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The complete understanding of the genomic contribution to complex traits, diseases, and response to treatments, as well as genomic medicine application to the well-being of all humans will be achieved through the global variome that encompasses fine-scale genetic diversity. Despite significant efforts in recent years, uneven representation still characterizes genomic resources and among the underrepresented European populations are the Western Balkans including the Serbian population. Our research addresses this gap and presents the first ever targeted sequencing dataset of variants in clinically relevant genes. By measuring population differentiation and applying the Principal Component and Admixture analysis we demonstrated that the Serbian population differs little from other European populations, yet we identified several novel and more frequent variants that appear as its unique genetic determinants. We explored thoroughly the functional impact of frequent variants and its correlation with the health burden of the population of Serbia based on a sample of 144 individuals. Our variants catalogue improves the understanding of genetics of modern Serbia, contributes to research on ancestry, and aids in improvements of well-being and health equity. In addition, this resource may also be applicable in neighboring regions and valuable in worldwide functional analyses of genetic variants in individuals of European descent.

Based on the finding that a central antihypertensive agent with high affinity for I1-type imidazoline receptors ? rilmenidine, shows cytotoxic effects on cultured cancer cell lines, it has been suggested that imidazoline receptors agonists might have a therapeutic potential in the cancer therapy. Nevertheless, potential rilmenidine side effects caused by activation of α-adrenoceptors, or other associated receptors and enzymes, might hinder its therapeutic benefits. Considering that human α-adrenoceptors belong to the rhodopsin-like class A of G-protein-coupled receptors (GPCRs) it is reasonable to assume that imidazolines might have the affinity for other receptors from the same class. Therefore, to investigate possible off-target effects of imidazoline ligands we have prepared a reverse docking protocol on class A GPCRs, using imidazoline ligands and their decoys. To verify our in silico results, three ligands with high scores and three ligands with low scores were tested for antagonistic activity on α2- adrenoceptors.

Recent outbreaks of NDM-1-positive Entero-bacteriaceae in Great Britain and India and the highly pathogenic Escherichia coli strain EHEC O104:H4 in Germany and some other E.U. countries point out an urgent need for the ability to decide on appropriate antibiotics to treat multi-drug-resistant (MDR) bacteria. Here we propose a simple criterion for choosing antibiotics based on characteristics of electron donor and acceptor properties. Using molecular descriptors, such as electron-ion interaction potential (EIIP) and average quasi-valence number (AQVN), which can describe potential long-range interactions between therapeutic molecules and their targets, we have been able to suggest appropriate antibiotics for treatment of MDR bacterial infections. To demonstrate the prospective usefulness of these molecular descriptors we have used this informatics system to propose that pleuromutilins and nitrofurans could be effective against of NDM-1-positive Enterobacteriacea and that aminoglycosides, macrolides and pluromutilins (and possibly nitrofurans) could be suitable for treatment of the highly pathogenic Escherichia coli strain EHEC O104:H4. Similarly, because of their specific electronic properties, we can also suggest antibiotics that could be potentially effective against other MDR bacteria. The proposed antibiotics should be further evaluated for their treatment potentials.

The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I-1-type imidazoline receptors (I-1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from alpha(2)-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine- derived compounds with anticancer potential and devoid of alpha(2)-adrenoceptor effects by means of ligand-and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to alpha(2)-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers. (C) 2016 Elsevier Ltd. All rights reserved.

The Ebola 2014/2015 outbreak has had devastating effects on the people living in West Africa. The spread of the disease in endemic countries and the potential introduction of sporadic cases in other continents points out the global health threat of Ebola virus disease (EVD). Despite the urgent need for treating EVD, there are no approved treatments. Given the lack of treatments available, alternative therapeutic strategies have had to be used.This article summarizes the unregistered therapeutics that were used to treat patients during the Ebola 2014/2015 outbreak, in addition to approaches used for the selection of candidate drugs. The article also proposes potential theoretical criterion for use in virtual screening of molecular libraries for candidate Ebola drugs.In the absence of approved therapeutics for EVD, experimental drugs have had to be used. The repurposing of approved drugs for the treatment of EVD, as an alternative therapeutic strategy, has also been suggested. Screening in vitro- and in silico-approved drugs revealed several promising candidates but further testing is required to test their efficacy. All these therapeutic approaches are, however, only short-term solutions and there is still an urgent need for the development of specific drugs for the current and future outbreaks.

The group of imidazoline-1 receptors (I(1)-IR) agonists encompasses drugs are currently used in treatment of high blood pressure and hyperglycemia. The I(1)-IR protein structures have not been determined yet, but Nischarin protein that binds numerous imidazoline ligands inducing initiation of various cell-signaling cascades, including apoptosis, is identified as strong I(1)-IR candidate. In this study we examined apoptotic activity of rilmenidine (potent I(1)-IR agonist), moxonidine (moderate I(1)-IR agonist), and efaroxan (I(1)-IR partial agonist) on cancer cell line (K562) expressing Nischarin. The Nischarine domains mapping was performed by use of the Informational Spectrum Method (ISM). The 3D-Quantitative Structure-Activity Relationship (3D-QSAR) and virtual docking studies of 29 I(1)-IR ligands (agonists, partial agonists, and antagonists) were carried out on I(1)-IR receptors binding affinities. The 3D-QSAR study defined 3D-pharmacophore models for I(1)-IR agonistic and I(1)-IR antagonistic activity and created regression model for prediction of I(1)-IR activity of novel compounds. The 3D-QSAR models were applied for design and evaluation of novel I(1)-IR agonists and I(1)-IR antagonists. The most promising I(1)-IR ligands with enhanced activities than parent compounds were proposed for synthesis. The results of 3D-QSAR, ISM, and virtual docking studies were in perfect agreement and allowed precise definition of binding mode of I(1)-IR agonists (Arg 758, Arg 866, Val 981, and Glu 1057) and significantly different binding modes of I(1)-IR antagonists or partial I(1)-IR agonists. The performed theoretical study provides reliable system for evaluation of I(1)-IR agonistic and I(1)-IR antagonistic activity of novel I(1)-IR ligands, as drug candidates with anticancer activities.

Influenza A virus (IAV) subtypes against which little or no pre-existing immunity exists in humans represent a serious threat to global public health. Monitoring of IAV in animal hosts is essential for early and rapid detection of potential pandemic IAV strains to prevent their spread. Recently, the increased pandemic potential of the avian-like swine H1N1 IAV A/swine/Guangdong/104/2013 has been suggested. The virus is infectious in humans and the general population seems to lack neutralizing antibodies against this virus. Here we present an in silico analysis that shows a strong human propensity of this swine virus further confirming its pandemic potential. We suggest mutations which would further enhance its human propensity. We also propose conserved antigenic determinants which could serve as a component of a prepandemic vaccine. The bioinformatics tool, which can be used to further monitor the evolution of swine influenza viruses towards a pandemic virus, are described here and are made publically available (http://www.vin.bg.ac.rs/180/tools/iav_mon.php; http://www.biomedprotection.com/iav_mon.php).

Recently, the new concept of the long-range intermolecular interactions in biological systems has been proposed. Combined use of molecular modeling techniques and the screening techniques based on the long-range interaction concept could significantly improve and accelerate discovery of new HIV drugs. However, any hit identified in silico needs to be characterized with respect to its biological target by enzymatic studies. Combined use of the in silico screening and the enzymatic studies allows an efficient selection of new anti-HIV drugs.The focus of this article is on the in silico screening of molecular libraries for candidate new HIV drugs, which is based on the molecular descriptors determining the long-range interaction between the drugs and their therapeutic target. This article also reviews the techniques for enzyme kinetic studies which are required for optimization of in silico selected candidate anti-HIV drugs.The novel approach of combining in silico screening techniques with enzymatic studies enables the accurate measurement of the quantitative descriptors of ligand-enzyme interactions. This novel method is a powerful tool for new anti-HIV drug discovery which can also reduce the drug development costs.

Coronary artery disease (CAD) and myocardial infarction (MI) are recognized as leading causes of mortality in developed countries. Although typically associated with behavioral risk factors, such as smoking, sedentary lifestyle, and poor dietary habits, such vascular phenotypes have also long been recognized as being related to genetic background. We review the currently available data concerning genetic markers for CAD in English and non-English articles with English abstracts published between 2003 and 2018. As genetic testing is increasingly available, it may be possible to identify adequate genetic markers representing the risk profile and to use them in a clinical setting. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.

The field of bioinformatics has become a major part of the drug discovery pipeline playing a key role in improvement and acceleration of this time and money consuming process. Here we review the application of the informational spectrum method (ISM), a virtual spectroscopy method for structure/function analysis of proteins, in identification of functional protein domains representing candidate therapeutic targets for drugs against human immunodeficiency virus (HIV)-1, anthrax, highly pathogenic influenza virus H5N1 and cardiovascular diseases.

Human immunodeficiency virus (HIV) has infected 50 million people worldwide and killed 16 million so far, and the epidemic is still spreading with 16,000 new cases of HIV infection daily and a projection of 100million infected individuals by the end of the next decade. There is no question that a safe and effective acquired immunodeficiency syndrome (AIDS) vaccine is urgently needed to bring the current AIDS pandemic under control. But, is preventive AIDS vaccine an attainable goat? Unfortunately, the results of many laboratory and clinical studies over the past two decades are not encouraging. We comment on the efficacy, safety and ethics of AIDS vaccine, and the urgent need for a new strategy for AIDS vaccine development. (c) 2007 Elsevier Ltd. All. rights reserved. 1st International Symposium on Genetic and Immune Correlates of HIV Infection and Vaccine-Induced Immunity, Jun 10-13, 2007, Budapest, Hungary

The C-terminus of the second conserved region of HIV-1 gp120 represents a functionally important domain, as it encompasses amino acids directly involved in the binding to the CD4 receptor and in post-receptor binding events. Previous studies have suggested that antibodies with specific affinity to a 23 amino acids-long NTM polypeptide, derived from this HIV-1 gp120 domain, may be involved in the control of HIV disease progression. In the current work, we searched for NTM-recognizing antibodies in specific cohorts of HIV-1 infected individuals, including long-term nonprogressors (LTNP) and progressors. For this purpose, we employed a previously defined bioinformatics criterion for design of an NTM peptide mimetic to select an octapeptide, NTMs (FTDNAKTI), which is more suitable for use in a solid-state enzyme-linked immunosorbent assay (ELISA). Our results show that NTMs-reactive antibodies are significantly more prevalent (p < 0.01) in LTNP as compared to progressors and healthy control subjects, indicating their association with non-progressive infection. The presence of antibodies recognizing the second conserved region of the HIV-1 gp120 derived peptide, NTMs, in LTNP sera suggest that these antibodies could be of considerable interest for development of anti-HIV immune-based therapies and vaccines.

The influenza virus represents a permanent global health threat because it circulates not only within but also between numerous host populations, thereby frequently causing unexpected outbreaks in animals and humans with a generally unpredictable course of disease and epidemiology. Conventional influenza therapy is directed against the viral neuraminidase protein, which promotes virus release from infected cells, and the viral ion channel M2, which facilitates viral uncoating. However, these drugs, albeit effective, have a major drawback: their targets are of a highly variable sequence. As a consequence, the virus can readily acquire resistance by mutating the drug targets. Indeed, most seasonal A/H1N1 viruses and the 2009 H1N1 virus are resistant to M2 inhibitors, and a significant proportion of the seasonal A/H1N1 viruses are resistant to the neuraminidase inhibitor oseltamivir. Development of new effective drugs for treatment of disease during the regular influenza seasons and the possible influenza pandemic represents an important goal. The results presented here point out natural products as a promising source of low toxic and widely accessible drug candidates for treatment of the influenza disease. Natural products combined with new therapeutic targets and drug repurposing techniques, which accelerate development of new drugs, serve as an important platform for development of new influenza therapeutics.

The large 2014/2015 Ebola virus outbreak in West Africa points out the urgent need to develop new preventive and therapeutic approaches that are effective against Ebola viruses and can be rapidly utilized. Recently, a simple theoretical criterion for the virtual screening of molecular libraries for candidate inhibitors of Ebola virus infection was proposed. Using this method the ‘drug space’ was screened and 267 approved and 382 experimental drugs as candidates for treatment of the Ebola virus disease (EVD) have been selected. Detailed analysis of these drugs revealed the non-steroidal anti-inflammatory drug ibuprofen as an inexpensive, widely accessible and minimally toxic candidate for prevention and treatment of EVD. Furthermore, the molecular mechanism underlying this possible protective effect of ibuprofen against EVD is suggested in this article.

Maraviroc is a first-in-class antiretroviral (ARV) drug acting on a host cell target (CCR5), which blocks the entry of the HIV virus into the cell. Maraviroc is currently indicated for combination ARV treatment in adults infected only with CCR5-tropic HIV-1.This drug discovery case history focuses on the key studies that led to the discovery and approval of maraviroc, as well as on post-launch clinical reports. The article is based on the data reported in published preclinical and clinical studies, conference posters and on drug package data.The profound understanding of HIV's entry mechanisms has provided a strong biological rationale for targeting the chemokine receptor CCR5. The CCR5-antagonist mariviroc, with its unique mode of action and excellent safety profile, is an important therapeutic option for HIV patients. In general, the authors believe that targeting host factors is a useful approach for combating new and re-emerging transmissible diseases, as well as pathogens that easily become resistant to common antiviral drugs. Maraviroc, offering a potent and safe cellular receptor-mediated pharmacological response to HIV, has paved the way for the development of a new generation of host-targeting antivirals.

The worst Ebola virus (EV) outbreak in history has hit Liberia, Sierra Leone and Guinea hardest and the trend lines in this crisis are grave, and now represents a global public health threat concern. Limited therapeutic and/or prophylactic options are available for people suffering from Ebola virus disease (EVD) and further complicate the situation. Previous studies suggested that the EV glycoprotein (GP) is the main determinant causing structural damage of endothelial cells that triggers the hemorrhagic diathesis, but molecular mechanisms underlying this phenomenon remains elusive. Using the informational spectrum method (ISM), a virtual spectroscopy method for analysis of the protein-protein interactions, the interaction of GP with endothelial extracellular matrix (ECM) was investigated. Presented results of this in silico study suggest that Elastin Microfibril Interface Located Proteins (EMILINs) are involved in interaction between GP and ECM. This finding could contribute to a better understanding of EV/endothelium interaction and its role in pathogenesis, prevention and therapy of EVD.

Aim: Chemokine CXC ligand 16 (CXCL16) has chemoattractive, adhesive and scavenging properties and may play a role in the formation of atherosclerotic lesions. However, studies of CXCL16 polymorphisms in patients with atherosclerosis are scarce. The missense polymorphisms I123T and A181V are potentially important factors in the regulation of presentation and shedding of the CXCL16 chemokine domain. The aim of this study was to analyze the association between I123T and A181V polymorphism haplotypes and the accumulation of carotid plaque as well as the effect of the haplotype on the CXCL16 mRNA expression in carotid plaques in patients with advanced atherosclerosis. Additionally, we performed a bioinformatic prediction analysis of the impact of CXCL16 protein sequence variation on CXCL16-CXCR6 interactions and analyzed the soluble CXCL16 plasma levels according to the CXCL16 haplotype. Methods: This study evaluated a total of 733 participants, including 283 controls and 450 patients with carotid atherosclerosis (CA) undergoing endarterectomy. Analyses of the polymorphisms and the gene expression were performed using real-time PCR. The soluble CXCL16 levels were measured with ELISA. Results: The missense allele haplotype, T123V181, was found to be significantly and independently associated with the occurrence of CA plaque (OR=1.27; 1.02-1.57, p=0.03). This haplotype was predicted to significantly change the CXCL16-CXCR6 interaction, compared to I123A181. Neither the CXCL16 mRNA expression in the human plaques nor the soluble CXCL16 plasma levels differed according to the haplotype. Conclusions: These results indicate that the CXCL16 T123V181 haplotype is a moderate genetic risk factor for the development of carotid plaque. Further functional and replication studies are needed to clarify the mechanisms by which this combination of alleles promotes advanced CA and validate its impact on disease progression.

The Informational Spectrum Method (ISM) is the tool for the in silico analysis of proteins which interprets protein sequence linear information using signal analyses methods. In this paper the ISM was employed to characterize the products of genetic variants of tumor suppressor gene p53 and its natural binding regulator protein Mdm2. Based on this we propose the criterion for identification of missense mutations that have impact on the p53-Mdm2 feedback loop. The efficiency of the proposed criterion was confirmed by the ISM analyses of p53 mutants reported in: (i) healthy individuals, (ii) germline mutations database and (iii) somatic mutations database.

A broad range of similarities between HIV-1 gp120 and human proteins-especially those participating in immune responses-highlight gp120 as a pleiotropic protein which can influence many important functions of the human immune system. The molecular mimicry that serves to the human immunodeficiency virus as potent destructive arms against immune system could be the weak point we are in search of over decades. Examples involving sequence and informational similarities of HIV-1 gp120 and immunerelated host cell proteins important for prevention and treatment of HIV infection are presented. .

A broad range of structural, functional, and immunological similarities between HIV-1 gp120 and human proteins, especially those participating in immune responses, highlight gp120 as a pleiotropic protein that can in different ways affect many important functions of the human immune system. Here we described some of these properties of HIV-1 gp120 that represent the main obstacle in the development of effective and safe AIDS vaccine.

Glucose metabolism is under the cooperative regulation of both insulin receptor (IR) and beta(2)-adrenergic receptor (beta(2)AR), which represent the receptor tyrosine kinases (RTKs) and seven transmembrane receptors (7TMRs), respectively. Studies demonstrating cross-talk between these two receptors and their endogenous coexpression have suggested their possible interactions. To evaluate the effect of IR and prospective heteromerization on beta(2)AR properties, we showed that IR coexpression had no effect on the ligand binding properties of beta(2)AR; however, IR reduced beta(2)AR surface expression and accelerated its internalization. Additionally, both receptors displayed a similar distribution pattern with a high degree of colocalization. To test the possible direct interaction between beta(2)AR and IR, we employed quantitative BRET 2 saturation and competition assays. Saturation assay data suggested constitutive beta(2)AR and IR homo-and heteromerization. Calculated acceptor/donor (AD(50)) values as a measure of the relative affinity for homo-and heteromer formation differed among the heteromers that could not be explained by a simple dimer model. In heterologous competition assays, a transient increase in the BRET2 signal with a subsequent hyperbolical decrease was observed, suggesting higher-order heteromer formation. To complement the BRET2 data, we employed the informational spectrum method (ISM), a virtual spectroscopy method to investigate protein-protein interactions. Computational peptide scanning of beta(2)AR and IR identified intracellular domains encompassing residues at the end of the 7th TM domain and C-terminal tail of beta(2)AR and a cytoplasmic part of the IR beta chain as prospective interaction domains. ISM further suggested a high probability of heteromer formation and homodimers as basic units engaged in heteromerization. In summary, our data suggest direct interaction and higher-order beta(2)AR: IR oligomer formation, likely comprising heteromers of homodimers.

Background/Aim. High sera reactivity with a peptide derived from human immunodeficiency virus HIV-1 envelope protein gp120, NTM1, correlate with non-progressive HIV-1 infection and also may have protective role in breast and prostate cancer. We also detected a low NTM1 reactive antibodies titer in healthy HIV negative sera and showed that antibody levels can be significantly increased with vigorous physical activity. However, the immune system seems to be unresponsive or tolerant to this peptide, implicating that the NTM1 sequence encompasses or overlaps a certain innate immune epitope. The aim of this study was to present evidences that NTM1 - binding antibodies - are components of innate immune humoral response, by confirming their presence in sera of newborn babies. For this purpose we collected a set of 225 innate antigen sequences reported in the literature and screened it for candidate antigens with the highest sequence and spectral similarity to NTM1 derived from HIV-1 gp120. Methods. Sera from 18 newborns were tested using ELISA, with peptide NTM1. Sequences from innate antigen database were aligned by an EMBOSS Water bioinformatics tool. Results. We identified NTM1 reactive antibodies in sera of HIV negative newborn babies. Further, in order to identify which of already known innate antigens are the most similar to NTM1 peptide we screened innate immune antigen sequence database collected from the literature. This screening revealed that the most similar sequence are ribonucleoproteins RO60, in addition to previously identified Nterminus of vasoactive intestinal peptide. Conclusion. The results of this study confirm the hypothesis that NTM1 recognizing antibodies are a part of humoral innate immune response. Further, computational similarity screening revealed a vasoactive intestinal peptide and RO60 as the most similar sequences and the strongest candidate antigens. In the light of the presented results, it is appealing that testing blood reactivity at birth, with specific innate antigens, particularly a vasoactive intestinal peptide, can reveal the potential to develop or boost protective immune response in breast and prostate cancer and HIV infection later in life. [Projekat Ministarstva nauke Republike Srbije, br. 173001]

Years of endemic infections with highly pathogenic avian influenza (HPAI) A subtype H5N1 virus in poultry and high numbers of infections in humans provide ample opportunity in Egypt for H5N1-HPAIV to develop pandemic potential. In an effort to better understand the viral determinants that facilitate human infections of the Egyptian H5N1-HPAIVvirus, we developed a new phylogenetic algorithm based on a new distance measure derived from the informational spectrum method (ISM). This new approach, which describes functional aspects of the evolution of the hemagglutinin subunit 1 (HA1), revealed a growing group G2 of H5N1-HPAIV in Egypt after 2009 that acquired new informational spectrum (IS) properties suggestive of an increased human tropism and pandemic potential. While in 2006 all viruses in Egypt belonged to the G1 group, by 2011 these viruses were virtually replaced by G2 viruses. All of the G2 viruses displayed four characteristic mutations (D43N, S120(D,N), (S,L)129 Delta and I151T), three of which were previously reported to increase binding to the human receptor. Already in 2006-2008 G2 viruses were significantly (p LT 0.02) more often found in humans than expected from their overall prevalence and this further increased in 2009-2011 (p LT 0.007). Our approach also identified viruses that acquired additional mutations that we predict to further enhance their human tropism. The extensive evolution of Egyptian H5N1-HPAIV towards a preferential human tropism underlines an urgent need to closely monitor these viruses with respect to molecular determinants of virulence.

Highly active antiretroviral therapy (HAART) dramatically has changed the course of HIV infection. Currently, this therapy involves the use of agents from at least two distinct classes of antivirals: a protease inhibitor in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with NRTIs. Recently, the third family of antivirals started to be used clinically, with the advent of enfuvirtide, the first fusion inhibitor. This broad spectrum of anti-HIV agents recently was extended with compounds inhibiting HIV integrase and vital entry. But these advances did not come without a cost: there were the short- and long-term drug toxicities, emergence of drug resistance, and persistence of viral reservoirs. For these reasons, there is a pressing need for novel anti-HIV drugs, particularly those that have a novel action mechanism, as these might be less likely to show cross-resistance with current therapies. The field of bioinformatics has become a major part of the drug discovery pipeline playing a key role in improvement and acceleration of the time and money consuming process of the drug development. Here we review the application of the EIIP/AQVN (Electron-Ion Interaction Potential, EIIP; Average Quasi Valence Number, AQVN) bioinformatics concept in the development of new anti-HIV drugs and propose a simple theoretical criterion for a virtual screening of molecular libraries for promising lead anti-HIV compounds and refinement of selected lead compounds in order to increase their biological activity.

Hepatitis C virus (HCV) infection is a major and rising global health problem, affecting about 170 million people worldwide. The current standard of care treatment with interferon alpha and ribavirin in patients with the genotype 1 infection, the most frequent genotype in the USA and Western Europe, leads to a successful outcome in only about 50% of individuals. Accurate prediction of hepatitis C treatment response is of great benefit to patients and clinicians. The informational spectrum method, a virtual spectroscopy method for structure/function analysis of nucleotide and protein sequences, is applied here for the identification of the conserved information of the HCV proteins that correlate with the combination therapy outcome. Among the HCV proteins that we have analyzed the informational property of the p7 of HCV genotype 1b was best related to the therapy outcome. On the basis of these results, a simple bioinformatics criterion that could be useful in assessment of the response of HCV-infected patients to the combination therapy has been proposed.

We investigated the association of CX3CR1 genotypes/haplotypes with MS and performed the prediction analysis of protein sequence variants effects on CX3CL1/CX3CR1 interaction. We found no association of CX3CR1 with MS susceptibility. Frequency of I249T280 haplotype was significantly lower in SP compared to RR patients (RR GT 10 years, OR=0.30, 95%CI=0.11-0.79, p=0.01: OR=0.53, 95%CI=0.18-1.56, p=0.2, in sP LT 10 years vs. RR GT 10 years). Prediction analysis showed that I249 T280 protein variant would significantly affect CX3CL1/CX3CR1 interaction. Our results suggest that CX3CR1 I249T280 haplotype could have protective effect for switch to SP MS. Further research is warranted to validate and replicate currently observed results. (C) 2012 Elsevier B.V. All rights reserved.

Objectives: The incidence of non-AIDS-defining cancer is remarkably higher in HIV-infected than in the general population. In contrast, breast cancer risk is significantly reduced in the HIV-infected population. The molecular mechanisms underlying the phenomenon of suppression of breast cancer in the HIV-infected population may serve as a basis for development of a new platform for prevention and treatment of breast cancer. Hypothesis: Various evidences indicate that vasoactive intestinal peptide (VIP) plays an important role in growth, and differentiation of breast cancer. We previously showed (i) that natural antibodies recognizing VIP and the gp120-derived peptide NTM significantly contribute to the control of HIV disease progression by suppression of VIP-like activity of HIV-1 gp120 and (ii) that physical exercise stimulates production of these natural antibodies. These findings suggest that natural anti-VIP/NTM antibodies could contribute to a decrease of breast cancer in the HIV-infected population by suppression of VIP, which may play a pro/oncogenic function. Aerobic exercise which stimulates production of anti-VIP/NTM antibodies could be used as prevention and supportive treatment of breast cancer. Impact: Immunotherapy based on natural anti-VIP/NTM antibodies could serve as an effective adjunct therapy for the treatment of breast cancer. Similarly, aerobic exercise, which stimulates production of these antibodies, should be considered as an inexpensive and safe preventive and supportive breast cancer therapy. Natural anti-VIP/NTM antibodies also represent promising prognostic marker for breast cancer. (C) 2011 Elsevier Ltd. All rights reserved.

Natural autoantibodies (NAbs) are continually produced throughout life and have an ability to recognize self and altered self, as well as foreign antigens, by recognizing cellular pattern recognition receptors. Sometimes NAb specificity demonstrates overlap between human and pathologic proteomes. This information can be useful in selecting target sequences for screening purposes. In this study we undertook a multi-step bioinformatics search to predict a virus-derived peptide that can be recognized by NAbs in sera of uninfected individuals. We selected protein hepatitis C virus (HCV) NS5A as a target sequence, motivated by the fact that the HCV proteome is characterized by extensive sequence similarities to the human proteome, and because screening for anti-HCV antibodies, including anti-NS5A, is important clinically, particularly in screening of potential blood donors. The virus-specific peptide P1, and the homologous human peptide derived from enzyme-inducible nitric oxide synthase (iNOS), P2, exhibiting not only simple homology, but also complementarities of physicochemical patterns, were synthesized and 80 HCV-negative and 50 HCV-positive blood donor sera were tested by ELISA. These peptides reacted similarly (p LT 0.001) with HCV-negative sera, and in several cases the measured reactivity was significantly above the cut-off value of commercial anti-HCV screening assays. In HCV-positive sera, the titers of antibodies reactive with analyzed HCV NS5A peptide were not significantly increased (p LT 0.001) compared to host peptide, the implications of which are unclear, but may be consistent with these antibodies being naturally produced. Finally, we extended our bioinformatics analyses to the dataset of human self-binding sequences, and propose a general approach for the selection of specific diagnostic and screening antigens for use in immunoassays.

Background Epidemics caused by highly pathogenic avian influenza virus (HPAIV) are a continuing threat to human health and to the world's economy. The development of approaches, which help to understand the significance of structural changes resulting from the alarming mutational propensity for human-to-human transmission of HPAIV, is of particularly interest. Here we compare informational and structural properties of the hemagglutinin (HA) of H5N1 virus and human influenza virus subtypes, which are important for the receptor/virus interaction. Results Presented results revealed that HA proteins encode highly conserved information that differ between influenza virus subtypes H5N1, H1N1, H3N2, H7N7 and defined an HA domain which may modulate interaction with receptor. We also found that about one third of H5N1 viruses which are isolated during the 2006/07 influenza outbreak in Egypt possibly evolve towards receptor usage similar to that of seasonal H1N1. Conclusion The presented results may help to better understand the interaction of influenza virus with its receptor(s) and to identify new therapeutic targets for drug development.

The ongoing Ebola virus epidemic has presented numerous challenges with respect to control and treatment because there are no approved drugs or vaccines for the Ebola virus disease (EVD). Herein is proposed simple theoretical criterion for fast virtual screening of molecular libraries for candidate inhibitors of Ebola virus infection. We performed a repurposing screen of 6438 drugs from DrugBank using this criterion and selected 267 approved and 382 experimental drugs as candidates for treatment of EVD including 15 anti-malarial drugs and 32 antibiotics. An open source Web server allowing screening of molecular libraries for candidate drugs for treatment of EVD was also established.

It has been reported that antibodies reactive with peptide RSANFTDNAKTIIVQLNQSVEIN (peptide NTM) derived from the C-terminus of the second conserved domain of HIV-1 envelope glycoprotein gp120 could represent an important factor in control of the HIV disease. In order to check this notion we (i) tested reactivity with peptide NTM serum samples collected from 310 consecutive HIV-1 infected patients with a CD4(+) lymphocyte count ranging from 10 to 800/muL and (ii) performed the longitudinal study that included 107 sera samples collected from 29 HIV patients. Results of these studies demonstrated correlation between presence of anti-NTM antibodies in sera of HIV patients and disease progression measured by the CD4(+) cell count. Based on these findings we proposed the anti-NTM antibodies as useful prognostic marker for HIV disease. (C) 2004 Elsevier B.V. All rights reserved.

Current expansion of AIDS pandemic significantly accelerates AIDS vaccine research resulting in development and clinical testing of several AIDS vaccine candidates. At the same time, available experimental and clinical data demonstrate that current AIDS vaccine strategy is unsuccessful resulting in development of inefficient and harmful vaccines. This overview briefly summarizes reported results which point out the requirement for moratorium on the current clinical trials of HIV-1 gp120/160 vaccines and urgent need for development of a new, efficient and safe AIDS vaccine strategy.

Background The novel A/H1N1 influenza virus, which recently emerged in North America is most closely related to North American H1N1/N2 swine viruses. Until the beginning of 2009, North American swine H1N1/N2 viruses have only sporadically infected humans as dead-end hosts. In 2009 the A/H1N1 virus acquired the capacity to spread efficiently by human to human transmission. The novel A/H1N1 influenza virus has struck thousands of people in more than 70 countries and killed more than 140, representing a public health emergency of international concern. Here we have studied properties of hemagglutinin of A/H1N1 which may modulate virus/receptor interaction. Results Analyses by ISM bioinformatics platform of the HA1 protein of North American swine H1N1/N2 viruses and the new A/H1N1 showed that both groups of viruses differed in conserved characteristics that reflect a distinct propensity of these viruses to undergo a specific interaction with swine or human host proteins or receptors. Swine H1N1/N2 viruses that sporadically infected humans featured both the swine and the human interaction pattern. Substitutions F71S, T128S, E302K, M314L in HA1 of swine H1N1 viruses from North America are identified as critical for the human interaction pattern of A/H1N1 and residues D94, D196 and D274 are predicted to be "hot-spots" for polymorphisms which could increase infectivity of A/H1N1 virus. At least one of these residues has already emerged in the A/H1N1 isolates from Spain, Italy and USA. The domain 286-326 was identified to be involved in virus/receptor interaction. Conclusion Our results (i) contribute to better understanding of the origin of the novel A/H1N1 influenza virus, (ii) provide a tool for monitoring its molecular evolution (iii) predicts hotspots associated with enhanced infectivity in humans and (iv) identify therapeutic and diagnostic targets for prevention and treatment of A/H1N1 infection.