Type 1 Diabetes Mellitus and Cognitive Impairments: A Systematic Review

Type 1 diabetes mellitus (T1DM) is a major subtype of diabetes and is usually diagnosed at a young age with insulin deficiency. The life expectancy of T1DM patients has increased substantially in comparison with that three decades ago due to the availability of exogenous insulin, though it is still shorter than that of healthy people. However, the relation remains unclear between T1DM and dementia as an aging-related disease. We conducted a systematic review of existing literature on T1DM and cognition impairments by carrying out searches in electronic databases Medline, EMBASE, and Google Scholar. We restricted our review to studies involving only human subjects and excluded studies on type 2 diabetes mellitus or non-classified diabetes. A meta-analysis was first performed on the relationship between T1DM and cognitive changes in youths and adults respectively. Then the review focused on the cognitive complications of T1DM and their relation with the characteristics of T1DM, glycemic control, diabetic complications, comorbidities, and others. First, age at onset, disease duration, and glycemic dysregulation were delineated for their association with cognitive changes. Then diabetic ketoacidosis, angiopathy, and neuropathy were examined as diabetic complications for their involvement in cognitive impairments. Lastly, body mass index and blood pressure were discussed for their relations with the cognitive changes. Future studies are needed to elucidate the pathogenesis of T1DM-related cognitive impairments or dementia

Cryptanalysis on Two Certificateless Signature Schemes

Certificateless cryptography has attracted a lot of attention from the research community, due to its applicability in information security. In this paper, we analyze two recently proposed certificateless signature schemes and point out their security flaws. In particular, we demonstrate universal forgeries against these schemes with known message attacks

PO-193 Exercise training decreased lipid accumulation in murine skeletal muscle through Sestrin2-mediated SHIP2-JNK signaling pathway

Objective Obesity is becoming increasingly prevalent and is an important contributor to the worldwide burden of diseases. It is widely accepted that exercise training is beneficial for the prevention and treatment of obesity. However, the underlying mechanism by which exercise training improving skeletal muscle lipid metabolism is still not fully described. Sestrins (Sestrin1-3) are highly conserved stress-inducible protein. Concomitant ablation of Sestrin2 and Sestrin3 has been reported to provoke hepatic mTORC1/S6K1 activation and insulin resistance even without nutritional overload and obesity, implicating that Sestrin2 and Sestrin3 have an important homeostatic function in the control of mammalian glucose and lipid metabolism. Our previous results demonstrated that physical exercise increased Sestrin2 expression in murine skeletal muscle, while the role of Sestrin2 in regulating lipid metabolism remains unknown.  SH2 domain containing inositol 5-phosphatase (SHIP2) acts as a negative regulator of the insulin signaling both in vitro and in vivo. An increased expression of SHIP2 inhibits the insulin-induced Akt activation, glucose uptake, and glycogen synthesis in 3T3-L1 adipocytes, L6 myotubes and tissues of animal models. Alterations of SHIP2 expression and/or enzymatic function appear to have a profound impact on the development of insulin resistance. However, the regulatory function of SHIP2 in lipid metabolism after exercise remains unclear. It has been reported that SHIP2 modulated lipid metabolism through regulating the activity of c-Jun N-terminal kinase (JNK) and Sterol regulatory element-binding protein-1 (SREBP-1). JNK is a subclass of mitogen-activated protein kinase (MAPK) signaling pathway in mammalian cells and plays a crucial role in metabolic changes and inflammation associated with a high-fat diet. Inhibition of JNK reduces lipid deposition and proteins level of fatty acid de novo synthesis in liver cells. It has been reported that Sestrin2 regulated the phosphorylation of JNK, however the underlying mechanism remains unclear. SREBP-1 is important in regulating cholesterol biosynthesis and uptake and fatty acid biosynthesis, and SREBP-1 expression produces two different isoforms, SREBP-1a and SREBP-1c. SREBP-1c is responsible for regulating the genes required for de novo lipogenesis and its expression is regulated by insulin. SREBP-1a regulates genes related to lipid and cholesterol production and its activity is regulated by sterol levels in the cell. Altogether, the purpose of this study was to explore the effect and underlying mechanism of Sestrin2 on lipid accumulation after exercise training. Methods Male wild type and SESN2−/− mice were divided into normal chow (NC) and high-fat diet (HFD) groups to create insulin resistance mice model. After 8 weeks the IR model group was then divided into HFD sedentary control and HFD exercise groups (HE). Mice in HE group underwent 6-week treadmill exercise to reveal the effect of exercise training on lipid metabolism in insulin resistance model induced by HFD. We explored the mechanism through which Sestrin2 regulated lipid metabolism in vitro by supplying palmitate, overexpressing or inhibiting SESNs, SHIP2 and JNK in myotubes. Results We found that 6-week exercise training decreased body weight, BMI and fat mass in wild type and SESN2-/- mice after high-fat diet (HFD) feeding. And exercise training decreased the level of plasma glucose, serum insulin, triglycerides and free fatty acids in wild type but not in Sestrin2-/- mice. Lipid droplet in skeletal muscle was also decreased in wild type but did not in Sestrin2-/- mice. Moreover, exercise training increased the proteins expression involved in fatty acid oxidation and decreased the proteins which related to fatty acid de novo synthesis. The results of oil red staining and the change of proteins related to fatty acid de novo synthesis and beta oxidation in myotubes treated with palmitate, Ad-SESN2 and siRNA-Sestrin2 were consisted with the results in vivo, which suggested that Sestrin2 was a key regulator in lipid metabolism. Exercise training increased Sestrin2 expression and reversed up-regulation of SHIP2 and pJNK induced by HFD in wild type mice but not in Sestrin2-/- mice. In parallel, overexpression of Sestrin2 decreased the level of SHIP2 and pJNK induced by palmitate while Sestrin2 knock down by siRNA-Sestrin2 treatment did not change the expression of SHIP2 and pJNK, which suggested that Sestrin2 modulated SHIP2 and JNK in the state of abnormal lipid metabolism. Inhibition of SHIP2 reduced the activity of JNK, increased lipid accumulation and the proteins of fatty acid synthesis after palmitate treatment and over expression of Sestrin2, which suggest that Sestrin2 modulated lipid metabolism through SHIP2/JNK pathway. Conclusions Sestrin2 plays an important role in improving lipid metabolism after exercise training, and Sestrin2 regulates lipid metabolism by SHIP2-JNK pathway in skeletal muscle

Orbital-angular-momentum fluorescence emission based on photon–electron interaction in a vortex field of an active optical fiber

We develop a model of interaction between photons and electrons in an active vortex field, which can generate a fluorescence spectrum with the characteristics of orbital angular momentum (OAM). In an active optical fiber, our findings generalize the notion of photon–electron interaction and point to a new kind of OAM-mode broad-spectrum light source, which could be interpreted in two processes: one microscopically is the excitation of OAM-carrying photons based on the photon–electron interaction; the other macroscopically is the emission and transmission of a donut-shaped fluorescence in a vortex field with a spiral phase wavefront in a ring-core active fiber. Here we present a straightforward experimental method that the emission of broad-spectrum fluorescence with an OAM feature is actualized and validated in a ring-core erbium-doped fiber. The spectrum has a broad spectral width up to 50 nm. Furthermore, four wavelengths are extracted from the fluorescence spectrum and superimposed with their corresponding Gaussian beams, from which the spiral-shaped interferograms of OAM modes in a broad spectrum are identified with high purity. The application of the OAM-based fluorescence light source may range from classical to quantum information technologies, and enable high-capacity communication, high-sensitivity sensing, high-resolution fluorescence imaging, etc

FGL2 deficiency alleviates maternal inflammation-induced blood-brain barrier damage by blocking PI3K/NF-κB mediated endothelial oxidative stress

IntroductionThe impairment of blood-brain barrier (BBB) is one of the key contributors to maternal inflammation induced brain damage in offspring. Our previous studies showed Fibrinogen-like protein 2 (FGL2) deficiency alleviated maternal inflammation induced perinatal brain damage. However, its role in BBB remains undefined.MethodsLipopolysaccharide (LPS) was intraperitoneally injected to dams at Embryonic day 17 to establish maternal inflammation model. FGL2 knockout mice and primary brain microvascular endothelial cells (BMECs) were used for the in-vivo and in-vitro experiments. BBB integrity was assessed by sodium fluorescein extravasation and tight junction (TJ) protein expression. Oxidative stress and the activation of PI3K/NF-κB pathway were evaluated to explore the mechanisms underlying.ResultsUpon maternal inflammation, BBB integrity was remarkedly reduced in neonatal mice. Meanwhile, FGL2 expression was consistently increased in BBB-impaired brain as well as in LPS-treated BMECs. Moreover, FGL2 deficiency attenuated the hyperpermeability of BBB, prevented the decline of TJ proteins, and reduced the cytokine expressions in LPS-exposed pups. Mechanistically, the indicators of oxidative stress, as well as the activation of PI3K/NF-κB pathway, were upregulated after LPS exposure in vivo and in vitro. FGL2 deletion decreased the generation of ROS and NO, reduced the endothelial iNOS and NOX2 expressions, and suppressed the PI3K/NF-κB pathway activation. Besides, inhibition of PI3K by LY294002 decreased the oxidative stress in LPS-treated wild-type BMECs. While, overexpression of PI3K by lentivirus reemerged the induction of NOX2 and iNOS as well as NF-κB activation in FGL2-deleted BMECs.ConclusionOur findings indicate that FGL2 deficiency alleviates the maternal inflammation-induced BBB disruption by inhibiting PI3K/NF-κB mediated oxidative stress in BMECs. Targeting FGL2 may provide a new therapy for prenatal brain damage of offspring

Chloroplast genomes in seven Lagerstroemia species provide new insights into molecular evolution of photosynthesis genes

Lagerstroemia indica is an important commercial tree known for the ornamental value. In this study, the complete chloroplast genome sequence of Lagerstroemia indica “Pink Velour” (Lagerstroemia “Pink Velour”) was 152,174 bp in length with a GC content of 39.50%. It contained 85 protein coding genes (PCGs), 37 tRNAs, and 8 rRNA genes. 207 simple sequence repeats (SSRs) and 31 codons with relative synonymous codon (RSCU)value > 1 were detected. Phylogenetic analysis divided 10 Lagerstroemia species into evolutionary branches of clade A and clade B. We conducted a comparative analysis of Lagerstroemia “Pink Velours” complete chloroplast genome with the genomes of six closely related Lagerstroemia species from different origins. The structural features of all seven species were similar, except for the deletion of ycf1 nucleobases at the JSA boundary. The large single-copy (LSC) and the small single-copy (SSC) had a higher sequence divergence than the IR region, and 8 genes that were highly divergent (trnK-UUU, petN, psbF, psbJ, ndhE, ndhD, ndhI, ycf1) had been identified and could be used as molecular markers in future studies. High nucleotide diversity was present in genes belonging to the photosynthesis category. Mutation of single nucleic acid was mainly influenced by codon usage. The value percentage of nonsynonymous substitutions (Ka) and synonymous substitutions (Ks) in 6 Lagerstroemia species revealed that more photosynthesis genes have Ka or Ks only in Lagerstroemia fauriei, Lagerstroemia limii, and Lagerstroemia subcostata. These advances will facilitate the breeding of closely related Lagerstroemia species and deepen understanding on climatic adaptation of Lagerstroemia plants

Improving the anti-acute myeloid leukemia activity of CD123-specific engager T cells by MyD88 and CD40 costimulation

The outcome of patients with acute myeloid leukemia remains poor, and immunotherapy has the potential to improve this. T cells expressing chimeric antigen receptors or bispecific T-cell engagers targeting CD123 are actively being explored in preclinical and/or early phase clinical studies. We have shown that T cells expressing CD123-specific bispecific T-cell engagers (CD123.ENG T cells) have anti-acute myeloid leukemia activity. However, like chimeric antigen receptor T cells, their effector function diminishes rapidly once they are repeatedly exposed to antigen-positive target cells. Here we sought to improve the effector function of CD123.ENG T cells by expressing inducible co-stimulatory molecules consisting of MyD88 and CD40 (iMC), MyD88 (iM), or CD40 (iC), which are activated by a chemical inducer of dimerization. CD123.ENG T cells expressing iMC, iM, or iC maintained their antigen specificity in the presence of a chemical inducer of dimerization, as judged by cytokine production (interferon-γ, interleukin-2) and their cytolytic activity. In repeat stimulation assays, activating iMC and iM, in contrast to iC, enabled CD123.ENG T cells to secrete cytokines, expand, and kill CD123-positive target cells repeatedly. Activating iMC in CD123.ENG T cells consistently improved antitumor activity in an acute myeloid leukemia xenograft model. This translated into a significant survival advantage in comparison to that of mice that received CD123.ENG or CD123.ENG.iC T cells. In contrast, activation of only iM in CD123.ENG T cells resulted in donor-dependent antitumor activity. Our work highlights the need for both toll-like receptor pathway activation via MyD88 and provision of co-stimulation via CD40 to consistently enhance the antitumor activity of CD123.ENG T cells

Changes in the mental health status of the general Chinese population during the COVID-19 pandemic: A longitudinal study

The study is based on a longitudinal evaluation of the public, during the initial COVID-19 outbreak in China and 8 months after. It aimed to explore the changes in the mental health of the public at the beginning of the pandemic and during the regular epidemic prevention and control. An online survey questionnaire was used to collect data during the initial COVID-19 outbreak (February 10, 2020–February 18, 2020; T1) and 8 months after the outbreak (October 21, 2020–December 29, 2020; T2). Psychological distress was assessed using the Patient Health Questionnaire-9 (PHQ-9), Self-rating Anxiety Scale (SAS), and Post-traumatic Stress Disorder Checklist (PCL-5). A chi-square test was used to compare the changes in the depression and anxiety scores at T1 and T2, and the correlation between symptoms was analyzed through Spearman's rank correlation. In T1, 1,200 people were recruited, while 168 people responded in T2. Depression (48.2–31.0%; p=0.001) and anxiety (17.9–9.5%; p = 0.026) symptoms decreased over time; two participants developed post-traumatic stress disorder (PTSD) in T2. The scores of the PHQ-9 scale and the SAS scale were both positively correlated with the score of the PCL-5 scale and negatively correlated with sleep time. During the COVID-19 pandemic, part of the general population's anxiety and depression significantly reduced with time, and they rarely developed PTSD. PTSD occurrence was related to severe depression and anxiety

Particle Swarm Optimization with Reinforcement Learning for the Prediction of CpG Islands in the Human Genome

BACKGROUND: Regions with abundant GC nucleotides, a high CpG number, and a length greater than 200 bp in a genome are often referred to as CpG islands. These islands are usually located in the 5' end of genes. Recently, several algorithms for the prediction of CpG islands have been proposed. METHODOLOGY/PRINCIPAL FINDINGS: We propose here a new method called CPSORL to predict CpG islands, which consists of a complement particle swarm optimization algorithm combined with reinforcement learning to predict CpG islands more reliably. Several CpG island prediction tools equipped with the sliding window technique have been developed previously. However, the quality of the results seems to rely too much on the choices that are made for the window sizes, and thus these methods leave room for improvement. CONCLUSIONS/SIGNIFICANCE: Experimental results indicate that CPSORL provides results of a higher sensitivity and a higher correlation coefficient in all selected experimental contigs than the other methods it was compared to (CpGIS, CpGcluster, CpGProd and CpGPlot). A higher number of CpG islands were identified in chromosomes 21 and 22 of the human genome than with the other methods from the literature. CPSORL also achieved the highest coverage rate (3.4%). CPSORL is an application for identifying promoter and TSS regions associated with CpG islands in entire human genomic. When compared to CpGcluster, the islands predicted by CPSORL covered a larger region in the TSS (12.2%) and promoter (26.1%) region. If Alu sequences are considered, the islands predicted by CPSORL (Alu) covered a larger TSS (40.5%) and promoter (67.8%) region than CpGIS. Furthermore, CPSORL was used to verify that the average methylation density was 5.33% for CpG islands in the entire human genome