Changes in DNA Sequence and Methylation Contribute to the Predisposition of Schizophrenia: Toward an Epigenetic Therapy

Schizophrenia has a heterogeneous and complex etiology that includes multiple candidate genes affected by a variety of mutational mechanisms including epigenetics, functional pathways, and environmental factors. This chapter mainly focuses on reviewing two sets of studies. The first one is whole‐genome next‐generation sequencing datasets involving monozygotic twins discordant for schizophrenia. The findings suggest that de novo sequence variations may underlie the discordance of monozygotic twins for schizophrenia. Second, whole‐genome DNA methylation study suggesting the role of DNA methylation in the mechanisms of actions of antipsychotic drugs in treating the disorder as well as the manifestation of side effects such as metabolic disorders. Furthermore, we are reporting original research results using next‐generation mitochondrial DNA sequence analysis of a pair of monozygotic twins discordant for schizophrenia as well as their mother. The chapter sheds light on the interplay between sequence variations and epigenetic signatures, including DNA methylation changes, in the etiology and pathophysiology of schizophrenia. Given the dynamic nature of methylation, it may be possible to develop a new treatment strategy for schizophrenia that is based on reversion of genomic methylation. This may involve environmental, dietary, and/or pharmaceutical approaches

Pengaruh Promosi Terhadap Loyalitas Nasabah Di PT. Bank Mandiri Kantor Cabang Dotulolong Lasut Manado.

PT. Bank Mandiri Branch Office Dotulolong lasut Manado realized that to stimulate customer loyalty, then the sale becomes important in influencing the loyalty of its customers. The purpose of this study was to determine whether there is a relationship between customer loyalty promotion with the PT. Bank Mandiri Branch Office Dotulolong Lasut Manado. The method used in this research is quantitative method associative approach and datasource are customers of PT. Bank Mandiri Branch Office Dotulolong Lasut Manado. The result showed that, there is a significant relationship between promotion with customer loyalty in the PT. Bank Mandiri Branch Office Dotulolong Lasut Manado, where the relationship is detected at r = 0.73 .Perhitungan KP detected that the factors determining the sale of 52.8% Changes in customer loyalty factor while 42.8% Changes in customer loyalty determined other factors. It is recommended that PT Bank Mandiri Branch Office Manado keep doing promotion to continue to stimulate the customer so that it can improve their Clients Loyalty. This also will affect postitif not only short term but also for the long term. Keywords: Promotion, Customer Loyalty

Insights into the Origin of DNA Methylation Differences between Monozygotic Twins Discordant for Schizophrenia

BACKGROUND: DNA methylation differences between monozygotic twins discordant for schizophrenia have been previously reported. However, the origin of methylation differences between monozygotic twins discordant for schizophrenia is not clear. The findings here argue that all DNA methylation differences may not necessarily represent the cause of the disease; rather some may result from the effect of antipsychotics. METHODS: Methylation differences in rat brain regions and also in two pairs of unrelated monozygotic twins discordant for schizophrenia have been studied using genome-wide DNA methylation arrays at Arraystar Inc. (Rockville, Maryland, USA). The identified gene promoters showing significant alterations to DNA methylation were then further characterized using ingenuity pathway analysis (Ingenuity System Inc, CA, USA). RESULTS: Pathway analysis of the most significant gene promoter hyper/hypomethylation revealed a significant enrichment of DNA methylation changes in biological networks and pathways directly relevant to neural development and psychiatric disorders. These included HIPPO signaling (p = 3.93E-03) and MAPK signaling (p = 4.27E-03) pathways involving hypermethylated genes in schizophrenia-affected patients as compared to their unaffected co-twins. Also, a number of significant pathways and networks involving genes with hypomethylated gene promoters have been identified. These included CREB signaling in neurons (p = 1.53E-02), Dopamine-DARPP32 feedback in cAMP signaling (p = 7.43E-03) and Ephrin receptors (p = 1.13E-02). Further, there was significant enrichment for pathways involved in nervous system development and function (p = 1.71E-03-4.28E-02). CONCLUSION: The findings highlight the significance of antipsychotic drugs on DNA methylation in schizophrenia patients. The unique pathways affected by DNA methylation in the two pairs of monozygotic twins suggest that patient-specific pathways are responsible for the disease; suggesting that patient-specific treatment strategies may be necessary in treating the disorder. The study reflects the need for developing personalized medicine approaches that take into consideration epigenetic variations between patients

Olanzapine-Induced Methylation Alters Cadherin Gene Families and Associated Pathways Implicated in Psychosis

BACKGROUND: The complex aetiology of most mental disorders involves gene-environment interactions that may operate using epigenetic mechanisms particularly DNA methylation. It may explain many of the features seen in mental disorders including transmission, expression and antipsychotic treatment responses. This report deals with the assessment of DNA methylation in response to an antipsychotic drug (olanzapine) on brain (cerebellum and hippocampus), and liver as a non-neural reference in a rat model. The study focuses on the Cadherin/protocadherins encoded by a multi-gene family that serve as adhesion molecules and are involved in cell-cell communication in the mammalian brain. A number of these molecules have been implicated in the causation of schizophrenia and related disorders. RESULTS: The results show that olanzapine causes changes in DNA methylation, most specific to the promoter region of specific genes. This response is tissue specific and involves a number of cadherin genes, particularly in cerebellum. Also, the genes identified have led to the identification of several pathways significantly affected by DNA methylation in cerebellum, hippocampus and liver. These included the Gα12/13 Signalling (p = 9.2E-08) and Wnt signalling (p = 0.01) pathways as contributors to psychosis that is based on its responsiveness to antipsychotics used in its treatment. CONCLUSION: The results suggest that DNA methylation changes on the promoter regions of the Cadherin/protocadherin genes impact the response of olanzapine treatment. These impacts have been revealed through the identified pathways and particularly in the identification of pathways that have been previously implicated in psychosis

Red blood cells tracking and cell-free layer formation in a microchannel with hyperbolic contraction: a CFD model validation

Background and Objective: In recent years, progress in microfabrication technologies has attracted the attention of researchers across disciplines. Microfluidic devices have the potential to be developed into powerful tools that can elucidate the biophysical behavior of blood flow in microvessels. Such devices can also be used to separate the suspended physiological fluid from whole in vitro blood, which includes cells. Therefore, it is essential to acquire a detailed description of the complex interaction between erythrocytes (red blood cells; RBCs) and plasma. RBCs tend to undergo axial migration caused by occurrence of the Fåhræus-Lindqvist effect. These dynamics result in a cell-free layer (CFL), or a low volume fraction of cells, near the vessel wall. The aim of the paper is to develop a numerical model capable of reproducing the behavior of multiphase flow in a microchannel obtained under laboratory conditions and to compare two multiphase modelling techniques Euler-Euler and Euler-Lagrange. Methods: In this work, we employed a numerical Computational Fluid Dynamics (CFD) model of the blood flow within microchannels with two hyperbolic contraction shapes. The simulation was used to reproduce the blood flow behavior in a microchannel under laboratory conditions, where the CFL formation is visible downstream of the hyperbolic contraction. The multiphase numerical model was developed using Euler-Euler and hybrid Euler-Lagrange approaches. The hybrid CFD simulation of the RBC transport model was performed using a Discrete Phase Model. Blood was assumed to be a nonhomogeneous mixture of two components: dextran, whose properties are consistent with plasma, and RBCs, at a hematocrit of 5% (percent by volume of RBCs). Results: The results show a 5 μm thick CFL in a microchannel with a broader contraction and a 35 μm thick CFL in a microchannel with a narrower contraction. The RBC volume fraction in the CFL is less than 2%, compared to 7–8% in the core flow. The results are consistent for both multiphase simulation techniques used. The simulation results were then validated against the experimentally-measured CFL in each of the studied microchannel geometries. Conclusions: Reasonable agreement between experiments and simulations was achieved. A validated model such as the one tested in this study can expedite the microchannel design process by minimizing the need to prefabricate prototypes and test them under laboratory conditions.The work was partially supported by the Faculty of Energy and Environmental Engineering, Silesian University of Technology (SUT) within Ministry of Education and Science (Poland) statutory research funding scheme (MG, ZO) and by the Silesian University of Technology rector’s pro-quality grants No. 02/040/RGJ21/1011 (SS) and 08/060/RGJ21/1017 (ZO) and National Center of Science (Poland) No. 2017/27/B/ST8/01046 (BM). Rui Lima and João M. Miranda were partially funded by Portuguese national funds of FCT/MCTES (PIDDAC) through the base funding from the following research units: UIDB/00532/2020 (Transport Phenomena Research Center CEFT) and UIDB/04077/2020 (MEtRICs)

DNA Methylation Differences in Monozygotic Twin Pairs Discordant for Schizophrenia Identifies Psychosis Related Genes and Networks

Background Despite their singular origin, monozygotic twin pairs often display discordance for complex disorders including schizophrenia. It is a common (1%) and often familial disease with a discordance rate of ~50% in monozygotic twins. This high discordance is often explained by the role of yet unknown environmental, random, and epigenetic factors. The involvement of DNA methylation in this disease appears logical, but remains to be established. Methods We have used blood DNA from two pairs of monozygotic twins discordant for schizophrenia and their parents in order to assess genome-wide methylation using a NimbleGen Methylation Promoter Microarray. Results The genome-wide results show that differentially methylated regions (DMRs) exist between members representing discordant monozygotic twins. Some DMRs are shared with parent(s) and others appear to be de novo. We found twenty-seven genes affected by DMR changes that were shared in the affected member of two discordant monozygotic pairs from unrelated families. Interestingly, the genes affected by pair specific DMRs share specific networks. Specifically, this study has identified two networks; “cell death and survival” and a “cellular movement and immune cell trafficking”. These two networks and the genes affected have been previously implicated in the aetiology of schizophrenia. Conclusions The results are compatible with the suggestion that DNA methylation may contribute to the discordance of monozygotic twins for schizophrenia. Also, this may be accomplished by the direct effect of gene specific methylation changes on specific biological networks rather than individual genes. It supports the extensive genetic, epigenetic and phenotypic heterogeneity implicated in schizophrenia

Experimental study of a R290 variable geometry ejector

Ejectors are classified as fluid-dynamics controlled devices where the "component-scale"performances are imposed by the local-scale fluid dynamic phenomena. For this reason, ejector performances (measured by the pressure-entrainment ratio coordinate of the critical point) are determined by the connection of operation conditions, working fluid and geometrical parameters. Given such a connection, variable geometry ejector represents a promising solution to increase the flexibility of ejector-based systems. The present study aims to extend knowledge on variable geometry systems, evaluating the local and global performances of the R290 ejector equipped with a spindle. The prototype ejector was installed at the R290 vapour compression test rig adapted and modified for the required experimental campaign. The test campaign considered global parameter measurements, such as the pressure and the temperature at inlets and outlet ports together with the mass flow rates at both inlet nozzles, and the local pressure drop measurements inside the ejector. In addition, the experimental data were gathered for different spindle positions starting from fully open position the spindle position limited by the mass flow rate inside the test rig with the step of 1.0 mm

Smallholder farmers' adaptation to climate change and determinants of their adaptation decisions in the Central Rift Valley of Ethiopia

Background: The agricultural sector remains the main source of livelihoods for rural communities in Ethiopia, but faces the challenge of changing climate. This study investigated how smallholder farmers perceive climate change, what adaptation strategies they practice, and factors that influence their adaptation decisions. Both primary and secondary data were used for the study, and a multinomial logit model was employed to identify the factors that shape smallholder farmers’ adaptation strategies. Results: The results show that 90% of farmers have already perceived climate variability, and 85% made attempts to adapt using practices like crop diversification, planting date adjustment, soil and water conservation and management, increasing the intensity of input use, integrating crop with livestock, and tree planting. The econometric model indicated that education, family size, gender, age, livestock ownership, farming experience, frequency of contact with extension agents, farm size, access to market, access to climate information and income were the key factors determining farmers’ choice of adaptation practice. Conclusion: In the Central Rift Valley of Ethiopia, climate change is a pressing problem, which is beyond the capacity of smallholders to respond to autonomously. Farmers’ capacity to choose effective adaptation options is influenced by household demography, as well as positively by farm size, income, access to markets, access to climate information and extension, and livestock production. This implies the need to support the indigenous adaptation strategies of the smallholder farmers with a wide range of institutional, policy, and technology support; some of it targeted on smaller, poorer or female-headed households. Moreover, creating opportunities for non-farm income sources is important as this helps farmers to engage in those activities that are less sensitive to climate change. Furthermore, providing climate change information, extension services, and creating access to markets are crucial