TY - JOUR A1 - Shityakov, Sergey A1 - Dandekar, Thomas A1 - Förster, Carola T1 - Gene expression profiles and protein-protein interaction network analysis in AIDS patients with HIV-associated encephalitis and dementia JF - HIV/AIDS: Research and Palliative Care N2 - Central nervous system dysfunction is an important cause of morbidity and mortality in patients with human immunodeficiency virus type 1 (HIV-1) infection and acquired immunodeficiency virus syndrome (AIDS). Patients with AIDS are usually affected by HIV-associated encephalitis (HIVE) with viral replication limited to cells of monocyte origin. To examine the molecular mechanisms underlying HIVE-induced dementia, the GSE4755 Affymetrix data were obtained from the Gene Expression Omnibus database and the differentially expressed genes (DEGs) between the samples from AIDS patients with and without apparent features of HIVE-induced dementia were identified. In addition, protein–protein interaction networks were constructed by mapping DEGs into protein–protein interaction data to identify the pathways that these DEGs are involved in. The results revealed that the expression of 1,528 DEGs is mainly involved in the immune response, regulation of cell proliferation, cellular response to inflammation, signal transduction, and viral replication cycle. Heat-shock protein alpha, class A member 1 (HSP90AA1), and fibronectin 1 were detected as hub nodes with degree values >130. In conclusion, the results indicate that HSP90A and fibronectin 1 play important roles in HIVE pathogenesis. KW - microarray KW - differentially expressed genes KW - protein-protein interaction network KW - gene ontology KW - encephalitis dementia KW - human immunodeficiency virus Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149494 VL - 7 ER - TY - JOUR A1 - Shityakov, Sergey A1 - Förster, Carola A1 - Rethwilm, Axel A1 - Dandekar, Thomas T1 - Evaluation and Prediction of the HIV-1 Central Polypurine Tract Influence on Foamy Viral Vectors to Transduce Dividing and Growth-Arrested Cells N2 - Retroviral vectors are potent tools for gene delivery and various biomedical applications. To accomplish a gene transfer task successfully, retroviral vectors must effectively transduce diverse cell cultures at different phases of a cell cycle. However, very promising retroviral vectors based on the foamy viral (FV) backbone lack the capacity to efficiently transduce quiescent cells. It is hypothesized that this phenomenon might be explained as the inability of foamy viruses to form a pre-integration complex (PIC) with nuclear import activity in growth-arrested cells, which is the characteristic for lentiviruses (HIV-1). In this process, the HIV-1 central polypurine tract (cPPT) serves as a primer for plus-strand synthesis to produce a “flap” element and is believed to be crucial for the subsequent double-stranded cDNA formation of all retroviral RNA genomes. In this study, the effects of the lentiviral cPPT element on the FV transduction potential in dividing and growth-arrested (G1/S phase) adenocarcinomic human alveolar basal epithelial (A549) cells are investigated by experimental and theoretical methods. The results indicated that the HIV-1 cPPT element in a foamy viral vector background will lead to a significant reduction of the FV transduction and viral titre in growth-arrested cells due to the absence of PICs with nuclear import activity. KW - Evaluation KW - Prognose KW - HIV KW - Spumaviren KW - Einfluss Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-112763 ER - TY - JOUR A1 - Shityakov, Sergey A1 - Bencurova, Elena A1 - Förster, Carola A1 - Dandekar, Thomas T1 - Modeling of shotgun sequencing of DNA plasmids using experimental and theoretical approaches JF - BMC Bioinformatics N2 - Background Processing and analysis of DNA sequences obtained from next-generation sequencing (NGS) face some difficulties in terms of the correct prediction of DNA sequencing outcomes without the implementation of bioinformatics approaches. However, algorithms based on NGS perform inefficiently due to the generation of long DNA fragments, the difficulty of assembling them and the complexity of the used genomes. On the other hand, the Sanger DNA sequencing method is still considered to be the most reliable; it is a reliable choice for virtual modeling to build all possible consensus sequences from smaller DNA fragments. Results In silico and in vitro experiments were conducted: (1) to implement and test our novel sequencing algorithm, using the standard cloning vectors of different length and (2) to validate experimentally virtual shotgun sequencing using the PCR technique with the number of cycles from 1 to 9 for each reaction. Conclusions We applied a novel algorithm based on Sanger methodology to correctly predict and emphasize the performance of DNA sequencing techniques as well as in de novo DNA sequencing and its further application in synthetic biology. We demonstrate the statistical significance of our results. KW - Shotgun method KW - Sanger sequencing KW - Virtual sequencing KW - Polymerase chain reaction KW - Gene expression vectors KW - Synthetic biology Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229169 VL - 2020 ER - TY - JOUR A1 - Rösing, Nils A1 - Salvador, Ellaine A1 - Güntzel, Paul A1 - Kempe, Christoph A1 - Burek, Malgorzata A1 - Holzgrabe, Ulrike A1 - Soukhoroukov, Vladimir A1 - Wunder, Christian A1 - Förster, Carola T1 - Neuroprotective Effects of Isosteviol Sodium in Murine Brain Capillary Cerebellar Endothelial Cells (cerebEND) After Hypoxia JF - Frontiers in Cellular Neuroscience N2 - Ischemic stroke is one of the leading causes of death worldwide. It damages neurons and other supporting cellular elements in the brain. However, the impairment is not only confined to the region of assault but the surrounding area as well. Besides, it also brings about damage to the blood-brain barrier (BBB) which in turn leads to microvascular failure and edema. Hence, this necessitates an on-going, continuous search for intervention strategies and effective treatment. Of late, the natural sweetener stevioside proved to exhibit neuroprotective effects and therapeutic benefits against cerebral ischemia-induced injury. Its injectable formulation, isosteviol sodium (STVNA) also demonstrated favorable results. Nonetheless, its effects on the BBB have not yet been investigated to date. As such, this present study was designed to assess the effects of STVNA in our in vitro stroke model of the BBB.The integrity and permeability of the BBB are governed and maintained by tight junction proteins (TJPs) such as claudin-5 and occludin. Our data show increased claudin-5 and occludin expression in oxygen and glucose (OGD)-deprived murine brain capillary cerebellar endothelial cells (cerebEND) after STVNa treatment. Likewise, the upregulation of the transmembrane protein integrin-αv was also observed. Finally, cell volume was reduced with the simultaneous administration of STVNA and OGD in cerebEND cells. In neuropathologies such as stroke, the failure of cell volume control is a major feature leading to loss of cells in the penumbra as well as adverse outcomes. Our initial findings, therefore, point to the neuroprotective effects of STVNA at the BBB in vitro, which warrant further investigation for a possible future clinical intervention. KW - isosteviol sodium KW - hypoxia KW - cerebEND cells KW - blood brain barrier KW - neuroprotection Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215013 SN - 1662-5102 VL - 14 ER - TY - JOUR A1 - Shityakov, Sergey A1 - Skorb, Ekaterina V. A1 - Förster, Carola Y. A1 - Dandekar, Thomas T1 - Scaffold Searching of FDA and EMA-Approved Drugs Identifies Lead Candidates for Drug Repurposing in Alzheimer’s Disease JF - Frontiers in Chemistry N2 - Clinical trials of novel therapeutics for Alzheimer’s Disease (AD) have consumed a significant amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA), European Medicines Agency (EMA), or Worldwide for another indication is a more rapid and less expensive option. Therefore, we apply the scaffold searching approach based on known amyloid-beta (Aβ) inhibitor tramiprosate to screen the DrugCentral database (n = 4,642) of clinically tested drugs. As a result, menadione bisulfite and camphotamide substances with protrombogenic and neurostimulation/cardioprotection effects were identified as promising Aβ inhibitors with an improved binding affinity (ΔGbind) and blood-brain barrier permeation (logBB). Finally, the data was also confirmed by molecular dynamics simulations using implicit solvation, in particular as Molecular Mechanics Generalized Born Surface Area (MM-GBSA) model. Overall, the proposed in silico pipeline can be implemented through the early stage rational drug design to nominate some lead candidates for AD, which will be further validated in vitro and in vivo, and, finally, in a clinical trial. KW - scaffold search KW - approved drugs KW - drug repurposing KW - alzheimer's disease KW - chemical similarity KW - molecular modeling Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248703 SN - 2296-2646 VL - 9 ER -