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Official websites use. Share sensitive information only on official, secure websites. Heroin use disorder HUD is a complex disease resulting from interactions among genetic and other factors e. The mechanism of HUD development remains unknown. Newly developed network medicine tools provide a platform for exploring complex diseases at the system level. This study proposes that protein—protein interactions PPIs , particularly those among proteins encoded by casual or susceptibility genes, are extremely crucial for HUD development. The giant component of our constructed PPI network comprised nodes with edges, including 16 proteins with large degree k or high betweenness centrality BC , which were further identified as the backbone of the network. Heroin was originally synthesized in the late nineteenth century. Abstaining from heroin use is difficult, and it leads to a high relapse rate among past users 1 , 2. New heroin users easily become addicted to the drug, tend to have serious withdrawal symptoms, and finally develop heroin use disorder HUD. It has recently become a serious problem in South and East Asia 3 — 5 , and heroin users have the highest mortality rate among all the users of addictive substances in Taiwan 6. Similar to the other addictive disorders, HUD is a complex disorder resulting from the interplay between the environmental factors and the genetic predisposing factors 7 — Studies have suggested that HUD is a polygenic disorder and identified various susceptibility genes contributing to HUD through different mechanisms at different stages of HUD development 8 , 11 , However, the pathogenesis remains unclear. Previous studies evaluated the genetic influence on HUD rather than gene expression at the protein level. In addition to the genetic influence engendered by DNA, all biochemical processes are controlled by proteins. We propose that protein—protein interactions PPIs , particularly those among proteins encoded by the aforementioned casual or susceptibility genes, are essential for HUD development. In this study, we used the relevant gene biosignatures as the seeds to construct the PPI network associated with the development of HUD. The regulatory pathways were explored through topological analysis of the PPI network for the further understanding of the HUD mechanism. In a PPI network, nodes represent proteins, and edges represent interactions According to graph theory, the topological structure of the PPI network provides basic and direct information regarding the network and is associated with biological functions The combination of the topological structure of the PPI network with the relevant biological knowledge provides a promising tool for understanding the biological mechanisms of species. Recently, topological analyses have been applied to molecular networks including protein interaction networks 13 — 19 , gene regulatory networks 20 — 22 , and metabolic networks 23 — Connectivity degree k , betweenness centrality BC , closeness centrality CC , eigenvector centrality EC , and eccentricity are the fundamental measures of nodes in network theory 27 , In a PPI network, nodes with large degree, defined as hub proteins, are crucial proteins, because they might be corresponding to the disease-causing genes 15 , 29 , whereas nodes with high BC, defined as bottlenecks, tend to indicate essential genes since they can be analogized to heavily used intersection in major highways or bridges 14 , 30 , In this study, we mainly focused on the hubs or bottlenecks that were central to the PPI network, identified the proteins with large degree or high BC as the key proteins, and considered the sub-network of these key proteins as the backbone worth further investigating the signaling pathways involved in HUD development. Drug addiction is a psychiatric disorder resulting in maladaptive neuroplasticity that underlies the development of compulsive drug seeking and vulnerability to relapse during periods of attempted abstinence MiRNAs are small non-coding RNAs 18—25 nucleotides that post- transcriptionally modulated gene expression by either repressing translation or inducing degradation of mRNA 33 , Consequently, discovering miRNA-disease association makes an important contribution to understanding the pathogenesis of diseases as well as designing diagnostic and therapeutic approaches for diseases 39 — We have identified the susceptibility genes associated with HUD in our previous case-control studies 43 , 44 that included Han Chinese men from Taiwan as the cases fulfilling the diagnostic criteria of HUD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition DSM-5 , and demographically similar patients as the controls getting regular medical checkups at a local medical center. The details of the participants and the investigating methods are in the previous studies 43 , Briefly, we recruited no controls with substance-related disorders or substance use disorders except nicotine, and no participants with the other psychiatric diagnoses such as neurodevelopmental disorders, schizophrenia spectrum disorders, bipolar-related disorders, depressive disorders, neurocognitive disorders, etc. The study protocol was approved by the Ethical Committee of Bali Psychiatric Center approval number: IRB , the written informed consents were obtained from the participants after full explanation of the protocol, and we performed all methods in accordance with the relevant guidelines and regulations. Given a list of the proteins as input, STRING can search for their neighbor interactors, the proteins that have direct interactions with the inputted proteins; then STRING can generate the PPI network consisting of all these proteins and all the interactions between them. Based on the seed proteins as input, we first constructed the PPI network Fig. We further searched for the interactions derived from three sources, lab experiments, curated databases, and gene expression data, with the same confidence to construct the PPI network with the co-expression interactions Fig. S1 for comparison. In addition, Gephi 46 , a program for large network analysis, was used to analyze the structure of the PPI networks. To evaluate the nodes in the PPI networks, we adopted several topological measures including degree k , between centrality BC , eccentricity, closeness centrality CC , eigenvector centrality EC , and clustering coefficient 47 , The first two measures, degree k and BC, are often used for detecting the hub or bottleneck in a network. Degree k of a node is defined as the number of edges linked to it. A node with high degree k denotes a hub having many neighbors. BC of a node is the proportion of the number of shortest paths passing through it to the number of all the shortest paths in the network, quantifying how often a node acts as a bridge along the shortest paths between two other nodes. A node with high BC has great influence on what flows in the network and has more control over the network. It can represent the bottleneck in the network. Eccentricity and CC of a node are the measures of centrality in the network, defined as the maximum distance from the node to all other nodes and the inverse of the average length of the shortest paths between the node and all other nodes, respectively. A node with lower eccentricity or higher CC is closer to the other nodes and more central in the network. Moreover, the maximum eccentricity is the diameter of a network; the minimum eccentricity is the radius of a network. The center of a network is the set of nodes of eccentricity equal to the radius. EC assigns relative score to all nodes in the network based on the concept that connections to high-scoring nodes contribute more to the score of the node in question than equal connections to low-scoring nodes. A node with higher clustering coefficient has its neighbors closer to one another, and the world of its neighbors is smaller. The clustering coefficient is a measure of the local interconnectedness of the graph, whereas the shortest path length is an indicator of its overall connectedness. A graph is considered small-world if it has a low mspl and a high acc 49 — We considered the protein nodes with high degree k or BC as the hubs or bottlenecks. They were key to the PPI network and constituted the backbone of the network The giant component Fig. It suggested that the PPI network could be considered as a relatively small world in comparison with random graph, and the proteins might be biologically relevant. The similar findings were also revealed in the results of the global topological measurements including average degree, mspl, diameter D, and average clustering coefficient listed in Table 1. In addition, the giant component of the PPI network with co-expression interactions Fig. S1 ; Tables S4 , S5 demonstrated the similar results, too. Note: The average degrees of 16 key proteins in the giant component are They were extensively connected with their neighbors in the network the average degree: The backbone network consisted of 51 edges and 16 nodes. We also retrieved the backbone of the PPI network with co-expression interactions Fig. S2 and Table S8. Comparing the two backbones with and without co-expression interactions, we discovered 13 proteins in common, and the protein-subnetworks in the two backbones had the same structure Fig. The protein-subnetworks contained most nodes and edges of the backbones. As a result, the main part of the backbones was robust, no matter with or without co-expression interactions derived from gene expression data. It suggested that only the rest part of the backbones could be influenced by the perturbations of gene expression through co-expression interactions. The global topological characteristics of four PPI networks in this study were listed in Table 1. The nodes of the 2 nd extended PPI network involved in the KEGG pathways of amphetamine addiction, cocaine addiction, and alcoholism were colored in red, blue, and green, respectively, in Fig. Moreover, the 2 nd extended PPI network with co-expression interactions was Fig. S4 which demonstrated 10 nodes for the KEGG pathways of alcoholism, 5 nodes of amphetamine addiction, and 6 nodes of cocaine addiction in Table S9. The proteins in the 2 nd extended PPI network involved in the KEGG pathways of alcoholism, amphetamine addiction, and cocaine addition. The 2 nd extended PPI network. The green ones are nodes in alcoholism pathway. Several studies have been conducted on HUD and several related susceptibility genes have been reported; however, the potential mechanism underlying HUD development remains unclear 53 , Here, we studied the potential key proteins through topological analysis 18 , 55 , We used degree k and BC, the 2 measures widely used in network theory, as the main parameters for evaluating the nodes in the PPI network Initially, a total of proteins were included in our giant component network. By considering the important topological measures degree and BC in a large network, we selected 16 proteins to construct the backbone network: 11 with large degree, 11 with high BC, and 4 with both large degree and high BC. In the PPI network, there were 16 proteins involved in the alcoholism pathway, 7 proteins involved in the amphetamine addiction pathway, and 7 proteins involved in the cocaine addiction pathway in the KEGG. Nevertheless, although both morphine and heroin are synthesized from opium, proteins involved in the KEGG pathway of morphine addiction were absent in the network. According to gateway drug theory, alcohol and cannabis are frequently abused before illicit drugs such as cocaine and heroin. Cannabis use is not popular in Taiwan; therefore, the 16 proteins involved in alcoholism might be important for the further development of HUD. In Taiwan, the frequency of cocaine use is low; however, the frequency of amphetamine use, a cocaine-like stimulant, is high in clients with HUD It might be due to most individuals with HUD abusing other substance such as amphetamine 58 , They are the identified key proteins in substance diseases involved in HUD development revealed in this study. It has been implicated in cancer-related studies 60 as well as studies on psychological disorders such as Alzheimer disease and schizophrenia 61 , FOS is known to have interaction in an animal study All of them except FOSB are selected in to the backbone network. The FOS family play a role in the development and maintenance of drug addictions 70 , Some other nodes in the backbone network are worth to study although they are not recorded in the alcoholism, amphetamine addiction, and cocaine addiction pathways. The substrates of this kinase also include transcription regulator ATF2 on stress-activated protein kinases ATF2 is in the backbone network and is involved in all three substance diseases alcoholism, amphetamine addiction, and cocaine addiction in the KEGG pathways. PCK1, an enzyme in humans encoded by the PCK1 gene, is an important control point for the regulation of gluconeogenesis. PCK1 and MAPK14 were not found to be involved in any substance diseases previously but they were noticed in the study of schizophrenia The two nodes provide us the new cues for further study in HUD and other substance diseases. In addition, changes in miRNA expression levels are linked to neurodegeneration 84 with mounting of evidence supporting the dysregulation of miRNA expression in psychiatric and neurological disorders 35 — 37 , 85 — MiRNAs might play important functions in moderating the central stress response within different brain regions via the regulation of genes As a result, miRNAs can not only serve as biomarkers of addition, but also as promising therapies for the prevention or treatment of neurodevelopmental and neuropathological disorders The recent advances of specific miRNAs have emerged as key regulator leading to addiction, and further studies may be central for developing novel therapeutic approaches Implementing predictive computational models might be potential to discovery miRNA biomarkers for HUD in the future 39 — 42 , A limitation of this study is the lack of proteins strongly correlated with morphine addiction or HUD in the backbone network. This may be due to early-life exposure to alcohol or amphetamine having a greater impact on persons with HUD than later-life heroin use. Another limitation of this study is that we used peripheral blood as the sample, rather than brain tissue from areas such as nucleus accumbens 89 , based on a previous human study JUN is also involved in the development of amphetamine and cocaine addiction. All authors reviewed the manuscript and provided edits and suggestions. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Sci Rep. Find articles by Shaw-Ji Chen. Find articles by Ding-Lieh Liao. Find articles by Chia-Hsiang Chen. Find articles by Tse-Yi Wang. Find articles by Kuang-Chi Chen. Received Nov 15; Accepted Mar 11; Collection date Open in a new tab. Supplementary 6. Table S3 Table S5 Table S11 11KB, xlsx. Similar articles. Add to Collections. 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Construction and Analysis of Protein-Protein Interaction Network of Heroin Use Disorder

Taitung where can I buy cocaine

By the s, Japanese colonialists in Taiwan had set up acres of plantations for growing transplanted Peruvian coca leaves, a crop which enabled Taiwan-based Japanese pharmaceutical companies to manufacture around kg of processed cocaine per year. This bump of cocaine trivia is part of the fascinating history of the Fujian drug trade as outlined in a new book The Opium Business: A History of Crime and Capitalism in Maritime China by Peter Thilly, a history instructor at the University of Mississippi. Thilly takes a deep dive into the drug history of southern Fujian Province from the early 19th century up to the moment all drug commerce was wiped out in China with the Communist victory of , weaving together a saga of narcotics, politics and commerce that involved colonial traders, warlords, gangsters, politicians and the vast network of Fujianese merchants, who operated the mightiest trade networks in East and South China Seas. Though for some reason cocaine never really caught on in China, the drug was becoming popular throughout India, Burma and Malaya, where it was in very early days introduced by mixing it into betel nut paste. Distribution occurred via factory manufactured tins under the Fujitsuru, Buddha and Elephant brand names, which were ubiquitous from Honolulu to Bombay though of mysterious origin. The best evidence suggests these cocaine brands originated from Xiamen. From the mids until the end of the Chinese Civil War, the Xiamen vice trade was run by a group of Taiwanese gangster-politicians, who dressed in Western tailored suits and came to be known as the Eighteen Elder Brothers. Poppy farming began by in China, and though locally produced opium was said to cause headaches, by domestic production overtook imports. So for any opium either bought or sold in southern Fujian, Tseng took a cut. Though a Taiwanese citizen, Tseng was in reality born and bred in Fujian. Not that the Chinese government offered much in the way of stability. Between and , the cities and counties of southern Fujian were constantly switching hands between competing warlords, naval commanders and KMT military governors. Yet as each new figure entered into the seat of government, the Taiwanese opium kings were ready to negotiate a deal, offering their services in collecting opium taxes. This tax revenue amounted to several millions of silver dollars per year and was used to fund warlord armies and even the KMT itself. Several of the bald-faced contradictions seem almost unreal. Though the Qing government deemed the trade illegal, by the end of the s, the British were importing around 2. There, British holding ships would anchor in inconspicuous bays and leave the actual smuggling to local Chinese boatmen. But as a result of the Opium Wars between and , in which the British defeated Qing forces for the purpose of opening trade, opium achieved a de facto legality in China from to Moreover, as systems of opium taxes, both official and extralegal, formed through the 19th century, Thilly observes that even government officials who opposed the drug became addicted to the tax revenue. Nineteenth century Fujian, he contends, offers an early example of a narco-state that may help us understand Mexican and Colombian drug cartels today. On the whole, The Opium Business is a unique and detailed picture of a drug trade that was incredibly difficult to document. If there is a flaw, it is that despite the excellent scholarship, the text often reads like a work of forensic economics. If, for example, you go to any old temple in Taiwan, most of the god effigies come from China. And where in China? Odds are it is one of the cities or towns described in this book. On every corner of Kowloon, diners pack shoulder-to-shoulder over strong brews of Hong-Kong-style milk tea, chowing down on French Toast and Cantonese noodles. Artificial intelligence could help reduce some of the most contentious culture war divisions through a mediation process, researchers say. Experts say a system that can create group statements that reflect majority and minority views is able to help people find common ground. Chris Summerfield, a co-author of the research from the University of Oxford, who worked at Google DeepMind at the time the study was conducted, said the AI tool could have multiple purposes. Home Features. Most Popular 1. You might also like. Front Page. About Us.

Taitung where can I buy cocaine