Latest Articles from BioDiscovery Latest 84 Articles from BioDiscovery https://biodiscovery.pensoft.net/ Tue, 19 Mar 2024 06:11:27 +0200 Pensoft FeedCreator https://biodiscovery.pensoft.net/i/logo.jpg Latest Articles from BioDiscovery https://biodiscovery.pensoft.net/ The motility of breast cancer cells is stimulated by HMGB1/RAGE interaction but the truncated form lacking the C terminus has no effect https://biodiscovery.pensoft.net/article/93641/ BioDiscovery 24: e93641

DOI: 10.3897/biodiscovery.24.e93641

Authors: Jordana Todorova, Shazie Myashkova, Maria Petrova, Anastas Gospodinov, Evdokia Pasheva

Abstract: HMGB1/RAGE is identified as a ligand-receptor pair that plays an important role in tumorogenesis. HMGB1 and RAGE levels are higher in most human tumors and their overexpression is associated with tumor progression. The causes of breast cancer are still poorly understood. One reason might be the existence of subtypes within various cellular mechanisms as hormone-dependent and hormone -independent malignant processes. We investigated the effect of HMGB1 protein and its truncated form lacking the C terminus on the RAGE expression and cell motility of breast cancer cell lines; MCF7-noninvasive, MDA-MB-231-invasive and normal breast epithelial one MCF10. The results demonstrate that the effects of HMGB1 and HMGB1∆C through RAGE association are observed exclusively for the hormone independent MDA-MB-231 cell line. The mobility of MDA-MB-231 cells was stimulated only by the full length HMGB1. Our results suggest that HMGB1/RAGE signaling should be considered as an essential process for the development of hormone independent breast cancers with great invasive potential. The truncated form plays the role of a blocking molecule that ”locks” the receptor and inactivates it. This makes the tailless molecule a promising therapeutic agent that competes for the biologically active HMGB1 ligand and prevents the downstream signaling through RAGE.

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Research Article Mon, 12 Sep 2022 15:16:11 +0300
An “overlooked” habitat for thermophilic bacteria: the phyllosphere https://biodiscovery.pensoft.net/article/47033/ BioDiscovery 23: e47033

DOI: 10.3897/biodiscovery.23.e47033

Authors: Jean Jacques Godon, Amandine Galès, Eric Latrille, Pornpimol Ouichanpagdee, Jean-Philippe Seyer

Abstract: Thermophilic microbes are present everywhere around us and their only known natural biotope is far away and most usually associated with geothermal energy. To answer this paradox, we explore the hypothesis that the phyllosphere (surface of leaves), due to its exposition to the sun, could well be a thermophilic habitat for microbes and thus a source of thermophilic microbes growing around 50°C – 60°C. To support this hypothesis, we reviewed the heat sources on earth and associated microbial habitats, as well as the difficult identification of thermophilic microbes. We further present an experiment to show the presence and activity of thermophilic bacteria in the phyllosphere. Leaves were collected from eleven tree species from five locations on three continents belonging to three different biomes. On fresh leaves, 16S rDNA sequencing reveals the presence of 0.2 to 7% of clearly identified thermophilic bacteria. Moreover, after incubation at 55°C under aerobic and anaerobic conditions, 16S rDNA sequencing reveals the presence of 4 to 99% of clearly identified thermophilic bacteria. The accumulation of observations provides coherence to our hypothesis and allows the emergence of a new vision of leaves as a thermophilic biotope. We then propose a life cycle of microbes belonging to the thermophilic biotope associated with leaf surfaces.

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Research Article Mon, 30 Mar 2020 12:00:00 +0300
Aplastic Anemia induced by Nivolumab before a Treatment of Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia https://biodiscovery.pensoft.net/article/37211/ BioDiscovery 22: e37211

DOI: 10.3897/biodiscovery.22.e37211

Authors: Wenhan Cheng, Bryan Jackson

Abstract: As an Immune checkpoint blockade therapy (ICB), nivolumab has demonstrated efficacy in Acute Myeloid Leukemia (AML) and various other malignancies. Nivolumab is used as an anti-programmed cell death 1 (PD-1) agent. The toxicities are observed in more than 10% of patients, because of its ability, anti-PD-1 will upregulate the activity of T-cells. Over-activated T-cells will cause immune-related adverse events such as Aplastic Anemia (AA). Here, we present a case of an over 60-years old male patient with AML, and the possibility for him to receive an allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patient was treated with nivolumab and subsequently developed AA. As an additional consideration, we will also discuss whether allo-HSCT is transplantable when AA is performed during the treatment of AML.

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Case Study Mon, 26 Aug 2019 10:25:13 +0300
Environmental pollutants-dependent molecular pathways and carcinogenesis https://biodiscovery.pensoft.net/article/29242/ BioDiscovery 22: e29242

DOI: 10.3897/biodiscovery.22.e29242

Authors: Myriam El Helou, Pascale A. Cohen, Mona Diab-Assaf, Sandra Ghayad

Abstract: Exposure to environmental pollutants can modulate many biological and molecular processes such as gene expression, gene repair mechanisms, hormone production and function and inflammation, resulting in adverse effects on human health including the occurrence and development of different types of cancer. Carcinogenesis is a complex and long process, taking place in multiple stages and is affected by multiple factors. Some environmental molecules are genotoxic, able to damage the DNA or to induce mutations and changes in gene expression acting as initiators of carcinogenesis. Other molecules called xenoestrogens can promote carcinogenesis by their mitogenic effects by possessing estrogenic-like activities and consequently acting as endocrine disruptors causing multiple alterations in cellular signal transduction pathways. In this review, we focus on recent research on environmental chemicals-driven molecular functions in human cancers. For this purpose, we will be discussing the case of two receptors in mediating environmental pollutants effects: the established nuclear receptor, the Aryl hydrocarbon receptor (AhR) and the emerging membrane receptor, G-protein coupled estrogen receptor 1 (GPER1).

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Review Article Thu, 21 Feb 2019 13:39:37 +0200
Virtual patient simulations for cardiology education and research: A CircAdapt perspective https://biodiscovery.pensoft.net/article/28591/ BioDiscovery 21: e28591

DOI: 10.3897/biodiscovery.21.e28591

Authors: Dimitar Trifonov, Peter Huntjens, Erik Willemen, Tammo Delhaas, Joost Lumens

Abstract: Nowadays cardiac simulations are becoming increasingly sophisticated. This trend, part of the maturing field of computational medicine, has provided medical students and cardiologists alike with a new tool for education and research – their very own virtual “patient”. The CircAdapt biophysical model of the human heart and circulation (www.circadapt.org) allows the creation of a virtual “patient” for the study of the cardiovascular system and circulatory haemodynamics under diverse physiological and pathophysiological conditions in real time. The interactive CircAdapt model with its modular design based on established physical and physiologial principles allows dynamic monitoring of blood flow velocities, pressures and volumes in the heart and blood vessels, and across valves and shunts. As an educational tool, the CircAdapt model enables medical students and residents in cardiology, neonatology and intensive care medicine to analyze complex situations while improving their comprehension of cardiovascular physics and (patho)physiology. Moreover, the CircAdapt model has been successfully utilized as a research tool for cardiac resynchronization therapy as well as for various cardiovascular pathologies (e.g. pulmonary arterial hypertension, LBBB). All in all the CircAdapt perspective is as follows: bridge education and research - from classroom to bedside – to foster the future of clinical practice.

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Conference Abstract Wed, 15 Aug 2018 13:50:58 +0300
Antibacterial activity of thin films TiO2 doped with Ag and Cu on Gracilicutes and Firmicutes bacteria https://biodiscovery.pensoft.net/article/21596/ BioDiscovery 20: e21596

DOI: 10.3897/biodiscovery.20.e21596

Authors: Dragomira Stoyanova, Iliana Ivanova, Orlin Angelov, Todorka Vladkova

Abstract: This article aims to explore the antibacterial activity of thin films of TiO2 doped with Ag and Cu using two types of Gram-negative and Gram-positive test bacteria with clinical significance (Gracilicutes and Firmcutes bacteria). The thin films (thickness of about 60 nm) were deposited on glass substrates by radio frequency magnetron co-sputtering (r.f. power of 50 W) of TiO2 target with Ag and Cu pieces on its surface in an Ar atmosphere (0.8 Pa) without heating during the deposition. The total surface area of the Ag was 60 mm2 and that of the Cu was 100 mm2. Bacillus cereus, Staphylococcus epidermidis, Salmonella enterica, Escherichia coli and Pseudomonas sp. were used as test strains. The antibacterial actvity of the films was evaluated by the classical Koch's method and optical density measurements. The bactericidal effect was established at different time points between 30 min and 90 min for Pseudomonas sp. and S. enterica. The Firmicutes bacteria B. cereus and S. epidermidis were killed at the 4th and 8th hour of the treatment, respectively. The effect on E. coli was bacteriostatic until the 10th hour. The results were confirmed by assessment of the bacterial dehydrogenase activity. The studied thin films of TiO2 co-doped with Ag and Cu have a potential for application as antibacterial coatings.

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Research Article Fri, 15 Dec 2017 15:27:23 +0200
Identification of the gene complexes that determine some individual characteristics of a person https://biodiscovery.pensoft.net/article/21998/ BioDiscovery 20: e21998

DOI: 10.3897/biodiscovery.20.e21998

Authors: Irma Mosse, Alexander Kilchevsky, Alexander Gonchar, Maxim Ameliyanovich, Nikita Sedlyar

Abstract: There are some data about genes associated with certain traits of a person in the scientific literature, but these data are often contradictory. It is evident that complexes of genes that affect the manifestation of the trait can be more informative. We have investigated genotypes of 9000 people, using the PCR method, in order to determine their athletic abilities or predisposition to different diseases and pathologies. In particular, we tested about 3000 women with unknown causes of miscarriages for 14 genes associated with the pregnancy development. 1,5 years later we interviewed 700 women and have identified a high genetic risk of pregnancy loss due to hereditary thrombophilia. In most of the cases, doctors took into account our data and applied for these women treatment with anticoagulant drugs such as fragmin in the subsequent pregnancies. So 86.6% of pregnant women have successfully conceived and given birth, and we have received over 500 touching letters of gratitude. Thus, genetic testing allows to identify individual human properties in order to prevent some pathologies or to chose the most suitable kind of sport.

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Conference Abstract Mon, 6 Nov 2017 15:36:24 +0200
Innovative sterilization technology - bacterial inactivation by cold argon plasma https://biodiscovery.pensoft.net/article/21977/ BioDiscovery 20: e21977

DOI: 10.3897/biodiscovery.20.e21977

Authors: Yovana Todorova, Ivaylo Yotinov, Yana Topalova, Plamena Marinova, Evgenia Benova, Mariana Atanasova, Todor Bogdanov

Abstract: Non-thermal (cold) plasma is subject of intensive scientific interest as an alternative sterilization technique for advanced control of microbial quality and safety in food biotechnology. The cold plasma is a flow of weakly ionized gas at atmospheric pressure that includes radicals, H2O2, O3, ultraviolet radiation, charged particles, exited metastable atoms, electric fields. One of the major benefits of plasma-based technologies is the synergy between the strong effects of these highly active components that provides a high bactericidal efficiency at low costs, time-saving and non-toxicity. The aim of this study is to assess the bactericidal effect of cold argon plasma in liquids and surfaces, contaminated with Gram-negative and Gram-positive spore-forming bacteria. The used plasma source is surface-wave-sustained discharge (SWD) operating at 2.45 GHz in argon (plasma torch) produced by an electromagnetic wave launcher surfatron type. The bactericidal effect was studied by direct contact treatment of contaminated liquids and agar plates with Pseudomonas aureofaciens AP-9 and Brevibacillus laterosporus BT-271. The results show that the cold argon plasma is able to inactivate bacteria at short exposure time (under 1 min). The clear sterilization zones on treated surfaces with diameter depending on exposure time and initial bacterial density were obtained. In bacteria-contaminated liquids the partial disinfection was observed at least. The potential of plasma based technologies as innovative sterilization approach is high and can be used for various purposes related to microbial control and food safety.

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Conference Abstract Fri, 3 Nov 2017 20:47:28 +0200
Participation of NO-synthase in Control of Nitric Oxide Level in Rat Hippocampus after Modelling of Ischaemic and Haemorrhagic Insult https://biodiscovery.pensoft.net/article/14810/ BioDiscovery 20: e14810

DOI: 10.3897/biodiscovery.20.e14810

Authors: Khalil L. Gainutdinov, Svetlana G. Pashkevich, Vyatcheslav V. Andrianov, Guzel G. Yafarova, Margarita O. Dosina, Tatiana Kh. Bogodvid, Julia P. Stukach, Dinara I. Silant'eva, Aleksandra S. Zamaro, Timur V. Sushko, Vladimir Kulchitsky

Abstract: Electron paramagnetic resonance (EPR) was used as a method for recording the content of the nitric oxide (NO) in hippocampal tissues of intact rats and rats after modelling of ischaemic and haemorrhagic stroke. Based on direct measurements of NO by EPR spectroscopy, it was shown that, within 5 hours after the onset of symptoms of ischaemic and haemorrhagic stroke, the formation of NO in the hippocampus was reduced by a factor of 2-3 and this reduction was maintained for a period of between 24 and 72 hours. The results show that a systemic character of a decrease in the intensity of NO production during the modelling of ischaemic events in the brain reflects the effects of central dysregulation of the functions at the level of the whole organism such that it is appropriate to consider implementing the correction of the vital systems of the body in a stroke. It has indicated that non-selective NO-synthase blocker L-NAME reduced the low level of NO production by a factor of 3 by its administration within 72 hours after post-ischaemic and haemorrhagic stroke. It was discovered however that L-NAME returns the level of NO production to baseline (control) by its administration within 5 hours after ischaemia.

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Research Article Wed, 18 Oct 2017 12:05:23 +0300
Pilot assessment of cyanotoxins as potential risk factors for cancer in Bulgaria https://biodiscovery.pensoft.net/article/20501/ BioDiscovery 20: e20501

DOI: 10.3897/biodiscovery.20.e20501

Authors: Maya Stoyneva-Gärtner, Blagoy Uzunov, Petya Dimitrova

Abstract: Cyanoprokaryotes (=cyanobacteria, blue-green algae) are the most ancient oxygen-producing phototrophic microorganisms, spread all over the Globe, which form the important basis of different food chains in aquatic and terrestrial habitats. However, due to strong anthropogenic pressure during the last decades they are also responsible for causing nuisance algal blooms in different water bodies with deleterious effects on the mankind and ecosystems mainly due to production of toxic substances (cyanotoxins). Amongst them are the microcystins, nodularins, lyngbyatoxins and aplysiatoxins, known as tumor-promotors with increase of exposure routes through which humans and animals can be placed at risk (Meriluoto et al. 2017). However, the investigations on the relations between the occurrence and development of such diseases with the cyanotoxins and their producers are extremely scarce at a global scale (Yu and Chen 1994, Ueno et al. 1996, Fleming et al. 2002, Svircev et al. 2009, Drobac et al. 2011, Labine et al. 2015). During the last 15 years cyanoblooms and microcystins, nodularins and saxitoxins were detected in 16 different Bulgarian freshwater bodies, including some drinking-water reservoirs (Stoyneva-Gärtner et al. 2017). Amongst the detected toxins some new forms were recognized by their characteristic spectra (Pavlova 2007, Pavlova et al. 2007), and, more recently, a new potential producer of lyngbyatoxin was found in the Black Sea (Stoyneva et al. 2015). The poster shows a pilot assessment of the spread of cancer distribution and mortality vs. spread of cyanoblooms and cyanotoxins in Bulgaria. The pilot assessment is made on the basis of comparison of the general regions of spread of cyanotoxins in Bulgarian water bodies and toxin-producing cyanospecies during the period 2000-2017 (Stoyneva-Gärtner et al. 2017) with the spread of cancer in Bulgaria (e.g. Valerianova et al. 2015). The comparison shows general conformities between the spread of the “most dangerous” water bodies and main regions of cancer diseases in the country. The results obtained served as a basis for a new project proposal which aims at a deepening of the studies for improvement of prevention of cancer in the country.

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Conference Abstract Thu, 24 Aug 2017 15:09:52 +0300
Osteogenic, adipogenic and neurogenic differentiation of human adipose-derived mesenchymal stem cells before and after cryopreservation https://biodiscovery.pensoft.net/article/20272/ BioDiscovery 20: e20272

DOI: 10.3897/biodiscovery.20.e20272

Authors: Marina Hristova, Elena Hristova, Plamen Todorov

Abstract: Mesenchymal stem cells (MSCs) represent a promising tool for the regeneration of damaged tissues in cell therapy. They are characterized as undifferentiated progenitors, which have the ability for self-renewal and multilineage differentiation potential. The development of effective protocols for long-term storage, with the aim of subsequent clinical usage, is essential for their application as cellular therapeutics. In our experiments, we aimed to investigate fresh and cryopreserved human adipose tissue-derived MSCs (AT-MSCs) and their osteogenic, adipogenic and neurogenic differentiation potential. The obtained results pointed out that the cells possess spindle-like shape and form characteristic wave-like layers when reaching confluency. The immunophenotypic analysis shows that they express CD73, CD90 and CD105 and lack the hematopoiеtic lineage markers CD34 and CD45. Both cryopreserved and fresh hAT-MSCs maintain similar ability to specialize towards osteogenic, adipogenic and neural lineage. In conclusion, the present study indicates that the isolated cells are cryotolerant and are able to retain their morphological and immunophenotypical characteristics  after freezing, as well as their multilineage differentiation potential.

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Conference Abstract Mon, 21 Aug 2017 23:16:27 +0300
Two candidate genes for recurrent pregnancy loss and infertility: Could ZP3 and UPK3B give us new diagnostic and therapeutic approach? https://biodiscovery.pensoft.net/article/20113/ BioDiscovery 20: e20113

DOI: 10.3897/biodiscovery.20.e20113

Authors: Fatma Sılan, Baris Paksoy, Taner Karakaya, Onur Yildiz, Mine Urfali, Ozturk Ozdemir

Abstract: Introduction: Chromosomal indels are relatively common cytogenetic abnormalities. Nonetheless, clinical outcomes depend on the location, size and genes in deletion or duplication regions. The zona pellucida is an extracellular matrix that surrounds the oocyte and early embryo. It is composed primarily of three or four glycoproteins with various functions during fertilization and preimplantation development. The protein encoded by ZP3(Zona pellucida3) gene is a structural component of the zona pellucida and functions in primary binding and induction of the sperm acrosome reaction. UPK3B(Uroplakin 3B), a minor component of the apical plaques of mammalian urothelium that binds and dimerizes with uroplakin-1b(UPK1B), one of the major conserved urothelium membrane proteins. We herein report two cases presenting with the deletions encompassing POMZP3, UPK3B, ZP3, POM121 and POM121C genes. Case1: 25-year-old female presented to our clinic with recurrent pregnancy loss. After clinical and cytogenetic evaluation, which all of them do not feature, she was diagnosed as the deletion of POMZP3 and UPK3B genes with the array-CGH platform. (Agilent SurePrintG3 HumanCGH 60K) Case2: Ten-week embrio of 34-year-old female, infertile for ten years before and this is her first pregnancy after IVF, revealed the deletion of POM121,POM121C and ZP3 genes with the same array-CGH platform. Conclusion: We have evaluated the deletion of two consecutive genes -UPK3B and ZP3- in the genome by array-CGH analysis. Early abortion or infertility due to triploidic, tetraploidic embryos or uniparental disomy, resulting in a change in the structure of the zona pellucida with the mutations of ZP3 gene, may occur. Also mutations of UPK3B gene may cause abortion or infertility due to endometrial origin with defective function of the urothelium membrane proteins. ICSI could be a good choice for ZP3 deficient infertile woman and if PGS choosen without ICSI, uniparental disomia should be excluded.

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Conference Abstract Thu, 10 Aug 2017 14:04:33 +0300
Comet assay - a sensitive tool for genotoxicity assessment of environmental stress in Mytilus galloprovincialis from the Bulgarian Black Sea coast https://biodiscovery.pensoft.net/article/19265/ BioDiscovery 20: e19265

DOI: 10.3897/biodiscovery.20.e19265

Authors: Bela Vasileva, Lachezar Yakimov, Borislava Kukurina, Milena Georgieva, George Miloshev, Nesho Chipev

Abstract: Assessment of DNA damage is of primary concern when the pollution-related stress in living organisms has to be determined. The reason for this concern comes from the evidence that damages in DNA often lead to mutations which are potential threat for the sustainability of organisms and ecological systems. To monitor genotoxicity of the marine environment we have developed a special procedure for application of the method of Comet assay (CA) on the native populations of Mytilus galloprovincialis. Samples were collected from areas with different anthropogenic load along the Bulgarian South Black Sea coast. As the first organ to encounter marine pollutants the gills of the mussels turned-out to be the most appropriate tissue for obtaining a single-cell suspension. Comet assay tests were performed and DNA damage was quantified using several different methods including percentage of DNA in the tail, Comet head and tail area, Comet number, Tail moment, Comet shape, etc. The method allowed us to monitor and predict the genetic risk of marine environmental stressors, particularly persistent pollutants. It proved to be convenient for precise quantification of the on-site loads of genotoxic stress on coastal ecosystems.

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Conference Abstract Tue, 1 Aug 2017 22:58:49 +0300
Genetic changes in natural Taraxacum officinale populations obtained under pollution stress https://biodiscovery.pensoft.net/article/18712/ BioDiscovery 20: e18712

DOI: 10.3897/biodiscovery.20.e18712

Authors: Borislava Kukurina, George Miloshev

Abstract: Plant populations under stress undergo genotypic alterations which can drive the species towards extinction or adaptation. Defining a suitable plant model and the respective genetic markers for studying the perturbations in the population’s genetic diversity is of crucial importance for the needs of bioconservation and proper ecosystem management. In the current study we prove the usefulness of Taraxacum officinale (common dandelion) as a suitable model plant for genetic biomonitoring. We compared the genotype composition of four specific dandelion populations: 1) a population from the area around the closed “Kremikovtzi” metallurgical plant; 2) a population from the still working “Stomana”-Pernik metallurgical facility; 3) a population from a rural, but naturally rich in heavy metals region close to Bosnek village; 4) a control population from a clean site next to Lokorsko village. Four genetic markers of tree different kinds (a microsatellite, a ribosomal DNA marker and two chloroplastic DNA markers) were tested in order to reveal the genotype diversity in the chosen populations. Our results showed strong quantitative and qualitative genotypic differentiation between pollution-impacted and clean populations. The most interesting observation was that the unique genotypes, considered as result of mutations, were predominantly detected in the plants from the heavy metal polluted regions.

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Conference Abstract Tue, 1 Aug 2017 22:55:33 +0300
Basal and PGF2α-stimulated secretion of pro-inflammatory cytokines from 3T3-L1 adipocyte-like cells https://biodiscovery.pensoft.net/article/17757/ BioDiscovery 20: e17757

DOI: 10.3897/biodiscovery.20.e17757

Authors: Bilyana Ilieva, Elena Marinova, Hristo Gagov, Rossitza Konakchieva

Abstract: Adipocytes were recently identified as an important source of endocrine and paracrine mediators, regulating the metabolism and activity of various cell types and body functions. 3T3-L1 preadipocytes are useful model for physiological, pharmacological and cell signaling studies. Differentiation of 3T3-L1 murine fibroblasts into adipocyte-like cells was conducted in presence of IBMX, dexamethasone and insulin and demonstrated by Oil Red O staining of accumulated lipid droplets. Using Inflammatory Multi- Analyte Cytokines ELISArray Kit we investigated the release of cytokines under basal conditions, after PGF2α treatment for 24 hours to induce pro-inflammatory phenotype, and after PGF2α treatment and incubation in the presence of L-C-Propargylglycine (PGG, 1 mmol/l), a selective inhibitor of cystathionine-gamma-lyase (CSE). The last combination was used to explore the role of H2S, released from CSE, for cytokine and H2O2 release. We found that PGF2α strongly increased TNFα secretion from differentiated adipocytes, the latter effect being antagonized by PGG. The CSE inhibitor enhanced IL-6 production and suppressed IL-10 secretion. PGG enhanced H2O2 production of in PGF2α-treated cells. It is concluded that pro-inflammatory phenotype of differentiated 3T3-L1 adipocyte-like cells, induced by PGF2α is characterized by enhanced TNFα production which critically depends on the ability of CSE to produce H2S. 

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Conference Abstract Tue, 1 Aug 2017 19:14:03 +0300
Perivascular adipose tissue as regulator of the force of artery contractions in health and disease https://biodiscovery.pensoft.net/article/19831/ BioDiscovery 20: e19831

DOI: 10.3897/biodiscovery.20.e19831

Authors: Hristo Gagov, Radoslava Emilova, Daniela Dimitrova, Mitko Mladenov, Rudolf Schubert

Abstract: During the last two decades, perivascular adipose tissue (PVAT) has been revealed as an important regulator of vascular processes such as proliferation of smooth muscle cells, pro- and anti-oxidant reactions in the vascular wall, angiogenesis, inflammation, apoptosis of neutrophils, migration of monocytes and others. PVAT derived mediators either increase or decrease the amplitudes of the force of artery contraction measured using isometric small vessel myography. In healthy animals and humans predominates the relaxing effect while in diseases the contractile influence of PVAT is common. In aging and pathological conditions like atherosclerosis and diabetes, or with environmental factors like tobacco smoke and high-fat diet, the phenotype of perivascular adipocytes is changed from anti-inflammatory to pro-inflammatory. This change is accompanied by a significant rearrangement of mediators released from PVAT.

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Conference Abstract Tue, 1 Aug 2017 16:21:23 +0300
Ultrananocrystalline diamond coated implants for enhanced osseointegration https://biodiscovery.pensoft.net/article/19830/ BioDiscovery 20: e19830

DOI: 10.3897/biodiscovery.20.e19830

Authors: Silviya Stateva, Daniel Merker, Cyril Popov, Margarita Apostolova

Abstract: Osteoporosis causes bones to become weak and brittle. It is known that the alterations in bone metabolism associated to osteoporosis can impair bone healing around implants and affect their osseointegration. The main objective of this study was the development of new nanostructured implant materials based on ultrananocrystalline diamond (UNCD) coatings for enhancing osseointegration. The films were deposited on Ti substrates by microwave plasma CVD from 17% CH4/N2 gas mixtures and modified by O2 or NH3/N2 plasmas. The modifications rendered the H-terminated hydrophobic as-grown films hydrophilic. The interaction of endothelial (EA.hy926) and osteosarcoma (MG63) cells with differently modified UNCD surfaces was investigated by proteome analyses. It revealed the identification of over 19 000 proteins (extracellular and cytosolic). They correspond to 508 (Ti), 634 (UNCD), 651 (O-UNCD), and 668 (NH2-UNCD) protein groups. The interaction network analysis showed differences in the connectivity of inferred protein networks between the ECM niches, which suggests the presence of specific cell microenvironments on O- and NH2-terminated UNCD surfaces. Our results show that due to a favorable combination of surface chemical and topological properties the UNCD films, as-grown and especially after their plasma modifications, may serve as superior scaffolding for promoting the cell attachment and growth during osseointegration.

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Conference Abstract Tue, 1 Aug 2017 15:43:01 +0300
Testosterone as Diamine Oxidase Activity Regulator https://biodiscovery.pensoft.net/article/17372/ BioDiscovery 20: e17372

DOI: 10.3897/biodiscovery.20.e17372

Authors: Milena Mishonova, Hristo Gagov

Abstract: Diamine oxidase (DAO) is a key enzyme of the metabolism of polyamines. Its activity was assayed in homogenate of male immature rat liver and kidney.  The androgens are important regulators of polyamines’ metabolism. It was known that testosterone (T) activates DAO in murine kidney, an effect that might depend on the intracellular level of polyamines. The aim of this research was to study the participation of androgen receptor and ornithine decarboxylase (ODC) in DAO testosterone regulation. The rats were treated i.p. 4 hours before measurements with T, T + Hydroxyflutamide (HF), an androgen receptor antagonist or T + difluoromethylornithine (DFMO), an inhibitor of ODC. It was observed that i) T significantly increased DAO activity of rat liver and kidney; ii) the presence of HF abolished the effect of T ; iii) the presence of DFMO slowly reduced the effect of T on DAO activity. It is concluded that T activates DAO mainly by a mechanism, which includes androgen receptor binding and ODC stimulation.

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Conference Abstract Tue, 1 Aug 2017 11:07:33 +0300
New Mechanisms of Perinatal Hypoxia and Perspectives of Pathogenesis-oriented Treatment https://biodiscovery.pensoft.net/article/14945/ BioDiscovery 20: e14945

DOI: 10.3897/biodiscovery.20.e14945

Authors: Larisa A. Balykova, Ludmila V. Ledyajkina, Vladimir A. Trofimov, Alexei P. Vlasov, Irina S. Nazarova, Victor V. Revin

Abstract:

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Conference Abstract Mon, 17 Jul 2017 23:16:45 +0300
Change in morphometric and oxygen-binding properties of erythrocytes in vascular diseases patients https://biodiscovery.pensoft.net/article/15079/ BioDiscovery 20: e15079

DOI: 10.3897/biodiscovery.20.e15079

Authors: Natalia Gromova, Victor Revin, Nadezhda Revina, Anastasiya Kukina, Elvira Revina, Anastasiya Samonova, Ilya Solomadin, Alexander Tychkov, Inessa Moiseeva

Abstract:

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Conference Abstract Mon, 17 Jul 2017 20:57:38 +0300
Antibacterial activity of thin films TiO2 doped with Ag and Cu on Gracilicutes and Firmicutes bacteria https://biodiscovery.pensoft.net/article/15076/ BioDiscovery 20: e15076

DOI: 10.3897/biodiscovery.20.e15076

Authors: Dragomira Stoyanova, Iliana Ivanova, Orlin Angelov, Todorka Vladkova

Abstract:

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Conference Abstract Mon, 17 Jul 2017 20:24:58 +0300
Application of safe-by-design approach for curing osteoporosis – a lock at the future https://biodiscovery.pensoft.net/article/15099/ BioDiscovery 20: e15099

DOI: 10.3897/biodiscovery.20.e15099

Authors: Armine Grigoryan, Iliyan Kolev, Anelia Dimitrova, Margarita Apostolova

Abstract:

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Conference Abstract Mon, 17 Jul 2017 20:00:32 +0300
Antiviral activity of Stachys Thracica Dav. extracts against Human Herpes virus type 1 and 2 https://biodiscovery.pensoft.net/article/15022/ BioDiscovery 20: e15022

DOI: 10.3897/biodiscovery.20.e15022

Authors: Petya Angelova, Venelin Tsvetkov, Anton Hinkov, Daniel Todorov, Kalina Shishkova, Zhenya Yordanova, Veneta Kapchina-Toteva, Stoyan Shishkov

Abstract: Objective: Human Herpes Virus (HHV) type 1 and 2 are cause of hidden pandemics in global scale, as well as sever clinical symptoms associated with active replication in the human host. As until now there are 11 license anti-herpes drugs. Most of them are based on acyclovir and his derivative. Their frequent usage leads to the selection of drug resistance strains and patients offen experience unwanted side effects. Natural products (for ins. plant extracts) are tolerated better by living organisms and their complex composition prevent appearance of resistant virions. The aim of our work is to study the effect of Stachys Thracica Dav extracts against Human Herpes Virus type 1, strain F and Human Herpes Virus type 2, strain BA.Materials and methods: The extracts are obtained from in vivo, in vitro and ex vitro cultivated plants, using methanol extraction. All tests are done in in vitro experimental settings. We use MDBK cell line, and also laboratory strain F of HHV – 1. The following methods were applied: MTT assay to determine cell survival, direct contact assay to test virucidal activity and modified MTT assay to determine effect against virus replication in cell culture.  Results: Obtained data shows that two of the extracts – those from in vitro and ex vitro cultivated plants are with close MNC (maximal nontoxic concentration) (2mg/ml), and the third one is more toxic (MNC is 1mg/ml). The tested extracts do not influence the replication of HHV – 1 and HHV-2. The results about virucidal activity show that the extracts strongly inhibited extracellular virions of HHV-1, strain F (extracts from in vitro cultivated plants reach ~ 100% at 240 minutes of the contact), but the effect of the extracts on extracellular virons of HHV-2, strain BA is more slight.Conclusions: Tested extracts do not have effect against virus replication in cell culture but show strong virucidal activity against HHV-1 and slight activity against HHV-2.

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Conference Abstract Mon, 17 Jul 2017 16:38:18 +0300
Synthesis of a drug discovery library for the identification of sigma receptors modulators https://biodiscovery.pensoft.net/article/14958/ BioDiscovery 20: e14958

DOI: 10.3897/biodiscovery.20.e14958

Authors: Giacomo Rossino, Marta Rui, Marcello Di Giacomo, Daniela Rossi, Simona Collina

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Conference Abstract Mon, 17 Jul 2017 13:24:10 +0300
Recent advances in the structure-guided research and development of antimicrobial therapeutics https://biodiscovery.pensoft.net/article/14952/ BioDiscovery 20: e14952

DOI: 10.3897/biodiscovery.20.e14952

Authors: Dimitar Trifonov, Tom Evers

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Conference Abstract Mon, 17 Jul 2017 10:24:41 +0300
Validation of a novel HPLC-based serum thymidine kinase assay for breast cancer detection https://biodiscovery.pensoft.net/article/14563/ BioDiscovery 20: e14563

DOI: 10.3897/biodiscovery.20.e14563

Authors: Elena Kuzmanova, Marilena Spanou, Emma Leckie, Nikolai Zhelev

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Conference Abstract Wed, 5 Jul 2017 05:44:23 +0300
A step forward in the identification of compounds interfering with the Embryonic Lethal Abnormal Vision (ELAV) protein - RNA complexes https://biodiscovery.pensoft.net/article/14670/ BioDiscovery 20: e14670

DOI: 10.3897/biodiscovery.20.e14670

Authors: Serena Della Volpe, Daniela Rossi, Francesca Vasile, Donatella Potenza, Marialaura Amadio, Alessia Pascale, Simona Collina

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Conference Abstract Wed, 5 Jul 2017 04:44:08 +0300
Sigma 1 receptor modulators as a new weapon against multiple sclerosis https://biodiscovery.pensoft.net/article/14565/ BioDiscovery 20: e14565

DOI: 10.3897/biodiscovery.20.e14565

Authors: Simona Collina, Marta Rui, Giacomo Rossino, Serena Della Volpe, Daniela Rossi, Arianna Scuteri, Alessio Malacrida, Guido Cavaletti

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Conference Abstract Wed, 5 Jul 2017 03:40:56 +0300
Cryogenic pretreatment of keratinous waste for enhanced methane production https://biodiscovery.pensoft.net/article/14096/ BioDiscovery 20: e14096

DOI: 10.3897/biodiscovery.20.e14096

Authors: Elena Kuzmanova, Joseph Akunna, Nikolai Zhelev

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Conference Abstract Wed, 5 Jul 2017 02:40:27 +0300
The effects of changes in composition and state of the lipids on erythrocytes’ oxygen-transport function in pathological conditions associated with the development of hypoxia https://biodiscovery.pensoft.net/article/14701/ BioDiscovery 20: e14701

DOI: 10.3897/biodiscovery.20.e14701

Authors: Victor V. Revin, Natalia V. Gromova, Elvira S. Revina, Ilya N. Solomadin, Alexander Yu. Tychkov

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Conference Abstract Wed, 5 Jul 2017 01:39:59 +0300
Phosphorylase Kinase Inhibition Therapy in Burns and Scalds https://biodiscovery.pensoft.net/article/11207/ BioDiscovery 20: e11207

DOI: 10.3897/biodiscovery.20.e11207

Authors: Madalene Heng

Abstract: Severe burns and scalds almost always result in unsightly hypertrophic scarring. Among the important processes involved in scarring are fibroblast formation and transformation of fibroblasts into myofibroblasts. Myofibroblasts contain α-smooth muscle actin which has contractile properties and can lead to wound contraction and hypertrophic scarring. Phosphorylase kinase (PhK), expressed within 5 mins of injury, is among the earliest enzymes released after tissue damage. It is responsible for activation of NF-kB, which in turn activates over 200 different genes related to inflammation, fibroblastic proliferation, myofibroblast conversion, and eventual scar tissue formation. The sequence and approximate timing of events following injury include the following: activation of PhK (5 mins), followed by appearance of neutrophils (30 mins), macrophages (hours to days), fibroblasts (1 week) and myofibroblasts (2 weeks). Cytokines and growth factors secreted by macrophages include fibroblast growth factor (FGF) and transforming growth factors α and β (TGFα and TGFβ). Fibroblast growth factor is responsible for fibroblastic proliferation, and TGFβ1 for conversion of fibroblasts into myofibroblasts. After thermal injury, the use of topical curcumin, a non-competitive, selective PhK inhibitor that blocks PhK activity upstream of NF-kB activation, was found to be associated with more rapid and improved skin healing, as well as less severe or absent scarring.

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Research Article Fri, 24 Feb 2017 10:49:14 +0200
Drug resistance of cancer cells is crucially affected by expression levels of ABC-transporters https://biodiscovery.pensoft.net/article/11211/ BioDiscovery 20: e11211

DOI: 10.3897/biodiscovery.20.e11211

Authors: Petr Mlejnek, Petr Dolezel, Eliska Ruzickova

Abstract: Dasatinib (DAS), a second generation of tyrosine kinase inhibitor (TKI), represents excellent choice for the treatment of chronic myeloid leukemia resistant to imatinib. Unfortunately, recent laboratory studies suggested that antiproliferative effect of DAS might be significantly reduced due to the overexpression of the ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2. However, whether these drug transporters might compromise therapeutic effect of DAS in clinic is unclear. We believe that the drug transporter expression level is a crucial factor that affects the results and its consideration may help to explain the existing controversy. In addition, clinically relevant concentrations of drug must be used. In our study, human leukemia K562 cells with high and low expression levels of ABCB1 or ABCG2 were used. DAS was applied at nanomolar concentrations. We observed that K562 cells expressing high levels of ABCB1 and ABCG2 contained significantly reduced intracellular levels of DAS and these cells exhibited significantly increased resistance to this drug. Importantly, cells with the low expression of ABCB1 or ABCG2 effluxed DAS less efficiently, however, still significantly. Accordingly, the observed resistance was lower but significant. Conclusions: The antiproliferative effects of DAS might be reduced by ABCB1 or ABCG2. However, the actual effect of these ABC transporters on DAS efficiency depends on their expression levels. The lower expression levels of ABC transporters mediate lower resistance. Considering the fact that expression levels of ABCB1 and ABCG2 transporters are usually low in clinical samples, their contribution to the overall resistance to DAS is probably low but significant.

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Research Article Wed, 8 Feb 2017 10:52:09 +0200
Screening an Archetypal Collection of Microorganisms for the Presence of Unexplored Antimicrobial Compounds https://biodiscovery.pensoft.net/article/10763/ BioDiscovery 20: e10763

DOI: 10.3897/biodiscovery.20.e10763

Authors: Lucia Cimarelli, Anna Maria Giuliodori, Anna Brandi, Karolina Adamkiewicz, Roberto Spurio, Attilio Fabbretti

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Research Poster Wed, 8 Feb 2017 09:26:49 +0200
The success of stem cell transplantations and the potential post-transplantation complications may be dependent, among other factors, on the capacity of the recipient and the transplanted cells to repair DNA damage https://biodiscovery.pensoft.net/article/9076/ BioDiscovery 19: e9076

DOI: 10.3897/BioDiscovery.19.e9076

Authors: Lewis Reynolds

Abstract: Cell therapy is presently a treatment of choice for many types of haematological and metabolic diseases and is likely to become a therapeutic option for other severe human diseases and conditions in the near future. The success of cell transplantation depends on a variety of factors, including the degree of HLA match between the donor and the recipient, the infectious burden of the graft, cell dosage, age, general state of the recipient and other incompletely characterised features of the donor and the recipient. It is likely that the individual capacity for identification and repair of DNA damage and maintenance of genomic integrity may account, at least in part, for these elusive factors that modulate transplantation outcome in terms of success rate and both long and short term post-transplantation complications. This paper outlines the role of individual repair capacity of the donor and recipient in cell transplantations, summarising the little knowledge already accumulated in the field whilst analysing the known major issues of the use of different types of stem cells. Attention will be given to their capacity to maintain the integrity of their genome, the ability to renew their own population, differentiate into various cell types and in some cases, succumb to carcinogenic transformation. Analysis of the individual capacity may become a useful tool in the assessment of the suitability of a set of freshly collected stem cells or an in vitro propagated cell line for potential clinical applications.

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Review Article Tue, 29 Mar 2016 15:59:32 +0300
An old wives' tale. Reproductive outcomes in pregnant women aged 35 or older: the role of individual repair capacity https://biodiscovery.pensoft.net/article/8970/ BioDiscovery 18: e8970

DOI: 10.7750/BioDiscovery.2015.18.2

Authors: Rumena Petkova, V Dimitrova, Nikolai Zhelev, Stoyan Chakarov

Abstract: At present, childbirth is being progressively postponed until later age. Women aged 35 or older may have to wait longer to conceive than younger women and are more likely to be referred to fertility evaluations, but in a significant proportion a spontaneous conception would be achieved in the timeframe typical of younger women. Pregnancies where mothers are ≥ 35 are associated with more risks for pregnancy loss, chromosomal disease, pregnancy-associated complications, prematurity and low birthweight. These concerns, however, are not uncommon in younger women as well. This puts forward the question whether advanced age per se is the underlying cause for the increased risk for adverse outcomes in older pregnant women, or whether there might be other factors that account for it but do not radically worsen the prospects for favourable outcomes. The individual risks associated with childbirth late in life may stem from maternal genetic background rather than being a simple function of age. There is plenty of preliminary evidence that individual capacity for identification and repair of DNA damage may constitute a major factor in female fertility and fecundity. Subtle deficiencies in the repair capacity may have little to no importance in younger pregnant women but may make a significant difference in older women. The outcomes of pregnancies in women >35 are largely dependent on the pre-pregnancy health status and the quality of antenatal care, and may not be dramatically different from outcomes in younger women.

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Review Article Wed, 23 Dec 2015 00:00:00 +0200
A de novo microdeletion 2p24.3-25.1 identified in a girl with global development delay https://biodiscovery.pensoft.net/article/8967/ BioDiscovery 18: e8967

DOI: 10.7750/BioDiscovery.2015.18.1

Authors: Hristo Y. Ivanov, Vili K. Stoyanova, Radoslava Vazharova, Aleksandar Linev, Ivan Ivanov, Samuil Ivanov, Lubomir Balabanski, Draga Toncheva

Abstract: Interstitial microdeletions of the distal 2p are very rare. A small number of cases have been reported in the literature, involving regions 2p23-p25, 2p23-p24 and 2p24-p25. The most common symptoms involve: intrauterine growth retardation, developmental delay, mental retardation, microcephaly, craniofacial anomalies, musculoskeletal abnormalities, congenital heart defect and hearing impairment. Herein we report on a Caucasian girl, born after in vitro fertilization with discrete facial dysmorphism, growth failure, borderline neurodevelopment and congenital heart defect. A de novo pericentric inversion of chromosome 2 was identified by routine karyotyping. An interstitial microdeletion of 2p24.3p25.1 was found by array karyotyping and following FISH analysis revealed that the deletion affects the inverted chromosome 2. This case illustrates the utility of high resolution methods to identify submicroscopic quantitative changes in structurally rearranged chromosomes. The precise determination of the genetic content of small quantitative changes in the genome provides important information for genetic counseling, enabling to predict the course of disease and the planning of adequate therapy and prophylaxis in affected families.

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Short Communication Sat, 10 Oct 2015 00:00:00 +0300
Blood-Based Gene Expression in children with Autism spectrum disorder https://biodiscovery.pensoft.net/article/8966/ BioDiscovery 17: e8966

DOI: 10.7750/BioDiscovery.2015.17.2

Authors: Hristo Y. Ivanov, Vili K. Stoyanova, Nikolay T. Popov, M. Bosheva, Tihomir I. Vachev

Abstract: Comparative gene expression profiling analysis is useful in discovering differentially expressed genes associated with various diseases, including mental disorders. Autism spectrum disorder (ASD) is a severe neuropsychiatric disorder which has complex pathobiology with profound influences of genetic factors in its development. Although numerous autism susceptible genes were identified, the etiology of autism is not fully explained. The study aimed to examine gene expression profiling in peripheral blood from 60 individuals divided into two groups: children with ASD and age- and gender-matched healthy subjects (ASD control). A genome-wide sequencing of copy DNA molecules was conducted to obtain information for quantitative expression of all genes subject to this study and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway-based analysis was used to further understand genes’ biological functions. Based on the conducted expression analysis 23 differentially expressed genes and 21 KEGG signaling pathways with statistical significant change were identified. Blood-based comparative gene expression profiling analysis is useful in discovering genetic markers associated with ASD. Our data will provide a valuable resource for discovery purposes and for comparison to other gene expression-based, genome-wide studies and other functional data.

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Research Article Wed, 30 Sep 2015 00:00:00 +0300
APOE4, oxidative stress and decreased repair capacity - a no-brainer. Faulty lipid metabolism and increased levels of oxidative damage may be risk factors in the pathogenesis of late-onset dementia https://biodiscovery.pensoft.net/article/8969/ BioDiscovery 17: e8969

DOI: 10.7750/BioDiscovery.2015.17.1

Authors: Ashima Nayyar, Lubomira Chakalova

Abstract: Dementia is very common in the elderly and its incidence increases in an age-dependent fashion. Alzheimer''s disease and vascular cognitive decline are the most common cases of dementia in the elderly. Amyloid burden and increased levels of oxidative damage have been implicated to play significant roles in the pathogenesis of late-onset dementia. In this paper we propose that there are three major genetic factors that may modulate the risk for dementia in later life: carriership of <em>APOE</em> variant alleles, carriership of mitochondrial DNA of haplogroups associated with ineffective oxygen utilisation (specifically, haplogroup H) and carriership of genetic polymorphisms conferring subtly deficient DNA repair. All three factors are quite common in the European populations. Each of these three factors may not have significant effect on the phenotype when taken separately, but when combined in the same genotype, the effects may be cumulative. Further studies are needed in order to elucidate the genotype-phenotype relationships and provide a reliable basis for assessment of the genetic risk for sporadic late-onset dementia. Lifestyle alterations and therapies targeted at decreasing the oxidative burden to aging cells and tissues may decrease the risk for neurological decline in later life.

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Review Article Thu, 24 Sep 2015 00:00:00 +0300
Human pluripotent stem-cell-derived cardiomyocytes in cardiovascular drug discovery and development https://biodiscovery.pensoft.net/article/8965/ BioDiscovery 16: e8965

DOI: 10.7750/BioDiscovery.2015.16.1

Authors: Kirsty Lewis, Kerry Falconer

Abstract: Cardiovascular disease (CVD) is an alarming health problem responsible for a large percentage of fatality worldwide. Current treatment is limited and research is ongoing to address this serious health problem. As mortality rates rise, the demand for novel therapeutics has pressed the pharmaceutical industry to explore alternative approaches for CVD drug development. Human pluripotent stem cells (hPSCs) hold great promise in bringing new effective cardiovascular treatments to the market through providing an improved testing platform for pre-clinical drug screening. Both stem cells derived from pre-implantation human embryos or somatic cells by reprogramming are under intense investigation for their potentially valuable attributes of cell renewal and pluripotency. This approach aims to overcome the lack of appropriate human cardiac disease models for toxicology testing by providing a novel system that is scalable, reproducible and from an inexhaustible source. Here we review the opportunities for cardiomyocytes derived from human stem cells in the field of cardiovascular drug development.

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Review Article Sun, 28 Jun 2015 00:00:00 +0300
Small molecules and human cardiomyogenesis: Is there a bottleneck in current research? https://biodiscovery.pensoft.net/article/8968/ BioDiscovery 15: e8968

DOI: 10.7750/BioDiscovery.2015.15.2

Authors: Dimitar Trifonov

Abstract: Human pluripotent stem cell derived cardiomyocytes (hPSC-derived CMs) have a vast potential in drug discovery, disease modeling and regenerative medicine. In recent years various differentiation protocols for hPSC-derived CMs have been developed. Most of them utilize the modulation of human cardiomyogenesis via small-molecule compounds. However, setbacks to the large-scale application of hPSC-derived CMs still abound: insufficient insight into important signaling pathways for cardiac lineage-specific differentiation and identification of suitable small-molecule modulators; inconsistent results due to unstandardised culturing techniques; lack of effective maturation of hPSC-derived CMs in vitro. So is there a bottleneck in current research? This paper attempts to answer this question.

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Commentary Tue, 31 Mar 2015 00:00:00 +0300
NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response https://biodiscovery.pensoft.net/article/8964/ BioDiscovery 15: e8964

DOI: 10.7750/BioDiscovery.2015.15.1

Authors: Hilal S Khalil, Yusuf Deeni

Abstract: Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of the antioxidant response (AR) pathway and functions as a transcription factor for basal and oxidative stress-induced expression of a battery of detoxification enzymes and cytoprotective genes. Recent evidence has also demonstrated a role of NRF2 in driving resistance of numerous cancers to chemotherapeutic agents. ATM and ATR are serine/threonine kinases that are activated following DNA damage and function as central components of DNA Damage Response (DDR) pathway. Activities of these kinases cause cell cycle arrest and activate DNA repair signals leading to cytoprotection against genotoxic agents. In this study, we elucidated the roles of ATM- and ATR- dependent DDR and NRF2- mediated AR pathways in promoting cytoprotection following cisplatin challenge in ovarian cancer cell line models. We also determined whether these pathways were inter-dependent for full activation following genotoxic insults and as such demonstrated crosstalk in their signaling mechanism to elicit cytoprotective pathways. Treatment with cisplatin caused NRF2 induction and generation of reactive oxygen species (ROS) that caused cytotoxicity in ovarian cancer cells. This was attenuated by the ROS scavenger N-Acetyl cysteine, implicating NRF2 function in cytoprotection against cisplatin. Treatment with retinoic acid (RA) caused down regulation of NRF2, disruption of AR pathway, significant accumulation of ROS and enhanced cisplatin cytotoxicity. Interestingly, RA treatment also led to repression of total ATM and ATR proteins and aberrant DDR activation following cisplatin challenge. In order to determine whether the RA induced ATM and ATR repression was dependent on NRF2 inhibition, we silenced NRF2 using SiRNA. This caused transcriptional repression of both <em>ATM</em> and <em>ATR</em> expression as determined by their promoter driven luciferase assays. Thus, NRF2 inhibition led to DDR suppression by down-regulating ATM and ATR that led to enhanced cytotoxicity. These findings demonstrate mechanism of crosstalk between the AR and the DDR pathways and extend the scope of NRF2 in promoting cancer therapeutic resistance.

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Research Article Sat, 28 Mar 2015 00:00:00 +0200
We heart cultured hearts. A comparative review of methodologies for targeted differentiation and maintenance of cardiomyocytes derived from pluripotent and multipotent stem cells https://biodiscovery.pensoft.net/article/8962/ BioDiscovery 14: e8962

DOI: 10.7750/BioDiscovery.2014.14.2

Authors: A. Arabadjiev, Rumena Petkova, Stoyan Chakarov, Rumen Pankov, Nikolai Zhelev

Abstract: Human cell lines, including disease cell lines are often superior to routine animal models for the purposes of rapid and safe assessment of the effects of different agents that may modulate myocardial functioning under physiological and pathological conditions. There are several currently existing methodologies for derivation of cardiomyocyte-like cells by targeted differentiation from pluripotent cells and by reprogramming/transdifferentiation from other types of cells (multipotent progenitors, somatic cells, etc). The present paper reviews the potential sources of cells capable of differentiation along the cardiomyocyte lineage; the existing methodologies for targeted differentiation, outlining the specificities of each method; and the markers for differentiation along the mesodermal and the cardiogenic lineage. The yield of robustly beating cells expressing cardio-specific proteins derived by any of the existing methods, however, still rarely exceeds 70-90 %, even with the newly developed approaches for increasing the differentiation capacity. There still is significant variance in the results obtained by different research groups and even between different experiments carried out in the same laboratory, with the same type of cells and same general type of protocol. Derivation of new lines of human pluripotent and multipotent stem cells according to standardised protocols and in completely defined; xeno-free conditions may increase the reliability and reproducibility of research and speed up the development of potential clinical applications.

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Review Article Tue, 23 Dec 2014 00:00:00 +0200
Multiplexed heat shock protein microarray as a screening platform for the selection of novel drug compounds https://biodiscovery.pensoft.net/article/8963/ BioDiscovery 14: e8963

DOI: 10.7750/BioDiscovery.2014.14.1

Authors: Emilia Schax, Janek Neunaber, Frank Stahl, Johanna-Gabriela Walter, Thomas Scheper, Simone Eichner, Andreas Kirschning, Carsten Zeilinger

Abstract: In diseases such as cancer, Alzheimer’s disease or malaria, disease-related proteins take advantage of the heat shock protein (HSP) control system for their own activation or maturation. There is a quest to find inhibitors that specifically bind to the HSPs. Here, we report on a novel multiplexed assay system for inhibitor screening based on a protein microarray (MA) technique that was developed for routine applications with storable MAs. Purified HSPs are printed as full-length proteins on microarrays and used as a drug target for the screening of new inhibitors. Derivatives obtained by a combination of biological and chemical synthesis were tested as competitors of ATP with a suggested affinity for several HSP proteins which are hHSP from human, AtHSP83 (<em>Arabidopsis thaliana</em>) and HtpG from <em>Helicobacter pylori</em>. Some of these new derivatives exerted selectivity between human and bacterial heat shock proteins. Printed human HSP90 was used to test the binding of denatured proteins on the client binding site of human HSP90, since the full-length HSP maintains the capability to bind putative clients or cochaperones. Initial data revealed that the microarray application can be used to identify directly elevated heat-shock protein levels in cancer cell lysates. We suggest that microarray-based assaying of HSP levels can be used as a marker for determining stress levels.

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Short Communication Mon, 22 Dec 2014 00:00:00 +0200
DNA repair systems https://biodiscovery.pensoft.net/article/8961/ BioDiscovery 13: e8961

DOI: 10.7750/BioDiscovery.2014.13.2

Authors: Stoyan Chakarov, Rumena Petkova, George Ch Russev

Abstract: This paper provides detailed insight into the mechanisms of repair of different types of DNA damage and the direct molecular players (enzymes repairing the damage or tagging the damaged site for further processing; damage sensor molecules; other signalling and effector molecules). The genetic bases of diseases and conditions associated with defective DNA repair are comprehensively reviewed, from the ''classic'' severe diseases such as xeroderma pigmentosum and Cockayne syndrome to the much more subtle UV sensitivity syndromes. The review analyses the basic molecular mechanisms underlying the relatively rare monogenic diseases of DNA repair and management of genome integrity as well as the common multifactorial diseases and conditions with late onset that are associated with increased levels of oxidative stress (metabolic syndrome, diabetes type 2, cardiovascular disease) and with accumulation of ''errors'' in DNA (normal and pathological ageing phenotypes, various cancers). The role of cell cycle checkpoints in dividing cells and the mechanisms of decision-making for the fate of a damaged cell are discussed with regards to the cell homeostasis in normal and cancerous tissues. The role of major DNA damage-associated signalling and effector molecules (p53, ATM, poly-(ADP-ribose)-polymerase, DNA-dependent protein kinase, BRCA proteins, retinoblastoma protein, and others) is discussed and illustrated with examples in the context of health and disease. DNA repair and programmed cell death are viewed together as a unified mechanism for limiting the presence of damaged cells and cells with potentially oncogenic transformation in multicellular organisms. Special attention is paid to ageing as a natural phenomenon and an adaptive evolutionary mechanism, with a brief outline of ''successful ageing''. The differential rates of repair of DNA in transcribed and nontranscribed regions of the genome and the specificities of DNA repair profile in some types of cells (terminally differentiated cells, pluripotent stem cells, etc.) and in certain taxonomic groups (e.g. ''the rodent repairadox'') are discussed with regards to replicative ageing and the evolutionary processes on micro- and macroscale. The role of mutagenesis as a ''hit and miss'' mechanism and the ''leakiness'' of DNA repair for increasing genetic diversity in the course of individual life and on evolutionary scale and the phenomenology of ongoing molecular evolution are extensively reviewed.

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Review Article Mon, 22 Sep 2014 00:00:00 +0300
DNA damage and the circadian clock https://biodiscovery.pensoft.net/article/8960/ BioDiscovery 13: e8960

DOI: 10.7750/BioDiscovery.2014.13.1

Authors: Stoyan Chakarov, Rumena Petkova, George Ch Russev, Nikolai Zhelev

Abstract: The role of the circadian clock has already been demonstrated for virtually all physiological processes, but it was only recently shown that cells were more sensitive to DNA damage at specific times of the day; that the peak of synthesis of mRNA and proteins of genes coding for products involved directly or indirectly in DNA repair was differentially timed in different tissues; and that the growth of some types of cancer followed a circadian pattern. The paper reviews the specificities of the clockwork mechanism in living cells associated with repair of DNA damage with regards to its role in ageing and carcinogenesis. The role of heritable polymorhisms and somatic mutations in the risk for development of common diseases (cancer, but also other types of diseases and conditions, such as obesity and metabolic syndrome), their course and the possible outcomes is reviewed in animal models and in man. The circadian oscillations in the levels of major proteins of DNA-damage related signalling and DNA repair are discussed in relation to differential mechanisms of defence against genotoxic damage. The paper outlines the modern concept of ''chronotherapy'' - that is, anticancer therapy administered at specific times of the day/ night cycle that could be associated with better outcomes in some patients and analyses the individual variance in the tolerability of chronotherapy vs. maximum-dose anticancer therapy.

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Review Article Sun, 14 Sep 2014 00:00:00 +0300
DNA repair and carcinogenesis https://biodiscovery.pensoft.net/article/8959/ BioDiscovery 12: e8959

DOI: 10.7750/BioDiscovery.2014.12.1

Authors: Stoyan Chakarov, Rumena Petkova, George Ch Russev, Nikolai Zhelev

Abstract: The paper is dedicated to the natural phenomenon of cancer, with its possible causes, lifetime risks, mechanisms and possible outcomes discussed in fine detail. The molecular events resulting in uncontrolled cell growth and increased capacity to colonise distant topological sites are reviewed with regards to their impact as separate factors as well as their function as parts of a common mechanism. The basic classifications of cell genes coding for products involved directly or indirectly in carcinogenesis (proto-oncogenes, tumour-suppressor genes, mutator genes and gatekeeper/caretaker genes) are given in parallel in order to provide a better understanding of the functions of the encoded proteins. The mechanisms commonly used by cancer cells to evade the control of the DNA damage check/DNA repair/apoptosis system and for deactivation and/or elimination of anticancer drugs are reviewed. The current and future opportunities for establishing control over carcinogenesis (for common types of cancer as well as for ''cancer'' in general) are evaluated in the light of the theory that cancer is a physiological mechanism set in place by Nature so as to minimise the risk of evolutionary stagnation.

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Review Article Sun, 8 Jun 2014 00:00:00 +0300
Individual capacity for detoxification of genotoxic compounds and repair of DNA damage. Commonly used methods for assessment of capacity for DNA repair https://biodiscovery.pensoft.net/article/8958/ BioDiscovery 11: e8958

DOI: 10.7750/BioDiscovery.2014.11.2

Authors: Stoyan Chakarov, Rumena Petkova, George Ch Russev

Abstract: The first part of this paper reviews the major achievements in the rapidly expanding field of research of individual capacity for repair of genotoxic damage. The issues of individual repair capacity are addressed from multiple sides, analyzing the impact of the heritable components of the capacity for detoxification of genotoxic compounds, on the one hand (determining the risk for occurrence of DNA damage) and of the capacity for repair of DNA damage (when it has already occurred), on the other hand. The role of the capacity for repair of damage to DNA is discussed in the constitution of the risk for development of disease (mainly cancer, but also other common diseases and conditions, such as diabetes, atherosclerosis and cardiovascular disease) and as a major factor in the outcomes of genotoxic therapies (eligibility for therapy with specific agents, risk for severe adverse effects, post-therapeutic survival rates, etc.). The paper contains an extensive list of biomarkers (mainly DNA polymorphisms, but also enzymes and other phenotypic markers, such as markers of the capacity for self-renewal of cell populations) that may be potentially applicable in the assessment of the risk for carcinogenesis or for development other types of human disease.The second part of the paper provides a brief glimpse of the basic methodology used to obtain experimental results in assessment of the efficiency of DNA repair in living cells for research and diagnostic purposes.

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Review Article Fri, 28 Mar 2014 00:00:00 +0200
DNA damage and mutation. Types of DNA damage https://biodiscovery.pensoft.net/article/8957/ BioDiscovery 11: e8957

DOI: 10.7750/BioDiscovery.2014.11.1

Authors: Stoyan Chakarov, Rumena Petkova, George Ch Russev, Nikolai Zhelev

Abstract: This review outlines the basic types of DNA damage caused by exogenous and endogenous factors, analyses the possible consequences of each type of damage and discusses the need for different types of DNA repair. The mechanisms by which a minor damaging event to DNA may eventually result in the introduction of heritable mutation/s are reviewed. The major features of the role of DNA damage in ageing and carcinogenesis are outlined and the role of iatrogenic DNA damage in human health and disease (with curative intent as well as a long-term adverse effect of genotoxic therapies) are discussed in detail.

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Review Article Sun, 23 Feb 2014 00:00:00 +0200
From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development https://biodiscovery.pensoft.net/article/8956/ BioDiscovery 10: e8956

DOI: 10.7750/BioDiscovery.2013.10.1

Authors: Nikolai Zhelev, Dimitar Trifonov, Shudong Wang, Moustapha Hassan, Ibrahim El Serafi

Abstract: This monograph reviews the discovery and development of the cyclin-dependent kinase inhibitor roscovitine (R-roscovitine, CYC202, Seliciclib). The authors summarise the in vitro and in vivo data that have formed the basis for clinical investigation of Seliciclib as an anti-cancer drug. Kinase selectivity, cellular effects and the pharmacological properties of the drug are discussed in addition to the clinical results of Seliciclib being reviewed. Novel results on the effect of the drug in cardiac hypertrophy are summarized and potential applications of Seliciclib in other therapeutic areas, including, inflammation, virology, glomerulonephritis and polycystic kidney disease, are discussed. Finally the authors argue that optimisation of the therapeutic effect of kinase inhibitors such as Seliciclib can be enhanced using a systems biology approach involving mathematical modelling of the molecular pathways regulating cell growth and division.

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Monograph Mon, 30 Dec 2013 00:00:00 +0200
Reverse engineering of drug induced DNA damage response signalling pathway reveals dual outcomes of ATM kinase inhibition https://biodiscovery.pensoft.net/article/8954/ BioDiscovery 9: e8954

DOI: 10.7750/BioDiscovery.2013.9.4

Authors: Michael A. Idowu, Hilal S Khalil, James L. Bown, Nikolai Zhelev

Abstract: The DNA Damage Response (DDR) pathway represents a signalling mechanism that is activated in eukaryotic cells following DNA damage and comprises of proteins involved in DNA damage detection, DNA repair, cell cycle arrest and apoptosis. This pathway consists of an intricate network of signalling interactions driving the cellular ability to recognise DNA damage and recruit specialised proteins to take decisions between DNA repair or apoptosis. ATM and ATR are central components of the DDR pathway. The activities of these kinases are vital in DNA damage induced phosphorylational induction of DDR substrates. Here, firstly we have experimentally determined DDR signalling network surrounding the ATM/ATR pathway induced following double stranded DNA damage by monitoring and quantifying time dependent inductions of their phosphorylated forms and their key substrates. We next involved an automated inference of unsupervised predictive models of time series data to generate <em>in silico</em> (molecular) interaction maps. We characterized the complex signalling network through system analysis and gradual utilisation of small time series measurements of key substrates through a novel network inference algorithm. Furthermore, we demonstrate an application of an assumption-free reverse engineering of the intricate signalling network of the activated ATM/ATR pathway. We next studied the consequences of such drug induced inductions as well as of time dependent ATM kinase inhibition on cell survival through further biological experiments. Intermediate and temporal modelling outcomes revealed the distinct signaling profile associated with ATM kinase activity and inhibition and explained the underlying signalling mechanism for dual ATM functionality in cytotoxic and cytoprotective pathways.

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Research Article Wed, 11 Dec 2013 00:00:00 +0200
Progesterone significantly enhances the mobility of boar spermatozoa https://biodiscovery.pensoft.net/article/8955/ BioDiscovery 9: e8955

DOI: 10.7750/BioDiscovery.2013.9.5

Authors: Johan M. Campbell, Anne L. Savage, Oladipo Madamidola, Kshitij Tamhane, Renalyn Soriano, Ashok K. Adya, Sean G. Brown

Abstract: Progesterone released from the cumulus cells of the oocyte causes a number of physiological responses in human sperm cells including hyperactivation, acrosome reaction and chemotaxis. We employed a validated sperm mobility assay, which involves measuring the ability of sperm to penetrate an inert cell separation solution over time, to assess the ability of progesterone to enhance the mobility of boar spermatozoa. Cells maximally penetrate the solution over 50 minutes. 100nM progesterone significantly (P = 0.01) increased the mobility of non-capacitated sperm cells causing a doubling in the rate at which the cells penetrated through the cell separation solution (control half maximal penetration rate [Km] = 18.0±2.2; +100nM progesterone Km = 8.8±0.8min). Similarly, capacitated cells penetrated at a rate (Km = 19.2±3.0 min) not significantly different from non-capacitated cells and 100nM progesterone also significantly increased the rate of penetration of capacitated cells (Km = 9.5±1.0 min, P<0.05). The T-type voltage gated calcium channel blocker mibefradil (30mM) significantly inhibited both the control and progesterone enhanced mobility in non-capacitated and capacitated sperm. Only capacitated cells showed a significant increase in the acrosome reaction in response to 100nM progesterone (control non-reacted = 75±4%, +100nM progesterone non-reacted = 47±10%). Western blot analysis confirmed that there was an increase in the total protein tyrosine phosphorylation levels in capacitated cells. In conclusion, we have demonstrated that 100nM progesterone accelerates the mobility of boar sperm cells through an inert cell separation solution in an extracellular calcium dependent manner.

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Research Article Wed, 11 Dec 2013 00:00:00 +0200
The alternate GNB3 splice variant, Gβ3s, exhibits an altered signalling response to EGF stimulation, which leads to enhanced cell migration https://biodiscovery.pensoft.net/article/8953/ BioDiscovery 9: e8953

DOI: 10.7750/BioDiscovery.2013.9.3

Authors: Hemanth Tummala, Hilal S Khalil, Mohammad R. Islam, Sarah J. Jones, Ian R. Ellis, Isabella D’Ascanio, Nikolai Zhelev, Douglas H. Lester

Abstract: It has recently been reported that the duplication of the GNB3 gene has been shown to be directly linked to an obesity phenotype, both in humans and also in a humanised mouse model. Moreover, the common human GNB3 c.825C>T polymorphism (rs5443) causes this ubiquitously expressed gene to be aberrantly spliced approximately 50% of the time leading to the production of both a normal Gβ3 protein and a truncated, possibly less stable subunit, known as Gβ3s. The presence of the GNB3 825T allele has previously been shown to be associated with predisposition to hypertension, obesity, various cancers, Alzheimers, age related cognitive function, erectile dysfunction as well as a marker for pharmacogenetic drug action. Great controversy, however, currently exists as to whether these phenotypes associated with the 825T allele are a) mainly due to the presence of the smaller, possibly more active, Gβ3s subunit or b) merely down to the haploinsufficiency of the normal GNB3 transcript, due to its frequent aberrant splicing. In order to try and address these two conflicting hypothesis, we report on the identification and characterisation of signalling alterations unique to the presence of Gβ3s protein subunit. Moreover we also show the physiological consequences associated with altered signalling, directly induced by the Gβ3s subunit. For this, we used both an EBV transformed lymphoblast cell line homozygote for GNB3 825T/825T (TT) and a stable Gβ3s expressing recombinant COS-7 clone. In both of these cell lines that express the Gβ3s subunit, we found enhanced cytosolic calcium influx upon stimulation with EGF, TGFα and VEGF ligands, as compared to "normal" GNB3 controls with the 825C/825C (CC) genotype. This aberrant calcium influx also led to an increase in ERK, but not AKT1, phosphorylation. Despite the lack of AKT1 activation, we paradoxically observed a significant increase in phosphorylation of its downstream substrates, namely mTOR and p70<sup>S6k</sup> (KS6B2). Moreover we observed a decrease in phospho FoxO3a only in Gβ3s expressing cells, but not in the "normal" GNB3 (CC) control cell line. The presence of the Gβ3s subunit also appeared to alter the distinct localisation patterns of both Foxo3a and AKT1, while also increasing the colocalisation of mTOR and p70<sup>S6K</sup>. Subsequent growth factor stimulation studies revealed that EGF treatment, of Gβ3s expressing cells, appeared to cause a significant decrease in cAMP levels, which, in turn resulted in both enhanced caveolin-1a phosphorylation, and an increase in actin stress fibre formation. The identification of these distinct Gβ3s specific signalling alterations were indicative of a more aggressive migratory phenotype. This led us to further investigate and confirm that the presence of the Gβ3s subunit also appears to cause significantly enhanced migration and robust scratch wound healing kinetics, as compared to cells harbouring only the normal copy of the gene. These data therefore present convincing evidence that the Gβ3s subunit is stable, functional and its presence can significantly alter signalling pathways, in different cell types.

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Research Article Sat, 30 Nov 2013 00:00:00 +0200
Evolution of Conformational Disorder & Diversity of the P53 Interactome https://biodiscovery.pensoft.net/article/8952/ BioDiscovery 8: e8952

DOI: 10.7750/BioDiscovery.2013.8.5

Authors: Anne-Sophie Huart, Ted R. Hupp

Abstract: The tumour suppressor p53 is now known to be an ancient transcription factor that had already evolved interaction sites with its partner protein MDM2 at the dawn of multi-cellular eukaryotic animal life. The billion-year life history of the p53-MDM2 axis has permitted significant time for the proteins to integrate into a distinct range of cellular pathways including binding to hundreds of genomic promoters and regulatory protein-protein interactions with hundreds of distinct functions. This long age of p53 allows us to understand how the protein can regulate a range of functions such as energy generation of the cell, cell motility, genome integrity, virus infection, immune cell response, ageing, and oxidative stress. Due to this deep integration of p53 into the core of eukaryotic life, it is not surprising that the p53 pathway requires inactivation in order for human cancer cells to evade the normal growth controlling processes that have been shaped through evolution by natural selection. This review will focus on the emerging concepts in the protein science field that shed light on p53 protein evolution and function including the nature of thermodynamically unstable regulatory proteins and the growing realisation that the majority of protein-protein interactions in complex eukaryotic cells are driven by intrinsically unstructured and weakly interacting peptide motifs. These concepts help to explain how the vast number of dynamic and specific protein-protein interactions in the p53 pathway evolved, suggest how amino acid modifications like phosphorylation or acetylation in turn evolved to regulate dynamically the p53 interactome, and finally reveal therapeutic strategies for targeting the p53 interactome in human cancers.

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Review Article Wed, 14 Aug 2013 00:00:00 +0300
Changes in the connective tissue element of the thyroid gland in normal and recurrent euthyroid goiter https://biodiscovery.pensoft.net/article/8951/ BioDiscovery 9: e8951

DOI: 10.7750/BioDiscovery.2013.9.1

Authors: Kalin Vidinov, Nikolay Vidinov, Manol Kalniev, Dimo Krastev

Abstract: Goitre recurrence is a common problem following subtotal thyroid gland resection for multinodular goitre disease. The aim of our study was to trace out the ultrastructure of the thyroid gland of man after primary and redo operations for struma nodosa. We undertook the task to study the fine ultrastructural changes taking place in the stromal part of the gland. For ultrastructural examination we used routine transmission electron microscopy. The electron microscopy has been made on Hitachi H-500 microscope Our main goal was to compare the ultrastructural characteristics of the thyroid gland in two different groups - patients with primary disease and patients with recurrence.The results from our research showed that in the first group the stroma was presented by one or two rows of cells in the septum or in small groups in the interfolicular space. Studies by electron microscopically showed that the cells of the stroma had the ultrastructural characteristics of fibroblasts, but there was an increased number cisterne of Granular endoplasmic reticulum, well developed Goldgi complex, as well as relatively small amount of vesicles and vacuoles. The examination of the specimens from the second group showed a much thicker stroma between the follicles. There was an increased amount of stromal cells and collagen bundles in the interfolicular space. The proteoglycan complexes in the extracellular matrix were rarely situated.Our results suggest that the connective tissue of the thyroid gland reacts faster to the changes of the structure of the gland than the epithelial cells of the follicles.

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Research Article Sat, 27 Jul 2013 00:00:00 +0300
Small Molecule Inhibitors of MDM2-p53 and MDMX-p53 Interactions as New Cancer Therapeutics https://biodiscovery.pensoft.net/article/8950/ BioDiscovery 8: e8950

DOI: 10.7750/BioDiscovery.2013.8.4

Authors: Yujun Zhao, Denzil Bernard, Shaomeng Wang

Abstract: Inactivation of the function of tumor suppressor p53 is common in human cancers. In approximately half of human cancers, the tumor suppressor function of p53 is inactivated by deletion or mutation of TP53, the gene encoding p53 protein. In the remaining 50% of human cancers, p53 tumor suppressor function can be effectively inhibited by oncoprotein MDM2 or its homolog MDMX. Since inhibition of p53 by MDM2 or MDMX protein is mediated by their direct interaction with p53, small-molecule inhibitors designed to block the MDM2-p53 or MDMX-p53 protein-protein interaction (MDM2 or MDMX inhibitors) can activate p53 in tumor cells retaining wild-type p53. In the last few years, several classes of potent, selective, and efficacious small molecule MDM2 inhibitors have been designed and developed, and six such compounds are being evaluated in clinical trials as new anticancer drugs. Additionally, non-peptide, small-molecule MDMX inhibitors have been reported. We review herein the design and development of potent small-molecule MDM2 and MDMX inhibitors.

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Review Article Mon, 8 Jul 2013 00:00:00 +0300
Distinct target genes and effector processes appear to be critical for p53-activated responses to acute DNA damage versus p53-mediated tumour suppression https://biodiscovery.pensoft.net/article/8948/ BioDiscovery 8: e8948

DOI: 10.7750/BioDiscovery.2013.8.3

Authors: Liz J Valente, Andreas Strasser

Abstract: The p53 tumour suppressor is the most frequently mutated gene in human cancer. This transcription factor can be activated by diverse cellular stresses, including DNA damage and oncogene activation. Through transcriptional induction of appropriate target genes, p53 can stimulate activity in a broad range of effector pathways, most notably cell cycle arrest, cellular senescence and apoptotic cell death. Insensitivity to cell death-inducing signals and deregulated proliferation are two key hallmarks of cancer cells. Given that p53 inhibits proliferation and induces apoptosis, it was widely believed that these processes are the most critical ones for p53-mediated tumour suppression. However, this dogma has been challenged. In striking contrast to p53-deficient mice, which all develop tumours before 250 days of age, mutant mice in which expression of the p53 target genes that are critical for induction of cell cycle arrest and apoptosis is impaired or abrogated are not cancer-prone. This demonstrates that distinct effector processes are critical for the p53-mediated acute response to DNA damage versus p53-mediated tumour suppression. The discovery that cell cycle arrest, senescence and apoptosis are not essential for p53-mediated tumour suppression re-launches the search for the p53 target genes and effector processes that are critical to prevent tumour development, with coordination of DNA repair being a leading contender.

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Review Article Sun, 30 Jun 2013 00:00:00 +0300
Modulation of immune responses by the tumor suppressor p53 https://biodiscovery.pensoft.net/article/8947/ BioDiscovery 8: e8947

DOI: 10.7750/BioDiscovery.2013.8.2

Authors: Julie Lowe, Maria Shatz, Michael A. Resnick, Daniel Menendez

Abstract: The commonly held view of the tumor suppressor p53 as a regulator of cell proliferation, apoptosis and senescence has expanded greatly in recent years to cover many biological processes as well as external and internal stress responses. Since the discovery over 30 years ago of p53 as a cellular protein that co-precipitates with the large T antigen of Simian Virus SV40, there has been an intertwining of p53 activities with immune-related processes, especially as relates to cancer. A variety of interactions between the p53 and the immune stress systems are currently being addressed that suggest opportunities to utilize p53 in modulating immunological activities. Here, we discuss those interactions along with implications for human disease.

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Review Article Fri, 31 May 2013 00:00:00 +0300
Switching on p53: an essential role for protein phosphorylation? https://biodiscovery.pensoft.net/article/8946/ BioDiscovery 8: e8946

DOI: 10.7750/BioDiscovery.2013.8.1

Authors: Jayne Loughery, David Meek

Abstract: The p53 tumour suppressor protein coordinates widespread changes in gene expression in response to a range of stress stimuli. p53 is regulated primarily through ubiquitylation and protein turnover mediated by its transcriptional target, MDM2. Induction and activation of p53 is achieved largely through uncoupling the p53/MDM2 interaction, with various stress stimuli employing different but overlapping mechanisms to achieve this. p53 undergoes a range of post-translational modifications including multi-site phosphorylation, acetylation, methylation and ubiquitylation. DNA damage pathways in particular engender a large number of phosphorylation events, both in p53 itself and in regulatory partners including MDM2 and MDM4; these modifications mediate both the induction of p53 and stimulation of its activity. Surprisingly, other p53-activating stimuli do not promote multi-site phosphorylation. Moreover, simply uncoupling p53 and MDM2 pharmacologically can induce a robust p53 response. Various lines of evidence propose that activation of p53 via the DNA damage pathways is dispensable for p53-mediated tumour suppression and, by implication, that phosphorylation is not required. In contrast to this view, however, emerging evidence from animal models indicates that phosphorylation may indeed impact on tumour suppression, albeit in a possibly selective manner. Here we review the role of phosphorylation in regulating the p53 response in comparison to mechanisms employed by other stress signalling pathways. We consider its effects on biological outcome and reflect on issues that have yet to be addressed.

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Review Article Mon, 29 Apr 2013 00:00:00 +0300
Modelling c-Abl Signalling in Activated Neutrophils: The Anti-inflammatory Effect of Seliciclib https://biodiscovery.pensoft.net/article/8945/ BioDiscovery 7: e8945

DOI: 10.7750/BioDiscovery.2013.7.4

Authors: Robert C. Jackson, Tomas Radivoyevitch

Abstract: When mammalian tissues are infected by bacteria or fungi, inflammatory cytokines are released that cause circulating neutrophils to invade the infected tissue. The cytosolic tyrosine kinase, c-Abl, in these tissue neutrophils is activated by TNFα. c-Abl then phosphorylates STAT transcription factors, which results in production of the antiapoptotic protein Mcl-1. The normally short-lived tissue neutrophils are then unable to enter apoptosis. c-Abl also causes release of reactive oxygen species (ROS) from the mitochondria of the activated neutrophils. These ROS, and ROS generated by NADPH oxidase, are bactericidal agents of the innate immune system. In some inflammatory diseases, such as chronic obstructive pulmonary disease (COPD), the invading neutrophils become permanently activated, and the resulting ROS overproduction causes severe tissue damage. The cyclin-dependent kinase inhibitor, seliciclib, blocks transcription through inhibition of cdk9. This results in a relatively rapid decline of antiapoptotic Mcl-1 transcripts in activated neutrophils, an increase in neutrophil apoptosis, and less ROS leakage and oxidative damage. We present here a model of neutrophil kinetics that simulates the principal pathways of c-Abl signalling and use it to explore possible treatment options for inflammatory lung disease.

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Research Article Sun, 31 Mar 2013 00:00:00 +0200
Herpetofauna in the city of Blagoevgrad, south-western Bulgaria https://biodiscovery.pensoft.net/article/8943/ BioDiscovery 7: e8943

DOI: 10.7750/BioDiscovery.2013.7.3

Authors: Alexander Pulev, Lidia Sakelarieva

Abstract: The city of Blagoevgrad and its surroundings (about 16.4 km<sup>2</sup>) were researched in order to establish the diversity, distribution and level of synanthropy of the amphibian and reptile species. Data about the herpetofauna were obtained in the period 1988–2012. Totally 25 species were registered – 10 amphibians and 15 reptiles. The number of species, discovered around the city, was 23, and 6 of them were not found within the administrative boundaries of the city. The different urban zones are inhabited by 19 species. They represent 37% of the amphibians and 31% of the reptiles, found in Bulgaria, and 64% of the amphibians and 60% of the reptiles, distributed in the Blagoevgrad municipality, which is very high species richness. The herpetofauna has found quite favourable conditions in the territory of the city as a whole, and especially in the sparsely populated and built up areas and city periphery. The presence of great variety of urban habitats and the pattern of situation of the city residential districts are very important for the successful adaptation of herpetofauna for inhabiting in urban environment. The high species richness could be explained also by the fact, that comparatively great number of amphibians and reptiles are hemerodiaphoric species, which easily exist in landscapes, transformed by man. The results from the case study of the herpetofauna in Blagoevgrad show that the urban areas could provide good conditions for the wild animals and could be places of substantial biological diversity.

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Research Article Thu, 28 Mar 2013 00:00:00 +0200
Skeletal muscle: novel and intriguing characteristics as a secretory organ https://biodiscovery.pensoft.net/article/8942/ BioDiscovery 7: e8942

DOI: 10.7750/BioDiscovery.2013.7.2

Authors: Wataru Aoi, Kunihiro Sakuma

Abstract: Growing evidence has shown that skeletal muscle secretes several bioactive proteins from within the cell into extracellular fluid. The secretion of several proteins, whose levels increase in response to exercise, can regulate the functions of several organs via autocrine and paracrine actions, and mediate exercise-induced benefits such as metabolic improvement, anti-inflammation, and muscle building; this is known as the myokine theory. In addition, we found a novel muscle-secreted protein, secreted protein acidic and rich in cysteine (SPARC), a secreted matricellular glycoprotein. The muscle-secreted protein SPARC can support underlying mechanisms of epidemiological studies that suggest that regular exercise can prevent the incidence of colon cancer. Many different types of studies have suggested that many other proteins secreted from muscle have yet to be identified. In addition to the proteins, non-coding small RNA in exosome and metabolites which generate in process of nutrients metabolism with muscle contraction are also suggested to be secretory bioactive factors. These secretory factors may be biomarkers that reflect muscular function and beneficial adaptation achieved by exercise training, and could estimate adequate condition of exercise to obtain its beneficial effects.

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Review Article Sat, 2 Mar 2013 00:00:00 +0200
Chromosome rearrangements in sublines of human embryonic stem cell lines hESM01 and hESM03 https://biodiscovery.pensoft.net/article/8941/ BioDiscovery 7: e8941

DOI: 10.7750/BioDiscovery.2013.7.1

Authors: T.V. Karamysheva, Мaria А. Prokhorovich, Maria A. Lagarkova, Sergey L. Kiselev, Thomas Liehr, Nicolay Rubtsov

Abstract: Due to possible proliferative effects of karyotypic reorganization of human embryonic stem cell (hESC) lines detailed genetic analysis are indicated prior to any application of hESCs. Molecular cytogenetic analysis of two different hESC sublines was performed and revealed aberrant chromosomes in both of them, i.e. in hESM01r18 (46,ХХ,-18,+mar) and hESM0309 (46,ХХ,del(4),dup(9)). This study shows that microdissection and multicolor fluorescence <em>in situ</em> hybridization (mFISH) can be used to detect the chromosomal changes precisely of the derivative chromosomes that are difficult to identify by conventional G-banded chromosome analysis. In the present study chromosome microdissection and reverse FISH were applied using multicolor fluorescence <em>in situ</em> hybridization (mFISH) for detailed characterization of the derivative chromosomes. The karyotypes of hESC lines were described as: 46,ХХ,r(18)(::p11.31→q21.2::q21.2→p11.31::) and 46,XX,del(4)(q25q31.1),dup(9)(q12q33), respectively. The potential role of the chromosomal regions involved in rearrangements for cell proliferation is discussed.

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Research Article Fri, 25 Jan 2013 00:00:00 +0200
Advocating the need of a systems biology approach for personalised prognosis and treatment of B-CLL patients https://biodiscovery.pensoft.net/article/8939/ BioDiscovery 6: e8939

DOI: 10.7750/BioDiscovery.2012.6.4

Authors: Hemanth Tummala, Alexey Goltsov, Hilal S Khalil, Anne Sproul, Fiona Scott, Vanio Mitev, Nikolai Zhelev

Abstract: The clinical course of B-CLL is heterogeneous. This heterogeneity leads to a clinical dilemma: can we identify those patients who will benefit from early treatment and predict the survival? In recent years, mathematical modelling has contributed significantly in understanding the complexity of diseases. In order to build a mathematical model for determining prognosis of B-CLL one has to identify, characterise and quantify key molecules involved in the disease. Here we discuss the need and role of mathematical modelling in predicting B-CLL disease pathogenesis and suggest a new systems biology approach for a personalised therapy of B-CLL patients.

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Review Article Sun, 30 Dec 2012 00:00:00 +0200
The aromatase inhibitor letrozole enhances the effect of doxorubicin and docetaxel in an MCF7 cell line model https://biodiscovery.pensoft.net/article/8940/ BioDiscovery 6: e8940

DOI: 10.7750/BioDiscovery.2012.6.2

Authors: Mary O’Neill, Fiona E.M. Paulin, Julie Vendrell, Clinton W. Ali, Alastair M. Thompson

Abstract: <p>Introduction: Post-menopausal women with estrogen receptor (ER) positive breast cancer receive adjuvant chemotherapy and endocrine therapy sequentially since tamoxifen may antagonise the cytotoxicity of chemotherapy drugs. With increased use of aromatase inhibitors (AIs) in place of tamoxifen, the potential use of concomitant chemo-endocrine treatments with the AI letrozole, before clinical trials are undertaken, requires evaluation. </p> <p>Methods: MCF7-aro cells expressing the aromatase gene were treated with letrozole, doxorubicin and docetaxel. The effects of different drug concentrations, drug combinations and scheduling on cytotoxicity and aromatase activity were investigated. Key receptor, cell cycle regulation and apoptosis proteins were examined by immunoblotting.</p> <p>Results: Administration of letrozole with either doxorubicin or docetaxel resulted in increased levels of cytotoxicity under all treatment schedules (add in, sequential or simultaneous drug administration) with the greatest anti-proliferative effect observed using concomitant treatment (letrozole first with chemotherapy added in). The inhibitory effect of letrozole on aromatase activity was unchanged by the addition of doxorubicin or docetaxel. Letrozole treatment resulted in decreased HER2 expression and addition of doxorubicin and docetaxel to letrozole led to elevated ER-ß levels.</p> <p>Conclusions: <em>In vitro</em>, letrozole, unlike tamoxifen, enhances the cytotoxicity of both doxorubicin and docetaxel. This supports the prospect of trials using letrozole with chemotherapy in postmenopausal women with ER positive breast cancer. </p>

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Research Article Wed, 19 Dec 2012 00:00:00 +0200
Primed for the kill: occupying Bcl-2 to target death in acute myeloid leukaemia https://biodiscovery.pensoft.net/article/8938/ BioDiscovery 6: e8938

DOI: 10.7750/BioDiscovery.2012.6.1

Authors: Andrew Wei, Tse-Chieh Teh

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Commentary Fri, 7 Dec 2012 00:00:00 +0200
Bringing together all aspects of cancer research, prevention and treatment. A report from the 8th NCRI Cancer Conference https://biodiscovery.pensoft.net/article/8937/ BioDiscovery 6: e8937

DOI: 10.7750/BioDiscovery.2012.6.3

Authors: Dimitar Trifonov

Abstract: The 8<sup>th</sup> NCRI Cancer Conference took place from 4<sup>th</sup> until 7<sup>th</sup> of November 2012 in the BT Convention Centre, Liverpool, UK. This scientific event has established itself as the leading international oncology meeting in the UK and this year attracted more than 2,000 delegates: from researchers and data managers to clinicians, nurses and policy makers. The conference covered six main topics: 1) Diagnosis and therapy 2) Epidemiology and prevention 3) Information, patients and the public 4) Survivorship and end-of-life care 4) The cancer cell and model systems 6) Tumour specific research. This report presents the highlights of the conference.

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News and Views Sat, 1 Dec 2012 00:00:00 +0200
ATM in focus: A damage sensor and cancer target https://biodiscovery.pensoft.net/article/8936/ BioDiscovery 5: e8936

DOI: 10.7750/BioDiscovery.2012.5.1

Authors: Hilal S Khalil, Hemanth Tummala, Nikolai Zhelev

Abstract: The ability of a cell to conserve and maintain its native DNA sequence is fundamental for the survival and normal functioning of the whole organism and protection from cancer development. Here we review recently obtained results and current topics concerning the role of the ataxia-telangiectasia mutated (ATM) protein kinase as a damage sensor and its potential as therapeutic target for treating cancer. This monograph discusses DNA repair mechanisms activated after DNA double-strand breaks (DSBs), i.e. non-homologous end joining, homologous recombination and single strand annealing and the role of ATM in the above types of repair. In addition to DNA repair, ATM participates in a diverse set of physiological processes involving metabolic regulation, oxidative stress, transcriptional modulation, protein degradation and cell proliferation. Full understanding of the complexity of ATM functions and the design of therapeutics that modulate its activity to combat diseases such as cancer necessitates parallel theoretical and experimental efforts. This could be best addressed by employing a systems biology approach, involving mathematical modelling of cell signalling pathways.

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Review Article Fri, 30 Nov 2012 00:00:00 +0200
To see an interphase chromosome or: How a disease can be associated with specific nuclear genome organization https://biodiscovery.pensoft.net/article/8932/ BioDiscovery 4: e8932

DOI: 10.7750/BioDiscovery.2012.4.5

Authors: Ivan Y. Iourov

Abstract: The last hierarchical level of cellular genome organization is the spatial arrangement of chromosomes within the nuclear space. Despite of high regulatory potential and functional implications, issues concerning nuclear organization at chromosomal level are rarely addressed because of limitations in visualizing interphase chromosomes. The problem is especially seen when an attempt to associate specific patterns of nuclear genome organization with a pathological condition is made. Fortunately, advances in molecular cytogenetics have provided for a solution to visualize chromosomes in interphase nuclei at molecular resolution. A study in this issue of <em>BioDiscovery</em> shows the way of how to identify interphase chromosome architecture at molecular resolutions and demonstrates the involvement of specific nuclear genome organization in generating a cancer-causing chromosomal aberration (translocation between chromosomes 8 and 21 in acute myelogenous leukemia). Authors’ findings suggest interphase molecular cytogenetic techniques (i.e. interphase chromosome-specific multicolor banding or ICS-MCB) to be required to perform studies regarding nuclear genome organization at chromosomal level and its role in disease pathogenesis.

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Commentary Wed, 31 Oct 2012 00:00:00 +0200
What can systems pharmacology contribute to drug development? Disease modelling as a predictive tool https://biodiscovery.pensoft.net/article/8933/ BioDiscovery 4: e8933

DOI: 10.7750/BioDiscovery.2012.4.4

Authors: Robert C. Jackson

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Commentary Wed, 31 Oct 2012 00:00:00 +0200
Does positioning of chromosomes 8 and 21 in interphase drive t(8;21) in acute myelogenous leukemia? https://biodiscovery.pensoft.net/article/8934/ BioDiscovery 4: e8934

DOI: 10.7750/BioDiscovery.2012.4.2

Authors: Moneeb A.K. Othman, Amelie Lier, Susann Junker, Philipp Kempf, Franziska Dorka, Erich Gebhart, Frenny J. Sheth, Beata Grygalewicz, Samarth Bhatt, Anja Weise, Kristin Mrasek, Thomas Liehr, Marina Manvelyan

Abstract: The impact of chromosome architecture in the formation of chromosome aberrations is a recent finding of interphase directed molecular cytogenetic studies. There evidence was provided that disease specific chromosomal translocations could be due to tissue specific genomic organization. In a recent small pilot study using three-dimensional interphase fluorescence in situ hybridization, we showed that there might be a specific chromosome positioning in myeloid bone marrow cells, i.e. a co-localization of chromosomes 8 and 21. Here we could substantiate this finding in overall 21 studied cases with acute myeloid leukemia (AML) that there is even a co-localization of the genes AML1 and ETO. This finding led to the suggestion that a specific interphase architecture of myeloid bone marrow cells might promote the typical t(8;21)(q22;q22) leading to AML-M2.

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Research Article Tue, 23 Oct 2012 00:00:00 +0300
Prevalence of oral lesions in HIV infected adult population of Mangalore, Karnataka, India https://biodiscovery.pensoft.net/article/8935/ BioDiscovery 4: e8935

DOI: 10.7750/BioDiscovery.2012.4.3

Authors: Mithra N. Hegde, Nidarsh D. Hegde, Amit Malhotra

Abstract: The aim of this study was to find the prevalence of oral lesions in human immunodeficiency virus (HIV) positive patients and investigate if there was a relationship between oral manifestations and the level of immunosuppression. 125 patients infected with HIV in the age group of 20-40 years were examined for the presence of different oral lesions according to the EEC criterion. The CD4 count, as well as any therapy being instituted was recorded and correlated with the oral manifestations seen. Comparison of common oral lesions present to absent was done by chi square test using linear by linear association. The prevalence of oral lesions among the investigated HIV patients was found to be 71%, with periodontitis – 52% and erythematous candidiasis – 48% being the most prevalent oral lesions; as well, periodontitis and oral hairy leukoplakia were found to be significantly associated with the immunosuppression in the disease. Thus, oral lesions have been found to be associated with the early manifestation of HIV and a measure of disease severity.

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Research Article Tue, 23 Oct 2012 00:00:00 +0300
In vitro assessment of the cytotoxic effects of novel RGD analogues https://biodiscovery.pensoft.net/article/8931/ BioDiscovery 4: e8931

DOI: 10.7750/BioDiscovery.2012.4.1

Authors: Anelia Balacheva, Ivan Iliev, Roumyana Detcheva, Tatyana Dzimbova, Tamara Pajpanova, Evgeny Golovinsky

Abstract: The RGD sequence is present in many extracellular matrix proteins and intracellular proteins, including caspases. Synthetic RGD peptides may affect adhesion, migration and tumour metastasis, or directly induce apoptosis. Several RGD peptides were synthesized, and their anti-adhesive and cytotoxic properties were analyzed in vitro. Here we present the cytotoxic activities of RGD, R(NO2)GD, CavGD and RGD-OMe on non-tumour 3T3 cells and tumour cell lines HepG2 and MCF-7. The cell growth inhibitory effects of RGD-OMe are significantly higher than those of RGD on the cell lines used. Evidently the modification in the carboxylic group of RGD with simple esterification increases the cell growth inhibitory effects of the parent compound.

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Short Communication Tue, 16 Oct 2012 00:00:00 +0300
Lifestyle characteristics and dietary impact on plasma concentrations of beta-carotene and retinol https://biodiscovery.pensoft.net/article/8928/ BioDiscovery 3: e8928

DOI: 10.7750/BioDiscovery.2012.3.3

Authors: Rabindra Nath Das, Pradip K. Sarkar

Abstract: Mechanisms of dietary micronutrients and personal characteristics of the human body are intricately complicated. These mechanisms, however, can be easily interpreted through appropriate mathematical relationships. The present study aims to detect the statistically significant impact of personal characteristics and diet on plasma concentrations of retinol and beta-carotene using statistical modeling. The present analyses indicate that age, sex, smoking habit, quetelet, vitamin use, consumed calories, fiber, and dietary beta-carotene are statistically significant factors on plasma beta-carotene levels. On the other hand age, sex, smoking status, consumed fat, and dietary beta-carotene are significant factors on plasma retinol. These analyses indicate that changes in the variances of plasma beta-carotene and retinol are non-constant. Impacts of personal characteristics and dietary factors on human plasma concentrations of retinol and beta-carotene are explained based on mathematical relationships. These analyses support many earlier researches findings. However, the analyses also identify many additional casual factors that explain the means and variances of plasma beta-carotene and retinol, which earlier researches have not reported.

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Research Article Sun, 30 Sep 2012 00:00:00 +0300
The Apoe-/- Mouse PhysioLab® Platform: A Validated Physiologically-based Mathematical Model of Atherosclerotic Plaque Progression in the Apoe-/- Mouse https://biodiscovery.pensoft.net/article/8929/ BioDiscovery 3: e8929

DOI: 10.7750/BioDiscovery.2012.3.2

Authors: Jason R Chan, Gregory Vuillaume, Caitlin Bever, Stefan Lebrun, Michael Lietz, Yvonne Steffen, Katrin Stolle, Karim Wahba, Xiao Wang, Shonna Moodie, Julia Hoeng, Manuel C Peitsch, Lyn M Powell

Abstract: <em>Motivation:</em>Atherosclerosis is a complex multi-pathway inflammatory disease where accumulation of oxidatively modified lipids and leukocytes in the arterial intima leads to plaque formation over time. Translating Apoe<sup>-/-</sup> mouse results to the clinical setting is complicated by uncertainty around (a) mechanisms underlying disease etiology, (b) relative importance of these mechanisms as drivers of progression, and (c) how these roles change in response to perturbation by therapeutic intervention or lifestyle changes. <br><em>Results: </em>We describe a large-scale mechanistic, mathematical model of atherosclerosis in the Apoe<sup>-/-</sup> mouse and its validation with <em>in vivo</em> Apoe <sup>-/-</sup> data. Major physiological components include cholesterol/macrophage trafficking, inflammation, endothelial function, oxidative stress, and thrombosis. Heterogeneity in disease progression, observed despite genetic uniformity and experimentally controlled conditions, was captured through “virtual mice”. This model may be used to optimize <em>in vivo</em> experiments and paves the way for a similar modeling approach for human disease.<br><em>Availability: </em>The model is available by remote desktop client at Apoe.entelos.com.

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Research Article Sun, 30 Sep 2012 00:00:00 +0300
The dark side of light. Light pollution kills leatherback turtle hatchlings https://biodiscovery.pensoft.net/article/8930/ BioDiscovery 3: e8930

DOI: 10.7750/BioDiscovery.2012.3.4

Authors: Marina Zheleva

Abstract: The leatherback turtle is the largest and most migratory of all sea turtles and deepest diving air-breathing animal. It has unique physiology which allows it to adapt to various habitats ranging from sub-polar to equatorial during its migrations. The leatherback turtle is also the only sea turtle where no cases of tumours have been diagnosed. These unique features add to the arguments for preservation of this endangered species. Here we discuss the effect of light pollution on leatherback turtle hatchlings in Tobago and the measures for their protection.

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News and Views Sun, 30 Sep 2012 00:00:00 +0300
Of mice and men – differential mechanisms of maintaining the undifferentiated state in mESC and hESC https://biodiscovery.pensoft.net/article/8927/ BioDiscovery 3: e8927

DOI: 10.7750/BioDiscovery.2012.3.1

Authors: Borislav Arabadjiev, Rumena Petkova, Albena Momchilova, Stoyan Chakarov, Rumen Pankov

Abstract: The persistence of the defining characteristics of undifferentiated cells in vivo and in vitro is maintained via a complex interplay of several mechanisms, employing molecular events internal to the cell as well as signals originating outside the cell. The exogenous and the endogenous mechanisms maintaining stemness qualities of the cell are intricately interwoven with one another and susceptible to cross-interference. Mice and rats as animal models are almost universally considered to be close enough to humans so as to be used in research and applications eventually intended for use in human biology and medicine, at the same time being related distantly enough from primates so as not to overstep ethical boundaries. Studying the specific molecular features of both species in the context of maintenance of the undifferentiated state of mESC and hESC can provide researchers with an unique opportunity to unravel the network of interactions which take part in the decision about cell fate under different conditions; to glean interesting insights into the parallel evolution of the two species and to observe how different variants of basic cellular processes have been tried and tested in the evolutionary process. The present paper reviews the basic signalling pathways responsible for the maintenance of the undifferentiated state in mESC and hESC and analyses some specific aspects of the molecular physiology that are unique to the particular species.

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Review Article Thu, 20 Sep 2012 00:00:00 +0300
Parallel Researching with Online Collaboration (PROC), a new cost effective model for multicentre multinational research https://biodiscovery.pensoft.net/article/8926/ BioDiscovery 2: e8926

DOI: 10.7750/BioDiscovery.2012.2.3

Authors: Chaturaka Rodrigo, Senaka Rajapakse

Abstract: The traditional model of multicentre multinational studies is a costly exercise that limits its feasibility for resource limited settings. We propose an alternate model for such studies named Parallel Researching with Online Collaboration (PROC). If implemented, this hypothetical model will make multicentre trials feasible in many resource limited settings. PROC can be summarized in five phases; phase I – academics using free access social networking sites to collaborate and develop research questions, phase II – further consolidation of an idea and expansion of it with online contributions from experts, identification of key persons to carry out the study in parallel at different centres, phase III – drawing up a common research protocol and study tools, phase IV – each satellite centre functioning independently to carry out the common protocol, Phase V – pooling of data in a common summarized format and writing up the findings.

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Hypotheses Sun, 26 Aug 2012 00:00:00 +0300
Viability of unstimulated lymphocytes exposed to extremely low frequency electromagnetic fields is dependent on intensity https://biodiscovery.pensoft.net/article/8925/ BioDiscovery 2: e8925

DOI: 10.7750/BioDiscovery.2012.2.2

Authors: P Rajendra, HN Sujatha, RB Sashidhar, C Subramanyam, D Devendranath, RSS Aradhya

Abstract: The cell viability and DNA damage in unstimulated sheep primary lymphocytes subjected to different extremely low electromagnetic field intensities (5, 50 and 100 µT; 50 Hz) were studied with special emphasis on apoptosis. Sheep primary lymphocytes cultured in RPMI, supplemented with 10% FBS in the absence of mitogens, were exposed till 16 h. The cell viability assessment by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay showed a dose dependent enhancement of viability at 16 h. Further, quantitative DNA laddering and flow cytometric analysis showed a significant decrease in apoptosis of the cells subjected to 100 (p

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Research Article Wed, 22 Aug 2012 00:00:00 +0300
Up-regulation of Gr1 + CD11b + cell population in the spleen of NaClO-administered mice works to repair skin wounds https://biodiscovery.pensoft.net/article/8924/ BioDiscovery 2: e8924

DOI: 10.7750/BioDiscovery.2012.2.1

Authors: Mayu Hara, Naomi Nishio, Sachiko Ito, Masashi Akiyama

Abstract: In wound healing, early infiltration of neutrophils followed by macrophage infiltration are important defense mechanisms for repair of tissue damage. Here we examined the effects of neutrophils on wound healing. Administration of sodium hypochlorite (NaClO) to mouse skin induces neutrophil recruitment to the wound site and repeated administration of NaClO was shown to prolong wound healing. Examination of the spleens of mice whose wounds were repeatedly treated with NaClO, showed that GR-1<sup>+</sup>CD11b<sup>+</sup> cells were up regulated in the recovery phase of wounding. Many of the GR-1<sup>+</sup>CD11b <sup>+</sup> cells in the mouse bone marrow were neutrophils, as indicated by a ring-shaped nucleus, and some of the cells were immature myeloid-lineage cells. GR-1<sup>+</sup>CD11b<sup>+</sup> cells from bone marrow were sorted and injected intravenously to syngeneic Imprinting Control Region (ICR) mice. The mice that received GR-1<sup>+</sup>CD11b<sup>+</sup> cells recovered faster than the mice injected with the control, phosphate buffer saline (PBS).

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Research Article Mon, 6 Aug 2012 00:00:00 +0300
Targeting ATM pathway for therapeutic intervention in cancer https://biodiscovery.pensoft.net/article/8920/ BioDiscovery 1: e8920

DOI: 10.7750/BioDiscovery.2012.1.3

Authors: Hilal S Khalil, Hemanth Tummala, Stoyan Chakarov, Nikolai Zhelev, David P. Lane

Abstract: The Ataxia Telangiectasia Mutated gene encodes the ATM protein, a key element in the DNA damage response (DDR) signalling pathway responsible for maintaining genomic integrity within the cell. The ATM protein belongs to a family of large protein kinases containing the phosphatidylinositol-3 catalytic domain, including ATM, ATR and PI3K. ATM provides the crucial link between DNA damage, cell cycle progression and cell death by first sensing double stranded DNA breaks and subsequently phosphorylating and activating other downstream proteins functioning in DNA damage repair, cell cycle arrest and apoptotic pathways,. Mammalian cells are constantly challenged by genotoxic agents from a variety of sources and therefore require a robust sensing and repair mechanism to maintain DNA integrity or activate alternative cell fate pathways. This review covers the role of ATM in DDR signalling and describes the interaction of the ATM kinase with other proteins in order to fulfil its various functions. Special emphasis is given to how the growing knowledge of the DDR can help identify drug targets for cancer therapy, thus providing a rationale for exploiting the ATM pathway in anticancer drug development. Moreover, we discuss how a network modelling approach can be used to identify and characterise ATM inhibitors and predict their therapeutic potential.

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Review Article Sun, 29 Jul 2012 00:00:00 +0300
Identification of a novel deletion mutant strain in Saccharomyces cerevisiae that results in a microsatellite instability phenotype https://biodiscovery.pensoft.net/article/8918/ BioDiscovery 1: e8918

DOI: 10.7750/BioDiscovery.2012.1.4

Authors: Hanlee P. Ji, Shannon Morales, Katrina Welch, Cam Yuen, Kyle Farnam, James M Ford

Abstract: The DNA mismatch repair (MMR) pathway corrects specific types of DNA replication errors that affect microsatellites and thus is critical for maintaining genomic integrity. The genes of the MMR pathway are highly conserved across different organisms. Likewise, defective MMR function universally results in microsatellite instability (MSI) which is a hallmark of certain types of cancer associated with the Mendelian disorder hereditary nonpolyposis colorectal cancer. (Lynch syndrome). To identify previously unrecognized deleted genes or loci that can lead to MSI, we developed a functional genomics screen utilizing a plasmid containing a microsatellite sequence that is a host spot for MSI mutations and the comprehensive homozygous diploid deletion mutant resource for Saccharomyces cerevisiae. This pool represents a collection of non-essential homozygous yeast diploid (2N) mutants in which there are deletions for over four thousand yeast open reading frames (ORFs). From this screen, we identified a deletion mutant strain of the <i>PAU24</i> gene that leads to MSI. In a series of validation experiments, we determined that this <i>PAU24</i> mutant strain had an increased MSI-specific mutation rate in comparison to the original background wildtype strain, other deletion mutants and comparable to a MMR mutant involving the MLH1 gene. Likewise, in yeast strains with a deletion of <i>PAU24</i>, we identified specific de novo indel mutations that occurred within the targeted microsatellite used for this screen.

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Research Article Mon, 23 Jul 2012 00:00:00 +0300
Bisphosphonate-related osteonecrosis of the jaws: Report of two cases with breast cancer, a dental concern and review of the literature https://biodiscovery.pensoft.net/article/8917/ BioDiscovery 1: e8917

DOI: 10.7750/BioDiscovery.2012.1.2

Authors: Ahmet Ercan Şekerci, Halil Sahman, Murat Ulu, Osman A Etoz, Yıldıray Sisman

Abstract: Bisphosphonates are becoming increasingly important in the treatment of metabolic and oncological diseases involving the skeleton. In recent years, several cases of necrosis of the jaws associated with long-term use of bisphoshponates have been reported. The management of bisphosphonate-related osteonecrosis of the jaws (BRONJ) is emerging as a significant problem in the field of dentistry. In this article, we report two new cases of patients with osteonecrosis induced by bisphosphonates. Two unrelated female patients undergoing treatment with bisphosphonates for metastatic breast cancer were referred to the department of oral surgery due to non-healing extraction sockets and intraoral exposed bone after dental extraction. The treatment modality of case 1 included antibiotic therapy, sequestrectomy, periodontal flap, and chlorhexidine mouthwashes. After an eleven-month follow-up period the affected area has healed totally. The other patient refused any surgical intervention. In addition, this article reviews the current literature describing the dental procedures for patients with BRONJ.

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Research Article Sun, 15 Jul 2012 00:00:00 +0300
Modelling malignant progression with a finite state machine supports a two checkpoint theory of cancer https://biodiscovery.pensoft.net/article/8916/ BioDiscovery 1: e8916

DOI: 10.7750/BioDiscovery.2012.1.1

Authors: Robert C. Jackson

Abstract: We postulate the two checkpoints theory of cancer, a model of cancer development suggesting that malignant transformation of cells requires loss of function of both the G1 checkpoint and the mitotic spindle checkpoint. Malignant progression can be described as a process analogous to a genetic algorithm, which we term the malignant progression algorithm. There are two prerequisites for this process: first, there must be competition for reproductive resources, and this is driven by loss of the G1 checkpoint; second, there must be a source of genetic variation, and this is provided by loss of the mitotic spindle checkpoint, resulting in aneuploidy. These two factors then trigger a process of Darwinian selection, driving the emergence of cells with the various abnormalities that have been termed the “hallmarks of cancer”. Malignant progression is iterative, autocatalytic, and irreversible. The process can be modelled mathematically by describing the system as a finite state machine. The model indicates that loss of the two checkpoints is necessary and sufficient for tumour progression. The order of loss of the two checkpoints appears to be important: loss of the G1 checkpoint results in premalignant cells that replicate independently of physiological growth signals, but which remain diploid. Loss of the mitotic spindle checkpoint then results in aneuploid, malignant cells with highly error-prone replication, which rapidly progress to invasive, metastatic, hypoxia-tolerant, immortalised cells. This model of malignant progression has implications for the selection of anticancer drug targets and for tumour prevention strategies.

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Research Article Thu, 5 Jul 2012 00:00:00 +0300
Man of Science: Celebrating Professor Sir David Lane’s 60th anniversary https://biodiscovery.pensoft.net/article/8921/ BioDiscovery 1: e8921

DOI: 10.7750/BioDiscovery.2012.1.5

Authors: Nikolai Zhelev

Abstract: This article is devoted to the 60th anniversary of Professor Sir David Lane and summarises his renowned research career and scientific and business achievements to date. Professor Lane is one of the world’s foremost cancer biologists with more than 350 publications in the world leading science journals and was the second most highly cited UK-based scientist in the 1990’s. Sir David is best known for the discovery of the p53 protein which he termed “the guardian of the genome” due to its vital role in the defence against cancer. A decade later p53 was named “molecule of the year” by the scientific journal Science. Professor Lane has won many international prizes and awards for his outstanding work in the field of cancer research and drug development.

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Cover Story Sun, 1 Jul 2012 00:00:00 +0300