imagine (Institute of molecular genetics and genetic engineering)
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Positioning Europe for the EPITRANSCRIPTOMICS challenge
Get PDFThe genetic alphabet consists of the four letters: C, A, G, and T in DNA and C,A,G, and U in RNA. Triplets of these four letters jointly encode 20 different amino acids out of which proteins of all organisms are built. This system is universal and is found in all kingdoms of life. However, bases in DNA and RNA can be chemically modified. In DNA, around 10 different modifications are known, and those have been studied intensively over the past 20years. Scientific studies on DNA modifications and proteins that recognize them gave rise to the large field of epigenetic and epigenomic research. The outcome of this intense research field is the discovery that development, ageing, and stem-cell dependent regeneration but also several diseases including cancer are largely controlled by the epigenetic state of cells. Consequently, this research has already led to the first FDA approved drugs that exploit the gained knowledge to combat disease. In recent years, the similar to 150 modifications found in RNA have come to the focus of intense research. Here we provide a perspective on necessary and expected developments in the fast expanding area of RNA modifications, termed epitranscriptomics
Altered miR-17-5p expression pattern in response to chemotherapeutic drugs for metastatic colorectal cancer
No full textIn utero exposure to cigarette smoke and effects across generations: A conference of animals on asthma
Get PDFBackground: The prevalence of asthma and chronic obstructive pulmonary disease (COPD) has risen markedly over the last decades and is reaching epidemic proportions. However, underlying molecular mechanisms are not fully understood, hampering the urgently needed development of approaches to prevent these diseases. It is well established from epidemiological studies that prenatal exposure to cigarette smoke is one of the main risk factors for aberrant lung function development or reduced fetal growth, but also for the development of asthma and possibly COPD later in life. Of note, recent evidence suggests that the disease risk can be transferred across generations, that is, from grandparents to their grandchildren. While initial studies in mouse models on in utero smoke exposure have provided important mechanistic insights, there are still knowledge gaps that need to be filled. Objective: Thus, in this review, we summarize current knowledge on this topic derived from mouse models, while also introducing two other relevant animal models: the fruit fly Drosophila melanogaster and the zebrafish Danio rerio. Methods: This review is based on an intensive review of PubMed-listed transgenerational animal studies from 1902 to 2018 and focuses in detail on selected literature due to space limitations. Results: This review gives a comprehensive overview of mechanistic insights obtained in studies with the three species, while highlighting the remaining knowledge gaps. We will further discuss potential (dis)advantages of all three animal models. Conclusion/Clinical Relevance: Many studies have already addressed transgenerational inheritance of disease risk in mouse, zebrafish or fly models. We here propose a novel strategy for how these three model organisms can be synergistically combined to achieve a more detailed understanding of in utero cigarette smoke-induced transgenerational inheritance of disease risk
Next generation sequencing as a tool for pharmacogenomic profiling: Nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemia
Get PDFUvod/Cilj Sekvenciranje nove generacije (SNG) omogućilo je genomsko profilisanje svakog bolesnika. Nova saznanja u oblasti farmakogenomike omogućavaju primenu podataka dobijenih ovom metodom u cilju otkrivanja novih mogućih genetičkih markera za ciljanu terapiju mnogih, posebno malignih bolesti. Cilj ovog istraživanja je bio da se primenom SNG odre- di genetski profil akutne limfoblastne leukemije (ALL) kod dece u cilju procene mogućih molekularnih meta za ciljanu terapiju. Metode Analizirali smo DNK uzorke 17 bolesnika obolelih od ALL dečjeg doba koristeći ciljano SNG. Napredne bioinformatičke metode su korišćene da identifikuju nove mutacije u analiziranim genima i da predvide njihov uticaj i farmakogenomski potencijal. Rezultati Identifikovali smo devet genskih varijanti koje do sada nisu opisane u relevantnim bazama podataka. U navedenim varijantama identifikovane su dve 'besmislene' varijante, ABL1 p.Q252* i AKT1 p.W22*, jedna varijanta koja pomera okvir čitanja, STK11 p.G257fs*28, i šest nesinonimnih varijanti. Kreirali smo trodimenzionalni model za četiri proteina koji bi bili produkt novih nesinonimnih varijanti. Analizirali smo farmakogenomski potencijal svake varijante i otkrili da su dve, STK11 c.1023G gt T/ p.L341F i ERBB2 c.2341C gt T/ p.R781W, mogući kandidati za ciljanu terapiju. Zaključak Nove varijante otkrivene u ovoj studiji pripa- daju uglavnom genima povezanim sa Ras signalnim putem, koji je često zahvaćen mutacijama u ALL kod dece. Farmakogenomsko profilisanje svake dečje ALL biće nezamenljivo za nove terapijske pristupe. Detekcija i inicijalna analiza novih genskih varijanti, koja je predstavljena u ovoj studiji, postaće standardna procedura za dizajniranje i razvoj individualizovane terapije za decu obolelu od ALL.Introduction/Objective Next generation sequencing (NGS) technology has enabled genomic profiling of each patient. Growing knowledge in pharmacogenomics makes it possible to use NGS data for discovery of novel potential genetic markers for targeted therapy of many diseases, especially cancers. The aim of this study was to use targeted NGS to make a genetic profile of childhood acute lymphoblastic leukemia (cALL) in order to evaluate potential molecular targets for targeted therapy. Methods We analyzed DNA samples from 17 cALL patients using NGS targeted sequencing. Advanced bioinformatic analysis was used to identify novel mutations in analyzed genes and to predict their effect and pharmacogenomic potential. Results We identified nine variants that have not been previously reported in relevant databases, including two stop-gain variants, ABL1 p.Q252* and AKT1 p.W22*, one frameshift, STK11 p.G257fs*28, and six missense variants. We created three-dimensional models of four proteins harboring novel missense variants. We analyzed pharmacogenomic potential of each variant and found that two of them, STK11 c.1023G gt T/ p.L341F and ERBB2 c.2341C gt T/ p.R781W, are suitable candidates for targeted therapy. Conclusion Most new variants detected in this study were found in the genes associated with Ras signaling pathway, which is frequently mutated in cALL patients. Pharmacogenomic profiling of each cALL will be indispensable for novel therapy approaches. Detection and initial analysis of novel variants, presented in this study, will become a standard procedure for the design and development of individualized therapies for children with ALL, leading to improved patient outcomes
Using genetics for enhancement (liberal eugenics)
No full textThe fascinating progress of genetics has led to great achievements in the modern, medical, and nonmedical sciences. Genetic engineering is used in many fields, among which human enhancement is one of the most controversial. Most bioethicists agree on the definition of human enhancement as a physical, cognitive, or moral improvement. Genetic enhancement refers to the introduction of the changes into a genome or epigenome intended to improve nonpathological human traits. It is expected that implementation of genetic enhancement will be reached through the discovery of markers in enhancement related genes, such as athletic performance- or aging-related genes, but also through the development of approaches characteristic for personalized medicine, such as gene enhancement, molecular-targeted enhancement, and cellular enhancement. However, we should be aware that genetic enhancement creates significant ethical and regulatory challenges. Prompt and thorough discussion between liberal eugenicists and bioconservatives is indispensable, because genetics is moving extremely fast toward human genetic enhancement
Sudden death: Neurogenic causes, prediction and prevention
Get PDFSudden death is a major health problem all over the world. The most common causes of sudden death are cardiac but there are also other causes such as neurological conditions (stroke, epileptic attacks and brain trauma), drugs, catecholamine toxicity, etc. A common feature of all these diverse pathologies underlying sudden death is the imbalance of the autonomic nervous system control of the cardiovascular system. This paper reviews different pathologies underlying sudden death with emphasis on the autonomic nervous system contribution, possibilities of early diagnosis and prognosis of sudden death using various clinical markers including autonomic markers (heart rate variability and baroreflex sensitivity), present possibilities of management and promising prevention by electrical neuromodulation
Revealing new information from existing genomic data for pepper mild mottle virus pathotype determination
No full textPrimary goals of 21st century science involve eco-friendly solutions for detection, control and suppression of plant viruses. Even though we are accumulating knowledge and data on plant viruses' nucleotide sequences, we are still using a minimum of information available from the collected data. Applying bioinformatics tools and data mining approach to viral sequences is extremely useful in revealing the hidden knowledge, giving guidelines for further biological/bioinformatics studies and developing novel environmental-friendly virus specific defense strategies in crop protection. In this paper we tested to what extent modern bioinformatics methods are able to reveal new information that would bring us closer to our primary goals. On the date of the search (March 2015) we extracted all available PMMoV entries from publically available databases, represented by heterogeneous data set containing 231 nucleotide sequences covering different parts of the PMMoV genome, that were of different geographical origin, related to different time periods, associated with different pathotypes, and were not previously compared to each other. Results revealed that nucleotide content at genomic positions 552, 565, 639, 666, 708, 5921, 5975 and 6002 can be used to discern three distinct PMMoV genotype variants and their association to one of two virus pathotypes, P-1,P-2 or P-1,P-2,P-3. These sites have never been reported as informative before, probably because by being silent mutations they escaped usual research scrutiny of looking for pathotype determinants among nonsense, missense mutations and indels. Our model was further tested in predicting pathotype of ten newly deposited PMMoV sequences and the successful outcome of the test supported the model as an useful asset for discrimination among pathotypes P-1,P-2 and P-1,P-2,P-3 according to distinct nucleotide content in replicase and coat protein encoding genes. Based on the presented results, we also suggested new tests for fast and cost-effective screening of PMMoV pathotypes and eventually for inducing plant resistance against pepper mild mottle virus
Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction
No full textCandida spp. are leading causes of opportunistic mycoses, including life-threatening hospital-borne infections, and novel antifungals, preferably aiming targets that have not been used before, are constantly needed. Hydrazone-and guanidinecontaining molecules have shown a wide range of biological activities, including recently described excellent antifungal properties. In this study, four bis-guanylhydrazone derivatives (BG1-4) were generated following a previously developed synthetic route. Anti-Candida (two C. albicans, C. glabrata, and C. parapsilosis) minimal inhibitory concentrations (MICs) of bisguanylhydrazones were between 2 and 15.6 mu g/mL. They were also effective against preformed 48-h-old C. albicans biofilms. In vitroDNA interaction, circular dichroism, and molecular docking analysis showed the great ability of these compounds to bind fungal DNA. Competition with DNA-binding stain, exposure of phosphatidylserine at the outer layer of the cytoplasmic membrane, and activation of metacaspases were shown for BG3. This pro-apoptotic effect of BG3 was only partially due to the accumulation of reactive oxygen species in C. albicans, as only twofold MIC and higher concentrations of BG3 caused depolarization of mitochondrial membrane which was accompanied by the decrease of the activity of fungal mitochondrial dehydrogenases, while the activity of oxidative stress response enzymes glutathione reductase and catalase was not significantly affected. BG3 showed synergistic activity with amphotericin B with a fractional inhibitory concentration index of 0.5. It also exerted low cytotoxicity and the ability to inhibit epithelial cell (TR146) invasion and damage by virulent C. albicans SC5314. With further developments, BG3 may further progress in the antifungal pipeline as a DNA-targeting agent
Supplementary material for the article: Videnović, M.; Mojsin, M.; Stevanović, M.; Opsenica, I.; Srdić-Rajić, T.; Šolaja, B. Benzothiazole Carbamates and Amides as Antiproliferative Species. Eur. J. Med. Chem. 2018, 157, 1096–1114. https://doi.org/10.1016/j.ejmech.2018.08.067
No full textSupplementary material for: [https://doi.org/10.1016/j.ejmech.2018.08.067]Related to published version: [https://imagine.imgge.bg.ac.rs/handle/123456789/1148]Related to accepted version: [https://imagine.imgge.bg.ac.rs/handle/123456789/2813
Supplementary data for the article: Aleksić, I., Ristivojević, P., Pavić, A., Radojević, I., Comić, L. R., Vasiljević, B., Opsenica, D., Milojkovic-Opsenica, D., & Šenerović, L. (2018). Anti-quorum sensing activity, toxicity in zebrafish (Danio rerio) embryos and phytochemical characterization of Trapa natans leaf extracts. Journal of Ethnopharmacology, 222, 148–158. https://doi.org/10.1016/j.jep.2018.05.005
Get PDFRelated to published version: [https://imagine.imgge.bg.ac.rs/handle/123456789/1111]Related to accepted version:[https://imagine.imgge.bg.ac.rs/handle/123456789/1762]Supplementary material for: [https://doi.org/10.1016/j.jep.2018.05.005