating equation analysis showed that sevelamer increased insulin sensitivity (M value, +25.6%, p=0.022) and lowered plasma LDL (-16.4%, p=0.016) in obese subjects compared to placebo-treated obese subjects. Synbiotic did not significantly alter insulin sensitivity or lipids compared to placebo in obese subjects. Lean subjects saw no change in insulin sensitivity with either treatment. Neither treatment significantly altered plasma LPS or intestinal permeability in lean or obese subjects. In conclusion, sevelamer improves insulin sensitivity and LDL in obese subjects, and this effect is mostly independent of parameters of endotoxemia and intestinal permeability. Disclosure E. Baeuerle: None. H. Liang: None. V. Ganapathy: None. R. Fernandez: None. N. Sathavarodom: None. C. Wang: None. S.E. Espinoza: None. N. Musi: None. Funding American Diabetes Association (7-13-GSK-01 to N.M.); National Institutes of Health (T32GM113896)

Inhibition of the mechanistic target of rapamycin (mTOR) pathway by rapamycin (RAPA), an FDA-approved immunosuppressive drug used as a clinical therapy to prevent solid organ allograft rejection, enhances longevity in mice. Importantly, RAPA was efficacious even when initiated in relatively old animals, suggesting that mTOR inhibition could potentially slow the progression of aging-associated pathologies in older humans (Harrison et al., 2009; Miller et al., 2011). However, the safety and tolerability of RAPA in older human subjects have not yet been demonstrated. Towards this end, we undertook a placebo-controlled pilot study in 25 generally healthy older adults (aged 70–95 years); subjects were randomized to receive either 1 mg RAPA or placebo daily. Although three subjects withdrew, 11 RAPA and 14 controls completed at least 8 weeks of treatment and were included in the analysis. We monitored for changes that would indicate detrimental effects of RAPA treatment on basic metabolism, including both standard clinical laboratory assays (CBC, CMP, HbA1c) and oral glucose tolerance tests. In addition, we asked whether there were RAPA-induced modifications in parameters typically associated with aging. These included cognitive function which was assessed by three different tools: Executive Interview-25 (EXIT25); Saint Louis University Mental Status Exam (SLUMS); and Texas Assessment of Processing Speed (TAPS). In addition, physical performance was measured by handgrip strength and 40-foot timed walks. Lastly, changes in general parameters of healthy immune aging, including serum pro-inflammatory cytokine levels and blood cell subsets, were assessed. Five subjects reported potential adverse side effects; in the RAPA group, these were limited to facial rash (1 subject), stomatitis (1 subject) and gastrointestinal issues (2 subjects) whereas placebo treated subjects only reported stomatitis (1 subject). Although no other adverse events were reported, statistically significant decrements in several erythrocyte parameters including hemoglobin (HgB) and hematocrit (Hct) as well as in red blood cell count (RBC), red blood cell distribution width (RDW), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) were observed in the RAPA-treatment group. None of these changes manifested clinically significant effects during the short duration of this study. Similarly, no changes were noted in any other clinical laboratory, cognitive, physical performance, or self-perceived health status measure over the study period. Immune parameters were largely unchanged as well, possibly due to the advanced ages of the cohort (70–93 yrs; mean age 80.5). RAPA-associated increases in a myeloid cell subset and in T(REGS) were detected, but changes in most other PBMC cell subsets were not statistically significant. Importantly, the OGTTs revealed no RAPA-induced increase in blood glucose concentration, insulin secretion, and insulin sensitivity. Thus, based on the results of our pilot study, it appears that short-term RAPA treatment can be used safely in older persons who are otherwise healthy; a larger trial with a larger samples size and longer treatment duration is warranted.

Summary Older adults universally suffer from sarcopenia and approximately 60–70% are diabetic or prediabetic. Nonetheless, the mechanisms underlying these aging‐related metabolic disorders are unknown. NFκB has been implicated in the pathogenesis of several aging‐related pathologies including sarcopenia and type 2 diabetes and has been proposed as a target against them. NFκB also is thought to mediate muscle wasting seen with disuse, denervation, and some systemic diseases (e.g., cancer, sepsis). We tested the hypothesis that lifelong inhibition of the classical NFκB pathway would protect against aging‐related sarcopenia and insulin resistance. Aged mice with muscle‐specific overexpression of a super‐repressor IκBα mutant (MISR) were protected from insulin resistance. However, MISR mice were not protected from sarcopenia; to the contrary, these mice had decreases in muscle mass and strength compared to wild‐type mice. In MISR mice, NFκB suppression also led to an increase in proteasome activity and alterations in several genes and pathways involved in muscle growth and atrophy (e.g., myostatin). We conclude that the mechanism behind aging‐induced sarcopenia is NFκB independent and differs from muscle wasting due to pathologic conditions. Our findings also indicate that, while suppressing NFκB improves insulin sensitivity in aged mice, this transcription factor is important for normal muscle mass maintenance and its sustained inhibition is detrimental to muscle function.

A 34-year-old female had a fever and respiratory infection without other clinical symptoms, and her platelet count (PLT) was only 13×10

Metformin has beneficial effects on several age-related diseases (e.g., diabetes, obesity, cancer) and extends lifespan in nematodes and mice. Acarbose, an FDA-approved agent for treating type 2 diabetes, prevents breakdown of complex carbohydrates. Both compounds have been suggested as potential anti-aging interventions and acarbose has been shown to extend mouse longevity by the Intervention Testing Program (ITP). One potential next step is to assess the effect of these interventions on healthspan and lifespan in non-human primates. The common marmoset (Callithrix jacchus) is a small new world monkey with a relatively short life span and small size, both valuable for the translation potential of this nonhuman primate species for the study of aging and chronic disease. However, the dosing and assessment of potential side effects of either metformin or acarbose in this species have yet to be assessed. This study evaluated the pharmacokinetics of two dosage levels each of metformin or acarbose (given separately) in two small groups of young marmosets (n = 5/group) treated for 24 h to define the pharmacokinetics of each drug. The ability to rapidly and reliably dose socially housed marmosets with an oral form of acarbose or metformin that is well tolerated indicates that this species is a reliable model for testing acarbose and metformin in a safe and efficient way in a long-term intervention.

The purpose of this study is to provide detailed data on treatment persistence and clinical outcomes in Chinese patients with nonvalvular atrial fibrillation (NVAF). A single-center retrospective observational study was conducted. A total of 26,663 NVAF patients were enrolled from January 1, 2014 to December 31, 2017, clinical information of whom were from inpatient and outpatients data system was collected. The 1-year treatment persistence rates of 11,350 dabigatran users were 24.5% in 2014, 36.6% in 2015, 37.7% in 2016 and 51.8% in 2017. The predominant reason of non-persistence patients was the cost of treatment. Incidence rates of all-cause death, ischemic stroke and embolism were 1.99/100 person-years, 2.56/100 person-years and 0.77/100 person-years, respectively. Incidence rates of minor bleeding events, intracranial hemorrhage and gastrointestinal hemorrhage were 10.05/100 person-years, 0.51/100 person-years and 0.85/100 person-years, respectively. In conclusion, it is of importance for Chinese clinicians to know about these information because dabigatran is a relatively new drug in China. Compared with other reported data, patients of this study have (1) lower dabigatran persistence and lower incident rates of all-cause death, systemic embolism, minor bleeding events and gastrointestinal hemorrhage and (2) higher incident rates of ischemic stroke and intracranial hemorrhage.

Accumulating evidence suggests that Alzheimer's disease may manifest as a metabolic disorder with pathology and/or dysfunction in numerous tissues. Adults with Alzheimer's disease suffer with significantly more comorbidities than demographically matched Medicare beneficiaries (Zhao et al, BMC Health Serv Res 8:108, 2008b). Reciprocally, comorbid health conditions increase the risk of developing Alzheimer's disease (Haaksma et al, PLoS One 12(5):e0177044, 2017). Type 2 diabetes mellitus is especially notable as the disease shares many overlapping pathologies observed in patients with Alzheimer's disease, including hyperglycemia, hyperinsulinemia, insulin resistance, glucose intolerance, dyslipidemia, inflammation, and cognitive dysfunction, as described in Chap. 8 of this book (Yoshitake et al, Neurology 45(6):1161-1168, 1995; Leibson et al, Am J Epidemiol 145(4):301-308, 1997; Ott et al, Neurology 53(9):1937-1942, 1999; Voisin et al, Rev Med Interne 24(Suppl 3):288s-291s, 2003; Janson et al. Diabetes 53(2):474-481, 2004; Ristow M, J Mol Med (Berl) 82(8):510-529, 2004; Whitmer et al, BMJ 330(7504):1360, 2005, Curr Alzheimer Res 4(2):103-109, 2007; Ohara et al, Neurology 77(12):1126-1134, 2011). Although nondiabetic older adults also experience age-related cognitive decline, diabetes is uniquely associated with a twofold increased risk of Alzheimer's disease, as described in Chap. 2 of this book (Yoshitake et al, Neurology 45(6):1161-1168, 1995; Leibson et al, Am J Epidemiol 145(4):301-308, 1997; Ott et al. Neurology 53(9):1937-1942, 1999; Ohara et al, Neurology 77(12):1126-1134, 2011). Good glycemic control has been shown to improve cognitive status (Cukierman-et al, Diabetes Care 32(2):221-226, 2009), and the use of insulin sensitizers is correlated with a lower rate of cognitive decline in older adults (Morris JK, Burns JM, Curr Neurol Neurosci Rep 12(5):520-527, 2012). At the molecular level, the mechanistic/mammalian target of rapamycin (mTOR) plays a key role in maintaining energy homeostasis. Nutrient availability and cellular stress information, both extracellular and intracellular, are integrated and transduced through mTOR signaling pathways. Aberrant regulation of mTOR occurs in the brains of patients with Alzheimer's disease and in numerous tissues of individuals with type 2 diabetes (Mannaa et al, J Mol Med (Berl) 91(10):1167-1175, 2013). Moreover, modulating mTOR activity with a pharmacological inhibitor, rapamycin, provides wide-ranging health benefits, including healthy life span extension in numerous model organisms (Vellai et al, Nature 426(6967):620, 2003; Jia et al, Development 131(16):3897-3906, 2004; Kapahi et al, Curr Biol 14(10):885-890, 2004; Kaeberlein et al, Science 310(5751):1193-1196, 2005; Powers et al, Genes Dev 20(2):174-184, 2006; Harrison et al, Nature 460(7253):392-395, 2009; Selman et al, Science 326(5949):140-144, 2009; Sharp ZD, Strong R, J Gerontol A Biol Sci Med Sci 65(6):580-589, 2010), which underscores its importance to overall organismal health and longevity. In this chapter, we discuss the physiological role of mTOR signaling and the consequences of mTOR dysregulation in the brain and peripheral tissues, with emphasis on its relevance to the development of Alzheimer's disease and link to type 2 diabetes.

Premature infants have altered glucose regulation early in life and increased risk for diabetes in adulthood. Although prematurity leads to an increased risk of diabetes and metabolic syndrome in adult life, the role of hepatic glucose regulation and adaptation to an early extrauterine environment in preterm infants remain unknown. The purpose of this study was to investigate developmental differences in glucose metabolism, hepatic protein content, and gene expression of key insulin-signaling/gluconeogenic molecules. Fetal baboons were delivered at 67%, 75%, and term gestational age and euthanized at birth. Neonatal baboons were delivered prematurely (67% gestation), survived for two weeks, and compared with similar postnatal term animals and underwent serial hyperinsulinemic-euglycemic clamp studies. Premature baboons had decreased endogenous glucose production (EGP) compared with term animals. Consistent with these results, the gluconeogenic molecule, phosphoenolpyruvate carboxykinase messenger RNA, was decreased in preterm baboons compared with terms. Hepatic insulin signaling was altered by preterm birth as evidenced by decreased insulin receptor–β, p85 subunit of phosphoinositide 3-kinase, phosphorylated insulin receptor substrate 1, and Akt-1 under insulin-stimulated conditions. Furthermore, preterm baboons failed to have the normal increase in glycogen synthase kinase-α from fetal to postnatal life. The blunted responses in hepatic insulin signaling may contribute to the hyperglycemia of prematurity, while impaired EGP leads to hypoglycemia of prematurity.

In the wave of computers and the Internet, people’s production and lifestyle have been significantly changed, and many traditional offline economic activities have been gradually replaced by convenient online technologies. However, due to the particularity and complexity of the Internet structure, a variety of network security problems emerge in endlessly, among which the leakage of network password is the most serious. The security of network password is related to people’s information security and property security, so it is particularly urgent to explore efficient and reliable measures to protect network password. Therefore, this paper analyses the current network password security problems, and explores the feasible measures of network password data encryption and protection, which provides a new thinking direction for the research of network password security.

Accumulating evidence suggests that Alzheimer’s disease may manifest as a metabolic disorder with pathology and/or dysfunction in numerous tissues. Adults with Alzheimer’s disease suffer with significantly more comorbidities than demographically matched Medicare beneficiaries (Zhao et al, BMC Health Serv Res 8:108, 2008b). Reciprocally, comorbid health conditions increase the risk of developing Alzheimer’s disease (Haaksma et al, PLoS One 12(5):e0177044, 2017). Type 2 diabetes mellitus is especially notable as the disease shares many overlapping pathologies observed in patients with Alzheimer’s disease, including hyperglycemia, hyperinsulinemia, insulin resistance, glucose intolerance, dyslipidemia, inflammation, and cognitive dysfunction, as described in Chap. 8 of this book (Yoshitake et al, Neurology 45(6):1161–1168, 1995; Leibson et al, Am J Epidemiol 145(4):301–308, 1997; Ott et al, Neurology 53(9):1937–1942, 1999; Voisin et al, Rev Med Interne 24(Suppl 3):288s–291s, 2003; Janson et al. Diabetes 53(2):474–481, 2004; Ristow M, J Mol Med (Berl) 82(8):510–529, 2004; Whitmer et al, BMJ 330(7504):1360, 2005, Curr Alzheimer Res 4(2):103–109, 2007; Ohara et al, Neurology 77(12):1126–1134, 2011). Although nondiabetic older adults also experience age-related cognitive decline, diabetes is uniquely associated with a twofold increased risk of Alzheimer’s disease, as described in Chap. 2 of this book (Yoshitake et al, Neurology 45(6):1161–1168, 1995; Leibson et al, Am J Epidemiol 145(4):301–308, 1997; Ott et al. Neurology 53(9):1937–1942, 1999; Ohara et al, Neurology 77(12):1126–1134, 2011). Good glycemic control has been shown to improve cognitive status (Cukierman-et al, Diabetes Care 32(2):221–226, 2009), and the use of insulin sensitizers is correlated with a lower rate of cognitive decline in older adults (Morris JK, Burns JM, Curr Neurol Neurosci Rep 12(5):520–527, 2012). At the molecular level, the mechanistic/mammalian target of rapamycin (mTOR) plays a key role in maintaining energy homeostasis. Nutrient availability and cellular stress information, both extracellular and intracellular, are integrated and transduced through mTOR signaling pathways. Aberrant regulation of mTOR occurs in the brains of patients with Alzheimer’s disease and in numerous tissues of individuals with type 2 diabetes (Mannaa et al, J Mol Med (Berl) 91(10):1167–1175, 2013). Moreover, modulating mTOR activity with a pharmacological inhibitor, rapamycin, provides wide-ranging health benefits, including healthy life span extension in numerous model organisms (Vellai et al, Nature 426(6967):620, 2003; Jia et al, Development 131(16):3897–3906, 2004; Kapahi et al, Curr Biol 14(10):885–890, 2004; Kaeberlein et al, Science 310(5751):1193–1196, 2005; Powers et al, Genes Dev 20(2):174–184, 2006; Harrison et al, Nature 460(7253):392–395, 2009; Selman et al, Science 326(5949):140–144, 2009; Sharp ZD, Strong R, J Gerontol A Biol Sci Med Sci 65(6):580–589, 2010), which underscores its importance to overall organismal health and longevity. In this chapter, we discuss the physiological role of mTOR signaling and the consequences of mTOR dysregulation in the brain and peripheral tissues, with emphasis on its relevance to the development of Alzheimer’s disease and link to type 2 diabetes.

A convenient approach has been developed for the construction of quinolin-4(1H)-one frameworks, starting from (Z)-β-chlorovinyl aromatic ketones and amines. Intermolecular Michael addition of an amine to a (Z)-β-chlorovinyl ketone was followed by elimination of a chloride anion to give enamine intermediates, with full retention of the initial Z-configuration. The enamine intermediates were transformed into quinolin-4(1H)-one products by a palladium-catalyzed intramolecular N-arylation in a tandem one-pot manner, with good to excellent yields.

Older and obese subjects have increased levels of free fatty acids (FFA) in plasma that may mediate the inflammation and insulin resistance seen in these individuals. Data generated mostly in cells and rodents suggest that toll like receptor 4 (TLR4) mediates the inflammatory and insulin resistant states induced by FFA. In the present study, we tested the hypothesis that pharmacologic blockade of TLR4 would prevent lipid-induced insulin resistance. We recruited 10 lean, healthy subjects (Age: 51 ± 1 y, Sex: 6M/4F, BMI: 23.8 ± 0.7 kg/m2, Fasting plasma glucose (FPG): 5.5 ± 0.1 mmol/l). They were randomized to receive the following 72 h long i.v. treatments on separate occasions: saline (30 ml/h)+placebo (12 mg every 12 h); Intralipid (30 ml/h)+placebo; Intralipid (30 ml/h)+eritoran (12 mg every 12 h). After these infusions, insulin sensitivity was measured with an hyperinsulinemic clamp. Infusion of Intralipid significantly decreased insulin sensitivity (M value) by 14%. FPG and fasting plasma insulin concentrations increased with Intralipid infusion by 7% and 22%, respectively. Intralipid also caused a low-grade inflammatory state, evidenced by increases in plasma levels of TNFa (32%), lipopolysaccharide (14%), LPS binding protein (21%), and blood monocytes counts (15%). However, metabolic and inflammatory outcomes were not different between the Intralipid+placebo and the Intralipid+eritoran groups. We conclude that short-term TLR4 inhibition with eritoran fails to prevent lipid-induced inflammation and insulin resistance. Studies with longer acting TLR4 inhibitors may be needed to clarify the role of TLR4 on the pro-inflammatory and insulin resistant states seen with aging and obesity.

Abusive supervision, manifesting in nonphysical forms of hostility from supervisors toward subordinates (Tepper, 2000), has been found to cause serious harms to subordinates and organizations, such...

Free fatty acids (FFAs) have been implicated in the pathogenesis of insulin resistance. Reducing plasma FFA concentration in obese and type 2 diabetic (T2DM) subjects improves insulin sensitivity. However, the molecular mechanism by which FFA reduction improves insulin sensitivity in human subjects is not fully understood. In the present study, we tested the hypothesis that pharmacological FFA reduction enhances insulin action by reducing local (muscle) inflammation, leading to improved insulin signalling. Insulin-stimulated total glucose disposal (TGD), plasma FFA species, muscle insulin signalling, IBα protein, c-Jun phosphorylation, inflammatory gene (toll-like receptor 4 and monocyte chemotactic protein 1) expression, and ceramide and diacylglycerol (DAG) content were measured in muscle from a group of obese and T2DM subjects before and after administration of the antilipolytic drug acipimox for 7 days, and the results were compared to lean individuals. We found that obese and T2DM subjects had elevated saturated and unsaturated FFAs in plasma, and acipimox reduced all FFA species. Acipimox-induced reductions in plasma FFAs improved TGD and insulin signalling in obese and T2DM subjects. Acipimox increased IBα protein (an indication of decreased IB kinase-nuclear factor B signalling) in both obese and T2DM subjects, but did not affect c-Jun phosphorylation in any group. Acipimox also decreased inflammatory gene expression, although this reduction only occurred in T2DM subjects. Ceramide and DAG content did not change. To summarize, pharmacological FFA reduction improves insulin signalling in muscle from insulin-resistant subjects. This beneficial effect on insulin action could be related to a decrease in local inflammation. Notably, the improvements in insulin action were more pronounced in T2DM, indicating that these subjects are more susceptible to the toxic effect of FFAs.

The 'oxidative stress theory of aging' predicts that aging is primarily regulated by progressive accumulation of oxidized macromolecules that cause deleterious effects to cellular homeostasis and induces a decline in physiological function. However, our reports on the detection of higher level of oxidized protein carbonyls in the soluble cellular fractions of long-living rodent naked-mole rats (NMRs, lifespan ~30yrs) compared to short-lived mice (lifespan ~3.5yrs) apparently contradicts a key tenet of the oxidative theory. As oxidation often inactivates enzyme function and induces higher-order soluble oligomers, we performed a comprehensive study to measure global protein carbonyl level in different tissues of age-matched NMRs and mice to determine if the traditional concept of oxidation mediated impairment of function and induction of higher-order structures of proteins are upheld in the NMRs. We made three intriguing observations with NMRs proteins: (1) protein carbonyl is significantly elevated across different tissues despite of its exceptional longevity, (2) enzyme function is restored despite of experiencing higher level of protein carbonylation, and (3) enzymes show lesser sensitivity to form higher-order non-reducible oligomers compared to short-living mouse proteins in response to oxidative stress. These observations were made based on the global analysis of protein carbonyl and identification of two heavily carbonylated proteins in the kidney, triosephosphate isomerase (TPI) and cytosolic peroxiredoxin (Prdx1). These un-expected intriguing observations thus strongly suggest that oxidative modification may not be the only criteria for impairment of protein and enzyme function; cellular environment is likely be the critical determining factor in this process and may be the underlying mechanism for exceptional longevity of NMR.

Oxidative stress plays a significant role in the development of insulin resistance; however, the cellular targets of oxidation that cause insulin resistance have yet to be fully elucidated. Methionine sulfoxide reductases reduce oxidized methionine residues, thereby repairing and protecting proteins from oxidation. Recently, several genome-wide analyses have found human obesity to be strongly correlated with polymorphisms near the methionine sulfoxide reductase A (MsrA) locus. In this study, we tested whether modulation of MsrA expression significantly alters the development of obesity and/or insulin resistance in mice. We show that mice lacking MsrA (MsrA−/−) are prone to the development of high-fat-diet-induced insulin resistance and a reduced physiological insulin response compared to high-fat-fed wild-type mice. We also show that oxidative stress in C2C12 cell cultures reduces both insulin-stimulated phosphorylation and autophosphorylation of the insulin receptor. Tissues from high-fat-fed mice show similar reduction in insulin receptor function and increase in insulin receptor oxidation, which are further exacerbated by the lack of MsrA. Together, these data demonstrate for the first time that MsrA and protein oxidation play a role in the regulation of glucose homeostasis. In addition, these data support a novel hypothesis that obesity-induced insulin resistance is caused in part by reduced function of insulin signaling proteins arising from protein oxidation.