WorldWideScience

Sample records for human complex retroviruses

  1. Rev and Rex proteins of human complex retroviruses function with the MMTV Rem-responsive element

    Directory of Open Access Journals (Sweden)

    Dudley Jaquelin P

    2009-02-01

    Full Text Available Abstract Background Mouse mammary tumor virus (MMTV encodes the Rem protein, an HIV Rev-like protein that enhances nuclear export of unspliced viral RNA in rodent cells. We have shown that Rem is expressed from a doubly spliced RNA, typical of complex retroviruses. Several recent reports indicate that MMTV can infect human cells, suggesting that MMTV might interact with human retroviruses, such as human immunodeficiency virus (HIV, human T-cell leukemia virus (HTLV, and human endogenous retrovirus type K (HERV-K. In this report, we test whether the export/regulatory proteins of human complex retroviruses will increase expression from vectors containing the Rem-responsive element (RmRE. Results MMTV Rem, HIV Rev, and HTLV Rex proteins, but not HERV-K Rec, enhanced expression from an MMTV-based reporter plasmid in human T cells, and this activity was dependent on the RmRE. No RmRE-dependent reporter gene expression was detectable using Rev, Rex, or Rec in HC11 mouse mammary cells. Cell fractionation and RNA quantitation experiments suggested that the regulatory proteins did not affect RNA stability or nuclear export in the MMTV reporter system. Rem had no demonstrable activity on export elements from HIV, HTLV, or HERV-K. Similar to the Rem-specific activity in rodent cells, the RmRE-dependent functions of Rem, Rev, or Rex in human cells were inhibited by a dominant-negative truncated nucleoporin that acts in the Crm1 pathway of RNA and protein export. Conclusion These data argue that many retroviral regulatory proteins recognize similar complex RNA structures, which may depend on the presence of cell-type specific proteins. Retroviral protein activity on the RmRE appears to affect a post-export function of the reporter RNA. Our results provide additional evidence that MMTV is a complex retrovirus with the potential for viral interactions in human cells.

  2. Human retroviruses and AIDS 1994

    Energy Technology Data Exchange (ETDEWEB)

    Myers, G.; Korber, B. [Los Alamos National Lab., NM (United States); Wain-Hobson, S.; Jeang, Kuan-Teh; Henderson, L.E.; Pavlakis, G.N. [eds.

    1995-01-01

    This compendium, including accompanying floppy diskettes, is the result of an effort to compile and rapidly publish all relevant molecular data concerning the human immunodeficiency viruses (HIV) and related retroviruses. The scope of the compendium and database is best summarized by the five parts it comprises: (I) Nucleic Acid Alignments and Sequences; (II) Amino Acid Alignments; (III) Analysis; (IV) Related Sequences; (V) Database communications.

  3. Human endogenous retroviruses and ADHD.

    Science.gov (United States)

    Balestrieri, Emanuela; Pitzianti, Mariabernarda; Matteucci, Claudia; D'Agati, Elisa; Sorrentino, Roberta; Baratta, Antonia; Caterina, Rosa; Zenobi, Rossella; Curatolo, Paolo; Garaci, Enrico; Sinibaldi-Vallebona, Paola; Pasini, Augusto

    2014-08-01

    Several lines of evidences suggest that human endogenous retroviruses (HERVs) are implicated in the development of many complex diseases with a multifactorial aetiology and a strong heritability, such as neurological and psychiatric diseases. Attention deficit hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that results from a complex interaction of environmental, biological and genetic factors. Our aim was to analyse the expression levels of three HERV families (HERV-H, K and W) in patients with ADHD. The expression of retroviral mRNAs from the three HERV families was evaluated in peripheral blood mononuclear cells (PBMCs) from 30 patients with ADHD and 30 healthy controls by quantitative RT-PCR. The expression levels of HERV-H are significantly higher in patients with ADHD compared to healthy controls, while there are no differences in the expression levels of HERV-K and W. Since the ADHD aetiology is due to a complex interaction of environmental, biological and genetic factors, HERVs may represent one link among these factors and clinical phenotype of ADHD. A future confirmation of HERV-H overexpression in a larger number of ADHD patients will make possible to identify it as a new parameter for this clinical condition, also contributing to deepen the study on the role of HERVs in the neurodevelopment diseases.

  4. Human retroviruses and AIDS 1997

    Energy Technology Data Exchange (ETDEWEB)

    Korber, B.; Foley, B.; Leitner, T. [eds.] [and others

    1997-12-01

    This compendium is the result of an effort to compile, organize, and rapidly publish as much relevant molecular data concerning the human immunodeficiency viruses (HIV) and related retroviruses as possible. The scope of the compendium and database is best summarized by the four parts that it comprises: (1) Nucleic Acid Alignments, (2) Amino Acid Alignments, (3) Reviews and Analyses, and (4) Related Sequences. Information within all the parts is updated throughout the year on the Web site, http://hiv-web.lanl.gov. This year we are not including floppy diskettes as the entire compendium is available both at our Web site and at our ftp site. If you need floppy diskettes please contact either Bette Korber (btk@t10.lanl.gov) or Kersti Rock (karm@t10.lanl.gov) by email or fax ((505) 665-4453). While this publication could take the form of a review or sequence monograph, it is not so conceived. Instead, the literature from which the database is derived has simply been summarized and some elementary computational analyses have been performed upon the data. Interpretation and commentary have been avoided insofar as possible so that the reader can form his or her own judgments concerning the complex information. The exception to this are reviews submitted by experts in areas deemed of particular and basic importance to research involving AIDS viral sequence information. These are included in Part III, and are contributed by scientists with particular expertise in the area of interest. In addition to the general descriptions below of the parts of the compendium, the user should read the individual introductions for each part.

  5. Human-Specific Endogenous Retroviruses

    Directory of Open Access Journals (Sweden)

    Anton Buzdin

    2007-01-01

    Full Text Available This review focuses on a small family of human-specific genomic repetitive elements, presented by 134 members that shaped ~330 kb of the human DNA. Although modest in terms of its copy number, this group appeared to modify the human genome activity by endogenizing ~50 functional copies of viral genes that may have important implications in the immune response, cancer progression, and antiretroviral host defense. A total of 134 potential promoters and enhancers have been added to the human DNA, about 50% of them in the close gene vicinity and 22% in gene introns. For 60 such human-specific promoters, their activity was confirmed by in vivo assays, with the transcriptional level varying ~1000-fold from hardly detectable to as high as ~3% of β-actin transcript level. New polyadenylation signals have been provided to four human RNAs, and a number of potential antisense regulators of known human genes appeared due to human-specific retroviral insertional activity. This information is given here in the context of other major genomic changes underlining differences between human and chimpanzee DNAs. Finally, a comprehensive database, is available for download, of human-specific and polymorphic endogenous retroviruses is presented, which encompasses the data on their genomic localization, primary structure, encoded viral genes, human gene neighborhood, transcriptional activity, and methylation status.

  6. HERVd: the Human Endogenous Retrovirus Database: update

    Czech Academy of Sciences Publication Activity Database

    Pačes, Jan; Pavlíček, A.; Zíka, Radek; Jurka, J.; Pačes, Václav

    2004-01-01

    Roč. 32, č. 1 (2004), s. 50-50 ISSN 0305-1048 R&D Projects: GA MŠk LN00A079 Institutional research plan: CEZ:AV0Z5052915 Keywords : human * endogenous retrovirus * database Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.260, year: 2004

  7. Complex Codon Usage Pattern and Compositional Features of Retroviruses

    Directory of Open Access Journals (Sweden)

    Sourav RoyChoudhury

    2013-01-01

    Full Text Available Retroviruses infect a wide range of organisms including humans. Among them, HIV-1, which causes AIDS, has now become a major threat for world health. Some of these viruses are also potential gene transfer vectors. In this study, the patterns of synonymous codon usage in retroviruses have been studied through multivariate statistical methods on ORFs sequences from the available 56 retroviruses. The principal determinant for evolution of the codon usage pattern in retroviruses seemed to be the compositional constraints, while selection for translation of the viral genes plays a secondary role. This was further supported by multivariate analysis on relative synonymous codon usage. Thus, it seems that mutational bias might have dominated role over translational selection in shaping the codon usage of retroviruses. Codon adaptation index was used to identify translationally optimal codons among genes from retroviruses. The comparative analysis of the preferred and optimal codons among different retroviral groups revealed that four codons GAA, AAA, AGA, and GGA were significantly more frequent in most of the retroviral genes inspite of some differences. Cluster analysis also revealed that phylogenetically related groups of retroviruses have probably evolved their codon usage in a concerted manner under the influence of their nucleotide composition.

  8. Human retroviruses and AIDS, 1991. [CONTAINS GLOSSARY

    Energy Technology Data Exchange (ETDEWEB)

    Myers, G.; Korber, B. (eds.) (Los Alamos National Lab., NM (USA)); Berzofsky, J.A.; Pavlakis, G.N. (eds.) (National Cancer Inst., Bethesda, MD (USA)); Smith, R.F. (ed.) (Harvard Univ. (USA))

    1991-05-01

    This compendium and the accompanying floppy diskettes are the result of an effort to compile and rapidly publish all relevant molecular data concerning the human immunodeficiency viruses (HIV) and related retroviruses.The scope of the compendium and database is best summarized by the five parts that it comprises: (1) HIV and SIV Nucleotide Sequences; (2) Amino Acid Sequences; (3) Analyses; (4) Related Sequences; and (5) Database Communications. Information within all the parts is updated at least twice in each year, which accounts for the modes of binding and pagination in the compendium.

  9. Human endogenous retroviruses in neurologic disease.

    Science.gov (United States)

    Christensen, Tove

    2016-01-01

    Endogenous retroviruses are pathogenic - in other species than the human. Disease associations for Human Endogenous RetroViruses (HERVs) are emerging, but so far an unequivocal pathogenetic cause-effect relationship has not been established. A role for HERVs has been proposed in neurological and neuropsychiatric diseases as diverse as multiple sclerosis (MS) and schizophrenia (SCZ). Particularly for MS, many aspects of the activation and involvement of specific HERV families (HERV-H/F and HERV-W/MSRV) have been reported, both for cells in the circulation and in the central nervous system. Notably envelope genes and their gene products (Envs) appear strongly associated with the disease. For SCZ, for ALS, and for HIV-associated dementia (HAD), indications are accumulating for involvement of the HERV-K family, and also HERV-H/F and/or HERV-W. Activation is reasonably a prerequisite for causality as most HERV sequences remain quiescent in non-pathological conditions, so the importance of regulatory pathways and epigenetics involved in regulating HERV activation, derepression, and also involvement of retroviral restriction factors, is emerging. HERV-directed antiretrovirals have potential as novel therapeutic paradigms in neurologic disease, particularly in MS. The possible protective or ameliorative effects of antiretroviral therapy in MS are substantiated by reports that treatment of HIV infection may be associated with a significantly decreased risk of MS. Further studies of HERVs, their role in neurologic diseases, and their potential as therapeutic targets are essential. © 2016 APMIS. Published by John Wiley & Sons Ltd.

  10. Human retroviruses: their role in cancer.

    Science.gov (United States)

    Blattner, W A

    1999-01-01

    Viruses are etiologically linked to approximately 20% of all malignancies worldwide. Retroviruses account for approximately 8%-10% of the total. For human T-cell leukemia virus 1 (HTLV-I), the viral regulatory tax gene product is responsible for enhanced transcription of viral and cellular genes that promote cell growth by stimulating various growth factors and through dysregulation of cellular regulatory suppressor genes, such as p53. After a long latent period, adult T-cell leukemia/lymphoma (ATL) occurs in 1 per 1000 carriers per year, resulting in 2500-3000 cases per year worldwide and over half of the adult lymphoid malignancies in endemic areas. Human immunodeficiency virus 1 (HIV-1) accounts for a significant cancer burden, and its transactivating regulatory protein Tat enhances direct and indirect cytokine and immunological dysregulation to cause diverse cancers. Kaposi's sarcoma (KS) is a very rare tumor except after HIV-1 infection, when its incidence is greatly amplified reaching seventy thousand-fold in HIV-infected homosexual men. Human herpesvirus 8 (HHV-8), which is also known as Kaposi's sarcoma-associated virus (KSHV), is a necessary but not sufficient etiological factor in KS. The dramatic decline of KS since the introduction of highly active antiretroviral therapy (HAART) could be due to suppression of HIV-1 tat. B-cell non-Hodgkin's lymphoma occurs as their first acquired immunodeficiency syndrome-defining diagnosis in 3%-4% of HIV-infected patients. Hodgkin's lymphoma is also associated with HIV infection but at a lower risk. Human papillomaviruses are linked to invasive cervical cancer and anogenital cancers among HIV-infected patients. Human retroviruses cause malignancy via direct effects as well as through interactions with other oncogenic herpesviruses and other viruses.

  11. On the classification and evolution of endogenous retrovirus: human endogenous retroviruses may not be 'human' after all.

    Science.gov (United States)

    Escalera-Zamudio, Marina; Greenwood, Alex D

    2016-01-01

    Retroviruses, as part of their replication cycle, become integrated into the genome of their host. When this occurs in the germline the integrated proviruses can become an endogenous retrovirus (ERV) which may eventually become fixed in the population. ERVs are present in the genomes of all vertebrates including humans, where more than 50 groups of human endogenous retrovirus (HERVs) have been described within the last 30 years. Despite state-of-the-art genomic tools available for retroviral discovery and the large number of retroviral sequences described to date, there are still gaps in understanding retroviral macroevolutionary patterns and host-retrovirus interactions and a lack of a coherent systematic classification particularly for HERVs. Here, we discuss the current knowledge on ERV (and HERV) classification, distribution and origins focusing on the role of cross-species transmission in retroviral diversity. © 2016 APMIS. Published by John Wiley & Sons Ltd.

  12. Are human endogenous retroviruses triggers of autoimmune diseases?

    DEFF Research Database (Denmark)

    Nexø, Bjørn A; Villesen, Palle; Nissen, Kari K

    2016-01-01

    factors. Viruses including human endogenous retroviruses have long been linked to the occurrence of autoimmunity, but never proven to be causative factors. Endogenous viruses are retroviral sequences embedded in the host germline DNA and transmitted vertically through successive generations in a Mendelian...... manner. In this study by means of genetic epidemiology, we have searched for the involvement of endogenous retroviruses in three selected autoimmune diseases: multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. We found that at least one human endogenous retroviral locus...

  13. A historical reflection on the discovery of human retroviruses.

    Science.gov (United States)

    Vahlne, Anders

    2009-05-01

    The discovery of HIV-1 as the cause of AIDS was one of the major scientific achievements during the last century. Here the events leading to this discovery are reviewed with particular attention to priority and actual contributions by those involved. Since I would argue that discovering HIV was dependent on the previous discovery of the first human retrovirus HTLV-I, the history of this discovery is also re-examined. The first human retroviruses (HTLV-I) was first reported by Robert C. Gallo and coworkers in 1980 and reconfirmed by Yorio Hinuma and coworkers in 1981. These discoveries were in turn dependent on the previous discovery by Gallo and coworkers in 1976 of interleukin 2 or T-cell growth factor as it was called then. HTLV-II was described by Gallo's group in 1982. A human retrovirus distinct from HTLV-I and HTLV-II in that it was shown to have the morphology of a lentivirus was in my mind described for the first time by Luc Montagnier in an oral presentation at Cold Spring Harbor in September of 1983. This virus was isolated from a patient with lymphadenopathy using the protocol previously described for HTLV by Gallo. The first peer reviewed paper by Montagnier's group of such a retrovirus, isolated from two siblings of whom one with AIDS, appeared in Lancet in April of 1984. However, the proof that a new human retrovirus (HIV-1) was the cause of AIDS was first established in four publications by Gallo's group in the May 4th issue of Science in 1984.

  14. A historical reflection on the discovery of human retroviruses

    Directory of Open Access Journals (Sweden)

    Vahlne Anders

    2009-05-01

    Full Text Available Abstract The discovery of HIV-1 as the cause of AIDS was one of the major scientific achievements during the last century. Here the events leading to this discovery are reviewed with particular attention to priority and actual contributions by those involved. Since I would argue that discovering HIV was dependent on the previous discovery of the first human retrovirus HTLV-I, the history of this discovery is also re-examined. The first human retroviruses (HTLV-I was first reported by Robert C. Gallo and coworkers in 1980 and reconfirmed by Yorio Hinuma and coworkers in 1981. These discoveries were in turn dependent on the previous discovery by Gallo and coworkers in 1976 of interleukin 2 or T-cell growth factor as it was called then. HTLV-II was described by Gallo's group in 1982. A human retrovirus distinct from HTLV-I and HTLV-II in that it was shown to have the morphology of a lentivirus was in my mind described for the first time by Luc Montagnier in an oral presentation at Cold Spring Harbor in September of 1983. This virus was isolated from a patient with lymphadenopathy using the protocol previously described for HTLV by Gallo. The first peer reviewed paper by Montagnier's group of such a retrovirus, isolated from two siblings of whom one with AIDS, appeared in Lancet in April of 1984. However, the proof that a new human retrovirus (HIV-1 was the cause of AIDS was first established in four publications by Gallo's group in the May 4th issue of Science in 1984.

  15. The first sequenced carnivore genome shows complex host-endogenous retrovirus relationships.

    Directory of Open Access Journals (Sweden)

    Álvaro Martínez Barrio

    Full Text Available Host-retrovirus interactions influence the genomic landscape and have contributed substantially to mammalian genome evolution. To gain further insights, we analyzed a female boxer (Canis familiaris genome for complexity and integration pattern of canine endogenous retroviruses (CfERV. Intriguingly, the first such in-depth analysis of a carnivore species identified 407 CfERV proviruses that represent only 0.15% of the dog genome. In comparison, the same detection criteria identified about six times more HERV proviruses in the human genome that has been estimated to contain a total of 8% retroviral DNA including solitary LTRs. These observed differences in man and dog are likely due to different mechanisms to purge, restrict and protect their genomes against retroviruses. A novel group of gammaretrovirus-like CfERV with high similarity to HERV-Fc1 was found to have potential for active retrotransposition and possibly lateral transmissions between dog and human as a result of close interactions during at least 10.000 years. The CfERV integration landscape showed a non-uniform intra- and inter-chromosomal distribution. Like in other species, different densities of ERVs were observed. Some chromosomal regions were essentially devoid of CfERVs whereas other regions had large numbers of integrations in agreement with distinct selective pressures at different loci. Most CfERVs were integrated in antisense orientation within 100 kb from annotated protein-coding genes. This integration pattern provides evidence for selection against CfERVs in sense orientation relative to chromosomal genes. In conclusion, this ERV analysis of the first carnivorous species supports the notion that different mammals interact distinctively with endogenous retroviruses and suggests that retroviral lateral transmissions between dog and human may have occurred.

  16. Human endogenous retroviruses and cancer prevention: evidence and prospects

    Directory of Open Access Journals (Sweden)

    Cegolon Luca

    2013-01-01

    Full Text Available Abstract Background Cancer is a significant and growing problem worldwide. While this increase may, in part, be attributed to increasing longevity, improved case notifications and risk-enhancing lifestyle (such as smoking, diet and obesity, hygiene-related factors resulting in immuno-regulatory failure may also play a major role and call for a revision of vaccination strategies to protect against a range of cancers in addition to infections. Discussion Human endogenous retroviruses (HERVs are a significant component of a wider family of retroelements that constitutes part of the human genome. They were originated by the integration of exogenous retroviruses into the human genome millions of years ago. HERVs are estimated to comprise about 8% of human DNA and are ubiquitous in somatic and germinal tissues. Physiologic and pathologic processes are influenced by some biologically active HERV families. HERV antigens are only expressed at low levels by the host, but in circumstances of inappropriate control their genes may initiate or maintain pathological processes. Although the precise mechanism leading to abnormal HERVs gene expression has yet to be clearly elucidated, environmental factors seem to be involved by influencing the human immune system. HERV-K expression has been detected in different types of tumors. Among the various human endogenous retroviral families, the K series was the latest acquired by the human species. Probably because of its relatively recent origin, the HERV-K is the most complete and biologically active family. The abnormal expression of HERV-K seemingly triggers pathological processes leading to melanoma onset, but also contributes to the morphological and functional cellular modifications implicated in melanoma maintenance and progression. The HERV-K-MEL antigen is encoded by a pseudo-gene incorporated in the HERV-K env-gene. HERV-K-MEL is significantly expressed in the majority of dysplastic and normal naevi, as well

  17. Human endogenous retroviruses and cancer prevention: evidence and prospects.

    Science.gov (United States)

    Cegolon, Luca; Salata, Cristiano; Weiderpass, Elisabete; Vineis, Paolo; Palù, Giorgio; Mastrangelo, Giuseppe

    2013-01-03

    Cancer is a significant and growing problem worldwide. While this increase may, in part, be attributed to increasing longevity, improved case notifications and risk-enhancing lifestyle (such as smoking, diet and obesity), hygiene-related factors resulting in immuno-regulatory failure may also play a major role and call for a revision of vaccination strategies to protect against a range of cancers in addition to infections. Human endogenous retroviruses (HERVs) are a significant component of a wider family of retroelements that constitutes part of the human genome. They were originated by the integration of exogenous retroviruses into the human genome millions of years ago. HERVs are estimated to comprise about 8% of human DNA and are ubiquitous in somatic and germinal tissues.Physiologic and pathologic processes are influenced by some biologically active HERV families. HERV antigens are only expressed at low levels by the host, but in circumstances of inappropriate control their genes may initiate or maintain pathological processes. Although the precise mechanism leading to abnormal HERVs gene expression has yet to be clearly elucidated, environmental factors seem to be involved by influencing the human immune system.HERV-K expression has been detected in different types of tumors.Among the various human endogenous retroviral families, the K series was the latest acquired by the human species. Probably because of its relatively recent origin, the HERV-K is the most complete and biologically active family.The abnormal expression of HERV-K seemingly triggers pathological processes leading to melanoma onset, but also contributes to the morphological and functional cellular modifications implicated in melanoma maintenance and progression.The HERV-K-MEL antigen is encoded by a pseudo-gene incorporated in the HERV-K env-gene. HERV-K-MEL is significantly expressed in the majority of dysplastic and normal naevi, as well as other tumors like sarcoma, lymphoma, bladder and

  18. Human endogenous retroviruses and cancer prevention: evidence and prospects

    International Nuclear Information System (INIS)

    Cegolon, Luca; Salata, Cristiano; Weiderpass, Elisabete; Vineis, Paolo; Palù, Giorgio; Mastrangelo, Giuseppe

    2013-01-01

    Cancer is a significant and growing problem worldwide. While this increase may, in part, be attributed to increasing longevity, improved case notifications and risk-enhancing lifestyle (such as smoking, diet and obesity), hygiene-related factors resulting in immuno-regulatory failure may also play a major role and call for a revision of vaccination strategies to protect against a range of cancers in addition to infections. Human endogenous retroviruses (HERVs) are a significant component of a wider family of retroelements that constitutes part of the human genome. They were originated by the integration of exogenous retroviruses into the human genome millions of years ago. HERVs are estimated to comprise about 8% of human DNA and are ubiquitous in somatic and germinal tissues. Physiologic and pathologic processes are influenced by some biologically active HERV families. HERV antigens are only expressed at low levels by the host, but in circumstances of inappropriate control their genes may initiate or maintain pathological processes. Although the precise mechanism leading to abnormal HERVs gene expression has yet to be clearly elucidated, environmental factors seem to be involved by influencing the human immune system. HERV-K expression has been detected in different types of tumors. Among the various human endogenous retroviral families, the K series was the latest acquired by the human species. Probably because of its relatively recent origin, the HERV-K is the most complete and biologically active family. The abnormal expression of HERV-K seemingly triggers pathological processes leading to melanoma onset, but also contributes to the morphological and functional cellular modifications implicated in melanoma maintenance and progression. The HERV-K-MEL antigen is encoded by a pseudo-gene incorporated in the HERV-K env-gene. HERV-K-MEL is significantly expressed in the majority of dysplastic and normal naevi, as well as other tumors like sarcoma, lymphoma, bladder

  19. HERVd: database of human endogenous retroviruses

    Czech Academy of Sciences Publication Activity Database

    Pačes, Jan; Pavlíček, Adam; Pačes, Václav

    2002-01-01

    Roč. 30, č. 1 (2002), s. 205-206 ISSN 0305-1048 R&D Projects: GA MŠk LN00A079; GA ČR GA301/99/M023 Keywords : HERV * database * human genome Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.051, year: 2002

  20. Human cytomegalovirus (HCMV) induces human endogenous retrovirus (HERV) transcription.

    Science.gov (United States)

    Assinger, Alice; Yaiw, Koon-Chu; Göttesdorfer, Ingmar; Leib-Mösch, Christine; Söderberg-Nauclér, Cecilia

    2013-11-12

    Emerging evidence suggests that human cytomegalovirus (HCMV) is highly prevalent in tumours of different origin. This virus is implied to have oncogenic and oncomodulatory functions, through its ability to control host gene expression. Human endogenous retroviruses (HERV) are also frequently active in tumours of different origin, and are supposed to contribute as cofactors to cancer development. Due to the high prevalence of HCMV in several different tumours, and its ability to control host cell gene expression, we sought to define whether HCMV may affect HERV transcription. Infection of 3 established cancer cell lines, 2 primary glioblastoma cells, endothelial cells from 3 donors and monocytes from 4 donors with HCMV (strains VR 1814 or TB40/F) induced reverse transcriptase (RT) activity in all cells tested, but the response varied between donors. Both, gammaretrovirus-related class I elements HERV-T, HERV-W, HERV-F and ERV-9, and betaretrovirus-related class II elements HML-2 - 4 and HML-7 - 8, as well as spuma-virus related class III elements of the HERV-L group were up-regulated in response to HCMV infection in GliNS1 cells. Up-regulation of HERV activity was more pronounced in cells harbouring active HCMV infection, but was also induced by UV-inactivated virus. The effect was only slightly affected by ganciclovir treatment and was not controlled by the IE72 or IE86 HCMV genes. Within this brief report we show that HCMV infection induces HERV transcriptional activity in different cell types.

  1. Human Endogenous Retrovirus W Activity in Cartilage of Osteoarthritis Patients

    Directory of Open Access Journals (Sweden)

    Signy Bendiksen

    2014-01-01

    Full Text Available The etiology of viruses in osteoarthritis remains controversial because the prevalence of viral nucleic acid sequences in peripheral blood or synovial fluid from osteoarthritis patients and that in healthy control subjects are similar. Until now the presence of virus has not been analyzed in cartilage. We screened cartilage and chondrocytes from advanced and non-/early osteoarthritis patients for parvovirus B19, herpes simplex virus-1, Epstein Barr virus, cytomegalovirus, human herpes virus-6, hepatitis C virus, and human endogenous retroviruses transcripts. Endogenous retroviruses transcripts, but none of the other viruses, were detected in 15 out the 17 patients. Sequencing identified the virus as HERV-WE1 and E2. HERV-W activity was confirmed by high expression levels of syncytin, dsRNA, virus budding, and the presence of virus-like particles in all advanced osteoarthritis cartilages examined. Low levels of HERV-WE1, but not E2 envelope RNA, were observed in 3 out of 8 non-/early osteoarthritis patients, while only 3 out of 7 chondrocytes cultures displayed low levels of syncytin, and just one was positive for virus-like particles. This study demonstrates for the first time activation of HERV-W in cartilage of osteoarthritis patients; however, a causative role for HERV-W in development or deterioration of the disease remains to be proven.

  2. Packaging of human endogenous retrovirus sequences is undetectable in porcine endogenous retrovirus particles produced from human cells

    International Nuclear Information System (INIS)

    Suling, Kristen; Quinn, Gary; Wood, James; Patience, Clive

    2003-01-01

    The chronic shortage of human donor organs and tissues for allotransplantation could be relieved if clinical xenotransplantation were to become a viable clinical therapy. Balanced against the benefits of xenotransplantation are the possible consequences of zoonotic infections, and in particular, infection by porcine endogenous retrovirus (PERV). An often-proclaimed risk of PERV infection is the possible recombination of PERV with human endogenous retroviruses (HERV) . To address this issue, we examined the potential for HERV sequences to be cross-packaged into PERV particles produced from infected human 293 cells. Although HERV-K, W, E, R, and ERV-9 RNA transcripts are expressed in 293 cells, we did not detect cross-packaging of any of these HERV groups. Quantitative analysis indicated that less than approximately 1 in 10 4 -10 7 PERV particles might contain HERV sequences. In comparison, we found that murine leukemia virus (MLV)-based vector transcripts were cross-packaged at a rate of approximately one copy in 10 4 PERV particles. Our results indicate that the potential for recombination of PERV and HERV sequences is low and that novel viruses generated by this mechanism are unlikely to represent a significant risk for xenotransplantation

  3. Mutational definition of functional domains within the Rev homolog encoded by human endogenous retrovirus K.

    Science.gov (United States)

    Bogerd, H P; Wiegand, H L; Yang, J; Cullen, B R

    2000-10-01

    Nuclear export of the incompletely spliced mRNAs encoded by several complex retroviruses, including human immunodeficiency virus type 1 (HIV-1), is dependent on a virally encoded adapter protein, termed Rev in HIV-1, that directly binds both to a cis-acting viral RNA target site and to the cellular Crm1 export factor. Human endogenous retrovirus K, a family of ancient endogenous retroviruses that is not related to the exogenous retrovirus HIV-1, was recently shown to also encode a Crm1-dependent nuclear RNA export factor, termed K-Rev. Although HIV-1 Rev and K-Rev display little sequence identity, they share the ability not only to bind to Crm1 and to RNA but also to form homomultimers and shuttle between nucleus and cytoplasm. We have used mutational analysis to identify sequences in the 105-amino-acid K-Rev protein required for each of these distinct biological activities. While mutations in K-Rev that inactivate any one of these properties also blocked K-Rev-dependent nuclear RNA export, several K-Rev mutants were comparable to wild type when assayed for any of these individual activities yet nevertheless defective for RNA export. Although several nonfunctional K-Rev mutants acted as dominant negative inhibitors of K-Rev-, but not HIV-1 Rev-, dependent RNA export, these were not defined by their inability to bind to Crm1, as is seen with HIV-1 Rev. In total, this analysis suggests a functional architecture for K-Rev that is similar to, but distinct from, that described for HIV-1 Rev and raises the possibility that viral RNA export mediated by the approximately 25 million-year-old K-Rev protein may require an additional cellular cofactor that is not required for HIV-1 Rev function.

  4. Human endogenous retroviruses and chosen disease parameters in morphea

    Science.gov (United States)

    Dańczak-Pazdrowska, Aleksandra; Szramka-Pawlak, Beata; Żaba, Ryszard; Osmola-Mańkowska, Agnieszka; Silny, Wojciech

    2017-01-01

    Introduction Morphea (localized scleroderma) is a relatively rare disease characterized by excessive skin fibrosis. Human endogenous retroviruses (HERV) are largely distributed within the human genome with hundreds of thousands of elements. The HERV have been widely studied in autoimmune disorders, yet hardly ever assessed in diseases with a good prognosis such as morphea. Aim In this study we focus on the possible relations between the expression of chosen HERV and factors influencing the pathomechanism of the disease, such as age, sex, titres of anti-nuclear antibodies, as well as duration, activity, and severity of the disease (LoSSI index). Material and methods Real-time polymerase chain reaction (PCR) targeting six HERV sequences of interest were performed on samples derived from peripheral blood mononuclear cells (PBMC) and skin biopsies. Results In PBMC we found a statistically significant negative correlation between HERV-W env expression and LoSSI index (p = 0.01). Additionally, HERV-W env was downregulated in patients with the active form of morphea. In all other cases we found no correlation whatsoever nor statistically significant differences below the p = 0.05 threshold. Conclusions Morphea seems to be an autoimmune disease where the impact of HERV is not so apparent. It seems that probing many patients for the expression of just a few sequences is not as effective as previously expected. For initial studies of HERV in other diseases we recommend high throughput techniques such as HERV-dedicated DNA microarrays or massive parallel sequencing. PMID:28261031

  5. Human endogenous retroviruses and chosen disease parameters in morphea

    Directory of Open Access Journals (Sweden)

    Michał J. Kowalczyk

    2017-02-01

    Full Text Available Introduction: Morphea (localized scleroderma is a relatively rare disease characterized by excessive skin fibrosis. Human endogenous retroviruses (HERV are largely distributed within the human genome with hundreds of thousands of elements. The HERV have been widely studied in autoimmune disorders, yet hardly ever assessed in diseases with a good prognosis such as morphea. Aim: In this study we focus on the possible relations between the expression of chosen HERV and factors influencing the pathomechanism of the disease, such as age, sex, titres of anti-nuclear antibodies, as well as duration, activity, and severity of the disease (LoSSI index. Material and methods: Real-time polymerase chain reaction (PCR targeting six HERV sequences of interest were performed on samples derived from peripheral blood mononuclear cells (PBMC and skin biopsies. Results: In PBMC we found a statistically significant negative correlation between HERV-W env expression and LoSSI index (p = 0.01. Additionally, HERV-W env was downregulated in patients with the active form of morphea. In all other cases we found no correlation whatsoever nor statistically significant differences below the p = 0.05 threshold. Conclusions : Morphea seems to be an autoimmune disease where the impact of HERV is not so apparent. It seems that probing many patients for the expression of just a few sequences is not as effective as previously expected. For initial studies of HERV in other diseases we recommend high throughput techniques such as HERV-dedicated DNA microarrays or massive parallel sequencing.

  6. Human endogenous retroviruses and multiple sclerosis: innocent bystanders or disease determinants?

    Science.gov (United States)

    Antony, Joseph M; Deslauriers, Andre M; Bhat, Rakesh K; Ellestad, Kristofer K; Power, Christopher

    2011-02-01

    Human endogenous retroviruses (HERVs) constitute 5-8% of human genomic DNA and are replication incompetent despite expression of individual HERV genes from different chromosomal loci depending on the specific tissue. Several HERV genes have been detected as transcripts and proteins in the central nervous system, frequently in the context of neuroinflammation. The HERV-W family has received substantial attention in large part because of associations with diverse syndromes including multiple sclerosis (MS) and several psychiatric disorders. A HERV-W-related retroelement, multiple sclerosis retrovirus (MSRV), has been reported in MS patients to be both a biomarker as well as an effector of aberrant immune responses. HERV-H and HERV-K have also been implicated in MS and other neurological diseases but await delineation of their contributions to disease. The HERV-W envelope-encoded glycosylated protein, syncytin-1, is encoded by chromosome 7q21 and exhibits increased glial expression within MS lesions. Overexpression of syncytin-1 in glia induces endoplasmic reticulum stress leading to neuroinflammation and the induction of free radicals, which damage proximate cells. Syncytin-1's receptor, ASCT1 is a neutral amino acid transporter expressed on glia and is suppressed in white matter of MS patients. Of interest, antioxidants ameliorate syncytin-1's neuropathogenic effects raising the possibility of using these agents as therapeutics for neuroinflammatory diseases. Given the multiple insertion sites of HERV genes as complete and incomplete open reading frames, together with their differing capacity to be expressed and the complexities of individual HERVs as both disease markers and bioactive effectors, HERV biology is a compelling area for understanding neuropathogenic mechanisms and developing new therapeutic strategies. 2010 Elsevier B.V. All rights reserved.

  7. The role of human endogenous retroviruses in brain development and function.

    Science.gov (United States)

    Mortelmans, Kristien; Wang-Johanning, Feng; Johanning, Gary L

    2016-01-01

    Endogenous retroviral sequences are spread throughout the genome of all humans, and make up about 8% of the genome. Despite their prevalence, the function of human endogenous retroviruses (HERVs) in humans is largely unknown. In this review we focus on the brain, and evaluate studies in animal models that address mechanisms of endogenous retrovirus activation in the brain and central nervous system (CNS). One such study in mice found that TRIM28, a protein critical for mouse early development, regulates transcription and silencing of endogenous retroviruses in neural progenitor cells. Another intriguing finding in human brain cells and mouse models was that endogenous retrovirus HERV-K appears to be protective against neurotoxins. We also report on studies that associate HERVs with human diseases of the brain and CNS. There is little doubt of an association between HERVs and a number of CNS diseases. However, a cause and effect relationship between HERVs and these diseases has not yet been established. © 2016 APMIS. Published by John Wiley & Sons Ltd.

  8. Making a virtue of necessity: the pleiotropic role of human endogenous retroviruses in cancer.

    Science.gov (United States)

    Kassiotis, George; Stoye, Jonathan P

    2017-10-19

    Like all other mammals, humans harbour an astonishing number of endogenous retroviruses (ERVs), as well as other retroelements, embedded in their genome. These remnants of ancestral germline infection with distinct exogenous retroviruses display various degrees of open reading frame integrity and replication capability. Modern day exogenous retroviruses, as well as the infectious predecessors of ERVs, are demonstrably oncogenic. Further, replication-competent ERVs continue to cause cancers in many other species of mammal. Moreover, human cancers are characterized by transcriptional activation of human endogenous retroviruses (HERVs). These observations conspire to incriminate HERVs as causative agents of human cancer. However, exhaustive investigation of cancer genomes suggests that HERVs have entirely lost the ability for re-infection and thus the potential for insertional mutagenic activity. Although there may be non-insertional mechanisms by which HERVs contribute to cancer development, recent evidence also uncovers potent anti-tumour activities exerted by HERV replication intermediates or protein products. On balance, it appears that HERVs, despite their oncogenic past, now represent potential targets for immune-mediated anti-tumour mechanisms.This article is part of the themed issue 'Human oncogenic viruses'. © 2017 The Authors.

  9. Evolutionary relationships within a subgroup of HERV-K-related human endogenous retroviruses

    NARCIS (Netherlands)

    Zsíros, J.; Jebbink, M. F.; Lukashov, V. V.; Voûte, P. A.; Berkhout, B.

    1998-01-01

    The prototype endogenous retrovirus HERV-K10 was identified in the human genome by its homology to the exogenous mouse mammary tumour virus. By analysis of a short 244 bp segment of the reverse transcriptase (RT) gene of other HERV-K10-like sequences, it has become clear that these elements

  10. Long-term reinfection of the human genome by endogenous retroviruses

    Czech Academy of Sciences Publication Activity Database

    Belshaw, R.; Pereira, V.; Katzourakis, A.; Talbot, G.; Pačes, Jan; Burt, A.

    2004-01-01

    Roč. 101, č. 14 (2004), s. 4894-4899 ISSN 0027-8424 R&D Projects: GA MŠk LN00A079 Institutional research plan: CEZ:AV0Z5052915 Keywords : endogenous retroviruses * human genome * HERV Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 10.452, year: 2004

  11. Association of human endogenous retroviruses with multiple sclerosis and possible interactions with herpes viruses

    DEFF Research Database (Denmark)

    Christensen, Tove

    2005-01-01

    may be members of the Herpesviridae. Several herpes viruses, such as HSV-1, VZV, EBV and HHV-6, have been associated with MS pathogenesis, and retroviruses and herpes viruses have complex interactions. The current understanding of HERVs, and specifically the investigations of HERV activation...... and expression in MS are the major subjects of this review, which also proposes to synergise the herpes and HERV findings, and presents several possible pathogenic mechanisms for HERVs in MS. Copyright (c) 2005 ...

  12. DNA hypomethylation and aberrant expression of the human endogenous retrovirus ERVWE1/syncytin-1 in seminomas

    Czech Academy of Sciences Publication Activity Database

    Benešová, Martina; Trejbalová, Kateřina; Kovářová, Denisa; Vernerová, Z.; Hron, Tomáš; Kučerová, Dana; Hejnar, Jiří

    2017-01-01

    Roč. 14, č. 1 (2017), č. článku 20. ISSN 1742-4690 R&D Projects: GA ČR GA13-37600S; GA MZd NT14601 Institutional support: RVO:68378050 Keywords : Human endogenous retrovirus * ERVWE1 * Germ cell tumor * Seminoma * Promoter DNA methylation * 5-Hydroxymethylcytosine * Transcription * RNA splicing Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Virology Impact factor: 3.867, year: 2016

  13. 12th international conference on human retrovirology: HTLV and related retroviruses

    Directory of Open Access Journals (Sweden)

    Lairmore Michael D

    2005-10-01

    Full Text Available Abstract The 12th International Conference on Human Retrovirology: HTLV and Related Retroviruses, was held at the Half Moon Hotel in Montego Bay, Jamaica, from June 22nd to June 25th 2005. The scientific conference, sponsored by the International Retrovirology Association, is held biennially at rotating international venues around the world. The meeting brings together basic scientists, epidemiologists and clinical researchers to discuss findings to prevent HTLV infection or develop new therapies against HTLV-mediated diseases. The Association fosters the education and training of young scientists to bring new approaches to the complex problems of HTLV research, such as translational research to bring findings from the laboratory into clinical trials that benefit HTLV-infected patients. The breadth and quality of research presentations and workshops at the 12th International Conference indicate that these goals are being accomplished. As HTLV research enters its third decade a new generation of scientists face many challenges. However, HTLV scientists and clinicians displayed exciting new approaches and discoveries during plenary talks and poster sessions. The conference encouraged research in HTLV infections and disease, fostered collaborations, and stimulated new partnerships between clinicians and scientists to encourage clinical trials and novel therapeutic interventions.

  14. Human retroviruses and AIDS 1996. A compilation and analysis of nucleic acid and amino acid sequences

    Energy Technology Data Exchange (ETDEWEB)

    Myers, G.; Foley, B.; Korber, B. [eds.] [Los Alamos National Lab., NM (United States). Theoretical Div.; Mellors, J.W. [ed.] [Univ. of Pittsburgh, PA (United States); Jeang, K.T. [ed.] [National Institutes of Health, Bethesda, MD (United States). Molecular Virology Section; Wain-Hobson, S. [Pasteur Inst., Paris (France)] [ed.

    1997-04-01

    This compendium and the accompanying floppy diskettes are the result of an effort to compile and rapidly publish all relevant molecular data concerning the human immunodeficiency viruses (HIV) and related retroviruses. The scope of the compendium and database is best summarized by the five parts that it comprises: (1) Nuclear Acid Alignments and Sequences; (2) Amino Acid Alignments; (3) Analysis; (4) Related Sequences; and (5) Database Communications. Information within all the parts is updated throughout the year on the Web site, http://hiv-web.lanl.gov. While this publication could take the form of a review or sequence monograph, it is not so conceived. Instead, the literature from which the database is derived has simply been summarized and some elementary computational analyses have been performed upon the data. Interpretation and commentary have been avoided insofar as possible so that the reader can form his or her own judgments concerning the complex information. In addition to the general descriptions of the parts of the compendium, the user should read the individual introductions for each part.

  15. Association of endogenous retroviruses and long terminal repeats with human disorders

    Directory of Open Access Journals (Sweden)

    Iyoko eKatoh

    2013-09-01

    Full Text Available Since the human genome sequences became available in 2001, our knowledge about the human transposable elements which comprise ~40% of the total nucleotides has been expanding. Non- LTR (long terminal repeat retrotransposons are actively transposing in the present-day human genome, and have been found to cause ~100 identified clinical cases of varied disorders. In contrast, almost all of the human endogenous retroviruses (HERVs originating from ancient infectious retroviruses lost their infectivity and transposing activity at various times before the human-chimpanzee speciation (~6 million years ago, and no known HERV is presently infectious. Insertion of HERVs and mammalian apparent LTR retrotransposons (MaLRs into the chromosomal DNA influenced a number of host genes in various modes during human evolution. Apart from the aspect of genome evolution, HERVs and solitary LTRs being suppressed in normal biological processes can potentially act as extra transcriptional apparatuses of cellular genes by re-activation in individuals. There has been a reasonable prediction that aberrant LTR activation could trigger malignant disorders and autoimmune responses if epigenetic changes including DNA hypomethylation occur in somatic cells. Evidence supporting this hypothesis has begun to emerge only recently: a MaLR family LTR activation in the pathogenesis of Hodgkin’s lymphoma and a HERV-E antigen expression in an anti-renal cell carcinoma immune response. This mini review addresses the impacts of the remnant-form LTR retrotransposons on human pathogenesis.

  16. Friends-enemies: endogenous retroviruses are major transcriptional regulators of human DNA

    Science.gov (United States)

    Buzdin, Anton A.; Prassolov, Vladimir; Garazha, Andrew V.

    2017-06-01

    Endogenous retroviruses are mobile genetic elements hardly distinguishable from infectious, or “exogenous”, retroviruses at the time of insertion in the host DNA. Human endogenous retroviruses (HERVs) are not rare. They gave rise to multiple families of closely related mobile elements that occupy 8% of the human genome. Together, they shape genomic regulatory landscape by providing at least 320,000 human transcription factor binding sites (TFBS) located on 110,000 individual HERV elements. The HERVs host as many as 155,000 mapped DNaseI hypersensitivity sites, which denote loci active in the regulation of gene expression or chromatin structure. The contemporary view of the HERVs evolutionary dynamics suggests that at the early stages after insertion, the HERV is treated by the host cells as a foreign genetic element, and is likely to be suppressed by the targeted methylation and mutations. However, at the later stages, when significant number of mutations has been already accumulated and when the retroviral genes are broken, the regulatory potential of a HERV may be released and recruited to modify the genomic balance of transcription factor binding sites. This process goes together with further accumulation and selection of mutations, which reshape the regulatory landscape of the human DNA. However, developmental reprogramming, stress or pathological conditions like cancer, inflammation and infectious diseases, can remove the blocks limiting expression and HERV-mediated host gene regulation. This, in turn, can dramatically alter the gene expression equilibrium and shift it to a newer state, thus further amplifying instability and exacerbating the stressful situation.

  17. Expression of human adenosine deaminase in mice reconstituted with retrovirus-transduced hematopoietic stem cells

    International Nuclear Information System (INIS)

    Wilson, J.M.; Danos, O.; Grossman, M.; Raulet, D.H.; Mulligan, R.C.

    1990-01-01

    Recombinant retroviruses encoding human adenosine deaminase have been used to infect murine hematopoietic stem cells. In bone marrow transplant recipients reconstituted with the genetically modified cells, human ADA was detected in peripheral blood mononuclear cells of the recipients for at least 6 months after transplantation. In animals analyzed in detail 4 months after transplantation, human ADA and proviral sequences were detected in all hematopoietic lineages; in several cases, human ADA activity exceeded the endogenous activity. These studies demonstrate the feasibility of introducing a functional human ADA gene into hematopoietic stem cells and obtaining expression in multiple hematopoietic lineages long after transplantation. This approach should be helpful in designing effective gene therapies for severe combined immunodeficiency syndromes in humans

  18. Expression of the pol gene of human endogenous retroviruses HERV-K and -W in leukemia patients.

    Science.gov (United States)

    Bergallo, Massimiliano; Montanari, Paola; Mareschi, Katia; Merlino, Chiara; Berger, Massimo; Bini, Ilaria; Daprà, Valentina; Galliano, Ilaria; Fagioli, Franca

    2017-12-01

    The human endogenous retroviruses (HERVs) are a family of endogenous retroviruses that integrated into the germ cell DNA of primates over 30 million years ago. HERV expression seems impaired in several diseases, ranging from autoimmune to neoplastic disorders. The purpose of this study was to evaluate the overall endogenous retroviral transcription profile in bone marrow (BM) samples. A total of 30 paediatric high-risk leukaemia patients (lymphoid and myeloid malignancies) were tested for HERVs virus gene expression. Our findings show that HERV-K expression was significantly higher in leukaemia patients when compared to healthy donors of a similar median age. We observed a significantly high expression of HERV-K in acute lymphoblastic leukemia (ALL) patients. In this study, we also found a relative overexpression of the endogenous retrovirus HERV-K in BM cells from the majority of leukemia samples analyzed, in particular in ALL. This overexpression might be related to lymphatic leukemogenesis and it warrants further investigations.

  19. Detection of the human endogenous retrovirus ERV3-encoded Env-protein in human tissues using antibody-based proteomics.

    Science.gov (United States)

    Fei, Chen; Atterby, Christina; Edqvist, Per-Henrik; Pontén, Fredrik; Zhang, Wei Wei; Larsson, Erik; Ryan, Frank P

    2014-01-01

    There is growing evidence to suggest that human endogenous retroviruses (HERVs) have contributed to human evolution, being expressed in development, normal physiology and disease. A key difficulty in the scientific evaluation of this potential viral contribution is the accurate demonstration of virally expressed protein in specific human cells and tissues. In this study, we have adopted the endogenous retrovirus, ERV3, as our test model in developing a reliable high-capacity methodology for the expression of such endogenous retrovirus-coded protein. Two affinity-purified polyclonal antibodies to ERV3 Env-encoded protein were generated to detect the corresponding protein expression pattern in specific human cells, tissues and organs. Sampling included normal tissues from 144 individuals ranging from childhood to old age. This included more than forty different tissues and organs and some 216 different cancer tissues representing the twenty commonest forms of human cancer. The Rudbeck Laboratory, Uppsala University and Uppsala University Hospital, Uppsala, Sweden. The potential expression at likely physiological level of the ERV3Env encoded protein in a wide range of human cells, tissues and organs. We found that ERV3 encoded Env protein is expressed at substantive levels in placenta, testis, adrenal gland, corpus luteum, Fallopian tubes, sebaceous glands, astrocytes, bronchial epithelium and the ducts of the salivary glands. Substantive expression was also seen in a variety of epithelial cells as well as cells known to undergo fusion in inflammation and in normal physiology, including fused macrophages, myocardium and striated muscle. This contrasted strongly with the low levels expressed in other tissues types. These findings suggest that this virus plays a significant role in human physiology and may also play a possible role in disease. This technique can now be extended to the study of other HERV genomes within the human chromosomes that may have contributed to

  20. High copy number in human endogenous retrovirus families is associated with copying mechanisms in addition to reinfection

    Czech Academy of Sciences Publication Activity Database

    Belshaw, R.; Katzourakis, A.; Pačes, Jan; Burt, A.; Tristem, M.

    2005-01-01

    Roč. 22, č. 4 (2005), s. 814-817 ISSN 0737-4038 R&D Projects: GA MŠk(CZ) 1M0520 Institutional research plan: CEZ:AV0Z50520514 Keywords : human endogenous retrovirus * reinfection * retrotransposition Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.233, year: 2005

  1. (Some) Cellular Mechanisms Influencing the Transcription of Human Endogenous Retrovirus, HERV-Fc1

    DEFF Research Database (Denmark)

    Laska, Magdalena Janina; Nissen, Kari Konstantin; Nexø, Bjørn Andersen

    2013-01-01

    DNA methylation and histone acetylation are epigenetic modifications that act as regulators of gene expression. DNA methylation is considered an important mechanism for silencing of retroelements in the mammalian genome. However, the methylation of human endogenous retroviruses (HERVs) is not well...... investigated. The aim of this study was to investigate the transcriptional potential of HERV-Fc1 proviral 5'LTR in more detail, and examined the specific influence of CpG methylation on this LTR in number of cell lines. Specifically, the role of demethylating chemicals e.g. 5-aza-2' deoxycytidine...... and Trichostatin-A, in inducing or reactivating expression of HERV-Fc1 specific sequences and the mechanisms were investigated. In our present study, 5-aza-dC is shown to be a powerful inducer of HERV-Fc1, and at the same time it strongly inhibits methylation of DNA. Treatment with this demethylating agent 5-aza...

  2. Transcriptional Modulation of Human Endogenous Retroviruses in Primary CD4+ T Cells Following Vorinostat Treatment

    Directory of Open Access Journals (Sweden)

    Cory H. White

    2018-04-01

    Full Text Available The greatest obstacle to a cure for HIV is the provirus that integrates into the genome of the infected cell and persists despite antiretroviral therapy. A “shock and kill” approach has been proposed as a strategy for an HIV cure whereby drugs and compounds referred to as latency-reversing agents (LRAs are used to “shock” the silent provirus into active replication to permit “killing” by virus-induced pathology or immune recognition. The LRA most utilized to date in clinical trials has been the histone deacetylase (HDAC inhibitor—vorinostat. Potentially, pathological off-target effects of vorinostat may result from the activation of human endogenous retroviruses (HERVs, which share common ancestry with exogenous retroviruses including HIV. To explore the effects of HDAC inhibition on HERV transcription, an unbiased pharmacogenomics approach (total RNA-Seq was used to evaluate HERV expression following the exposure of primary CD4+ T cells to a high dose of vorinostat. Over 2,000 individual HERV elements were found to be significantly modulated by vorinostat, whereby elements belonging to the ERVL family (e.g., LTR16C and LTR33 were predominantly downregulated, in contrast to LTR12 elements of the HERV-9 family, which exhibited the greatest signal, with the upregulation of 140 distinct elements. The modulation of three different LTR12 elements by vorinostat was confirmed by droplet digital PCR along a dose–response curve. The monitoring of LTR12 expression during clinical trials with vorinostat may be indicated to assess the impact of this HERV on the human genome and host immunity.

  3. Human Endogenous Retrovirus HERV-Fc1 Association with Multiple Sclerosis Susceptibility: A Meta-Analysis

    Science.gov (United States)

    García-Montojo, Marta; Alcina, Antonio; Fedetz, María; Alloza, Iraide; Astobiza, Ianire; Leyva, Laura; Fernández, Oscar; Izquierdo, Guillermo; Antigüedad, Alfredo; Arroyo, Rafael; Álvarez-Lafuente, Roberto; Vandenbroeck, Koen; Matesanz, Fuencisla; Urcelay, Elena

    2014-01-01

    Background Human endogenous retroviruses (HERVs) are repetitive sequences derived from ancestral germ-line infections by exogenous retroviruses and different HERV families have been integrated in the genome. HERV-Fc1 in chromosome X has been previously associated with multiple sclerosis (MS) in Northern European populations. Additionally, HERV-Fc1 RNA levels of expression have been found increased in plasma of MS patients with active disease. Considering the North-South latitude gradient in MS prevalence, we aimed to evaluate the role of HERV-Fc1on MS risk in three independent Spanish cohorts. Methods A single nucleotide polymorphism near HERV-Fc1, rs391745, was genotyped by Taqman chemistry in a total of 2473 MS patients and 3031 ethnically matched controls, consecutively recruited from: Northern (569 patients and 980 controls), Central (883 patients and 692 controls) and Southern (1021 patients and 1359 controls) Spain. Our results were pooled in a meta-analysis with previously published data. Results Significant associations of the HERV-Fc1 polymorphism with MS were observed in two Spanish cohorts and the combined meta-analysis with previous data yielded a significant association [rs391745 C-allele carriers: pM-H = 0.0005; ORM-H (95% CI) = 1.27 (1.11–1.45)]. Concordantly to previous findings, when the analysis was restricted to relapsing remitting and secondary progressive MS samples, a slight enhancement in the strength of the association was observed [pM-H = 0.0003, ORM-H (95% CI) = 1.32 (1.14–1.53)]. Conclusion Association of the HERV-Fc1 polymorphism rs391745 with bout-onset MS susceptibility was confirmed in Southern European cohorts. PMID:24594754

  4. Human endogenous retrovirus type W (HERV-W) in schizophrenia: a new avenue of research at the gene-environment interface.

    Science.gov (United States)

    Leboyer, Marion; Tamouza, Ryad; Charron, Dominique; Faucard, Raphaél; Perron, Hervé

    2013-03-01

    Provide a synthetic review of recent studies evidencing an association between human endogenous retrovirus-W (HERV-W) and schizophrenia. Bibliography analysis and contextual synthesis. Epidemiological studies suggest that the aetiology of schizophrenia is complex and involves a complex interplay of genetic and environmental factors such as infections. Eight percentof the human genome consists of human endogenous retroviruses (HERV), and this part of the genome was previously thought to be without importance, but new research has refuted this. HERVs share similarities with viruses and it is assumed that HERVs are present in the genome as a result of retroviruses infecting germ line cells many million years ago. A specific type of HERVs, called HERV-W, has through several recent studies been associated with schizophrenia. Elevated transcription of HERV-W elements has been documented, and antigens of HERV-W envelope and capsid proteins have been found in blood samples from patients. Viruses that have been implicated in pathology of schizophrenia, such as herpes and influenza, have been shown to activate HERV-W elements, and such activation has been associated with elevated biomarkers of systemic inflammation. New research indicates that HERV-W may be an important genetic factor interplaying with the environmental risk factor of infections and that, through this, HERV-W may be important for disease pathogenesis. A lifelong scenario of a detrimental interaction between infectious agents and HERV-W genes may decipher the actual development and course of schizophrenia. Further research is needed to find out if specific treatment strategies could reduce the expression of HERV-W and if this will be associated with remission.

  5. HTLV-3/4 and simian foamy retroviruses in humans: discovery, epidemiology, cross-species transmission and molecular virology.

    Science.gov (United States)

    Gessain, Antoine; Rua, Réjane; Betsem, Edouard; Turpin, Jocelyn; Mahieux, Renaud

    2013-01-05

    Non-human primates are considered to be likely sources of viruses that can infect humans and thus pose a significant threat to human population. This is well illustrated by some retroviruses, as the simian immunodeficiency viruses and the simian T lymphotropic viruses, which have the ability to cross-species, adapt to a new host and sometimes spread. This leads to a pandemic situation for HIV-1 or an endemic one for HTLV-1. Here, we present the available data on the discovery, epidemiology, cross-species transmission and molecular virology of the recently discovered HTLV-3 and HTLV-4 deltaretroviruses, as well as the simian foamy retroviruses present in different human populations at risk, especially in central African hunters. We discuss also the natural history in humans of these retroviruses of zoonotic origin (magnitude and geographical distribution, possible inter-human transmission). In Central Africa, the increase of the bushmeat trade during the last decades has opened new possibilities for retroviral emergence in humans, especially in immuno-compromised persons. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. Infectious Entry Pathway Mediated by the Human Endogenous Retrovirus K Envelope Protein.

    Science.gov (United States)

    Robinson, Lindsey R; Whelan, Sean P J

    2016-01-20

    Endogenous retroviruses (ERVs), the majority of which exist as degraded remnants of ancient viruses, comprise approximately 8% of the human genome. The youngest human ERVs (HERVs) belong to the HERV-K(HML-2) subgroup and were endogenized within the past 1 million years. The viral envelope protein (ENV) facilitates the earliest events of endogenization (cellular attachment and entry), and here, we characterize the requirements for HERV-K ENV to mediate infectious cell entry. Cell-cell fusion assays indicate that a minimum of two events are required for fusion, proteolytic processing by furin-like proteases and exposure to acidic pH. We generated an infectious autonomously replicating recombinant vesicular stomatitis virus (VSV) in which the glycoprotein was replaced by HERV-K ENV. HERV-K ENV imparts an endocytic entry pathway that requires dynamin-mediated membrane scission and endosomal acidification but is distinct from clathrin-dependent or macropinocytic uptake pathways. The lack of impediments to the replication of the VSV core in eukaryotic cells allowed us to broadly survey the HERV-K ENV-dictated tropism. Unlike extant betaretroviral envelopes, which impart a narrow species tropism, we found that HERV-K ENV mediates broad tropism encompassing cells from multiple mammalian and nonmammalian species. We conclude that HERV-K ENV dictates an evolutionarily conserved entry pathway and that the restriction of HERV-K to primate genomes reflects downstream stages of the viral replication cycle. Approximately 8% of the human genome is of retroviral origin. While many of those viral genomes have become inactivated, some copies of the most recently endogenized human retrovirus, HERV-K, can encode individual functional proteins. Here, we characterize the envelope protein (ENV) of the virus to define how it mediates infection of cells. We demonstrate that HERV-K ENV undergoes a proteolytic processing step and triggers membrane fusion in response to acidic pH--a strategy

  7. Susceptibility of Human Endogenous Retrovirus Type K to Reverse Transcriptase Inhibitors.

    Science.gov (United States)

    Contreras-Galindo, Rafael; Dube, Derek; Fujinaga, Koh; Kaplan, Mark H; Markovitz, David M

    2017-12-01

    Human endogenous retroviruses (HERVs) make up 8% of the human genome. The HERV type K (HERV-K) HML-2 (HK2) family contains proviruses that are the most recent entrants into the human germ line and are transcriptionally active. In HIV-1 infection and cancer, HK2 genes produce retroviral particles that appear to be infectious, yet the replication capacity of these viruses and potential pathogenicity has been difficult to ascertain. In this report, we screened the efficacy of commercially available reverse transcriptase inhibitors (RTIs) at inhibiting the enzymatic activity of HK2 RT and HK2 genomic replication. Interestingly, only one provirus, K103, was found to encode a functional RT among those examined. Several nucleoside analogue RTIs (NRTIs) blocked K103 RT activity and consistently inhibited the replication of HK2 genomes. The NRTIs zidovudine (AZT), stavudine (d4T), didanosine (ddI), and lamivudine (3TC), and the nucleotide RTI inhibitor tenofovir (TDF), show efficacy in blocking K103 RT. HIV-1-specific nonnucleoside RTIs (NNRTIs), protease inhibitors (PIs), and integrase inhibitors (IIs) did not affect HK2, except for the NNRTI etravirine (ETV). The inhibition of HK2 infectivity by NRTIs appears to take place at either the reverse transcription step of the viral genome prior to HK2 viral particle formation and/or in the infected cells. Inhibition of HK2 by these drugs will be useful in suppressing HK2 infectivity if these viruses prove to be pathogenic in cancer, neurological disorders, or other diseases associated with HK2. The present studies also elucidate a key aspect of the life cycle of HK2, specifically addressing how they do, and/or did, replicate. IMPORTANCE Endogenous retroviruses are relics of ancestral virus infections in the human genome. The most recent of these infections was caused by HK2. While HK2 often remains silent in the genome, this group of viruses is activated in HIV-1-infected and cancer cells. Recent evidence suggests that these

  8. Structural characterization of the fusion core in syncytin, envelope protein of human endogenous retrovirus family W

    International Nuclear Information System (INIS)

    Gong Rui; Peng Xiaoxue; Kang Shuli; Feng Huixing; Huang Jianying; Zhang Wentao; Lin Donghai; Tien Po; Xiao Gengfu

    2005-01-01

    Syncytin is a captive retroviral envelope protein, possibly involved in the formation of the placental syncytiotrophoblast layer generated by trophoblast cell fusion at the maternal-fetal interface. We found that syncytin and type I viral envelope proteins shared similar structural profiling, especially in the regions of N- and C-terminal heptad repeats (NHR and CHR). We expressed the predicted regions of NHR (41 aa) and CHR (34 aa) in syncytin as a native single chain (named 2-helix protein) to characterize it. 2-helix protein exists as a trimer and is highly α-helix, thermo-stable, and denatured by low pH. NHR and CHR could form a protease-resistant complex. The complex structure built by the molecular docking demonstrated that NHR and CHR associated in an antiparallel manner. Overall, the 2-helix protein could form a thermo-stable coiled coil trimer. The fusion core structure of syncytin was first demonstrated in endogenous retrovirus. These results support the explanation how syncytin mediates cytotrophoblast cell fusion involved in placental morphogenesis

  9. Investigation of Human Cancers for Retrovirus by Low-Stringency Target Enrichment and High-Throughput Sequencing

    DEFF Research Database (Denmark)

    Vinner, Lasse; Mourier, Tobias; Friis-Nielsen, Jens

    2015-01-01

    -stringency in-solution hybridization method enables detection of discovery of hitherto unknown viral sequences by high-throughput sequencing. The sensitivity was sufficient to detect retroviral...... sequences in clinical samples. We used this method to conduct an investigation for novel retrovirus in samples from three cancer types. In accordance with recent studies our investigation revealed no retroviral infections in human B-cell lymphoma cells, cutaneous T-cell lymphoma or colorectal cancer...

  10. The role of human endogenous retroviruses in the pathogenesis of autoimmune diseases.

    Science.gov (United States)

    Brodziak, Andrzej; Ziółko, Ewa; Muc-Wierzgoń, Małgorzata; Nowakowska-Zajdel, Ewa; Kokot, Teresa; Klakla, Katarzyna

    2012-06-01

    This paper presents a new, recently formulated theory, which concerns the etiopathological process of autoimmune diseases. This theory takes into account the existence in the human genome, since approximately 40 million years, of so-called human endogenous retroviruses (HERVs), which are transmitted to descendants "vertically" by the germ cells. It was recently established that these generally silent sequences perform some physiological roles, but occasionally become active and influence the development of some chronic diseases like diabetes, some neoplasms, chronic diseases of the nervous system (eg, sclerosis multiplex), schizophrenia and autoimmune diseases. We present a short synopsis of immunological processes involved in the pathogenesis of autoimmune diseases, such as molecular mimicry, epitope spreading and activation of the superantigen. We then focus on experimental findings related to systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and some diseases of hepar and otorhinal tissues. We conclude the outline of this new model of the development of chronic diseases and indicate the conclusions important for the teaching of the basis of pathology.

  11. Establishment of a high production system for AIDS retroviruses with a human T-leukemic cell line Molt-4

    International Nuclear Information System (INIS)

    Koyanagi, Yoshio; Harada, Shinji; Yamamoto, Naoki

    1986-01-01

    A cell culture system was developed for the continuous and efficient production of acquired immune deficiency syndrome (AIDS) retrovirus. After infection of a human T-cell line Molt-4 with HTLV-III and LAV the cells grow permanently and produce large amounts of virus continuously. The yields of production of virus were assessed either with reverse transcriptase activity or a newly established biological quantitation assay of active virus. The amounts of virus with this cell system were much higher than those of the H9 cell system. This procedure enabled us first to compare the two viral isolates HTLV-III and LAV directly in the same cell lines. Establishment of the culture system, allowing efficient production of AIDS retroviruses, provides a useful tool for the isolation of the virus from patients with AIDS and for more basic research, such as the mechanisms of immune destruction caused by the virus leading to the occurence of various malignancies (author)

  12. Comparative Methylation of ERVWE1/Syncytin-1 and Other Human Endogenous Retrovirus LTRs in Placenta Tissues

    Science.gov (United States)

    Gimenez, Juliette; Montgiraud, Cécile; Oriol, Guy; Pichon, Jean-Philippe; Ruel, Karine; Tsatsaris, Vassilis; Gerbaud, Pascale; Frendo, Jean-Louis; Evain-Brion, Danièle; Mallet, François

    2009-01-01

    Human endogenous retroviruses (HERVs) are globally silent in somatic cells. However, some HERVs display high transcription in physiological conditions. In particular, ERVWE1, ERVFRDE1 and ERV3, three proviruses of distinct families, are highly transcribed in placenta and produce envelope proteins associated with placenta development. As silencing of repeated elements is thought to occur mainly by DNA methylation, we compared the methylation of ERVWE1 and related HERVs to appreciate whether HERV methylation relies upon the family, the integration site, the tissue, the long terminal repeat (LTR) function or the associated gene function. CpG methylation of HERV-W LTRs in placenta-associated tissues was heterogeneous but a joint epigenetic control was found for ERVWE1 5′LTR and its juxtaposed enhancer, a mammalian apparent LTR retrotransposon. Additionally, ERVWE1, ERVFRDE1 and ERV3 5′LTRs were all essentially hypomethylated in cytotrophoblasts during pregnancy, but showed distinct and stage-dependent methylation profiles. In non-cytotrophoblastic cells, they also exhibited different methylation profiles, compatible with their respective transcriptional activities. Comparative analyses of transcriptional activity and LTR methylation in cell lines further sustained a role for methylation in the control of functional LTRs. These results suggest that HERV methylation might not be family related but copy-specific, and related to the LTR function and the tissue. In particular, ERVWE1 and ERV3 could be developmentally epigenetically regulated HERVs. PMID:19561344

  13. [Antiretroviral drug supply in Argentina: National Program to Combat Human Retroviruses, AIDS, and STDs].

    Science.gov (United States)

    Colautti, Marisel; Luppi, Irene; Salamano, Mercedes; Traverso, María Luz; Botta, Carina; Palchik, Valeria

    2009-01-01

    To evaluate the supply cycle of antiretroviral (ARV) drugs, overseen by the National Program to Combat Human Retroviruses, AIDS, and STDs, through its order fulfillment indicators, and to obtain input from supply chain stakeholders. A study was carried out from April-September 2005 in the pharmacies of two hospitals in Rosario, Argentina, involving both a quantitative analysis of indicators and secondary sources and a qualitative evaluation using semistructured interviews. The indicators reveal the impact that interruptions in ARV supply stream from the Program (central level) have and the overstocking that takes place at the pharmacies (local level) to manage the shortages. Changes in ARV treatment account for over 50% of the prescriptions. Fulfillments fall short of the reference value. The interviewees shared possible strategies for overcoming the communication gaps between levels, for building-up stock, for guaranteeing availability, and for shortening waiting times; reached informal agreements to deal with the lack of policies and the shortage of staff; acknowledged the challenges facing the jurisdictions (central, intermediate, and local/community); and recognized local efforts to improve management. These challenges could be the starting point for building teams to work on effectively decentralizing the entire supply chain and allowing the Program to fulfill its much-needed oversight role.

  14. Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone

    International Nuclear Information System (INIS)

    Adachi, A.; Gendelman, H.E.; Koenig, S.; Folks, T.; Willey, R.; Rabson, A.; Martin, M.A.

    1986-01-01

    The authors considered an infectious molecular clone of acquired immunodeficiency syndrome-associated retrovirus. Upon transfection, this clone directed the production of infectious virus particles in a wide variety of cells in addition to human T4 cells. The progeny, infectious virions, were synthesized in mouse, mink, monkey, and several human non-T cell lines, indicating the absence of any intracellular obstacle to viral RNA or protein production or assembly. During the course of these studies, a human colon carcinoma cell line, exquisitely sensitive to DNA transfection, was identified

  15. Retrovirus-mediated gene transfer of a human c-fos cDNA into mouse bone marrow stromal cells.

    Science.gov (United States)

    Roux, P; Verrier, B; Klein, B; Niccolino, M; Marty, L; Alexandre, C; Piechaczyk, M

    1991-11-01

    A cDNA encoding a complete human c-fos protein was isolated and inserted into two different murine MoMuLV-derived recombinant retroviruses allowing expression of c-fos protein in different cell types. One c-fos-expressing retrovirus, chosen for its ability to express high levels of proteins in fibroblast-like cells, was shown to potentiate long-term cultures of mouse bone marrow stromal cells in vitro and therefore constitutes a potential tool for immortalizing such cells. Moreover, when tested in an in vitro differentiation assay, stromal cells constitutively expressing c-fos favor the granulocyte differentiation of hematopoietic precursors. Interestingly, retroviruses expressing v-src and v-abl oncogenes, included as controls in our experiments, do not produce any detectable effects, whereas those expressing polyoma virus middle T antigen facilitate long-term growth in vitro of stromal cells that favor the macrophage differentiation pathway of bone marrow stem cells. Our observation supports the idea that constitutive expression of some oncogenes, including c-fos and polyoma virus middle T antigen, may influence cytokine production by bone marrow stromal cells.

  16. Human endogenous retrovirus-R (ERV 3) env-like antigens ...

    African Journals Online (AJOL)

    Background: A substantial component of the vertebrate genome comprise of retrovirusrelated sequences named as endogenous retroviruses (ERVs). The role of these ERVrelated sequences in the biological processes of the host species is still unknown. However, they have been associated with tumourigenesis, ...

  17. Human endogenous retrovirus K Gag coassembles with HIV-1 Gag and reduces the release efficiency and infectivity of HIV-1.

    Science.gov (United States)

    Monde, Kazuaki; Contreras-Galindo, Rafael; Kaplan, Mark H; Markovitz, David M; Ono, Akira

    2012-10-01

    Human endogenous retroviruses (HERVs), which are remnants of ancestral retroviruses integrated into the human genome, are defective in viral replication. Because activation of HERV-K and coexpression of this virus with HIV-1 have been observed during HIV-1 infection, it is conceivable that HERV-K could affect HIV-1 replication, either by competition or by cooperation, in cells expressing both viruses. In this study, we found that the release efficiency of HIV-1 Gag was 3-fold reduced upon overexpression of HERV-K(CON) Gag. In addition, we observed that in cells expressing Gag proteins of both viruses, HERV-K(CON) Gag colocalized with HIV-1 Gag at the plasma membrane. Furthermore, HERV-K(CON) Gag was found to coassemble with HIV-1 Gag, as demonstrated by (i) processing of HERV-K(CON) Gag by HIV-1 protease in virions, (ii) coimmunoprecipitation of virion-associated HERV-K(CON) Gag with HIV-1 Gag, and (iii) rescue of a late-domain-defective HERV-K(CON) Gag by wild-type (WT) HIV-1 Gag. Myristylation-deficient HERV-K(CON) Gag localized to nuclei, suggesting cryptic nuclear trafficking of HERV-K Gag. Notably, unlike WT HERV-K(CON) Gag, HIV-1 Gag failed to rescue myristylation-deficient HERV-K(CON) Gag to the plasma membrane. Efficient colocalization and coassembly of HIV-1 Gag and HERV-K Gag also required nucleocapsid (NC). These results provide evidence that HIV-1 Gag heteromultimerizes with HERV-K Gag at the plasma membrane, presumably through NC-RNA interaction. Intriguingly, HERV-K Gag overexpression reduced not only HIV-1 release efficiency but also HIV-1 infectivity in a myristylation- and NC-dependent manner. Altogether, these results indicate that Gag proteins of endogenous retroviruses can coassemble with HIV-1 Gag and modulate the late phase of HIV-1 replication.

  18. Systematic identification and characterization of regulatory elements derived from human endogenous retroviruses.

    Directory of Open Access Journals (Sweden)

    Jumpei Ito

    2017-07-01

    Full Text Available Human endogenous retroviruses (HERVs and other long terminal repeat (LTR-type retrotransposons (HERV/LTRs have regulatory elements that possibly influence the transcription of host genes. We systematically identified and characterized these regulatory elements based on publicly available datasets of ChIP-Seq of 97 transcription factors (TFs provided by ENCODE and Roadmap Epigenomics projects. We determined transcription factor-binding sites (TFBSs using the ChIP-Seq datasets and identified TFBSs observed on HERV/LTR sequences (HERV-TFBSs. Overall, 794,972 HERV-TFBSs were identified. Subsequently, we identified "HERV/LTR-shared regulatory element (HSRE," defined as a TF-binding motif in HERV-TFBSs, shared within a substantial fraction of a HERV/LTR type. HSREs could be an indication that the regulatory elements of HERV/LTRs are present before their insertions. We identified 2,201 HSREs, comprising specific associations of 354 HERV/LTRs and 84 TFs. Clustering analysis showed that HERV/LTRs can be grouped according to the TF binding patterns; HERV/LTR groups bounded to pluripotent TFs (e.g., SOX2, POU5F1, and NANOG, embryonic endoderm/mesendoderm TFs (e.g., GATA4/6, SOX17, and FOXA1/2, hematopoietic TFs (e.g., SPI1 (PU1, GATA1/2, and TAL1, and CTCF were identified. Regulatory elements of HERV/LTRs tended to locate nearby and/or interact three-dimensionally with the genes involved in immune responses, indicating that the regulatory elements play an important role in controlling the immune regulatory network. Further, we demonstrated subgroup-specific TF binding within LTR7, LTR5B, and LTR5_Hs, indicating that gains or losses of the regulatory elements occurred during genomic invasions of the HERV/LTRs. Finally, we constructed dbHERV-REs, an interactive database of HERV/LTR regulatory elements (http://herv-tfbs.com/. This study provides fundamental information in understanding the impact of HERV/LTRs on host transcription, and offers insights into

  19. Maintenance of vascular endothelial cell-specific properties after immortalization with an amphotrophic replication-deficient retrovirus containing human papilloma virus 16 E6/E7 DNA

    NARCIS (Netherlands)

    Fontijn, R.; Hop, C.; Brinkman, H. J.; Slater, R.; Westerveld, A.; van Mourik, J. A.; Pannekoek, H.

    1995-01-01

    Primary human vascular endothelial cells were immortalized by the integration of a single DNA copy of an amphotrophic, replication-deficient retrovirus containing the E6/E7 genes of human papilloma virus. To date, the resulting cell lines, designated EC-RF7 and EC-RF24, have been cultured for more

  20. Presence of a Shared 5'-Leader Sequence in Ancestral Human and Mammalian Retroviruses and Its Transduction into Feline Leukemia Virus.

    Science.gov (United States)

    Kawasaki, Junna; Kawamura, Maki; Ohsato, Yoshiharu; Ito, Jumpei; Nishigaki, Kazuo

    2017-10-15

    Recombination events induce significant genetic changes, and this process can result in virus genetic diversity or in the generation of novel pathogenicity. We discovered a new recombinant feline leukemia virus (FeLV) gag gene harboring an unrelated insertion, termed the X region, which was derived from Felis catus endogenous gammaretrovirus 4 (FcERV-gamma4). The identified FcERV-gamma4 proviruses have lost their coding capabilities, but some can express their viral RNA in feline tissues. Although the X-region-carrying recombinant FeLVs appeared to be replication-defective viruses, they were detected in 6.4% of tested FeLV-infected cats. All isolated recombinant FeLV clones commonly incorporated a middle part of the FcERV-gamma4 5'-leader region as an X region. Surprisingly, a sequence corresponding to the portion contained in all X regions is also present in at least 13 endogenous retroviruses (ERVs) observed in the cat, human, primate, and pig genomes. We termed this shared genetic feature the commonly shared (CS) sequence. Despite our phylogenetic analysis indicating that all CS-sequence-carrying ERVs are classified as gammaretroviruses, no obvious closeness was revealed among these ERVs. However, the Shannon entropy in the CS sequence was lower than that in other parts of the provirus genome. Notably, the CS sequence of human endogenous retrovirus T had 73.8% similarity with that of FcERV-gamma4, and specific signals were detected in the human genome by Southern blot analysis using a probe for the FcERV-gamma4 CS sequence. Our results provide an interesting evolutionary history for CS-sequence circulation among several distinct ancestral viruses and a novel recombined virus over a prolonged period. IMPORTANCE Recombination among ERVs or modern viral genomes causes a rapid evolution of retroviruses, and this phenomenon can result in the serious situation of viral disease reemergence. We identified a novel recombinant FeLV gag gene that contains an unrelated

  1. Human endogenous retrovirus HERV-K(HML-2) activity in prostate cancer is dominated by a few loci.

    Science.gov (United States)

    Goering, Wolfgang; Schmitt, Katja; Dostert, Melanie; Schaal, Heiner; Deenen, René; Mayer, Jens; Schulz, Wolfgang A

    2015-12-01

    Increased expression of human endogenous retroviruses, especially HERV-K(HML-2) proviruses, has recently been associated with prostate carcinoma progression. In particular, a HML-2 locus in chromosome 22q11.23 (H22q) is upregulated in many cases. We therefore aimed at delineating the extent and repertoire of HML-2 transcription in prostate cancer tissues and cell lines and to define the transcription pattern and biological effects of H22q. Sanger and high throughput amplicon sequencing was used to define the repertoire of expressed HML-2 in a selected set of samples. qRT-PCR was used to quantify expression of selected proviruses in an extended set of prostate cancer tissues. Transcription factor binding sites (TFBS) were compared bioinformatically using the Transfac database. Expression of H22q was further characterized by siRNA-mediated knockdown, 5' RACE mapping of transcriptional start sites (TSS) and identification of splice sites. Functional effects of H22q knockdown were investigated by viability and apoptosis assays. In addition to H22q, a limited number of other proviruses were found expressed by sequencing. Of these, provirus ERVK-5 and to a lesser degree ERVK-15 were frequently upregulated in prostate cancer. In contrast, expression of ERVK-24, predominant in germ cell tumors, was not detectable in prostatic tissues. While HML-2 LTRs contain binding sites for the androgen receptor and cofactors, no consistent differences in transcription factor binding sites were found between expressed and non-expressed proviruses. The H22q locus contains two 5'-LTRs of which the upstream LTR is predominantly used in prostatic cells, with an imprecise TSS. Splicing of H22q transcripts is complex, generating, among others, a transcript with an Np9-like ORF. Knockdown of H22q did not significantly affect proliferation or apoptosis of prostate cancer cells. Our findings further underline that HML-2 expression is commonly highly tissue-specific. In prostate cancer, a limited

  2. Retroviruses As Myeloid Cell Riders: What Natural Human Siglec-1 “Knockouts” Tell Us About Pathogenesis

    Directory of Open Access Journals (Sweden)

    Javier Martinez-Picado

    2017-11-01

    Full Text Available Myeloid cells initiate immune responses and are crucial to control infections. In the case of retroviruses, however, myeloid cells also promote pathogenesis by enabling viral dissemination; a process extensively studied in vitro using human immunodeficiency virus type 1 (HIV-1. This viral hijacking mechanism does not rely on productive myeloid cell infection but requires HIV-1 capture via Siglec-1/CD169, a receptor expressed on myeloid cells that facilitates the infection of bystander target cells. Murine retroviruses are also recognized by Siglec-1, and this interaction is required for robust retroviral infection in vivo. Yet, the relative contribution of Siglec-1-mediated viral dissemination to HIV-1 disease progression remains unclear. The identification of human null individuals lacking working copies of a particular gene enables studying how this loss affects disease progression. Moreover, it can reveal novel antiviral targets whose blockade might be therapeutically effective and safe, since finding null individuals in natura uncovers dispensable functions. We previously described a loss-of-function variant in SIGLEC-1. Analysis of a large cohort of HIV-1-infected individuals identified homozygous and heterozygous subjects, whose cells were functionally null or partially defective for Siglec-1 activity in HIV-1 capture and transmission ex vivo. Nonetheless, analysis of the effect of Siglec-1 truncation on progression to AIDS was not conclusive due to the limited cohort size, the lack of complete clinical records, and the restriction to study only off-therapy periods. Here, we review how the study of loss-of-function variants might serve to illuminate the role of myeloid cells in viral pathogenesis in vivo and the challenges ahead.

  3. ‘There and back again’: revisiting the pathophysiological roles of human endogenous retroviruses in the post-genomic era

    Science.gov (United States)

    Magiorkinis, Gkikas; Belshaw, Robert; Katzourakis, Aris

    2013-01-01

    Almost 8% of the human genome comprises endogenous retroviruses (ERVs). While they have been shown to cause specific pathologies in animals, such as cancer, their association with disease in humans remains controversial. The limited evidence is partly due to the physical and bioethical restrictions surrounding the study of transposons in humans, coupled with the major experimental and bioinformatics challenges surrounding the association of ERVs with disease in general. Two biotechnological landmarks of the past decade provide us with unprecedented research artillery: (i) the ultra-fine sequencing of the human genome and (ii) the emergence of high-throughput sequencing technologies. Here, we critically assemble research about potential pathologies of ERVs in humans. We argue that the time is right to revisit the long-standing questions of human ERV pathogenesis within a robust and carefully structured framework that makes full use of genomic sequence data. We also pose two thought-provoking research questions on potential pathophysiological roles of ERVs with respect to immune escape and regulation. PMID:23938753

  4. Diminished humoral responses against and reduced gene expression levels of human endogenous retrovirus-K (HERV-K) in psoriasis.

    Science.gov (United States)

    Gupta, Rashmi; Michaud, Henri-Alexandre; Zeng, Xue; Debbaneh, Maya; Arron, Sarah T; Jones, R Brad; Ormsby, Christopher E; Nixon, Douglas F; Liao, Wilson

    2014-09-16

    Psoriasis is a multifactorial, chronic disease of skin affecting 2-3% of the world's population. Genetic studies of psoriasis have identified a number of susceptibility genes that are involved in anti-viral immunity. Furthermore, physiological studies have also found an increase in anti-viral proteins in psoriatic skin. These findings suggest the presence of an anti-viral state in psoriatic skin. However, the triggers for this anti-viral cascade and its consequences for host immunity are not known. Endogenous retroviruses have previously been described in many autoimmune diseases including psoriasis. In the present study we examined the humoral immune response against human endogenous retrovirus-K (HERV-K) proteins and the cutaneous expression levels of multiple HERV-K genes in psoriasis patients and healthy controls. In psoriatic sera we observed a significant decrease in IgM response against three HERV-K proteins: Env surface unit (SU), Env transmembrane protein (TM), and Gag capsid (CA) in comparison to sera obtained from blood bank healthy controls. A decrease in IgG response was also observed against CA. Furthermore, using quantitative RT-PCR we observed a decrease in the expression of HERV-K Env, Gag, Pol and Rec as well as ERV-9 genes in lesional psoriatic skin as compared to healthy skin. Together, our results suggest that the pro-inflammatory, anti-viral state in psoriasis is associated with diminished expression of HERV-K gene transcripts and a concomitant decrease in humoral responses to HERV-K. Our results indicate that a simple model where continuous, minimally changing HERV-K expression serves as an antigenic trigger in psoriasis might not be correct and further studies are needed to decipher the possible relationship between psoriasis and HERVs.

  5. Genetic alterations of the long terminal repeat of an ecotropic porcine endogenous retrovirus during passage in human cells

    International Nuclear Information System (INIS)

    Denner, Joachim; Specke, Volker; Thiesen, Ulla; Karlas, Alexander; Kurth, Reinhard

    2003-01-01

    Human-tropic porcine endogenous retroviruses (PERV) such as PERV-A and PERV-B can infect human cells and are therefore a potential risk to recipients of xenotransplants. A similar risk is posed by recombinant viruses containing the receptor-binding site of PERV-A and large parts of the genome of the ecotropic PERV-C including its long terminal repeat (LTR). We describe here the unique organization of the PERV-C LTR and its changes during serial passage of recombinant virus in human cells. An increase in virus titer correlated with an increase in LTR length, caused by multiplication of 37-bp repeats containing nuclear factor Y binding sites. Luciferase dual reporter assays revealed a correlation between the number of repeats and the extent of expression. No alterations have been observed in the receptor-binding site, indicating that the increased titer is due to the changes in the LTR. These data indicate that recombinant PERVs generated during infection of human cells can adapt and subsequently replicate with greater efficiency

  6. THE ROLE OF EPSTEIN-BARR VIRUS AND HUMAN ENDOGENOUS RETROVIRUSES IN THE PATHOGENESIS OF MULTIPLE SCLEROSIS

    Directory of Open Access Journals (Sweden)

    Zelenska, A. D.

    2018-04-01

    Full Text Available Multiple sclerosis (MS is an autoimmune demyelinating disease of the central nervous system (CNS, the development of which is associated with the action of a large number of pathogenetic factors which role can vary significantly at different stages of the disease. Although the etiology of MS still remains unclear, in recent years the hypothesis of the pathogenetic role of Epstein-Barr virus (EBV and human endogenous retroviruses, such as MSRV / HERV-W, is actively considered. EBV has a unique ability to infect, activate, and latently persist within B lymphocytes during human life. Immune control of EBV infection in healthy organisms is realized through humoral and cellular mechanisms – EBV virions are destroyed by neutralizing antibodies, and proliferating and lytically active EBV-infected B cells are the targets of specific CD8+ T cells. At the same time, EBV remains latent for most of the life of the infected individual, expressing a single gene (EBNA1 within memory B cells. EBNA1 protein is not well recognized by CD8+ T cells, allowing infected memory B cells to avoid detection. In addition to epidemiological data, association of EBV with MS is indicated by a significant increase in IgG titres to EBV antigens, mainly to EBNA1, in serum of patients a few years before the onset of clinical manifestations of the disease. Although the data on the presence of EBV in the CNS remain controversial due to a number of methodological difficulties, a number of studies have shown the presence of EBV-infected B cells in the CNS, as well as effector CD8+ T cells specific for them in meningeal inflammatory infiltrates and white matter lesions in brain samples of MS patients. At the same time, the EBV bystander damage hypothesis which considers CNS damage in multiple sclerosis as a result of EBV-targeted cytotoxic reactions of CD8+ T cells, does not explain the autoimmune nature of MS, although secondary autoimmune responses could develop as a result of

  7. Macroevolution of complex retroviruses

    DEFF Research Database (Denmark)

    Katzourakis, Aris; Gifford, Robert J; Tristem, Michael

    2009-01-01

    viruses were infecting mammals more than 100 million years ago and codiverged with their hosts across an entire geological era. Our analysis highlights the role of evolutionary constraint in maintaining viral genome structure and indicates that accessory genes and mammalian mechanisms of innate immunity...... are the products of macroevolutionary conflict played out over a geological time scale....

  8. Modulation of cGMP by human HO-1 retrovirus gene transfer in pulmonary microvessel endothelial cells.

    Science.gov (United States)

    Abraham, Nader G; Quan, Shuo; Mieyal, Paul A; Yang, Liming; Burke-Wolin, Theresa; Mingone, Christopher J; Goodman, Alvin I; Nasjletti, Alberto; Wolin, Michael S

    2002-11-01

    Carbon monoxide (CO) stimulates guanylate cyclase (GC) and increases guanosine 3',5'-cyclic monophosphate (cGMP) levels. We transfected rat-lung pulmonary endothelial cells with a retrovirus-mediated human heme oxygenase (hHO)-1 gene. Pulmonary cells that expressed hHO-1 exhibited a fourfold increase in HO activity associated with decreases in the steady-state levels of heme and cGMP without changes in soluble GC (sGC) and endothelial nitric oxide synthase (NOS) proteins or basal nitrite production. Heme elicited significant increases in CO production and intracellular cGMP levels in both pulmonary endothelial and pulmonary hHO-1-expressing cells. N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS, significantly decreased cGMP levels in heme-treated pulmonary endothelial cells but not heme-treated hHO-1-expressing cells. In the presence of exogenous heme, CO and cGMP levels in hHO-1-expressing cells exceeded the corresponding levels in pulmonary endothelial cells. Acute exposure of endothelial cells to SnCl2, which is an inducer of HO-1, increased cGMP levels, whereas chronic exposure decreased heme and cGMP levels. These results indicate that prolonged overexpression of HO-1 ultimately decreases sGC activity by limiting the availability of cellular heme. Heme activates sGC and enhances cGMP levels via a mechanism that is largely insensitive to NOS inhibition.

  9. Identification and detection of a novel human endogenous retrovirus-related gene, and structural characterization of its related elements

    Directory of Open Access Journals (Sweden)

    Qiaoyi Liang

    2009-01-01

    Full Text Available Up-regulation of human endogenous retroviruses (HERVs is associated with many diseases, including cancer. In this study, an H family HERV (HERV-H-related gene was identified and characterized. Its spliced transcript lacks protein-coding capacity and may belong to the emerging class of noncoding RNAs (ncRNAs. The 1.3-kb RNA consisting of four exons is transcribed from an Alu element upstream of a 5.0-kb structurally incomplete HERV-H element. RT-PCR and quantitative RT-PCR results indicated that expression of this HERV-related transcript was negatively associated with colon, stomach, and kidney cancers. Its expression was induced upon treatment with DNA methylation and histone deacetylation inhibitors. A BLAT search using long terminal repeats (LTRs identified 50 other LTR homogenous HERV-H elements. Further analysis of these elements revealed that all are structurally incomplete and only five exert transcriptional activity. The results presented here recommend further investigation into a potentially functional HERV-H-related ncRNA.

  10. Endogenous Retroviruses in the Genomics Era.

    Science.gov (United States)

    Johnson, Welkin E

    2015-11-01

    Endogenous retroviruses comprise millions of discrete genetic loci distributed within the genomes of extant vertebrates. These sequences, which are clearly related to exogenous retroviruses, represent retroviral infections of the deep past, and their abundance suggests that retroviruses were a near-constant presence throughout the evolutionary history of modern vertebrates. Endogenous retroviruses contribute in myriad ways to the evolution of host genomes, as mutagens and as sources of genetic novelty (both coding and regulatory) to be acted upon by the twin engines of random genetic drift and natural selection. Importantly, the richness and complexity of endogenous retrovirus data can be used to understand how viruses spread and adapt on evolutionary timescales by combining population genetics and evolutionary theory with a detailed understanding of retrovirus biology (gleaned from the study of extant retroviruses). In addition to revealing the impact of viruses on organismal evolution, such studies can help us better understand, by looking back in time, how life-history traits, as well as ecological and geological events, influence the movement of viruses within and between populations.

  11. Initial preclinical safety of non-replicating human endogenous retrovirus envelope protein-coated baculovirus vector-based vaccines against human papillomavirus.

    Science.gov (United States)

    Han, Su-Eun; Kim, Mi-Gyeong; Lee, Soondong; Cho, Hee-Jeong; Byun, Youngro; Kim, Sujeong; Kim, Young Bong; Choi, Yongseok; Oh, Yu-Kyoung

    2013-12-01

    Human endogenous retrovirus (HERV) envelope protein-coated, baculovirus vector-based HPV 16 L1 (AcHERV-HPV16L1) is a non-replicating recombinant baculoviral vaccine. Here, we report an initial evaluation of the preclinical safety of AcHERV-HPV16L1 vaccine. In an acute toxicity study, a single administration of AcHERV-HPV16L1 DNA vaccine given intramuscularly (i.m.) to mice at a dose of 1 × 10(8) plaque-forming units (PFU) did not cause significant changes in body weight compared with vehicle-treated controls. It did cause a brief increase in the weights of some organs on day 15 post-treatment, but by day 30, all organ weights were not significantly different from those in the vehicle-treated control group. No hematological changes were observed on day 30 post-treatment. In a range-finding toxicity study with three doses of 1 × 10(7) , 2 × 10(7) and 5 × 10(7) PFU once daily for 5 days, the group treated with 5 × 10(7) PFU showed a transient decrease in the body weights from day 5 to day 15 post-treatment, but recovery to the levels similar to those in the vehicle-treated control group by post-treatment day 20. Organ weights were slightly higher for lymph nodes, spleen, thymus and liver after repeated dosing with 5 × 10(7) PFU on day 15, but had normalized by day 30. Moreover, repeated administration of AcHERV-HPV16L1 did not induce myosin-specific autoantibody in serum, and did not cause immune complex deposition or tissue damage at injection sites. Taken together, these results provide preliminary evidence of the preclinical safety of AcHERV-based HPV16L1 DNA vaccines in mice. Copyright © 2012 John Wiley & Sons, Ltd.

  12. Involvement of Endogenous Retroviruses in Prion Diseases

    Directory of Open Access Journals (Sweden)

    Yong-Sun Kim

    2013-08-01

    Full Text Available For millions of years, vertebrates have been continuously exposed to infection by retroviruses. Ancient retroviral infection of germline cells resulted in the formation and accumulation of inherited retrovirus sequences in host genomes. These inherited retroviruses are referred to as endogenous retroviruses (ERVs, and recent estimates have revealed that a significant portion of animal genomes is made up of ERVs. Although various host factors have suppressed ERV activation, both positive and negative functions have been reported for some ERVs in normal and abnormal physiological conditions, such as in disease states. Similar to other complex diseases, ERV activation has been observed in prion diseases, and this review will discuss the potential involvement of ERVs in prion diseases.

  13. The Role of XMRV, a Novel Xenotropic Murine Retrovirus, in Human Prostate Cancers

    Science.gov (United States)

    2011-05-01

    ultimately determine the true prevalence of these viruses in humans and then to determine whether there is a link to any pathology. BODY...characterization of the novel XMRV virus , documenting its tissue tropism and interferon-sensitivity. We also documented the prevalence of the virus in human ...correlation of XMRV with prostate cancer prognosis. The recog- nition that human papilloma viruses most often initiate cervical carcinomas has focused

  14. Vaccination directed against the human endogenous retrovirus-K envelope protein inhibits tumor growth in a murine model system.

    Science.gov (United States)

    Kraus, Benjamin; Fischer, Katrin; Büchner, Sarah M; Wels, Winfried S; Löwer, Roswitha; Sliva, Katja; Schnierle, Barbara S

    2013-01-01

    Human endogenous retrovirus (HERV) genomes are chromosomally integrated in all cells of an individual. They are normally transcriptionally silenced and transmitted only vertically. Enhanced expression of HERV-K accompanied by the emergence of anti-HERV-K-directed immune responses has been observed in tumor patients and HIV-infected individuals. As HERV-K is usually not expressed and immunological tolerance development is unlikely, it is an appropriate target for the development of immunotherapies. We generated a recombinant vaccinia virus (MVA-HKenv) expressing the HERV-K envelope glycoprotein (ENV), based on the modified vaccinia virus Ankara (MVA), and established an animal model to test its vaccination efficacy. Murine renal carcinoma cells (Renca) were genetically altered to express E. coli beta-galactosidase (RLZ cells) or the HERV-K ENV gene (RLZ-HKenv cells). Intravenous injection of RLZ-HKenv cells into syngenic BALB/c mice led to the formation of pulmonary metastases, which were detectable by X-gal staining. A single vaccination of tumor-bearing mice with MVA-HKenv drastically reduced the number of pulmonary RLZ-HKenv tumor nodules compared to vaccination with wild-type MVA. Prophylactic vaccination of mice with MVA-HKenv precluded the formation of RLZ-HKenv tumor nodules, whereas wild-type MVA-vaccinated animals succumbed to metastasis. Protection from tumor formation correlated with enhanced HERV-K ENV-specific killing activity of splenocytes. These data demonstrate for the first time that HERV-K ENV is a useful target for vaccine development and might offer new treatment opportunities for diverse types of cancer.

  15. Humoral immunity response to human endogenous retroviruses K/W differentiates between amyotrophic lateral sclerosis and other neurological diseases.

    Science.gov (United States)

    Arru, G; Mameli, G; Deiana, G A; Rassu, A L; Piredda, R; Sechi, E; Caggiu, E; Bo, M; Nako, E; Urso, D; Mariotto, S; Ferrari, S; Zanusso, G; Monaco, S; Sechi, G; Sechi, L A

    2018-03-31

    Human endogenous retroviruses (HERV) K/W seem to play a role in fostering and exacerbation of some neurological diseases, including amyotrophic lateral sclerosis (ALS). Given these findings, the immunity response against HERV-K and HERV-W envelope surface (env-su) glycoprotein antigens in serum and cerebrospinal fluid (CSF) was investigated for ALS, multiple sclerosis (MS) and Alzheimer's disease patients and in healthy controls. Four antigenic peptides derived respectively from HERV-K and HERV-W env-su proteins were studied in 21 definite or probable ALS patients, 26 possible or definite relapsing-remitting MS patients, 18 patients with Alzheimer's disease and 39 healthy controls. An indirect enzyme-linked immunosorbent assay was set up to detect specific antibodies (Abs) against env-su peptides. Amongst the measured levels of Abs against the four different HERV-K peptide fragments, only HERV-K env-su 19-37 was significantly elevated in ALS compared to other groups, both in serum and CSF. Instead, amongst the Abs levels directed against the four different HERV-W peptide fragments, only HERV-W env-su 93-108 and HERV-W env-su 248-262 were significantly elevated, in the serum and CSF of the MS group compared to other groups. In ALS patients, the HERV-K env-su 19-37 Abs levels were significantly correlated with clinical measures of disease severity, both in serum and CSF. Increased circulating levels of Abs directed against the HERV-W env-su 93-108 and HERV-W env-su 248-262 peptide fragments could serve as possible biomarkers in patients with MS. Similarly, increased circulating levels of Abs directed against the HERV-K env-su 19-37 peptide fragment could serve as a possible early novel biomarker in patients with ALS. © 2018 EAN.

  16. Anti-inflammatory and vasoprotective activity of a retroviral-derived peptide, homologous to human endogenous retroviruses: endothelial cell effects.

    Directory of Open Access Journals (Sweden)

    George J Cianciolo

    Full Text Available Malignant and inflammatory tissues sometimes express endogenous retroviruses or their proteins. A highly-conserved sequence from retroviral transmembrane (TM proteins, termed the "immunosuppressive domain (ID", is associated with inhibition of immune and inflammatory functions. An octadecapeptide (MN10021 from the ID of retroviral TM protein p15E inhibits in vitro release of pro-inflammatory cytokines and increases synthesis of anti-inflammatory IL-10. We sought to determine if MN10021 has significant in vivo effects. MN10021, prepared by solid-phase synthesis, was dimerized through a naturally-occurring, carboxy-terminal cysteine. In vivo anti-inflammatory activity was determined using a murine model of sodium periodate (NaIO(4-induced peritonitis. In vivo vasoprotective effects were determined using: (1 a carrageenan-induced model of disseminated intravascular coagulation (DIC in mice; (2 a reverse passive Arthus model in guinea pigs; and (3 vasoregulatory effects in spontaneously hypertensive rats (SHR. In vitro studies included: (1 binding/uptake of MN10021 using human monocytes, cultured fibroblasts, and vascular endothelial cells (VEC; (2 gene expression by RT-PCR of MN10021-treated VEC; and (3 apoptosis of MN10021-treated VEC exposed to staurosporine or TNF-α. One-tenth nmol MN10021 inhibits 50 percent of the inflammatory response in the mouse peritonitis model. Furthermore, 73 nmol MN10021 completely protects mice in a lethal model of carrageenan-induced DIC and inhibits vascular leak in both the mouse DIC model and a guinea pig reverse passive Arthus reaction. MN10021 binds to and is taken up in a specific manner by both human monocytes and VEC but not by cultured human fibroblasts. Surprisingly, orally-administered MN10021 lowers blood pressure in SHR rats by 10-15% within 1 h suggesting a direct or indirect effect on the vascular endothelium. MN10021 and derived octapeptides induce iNOS (inducible nitric oxide synthase mRNA in VEC

  17. 75 FR 79006 - Submission for OMB Review; Comment Request; Transfusion-Transmitted Retrovirus and Hepatitis...

    Science.gov (United States)

    2010-12-17

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Submission for OMB Review; Comment Request; Transfusion- Transmitted Retrovirus and Hepatitis Virus Rates and Risk Factors: Improving... control number. Proposed Collection: Title: Transfusion-transmitted retrovirus and hepatitis virus rates...

  18. Human Retroviruses and AIDS. A compilation and analysis of nucleic acid and amino acid sequences: I--II; III--V

    Energy Technology Data Exchange (ETDEWEB)

    Myers, G.; Korber, B. [eds.] [Los Alamos National Lab., NM (United States); Wain-Hobson, S. [ed.] [Laboratory of Molecular Retrovirology, Pasteur Inst.; Smith, R.F. [ed.] [Baylor Coll. of Medicine, Houston, TX (United States). Dept. of Pharmacology; Pavlakis, G.N. [ed.] [National Cancer Inst., Frederick, MD (United States). Cancer Research Facility

    1993-12-31

    This compendium and the accompanying floppy diskettes are the result of an effort to compile and rapidly publish all relevant molecular data concerning the human immunodeficiency viruses (HIV) and related retroviruses. The scope of the compendium and database is best summarized by the five parts that it comprises: (I) HIV and SIV Nucleotide Sequences; (II) Amino Acid Sequences; (III) Analyses; (IV) Related Sequences; and (V) Database Communications. Information within all the parts is updated at least twice in each year, which accounts for the modes of binding and pagination in the compendium.

  19. Type W Human Endogenous Retrovirus (HERV-W) Integrations and Their Mobilization by L1 Machinery: Contribution to the Human Transcriptome and Impact on the Host Physiopathology.

    Science.gov (United States)

    Grandi, Nicole; Tramontano, Enzo

    2017-06-27

    Human Endogenous Retroviruses (HERVs) are ancient infection relics constituting ~8% of our DNA. While HERVs' genomic characterization is still ongoing, impressive amounts of data have been obtained regarding their general expression across tissues. Among HERVs, one of the most studied is the W group, which is the sole HERV group specifically mobilized by the long interspersed element-1 (LINE-1) machinery, providing a source of novel insertions by retrotransposition of HERV-W processed pseudogenes, and comprising a member encoding a functional envelope protein coopted for human placentation. The HERV-W group has been intensively investigated for its putative role in several diseases, such as cancer, inflammation, and autoimmunity. Despite major interest in the link between HERV-W expression and human pathogenesis, no conclusive correlation has been demonstrated so far. In general, (i) the absence of a proper identification of the specific HERV-W sequences expressed in a given condition, and (ii) the lack of studies attempting to connect the various observations in the same experimental conditions are the major problems preventing the definitive assessment of the HERV-W impact on human physiopathology. In this review, we summarize the current knowledge on the HERV-W group presence within the human genome and its expression in physiological tissues as well as in the main pathological contexts.

  20. Contribution of type W human endogenous retroviruses to the human genome: characterization of HERV-W proviral insertions and processed pseudogenes.

    Science.gov (United States)

    Grandi, Nicole; Cadeddu, Marta; Blomberg, Jonas; Tramontano, Enzo

    2016-09-09

    Human endogenous retroviruses (HERVs) are ancient sequences integrated in the germ line cells and vertically transmitted through the offspring constituting about 8 % of our genome. In time, HERVs accumulated mutations that compromised their coding capacity. A prominent exception is HERV-W locus 7q21.2, producing a functional Env protein (Syncytin-1) coopted for placental syncytiotrophoblast formation. While expression of HERV-W sequences has been investigated for their correlation to disease, an exhaustive description of the group composition and characteristics is still not available and current HERV-W group information derive from studies published a few years ago that, of course, used the rough assemblies of the human genome available at that time. This hampers the comparison and correlation with current human genome assemblies. In the present work we identified and described in detail the distribution and genetic composition of 213 HERV-W elements. The bioinformatics analysis led to the characterization of several previously unreported features and provided a phylogenetic classification of two main subgroups with different age and structural characteristics. New facts on HERV-W genomic context of insertion and co-localization with sequences putatively involved in disease development are also reported. The present work is a detailed overview of the HERV-W contribution to the human genome and provides a robust genetic background useful to clarify HERV-W role in pathologies with poorly understood etiology, representing, to our knowledge, the most complete and exhaustive HERV-W dataset up to date.

  1. Endogenous retrovirus sequences expressed in male mammalian ...

    African Journals Online (AJOL)

    In humans, one ERV family, human endogenous retrovirus- K (HERV-K) is abundantly expressed, and is associated with germ cell tumours, while ERV3 env is expressed in normal human testis. Conclusion: The expression of ERVs in male reproductive tissues suggests a possible role in normal and disease conditions ...

  2. Correction of acid beta-galactosidase deficiency in GM1 gangliosidosis human fibroblasts by retrovirus vector-mediated gene transfer: higher efficiency of release and cross-correction by the murine enzyme.

    Science.gov (United States)

    Sena-Esteves, M; Camp, S M; Alroy, J; Breakefield, X O; Kaye, E M

    2000-03-20

    Mutations in the lysosomal acid beta-galactosidase (EC 3.2.1.23) underlie two different disorders: GM1 gangliosidosis, which involves the nervous system and visceral organs to varying extents, and Morquio's syndrome type B (Morquio B disease), which is a skeletal-connective tissue disease without any CNS symptoms. This article shows that transduction of human GM1 gangliosidosis fibroblasts with retrovirus vectors encoding the human acid beta-galactosidase cDNA leads to complete correction of the enzymatic deficiency. The newly synthesized enzyme is correctly processed and targeted to the lysosomes in transduced cells. Cross-correction experiments using retrovirus-modified cells as enzyme donors showed, however, that the human enzyme is transferred at low efficiencies. Experiments using a different retrovirus vector carrying the human cDNA confirmed this observation. Transduction of human GM1 fibroblasts and mouse NIH 3T3 cells with a retrovirus vector encoding the mouse beta-galactosidase cDNA resulted in high levels of enzymatic activity. Furthermore, the mouse enzyme was found to be transferred to human cells at high efficiency. Enzyme activity measurements in medium conditioned by genetically modified cells suggest that the human beta-galactosidase enzyme is less efficiently released to the extracellular space than its mouse counterpart. This study suggests that lysosomal enzymes, contrary to the generalized perception in the field of gene therapy, may differ significantly in their properties and provides insights for design of future gene therapy interventions in acid beta-galactosidase deficiency.

  3. HIV-1 Infection of Primary CD4+ T Cells Regulates the Expression of Specific Human Endogenous Retrovirus HERV-K (HML-2) Elements.

    Science.gov (United States)

    Young, George R; Terry, Sandra N; Manganaro, Lara; Cuesta-Dominguez, Alvaro; Deikus, Gintaras; Bernal-Rubio, Dabeiba; Campisi, Laura; Fernandez-Sesma, Ana; Sebra, Robert; Simon, Viviana; Mulder, Lubbertus C F

    2018-01-01

    Endogenous retroviruses (ERVs) occupy extensive regions of the human genome. Although many of these retroviral elements have lost their ability to replicate, those whose insertion took place more recently, such as the HML-2 group of HERV-K elements, still retain intact open reading frames and the capacity to produce certain viral RNA and/or proteins. Transcription of these ERVs is, however, tightly regulated by dedicated epigenetic control mechanisms. Nonetheless, it has been reported that some pathological states, such as viral infections and certain cancers, coincide with ERV expression, suggesting that transcriptional reawakening is possible. HML-2 elements are reportedly induced during HIV-1 infection, but the conserved nature of these elements has, until recently, rendered their expression profiling problematic. Here, we provide comprehensive HERV-K HML-2 expression profiles specific for productively HIV-1-infected primary human CD4 + T cells. We combined enrichment of HIV-1 infected cells using a reporter virus expressing a surface reporter for gentle and efficient purification with long-read single-molecule real-time sequencing. We show that three HML-2 proviruses-6q25.1, 8q24.3, and 19q13.42-are upregulated on average between 3- and 5-fold in HIV-1-infected CD4 + T cells. One provirus, HML-2 12q24.33, in contrast, was repressed in the presence of active HIV replication. In conclusion, this report identifies the HERV-K HML-2 loci whose expression profiles differ upon HIV-1 infection in primary human CD4 + T cells. These data will help pave the way for further studies on the influence of endogenous retroviruses on HIV-1 replication. IMPORTANCE Endogenous retroviruses inhabit big portions of our genome. Moreover, although they are mainly inert, some of the evolutionarily younger members maintain the ability to express both RNA and proteins. We have developed an approach using long-read single-molecule real-time (SMRT) sequencing that produces long reads that

  4. Human leukemia antigen-A*0201-restricted epitopes of human endogenous retrovirus W family envelope (HERV-W env) induce strong cytotoxic T lymphocyte responses.

    Science.gov (United States)

    Tu, Xiaoning; Li, Shan; Zhao, Lijuan; Xiao, Ran; Wang, Xiuling; Zhu, Fan

    2017-08-01

    Human endogenous retrovirus W family (HERV-W) envelope (env) has been reported to be related to several human diseases, including autoimmune disorders, and it could activate innate immunity. However, there are no reports investigating whether human leukemia antigen (HLA)-A*0201 + restriction is involved in the immune response caused by HERV-W env in neuropsychiatric diseases. In the present study, HERV-W env-derived epitopes presented by HLA-A*0201 are described with the potential for use in adoptive immunotherapy. Five peptides displaying HLA-A*0201-binding motifs were predicted using SYFEPITHI and BIMAS, and synthesized. A CCK-8 assay showed peptides W, Q and T promoted lymphocyte proliferation. Stimulation of peripheral blood mononuclear cells from HLA-A*0201 + donors with each of these peptides induced peptide-specific CD8 + T cells. High numbers of IFN-γ-secreting T cells were also detectable after several weekly stimulations with W, Q and T. Besides lysis of HERV-W env-loaded target cells, specific apoptosis was also observed. These data demonstrate that human T cells can be sensitized toward HERV-W env peptides (W, Q and T) and, moreover, pose a high killing potential toward HERV-W env-expressing U251 cells. In conclusion, peptides W Q and T, which are HERV-W env antigenic epitopes, have both antigenicity and immunogenicity, and can cause strong T cell immune responses. Our data strengthen the view that HERV-W env should be considered as an autoantigen that can induce autoimmunity in neuropsychiatric diseases, such as multiple sclerosis and schizophrenia. These data might provide an experimental foundation for a HERV-W env peptide vaccine and new insight into the treatment of neuropsychiatric diseases.

  5. Suministro de antirretrovirales en Argentina: Programa Nacional de Lucha contra los Retrovirus del Humano, SIDA y ETS Antiretroviral drug supply in Argentina: National Program to Combat Human Retroviruses, AIDS, and STDs

    Directory of Open Access Journals (Sweden)

    Marisel Colautti

    2009-01-01

    Full Text Available OBJETIVOS: Evaluar el circuito de suministro de antirretrovirales (ARV dentro del Programa Nacional de Lucha contra los Retrovirus del Humano, SIDA y ETS, mediante indicadores de desempeño, y recuperar la perspectiva de actores involucrados en el circuito de provisión. Se busca mejorar las acciones programáticas satisfaciendo las necesidades de los pacientes. MÉTODOS: En el servicio de farmacia de dos hospitales de Rosario, Argentina, de abril a septiembre de 2005 se llevó a cabo una investigación evaluativa con un abordaje cuantitativo, mediante indicadores y basado en fuentes secundarias, y otro cualitativo, con entrevistas semiestructuradas. RESULTADOS: Los indicadores revelan el impacto de las interrupciones en la provisión de ARV desde el Programa (nivel central y la acumulación de stock en el nivel local para paliar esas faltas. Los cambios de tratamiento con ARV representan más de 50% de las prescripciones. El cumplimiento en el retiro de ARV se aleja del valor de referencia. Los entrevistados describieron estrategias alternativas para superar dificultades de comunicación entre niveles, acumular stock, garantizar disponibilidad y acortar tiempos de espera; se establecieron acuerdos informales ante la falta de normativas y la escasez de recursos humanos; las instancias jurisdiccionales (central, intermedia y local o municipal suman dificultades, y se reconocen esfuerzos del nivel local para mejorar la gestión. CONCLUSIONES: Estos hallazgos pueden ser el punto de partida para la construcción de propuestas que involucren equipos de trabajo afectados en el circuito de provisión en su totalidad, a fin de lograr una descentralización efectiva, en congruencia con el papel rector que le corresponde necesariamente al Programa.OBJECTIVES: To evaluate the supply cycle of antiretroviral (ARV drugs, overseen by the National Program to Combat Human Retroviruses, AIDS, and STDs, through its order fulfillment indicators, and to obtain input

  6. Morphology and ultrastructure of retrovirus particles

    Directory of Open Access Journals (Sweden)

    Wei Zhang

    2015-08-01

    Full Text Available Retrovirus morphogenesis entails assembly of Gag proteins and the viral genome on the host plasma membrane, acquisition of the viral membrane and envelope proteins through budding, and formation of the core through the maturation process. Although in both immature and mature retroviruses, Gag and capsid proteins are organized as paracrystalline structures, the curvatures of these protein arrays are evidently not uniform within one or among all virus particles. The heterogeneity of retroviruses poses significant challenges to studying the protein contacts within the Gag and capsid lattices. This review focuses on current understanding of the molecular organization of retroviruses derived from the sub-nanometer structures of immature virus particles, helical capsid protein assemblies and soluble envelope protein complexes. These studies provide insight into the molecular elements that maintain the stability, flexibility and infectivity of virus particles. Also reviewed are morphological studies of retrovirus budding, maturation, infection and cell-cell transmission, which inform the structural transformation of the viruses and the cells during infection and viral transmission, and lead to better understanding of the interplay between the functioning viral proteins and the host cell.

  7. RNAi and retroviruses: are they in RISC?

    Science.gov (United States)

    Vasselon, Thierry; Bouttier, Manuella; Saumet, Anne; Lecellier, Charles-Henri

    2013-02-01

    RNA interference (RNAi) is a potent cellular system against viruses in various organisms. Although common traits are observed in plants, insects, and nematodes, the situation observed in mammals appears more complex. In mammalian somatic cells, RNAi is implicated in endonucleolytic cleavage mediated by artificially delivered small interfering RNAs (siRNAs) as well as in translation repression mediated by microRNAs (miRNAs). Because siRNAs and miRNAs recognize viral mRNAs, RNAi inherently limits virus production and participates in antiviral defense. However, several observations made in the cases of hepatitis C virus and retroviruses (including the human immunodeficiency virus and the primate foamy virus) bring evidence that this relationship is much more complex and that certain components of the RNAi effector complex [called the RNA-induced silencing complex (RISC)], such as AGO2, are also required for viral replication. Here, we summarize recent discoveries that have revealed this dual implication in virus biology. We further discuss their potential implications for the functions of RNAi-related proteins, with special emphasis on retrotransposition and genome stability.

  8. Human algorithmic stability and human Rademacher complexity

    NARCIS (Netherlands)

    Vahdat, Mehrnoosh; Oneto, L.; Ghio, A; Anguita, D.; Funk, M.; Rauterberg, G.W.M.

    2015-01-01

    In Machine Learning (ML), the learning process of an algo- rithm given a set of evidences is studied via complexity measures. The way towards using ML complexity measures in the Human Learning (HL) domain has been paved by a previous study, which introduced Human Rademacher Complexity (HRC): in this

  9. Human murine mammary tumour virus-like agents are genetically distinct from endogenous retroviruses and are not detectable in breast cancer cell lines or biopsies

    International Nuclear Information System (INIS)

    Mant, Christine; Gillett, Cheryl; D'Arrigo, Corrado; Cason, John

    2004-01-01

    It has been reported that a human murine mammary tumour virus (MMTV)-like virus (HMLV), which may be an endogenous human retrovirus (HERV), occurs in the human breast cancer cell lines T47D and MCF-7 and, in 38% of human breast cancer biopsies. As the aetiology of most breast cancers remains unknown, it is important to verify these observations in differing breast cancer populations worldwide. Thus, we sought to determine the genetic relationships between HMLVs, MMTVs, and HERVs, and to investigate the association between HMLVs and breast cancer biopsies from South London, UK. Phylogenetic analyses of the env/pol region indicated that HMLVs are indistinct from MMTVs, and that MMTVS/HMLVs exhibit only low sequence homologies with HERVs. A search of the human genome confirmed that HMLVs are not endogenous. Using MMTV polymerase chain reaction (PCR) primers described previously, we amplified DNA from all cell lines except MCF-7 and from 7 of 44 (16%) breast cancer biopsies. A restriction fragment length polymorphism assay was designed to distinguish between HMLVs and MMTVs, and upon analyses, PCR amplicons appeared to be HMLVs. To confirm these findings, amplicons from the T47D cell line and from four randomly selected breast cancer patients were sequenced. Of 106 DNA sequences obtained, 103 were homologous with a short arm of human chromosome (Chr) 3 (3p13), two with Chr 4, and one with Chr 8. None of the sequences exhibited significant nucleotide homology with MMTVs, HMLVs, or with HERVs (all <50%). Thus, we conclude that (i) HMLVs are integral members of the MMTV family; (ii) MMTVs/HMLVs are genetically distinct from HERVs; (iii) MMTV/HMLV DNA is not present in human breast cancer cell lines or clinical biopsies in our locality

  10. Human endogenous retrovirus W env increases nitric oxide production and enhances the migration ability of microglia by regulating the expression of inducible nitric oxide synthase.

    Science.gov (United States)

    Xiao, Ran; Li, Shan; Cao, Qian; Wang, Xiuling; Yan, Qiujin; Tu, Xiaoning; Zhu, Ying; Zhu, Fan

    2017-06-01

    Human endogenous retrovirus W env (HERV-W env) plays a critical role in many neuropsychological diseases such as schizophrenia and multiple sclerosis (MS). These diseases are accompanied by immunological reactions in the central nervous system (CNS). Microglia are important immunocytes in brain inflammation that can produce a gasotransmitter-nitric oxide (NO). NO not only plays a role in the function of neuronal cells but also participates in the pathogenesis of various neuropsychological diseases. In this study, we reported increased NO production in CHME-5 microglia cells after they were transfected with HERV-W env. Moreover, HERV-W env increased the expression and function of human inducible nitric oxide synthase (hiNOS) and enhanced the promoter activity of hiNOS. Microglial migration was also enhanced. These data revealed that HERV-W env might contribute to increase NO production and microglial migration ability in neuropsychological disorders by regulating the expression of inducible NOS. Results from this study might lead to the identification of novel targets for the treatment of neuropsychological diseases, including neuroinflammatory diseases, stroke, and neurodegenerative diseases.

  11. Expression and activation by Epstein Barr virus of human endogenous retroviruses-W in blood cells and astrocytes: inference for multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Giuseppe Mameli

    Full Text Available BACKGROUND: Proposed co-factors triggering the pathogenesis of multiple sclerosis (MS are the Epstein Barr virus (EBV, and the potentially neuropathogenic MSRV (MS-associated retrovirus and syncytin-1, of the W family of human endogenous retroviruses. METHODOLOGY/PRINCIPAL FINDINGS: In search of links, the expression of HERV-W/MSRV/syncytin-1, with/without exposure to EBV or to EBV glycoprotein350 (EBVgp350, was studied on peripheral blood mononuclear cells (PBMC from healthy volunteers and MS patients, and on astrocytes, by discriminatory env-specific RT-PCR assays, and by flow cytometry. Basal expression of HERV-W/MSRV/syncytin-1 occurs in astrocytes and in monocytes, NK, and B, but not in T cells. This uneven expression is amplified in untreated MS patients, and dramatically reduced during therapy. In astrocytes, EBVgp350 stimulates the expression of HERV-W/MSRV/syncytin-1, with requirement of the NF-κB pathway. In EBVgp350-treated PBMC, MSRVenv and syncytin-1 transcription is activated in B cells and monocytes, but not in T cells, nor in the highly expressing NK cells. The latter cells, but not the T cells, are activated by proinflammatory cytokines. CONCLUSIONS/SIGNIFICANCE: In vitro EBV activates the potentially immunopathogenic and neuropathogenic HERV-W/MSRV/syncytin-1, in cells deriving from blood and brain. In vivo, pathogenic outcomes would depend on abnormal situations, as in late EBV primary infection, that is often symptomatic, or/and in the presence of particular host genetic backgrounds. In the blood, HERV-Wenv activation might induce immunopathogenic phenomena linked to its superantigenic properties. In the brain, toxic mechanisms against oligodendrocytes could be established, inducing inflammation, demyelination and axonal damage. Local stimulation by proinflammatory cytokines and other factors might activate further HERV-Ws, contributing to the neuropathogenity. In MS pathogenesis, a possible model could include EBV as

  12. Vaccination directed against the human endogenous retrovirus-K (HERV-K) gag protein slows HERV-K gag expressing cell growth in a murine model system.

    Science.gov (United States)

    Kraus, Benjamin; Fischer, Katrin; Sliva, Katja; Schnierle, Barbara S

    2014-03-26

    Human endogenous retroviruses (HERVs) are remnants of ancestral infections and chromosomally integrated in all cells of an individual, are transmitted only vertically and are defective in viral replication. However enhanced expression of HERV-K accompanied by the emergence of anti-HERV-K-directed immune responses has been observed inter-alia in HIV-infected individuals and tumor patients. Therefore HERV-K might serve as a tumor-specific antigen or even as a constant target for the development of an HIV vaccine. To verify our hypothesis, we tested the immunogenicity of HERV-K Gag by using a recombinant vaccinia virus (MVA-HKcon) expressing the HERV-K Gag protein and established an animal model to test its vaccination efficacy. Murine renal carcinoma cells (Renca) were genetically altered to express E. coli beta-galactosidase (RLZ cells) and the HERV-K Gag protein (RLZ-HKGag cells). Subcutaneous application of RLZ-HKGag cells into syngenic BALB/c mice resulted in the formation of local tumors in MVA vaccinated mice. MVA-HKcon vaccination reduced the tumor growth. Furthermore, intravenous injection of RLZ-HKGag cells led to the formation of pulmonary metastases. Vaccination of tumor-bearing mice with MVA-HKcon drastically reduced the number of pulmonary RLZ-HKGag tumor nodules compared to vaccination with wild-type MVA. The data demonstrate that HERV-K Gag is a useful target for vaccine development and might offer new treatment opportunities for cancer patients.

  13. KOALA RETROVIRUS: A REVIEW.

    Science.gov (United States)

    Kinney, Matthew E; Pye, Geoffrey W

    2016-06-01

    Koala retrovirus (KoRV) is a gammaretrovirus that has been identified in both captive and free-ranging koalas ( Phascolarctos cinereus ) with variable geographic distribution in Australia. KoRV is capable of both exogenous and endogenous transmission, which provides an interesting research platform for scientists to study active retrovirus endogenization into a host genome and offers veterinary scientists an opportunity to examine the clinical consequences of KoRV infection in koalas. Causation between KoRV and frequently recognized clinical conditions associated with immune suppression and neoplasia in koalas has not been definitively established, however research continues to evaluate a potential association. Three KoRV variants, KoRV-A, KoRV-B, and KoRV-J, have been the most thoroughly described and preliminary evidence suggests KoRV variability may be fundamental in host pathogenicity. In addition to reviewing what is currently known about KoRV, this article discusses treatment, management, and future research directions.

  14. Human endogenous retrovirus expression is inversely related with the up-regulation of interferon-inducible genes in the skin of patients with lichen planus.

    Science.gov (United States)

    Nogueira, Marcelle Almeida de Sousa; Gavioli, Camila Fátima Biancardi; Pereira, Nátalli Zanete; de Carvalho, Gabriel Costa; Domingues, Rosana; Aoki, Valéria; Sato, Maria Notomi

    2015-04-01

    Lichen planus (LP) is a common inflammatory skin disease of unknown etiology. Reports of a common transactivation of quiescent human endogenous retroviruses (HERVs) support the connection of viruses to the disease. HERVs are ancient retroviral sequences in the human genome and their transcription is often deregulated in cancer and autoimmune diseases. We explored the transcriptional activity of HERV sequences as well as the antiviral restriction factor and interferon-inducible genes in the skin from LP patients and healthy control (HC) donors. The study included 13 skin biopsies from patients with LP and 12 controls. Real-time PCR assay identified significant decrease in the HERV-K gag and env mRNA expression levels in LP subjects, when compared to control group. The expressions of HERV-K18 and HERV-W env were also inhibited in the skin of LP patients. We observed a strong correlation between HERV-K gag with other HERV sequences, regardless the down-modulation of transcripts levels in LP group. In contrast, a significant up-regulation of the cytidine deaminase APOBEC 3G (apolipoprotein B mRNA-editing), and the GTPase MxA (Myxovirus resistance A) mRNA expression level was identified in the LP skin specimens. Other transcript expressions, such as the master regulator of type I interferon-dependent immune responses, STING (stimulator of interferon genes) and IRF-7 (interferon regulatory factor 7), IFN-β and the inflammassome NALP3, had increased levels in LP, when compared to HC group. Our study suggests that interferon-inducible factors, in addition to their role in innate immunity against exogenous pathogens, contribute to the immune control of HERVs. Evaluation of the balance between HERV and interferon-inducible factor expression could possibly contribute to surveillance of inflammatory/malignant status of skin diseases.

  15. Down-regulation of human endogenous retrovirus type K (HERV-K) viral env RNA in pancreatic cancer cells decreases cell proliferation and tumor growth

    Science.gov (United States)

    Li, Ming; Radvanyi, Laszlo; Yin, Bingnan; Li, Jia; Chivukula, Raghavender; Lin, Kevin; Lu, Yue; Shen, JianJun; Chang, David Z.; Li, Donghui; Johanning, Gary L.; Wang-Johanning, Feng

    2017-01-01

    Purpose We investigated the role of the human endogenous retrovirus type K (HERV-K) envelope (env) gene in pancreatic cancer (PC). Experimental Design shRNA was employed to knockdown (KD) the expression of HERV-K in PC cells. Results HERV-K env expression was detected in seven PC cell lines and in 80% of PC patient biopsies, but not in two normal pancreatic cell lines or uninvolved normal tissues. A new HERV-K splice variant was discovered in several PC cell lines. RT activity and virus-like particles were observed in culture media supernatant obtained from Panc-1 and Panc-2 cells. HERV-K viral RNA levels and anti-HERV-K antibody titers were significantly higher in PC patient sera (N=106) than in normal donor sera (N=40). Importantly, the in vitro and in vivo growth rates of three PC cell lines were significantly reduced after HERV-K KD by shRNA targeting HERV-K env, and there was reduced metastasis to lung after treatment. RNA-seq results revealed changes in gene expression after HERV-K env KD, including RAS and TP53. Furthermore, downregulation of HERV-K Env protein expression by shRNA also resulted in decreased expression of RAS, p-ERK, p-RSK, and p-AKT in several PC cells or tumors. Conclusion These results demonstrate that HERV-K influences signal transduction via the RAS-ERK-RSK pathway in PC. Our data highlight the potentially important role of HERV-K in tumorigenesis and progression of PC, and indicate that HERV-K viral proteins may be attractive biomarkers and/or tumor-associated antigens, as well as potentially useful targets for detection, diagnosis and immunotherapy of PC. PMID:28679769

  16. Long-term expression of human adenosine deaminase in mice transplanted with retrovirus-infected hematopoietic stem cells

    International Nuclear Information System (INIS)

    Lim, B.; Apperley, J.F.; Orkin, S.H.; Williams, D.A.

    1989-01-01

    Long-term stable expression of foreign genetic sequences transferred into hematopoietic stem cells by using retroviral vectors constitutes a relevant model for somatic gene therapy. Such stability of expression may depend on vector design, including the presence or absence of specific sequences within the vector, in combination with the nature and efficiency of infection of the hematopoietic target cells. The authors have previously reported successful transfer of human DNA encoding adenosine deaminase (ADA) into CFU-S (colony-forming unit-spleen) stem cells using simplified recombinant retroviral vectors. Human ADA was expressed in CFU-S-derived spleen colonies at levels near to endogenous enzyme. However, because of the lack of an efficient dominant selectable marker and low recombinant viral titers, stability of long-term expression of human ADA was not examined. They report here the development of an efficient method of infection of hematopoietic stem cells (HSC) without reliance on in vitro selection. Peripheral blood samples of 100% of mice transplanted with HSC infected by this protocol exhibit expression of human ADA 30 days after transplantation. Some mice (6 of 13) continue to express human ADA in all lineages after complete hematopoietic reconstitution (4 months). The use of recombinant retroviral vectors that efficiently transfer human ADA cDNA into HSC leading to stable expression of functional ADA in reconstituted mice, provides an experimental framework for future development of approaches to somatic gene therapy

  17. Innate imune response against retrovirus.

    OpenAIRE

    Lucia González; Natalia Ibañez; Marcelo Mateus; Karina Romero; Otto Pritsch

    2015-01-01

    Los retrovirus son un diverso grupo de virus que se encuentran en los vertebrados. Su importancia biomédica radica en que son capaces de infectar humanos, produciendo importantes problemas de salud. El virus de la inmunodeficiencia humana (VIH) es capaz de producir un estado de inmunodeficiencia en el huésped determinando el desarrollo de enfermedades oportunistas en estadio avanzados de la enfermedad. Frente a la entrada de un retrovirus al organismo, nuestro sistema inmune presenta como pri...

  18. Differentiation of a medulloblastoma cell line towards an astrocytic lineage using the human T lymphotropic retrovirus-1.

    Science.gov (United States)

    Giraudon, P; Dufay, N; Hardin, H; Reboul, A; Tardy, M; Belin, M F

    1993-02-01

    Constituent cells of medulloblastoma, the most common brain tumor occurring in childhood, resemble the primitive neuroepithelial cells normally found in the developing nervous system. However, mutational events prevent their further differentiation. We used the human T cell lymphotrophic virus type 1 to activate these deregulated immature cells by means of its transactivating protein Tax. Concomitant with viral infection was a decrease in cell proliferation characterized by inhibition of [3H]thymidine incorporation and in the number of cells in the G2/M phase of the cell cycle. Morphological changes suggested that medulloblastoma cells differentiated along the astrocytic lineage. The glial phenotype was confirmed by the induction of the glial fibrillary acidic protein and the glial enzyme glutamine synthetase. A direct viral effect and/or secondary effects to viral infection via paracrine/autocrine pathways could counterbalance the maturational defect in these medulloblastoma cells.

  19. Induction of complex immune responses and strong protection against retrovirus challenge by adenovirus-based immunization depends on the order of vaccine delivery.

    Science.gov (United States)

    Kaulfuß, Meike; Wensing, Ina; Windmann, Sonja; Hrycak, Camilla Patrizia; Bayer, Wibke

    2017-02-06

    In the Friend retrovirus mouse model we developed potent adenovirus-based vaccines that were designed to induce either strong Friend virus GagL 85-93 -specific CD8 + T cell or antibody responses, respectively. To optimize the immunization outcome we evaluated vaccination strategies using combinations of these vaccines. While the vaccines on their own confer strong protection from a subsequent Friend virus challenge, the simple combination of the vaccines for the establishment of an optimized immunization protocol did not result in a further improvement of vaccine effectivity. We demonstrate that the co-immunization with GagL 85-93 /leader-gag encoding vectors together with envelope-encoding vectors abrogates the induction of GagL 85-93 -specific CD8 + T cells, and in successive immunization protocols the immunization with the GagL 85-93 /leader-gag encoding vector had to precede the immunization with an envelope encoding vector for the efficient induction of GagL 85-93 -specific CD8 + T cells. Importantly, the antibody response to envelope was in fact enhanced when the mice were adenovirus-experienced from a prior immunization, highlighting the expedience of this approach. To circumvent the immunosuppressive effect of envelope on immune responses to simultaneously or subsequently administered immunogens, we developed a two immunizations-based vaccination protocol that induces strong immune responses and confers robust protection of highly Friend virus-susceptible mice from a lethal Friend virus challenge.

  20. Multiple sclerosis-associated retrovirus, Epstein-Barr virus, and vitamin D status in patients with relapsing remitting multiple sclerosis.

    Science.gov (United States)

    Mostafa, Aliehossadat; Jalilvand, Somayeh; Shoja, Zabihollah; Nejati, Ahmad; Shahmahmoodi, Shohreh; Sahraian, Mohammad Ali; Marashi, Sayed Mahdi

    2017-07-01

    The relationship between infections and autoimmune diseases is complex and there are several reports highlighting the role of human endogenous retroviruses (HERVs) in these patients. The levels of multiple sclerosis-associated retrovirus (MSRV)-type DNA of Env gene was measured in peripheral blood mononuclear cells from 52 patients with relapsing-remitting multiple sclerosis (RRMS) and 40 healthy controls using specific quantitative PCR (qPCR) analysis. Furthermore, we analyzed the status of HERV-W/MSRV in these patients with regards to both EBV (DNA load and anti-EBNA1 IgG antibody) and vitamin D concentration. MSRV DNA copy number were significantly higher in RRMS patients than healthy controls (P < 0.0001). Interestingly, an inverse correlation was found between MSRV DNA copy number and serum vitamin D concentration (P < 0.01), but not for EBV load or anti-EBNA-1 IgG antibody. © 2017 Wiley Periodicals, Inc.

  1. Revealing the history of domesticated sheep using retrovirus integrations

    DEFF Research Database (Denmark)

    Chessa, Bernado; Pereira, Filipe; Arnaud, Frederick

    2009-01-01

    The domestication of livestock represented a crucial step in human history. By using endogenous retroviruses as genetic markers, we found that sheep differentiated on the basis of their "retrotype" and morphological traits dispersed across Eurasia and Africa via separate migratory episodes. Relic...

  2. B-lymphoblastoid cell lines from multiple sclerosis patients and a healthy control producing a putative new human retrovirus and Epstein-Barr virus

    DEFF Research Database (Denmark)

    Munch, M; Møller-Larsen, A; Christensen, T

    1995-01-01

    with MS who had a reactivated Epstein-Barr virus (EBV) infection. Both LCLs were found by EM to produce RVLP and EBV particles. Reverse transcriptase (RT) assays were positive in purified viral material from both LCLs. To substantiate these findings we initiated an intensified culturing procedure and were......On several occasions we have observed retrovirus-like particles (RVLPs) by transmission electron microscopy (EM) of cultured T cells from a patient with MS. Later we established spontaneously formed B-lymphoblastoid cell lines (LCLs) from a patient with an MS-like disease and from another patient...

  3. Human endogenous retrovirus K(HML-2) Gag and Env specific T-cell responses are not detected in HTLV-I-infected subjects using standard peptide screening methods.

    Science.gov (United States)

    Jones, R Brad; Leal, Fabio E; Hasenkrug, Aaron M; Segurado, Aluisio C; Nixon, Douglas F; Ostrowski, Mario A; Kallas, Esper G

    2013-01-10

    An estimated 10-20 million individuals are infected with the retrovirus human T-cell leukemia virus type 1 (HTLV-1). While the majority of these individuals remain asymptomatic, 0.3-4% develop a neurodegenerative inflammatory disease, termed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP results in the progressive demyelination of the central nervous system and is a differential diagnosis of multiple sclerosis (MS). The etiology of HAM/TSP is unclear, but evidence points to a role for CNS-inflitrating T-cells in pathogenesis. Recently, the HTLV-1-Tax protein has been shown to induce transcription of the human endogenous retrovirus (HERV) families W, H and K. Intriguingly, numerous studies have implicated these same HERV families in MS, though this association remains controversial. Here, we explore the hypothesis that HTLV-1-infection results in the induction of HERV antigen expression and the elicitation of HERV-specific T-cells responses which, in turn, may be reactive against neurons and other tissues. PBMC from 15 HTLV-1-infected subjects, 5 of whom presented with HAM/TSP, were comprehensively screened for T-cell responses to overlapping peptides spanning HERV-K(HML-2) Gag and Env. In addition, we screened for responses to peptides derived from diverse HERV families, selected based on predicted binding to predicted optimal epitopes. We observed a lack of responses to each of these peptide sets. Thus, although the limited scope of our screening prevents us from conclusively disproving our hypothesis, the current study does not provide data supporting a role for HERV-specific T-cell responses in HTLV-1 associated immunopathology.

  4. How Active Are Porcine Endogenous Retroviruses (PERVs?

    Directory of Open Access Journals (Sweden)

    Joachim Denner

    2016-08-01

    Full Text Available Porcine endogenous retroviruses (PERVs represent a risk factor if porcine cells, tissues, or organs were to be transplanted into human recipients to alleviate the shortage of human transplants; a procedure called xenotransplantation. In contrast to human endogenous retroviruses (HERVs, which are mostly defective and not replication-competent, PERVs are released from normal pig cells and are infectious. PERV-A and PERV-B are polytropic viruses infecting cells of several species, among them humans; whereas PERV-C is an ecotropic virus infecting only pig cells. Virus infection was shown in co-culture experiments, but also in vivo, in the pig, leading to de novo integration of proviruses in certain organs. This was shown by measurement of the copy number per cell, finding different numbers in different organs. In addition, recombinations between PERV-A and PERV-C were observed and the recombinant PERV-A/C were found to be integrated in cells of different organs, but not in the germ line of the animals. Here, the evidence for such in vivo activities of PERVs, including expression as mRNA, protein and virus particles, de novo infection and recombination, will be summarised. These activities make screening of pigs for provirus number and PERV expression level difficult, especially when only blood or ear biopsies are available for analysis. Highly sensitive methods to measure the copy number and the expression level will be required when selecting pigs with low copy number and low expression of PERV as well as when inactivating PERVs using the clustered regularly interspaced short palindromic repeats (CRISPR/CRISPR-associated nuclease (CRISPR/Cas technology.

  5. The potential roles of endogenous retroviruses in autoimmunity.

    Science.gov (United States)

    Nakagawa, K; Harrison, L C

    1996-08-01

    Endogenous retroviruses (ERVs) are estimated to comprise up to 1% of human DNA. While the genome of many ERVs is interrupted by termination codons, deletions or frame shift mutations, some ERVs are transcriptionally active and recent studies reveal protein expression or particle formation by human ERVs. ERVs have been implicated as aetiological agents of autoimmune disease, because of their structural and sequence similarities to exogenous retroviruses associated with immune dysregulation and their tissue-specific or differentiation-dependent expression. In fact, retrovirus-like particles distinct from those of known exogenous retroviruses and immune responses to ERV proteins have been observed in autoimmune disease. Quantitatively or structurally aberrant expression of normally cryptic ERVs, induced by environmental or endogenous factors, could initiate autoimmunity through direct or indirect mechanisms. ERVs may lead to immune dysregulation as insertional mutagens or cis-regulatory elements of cellular genes involved in immune function. ERVs may also encode elements like tax in human T-lymphotrophic virus type I (HTLV-I) or tat in human immunodeficiency virus-I (HIV-I) that are capable of transactivating cellular genes. More directly, human ERV gene products themselves may be immunologically active, by analogy with the superantigen activity in the long terminal repeat (LTR) of mouse mammary tumour viruses (MMTV) and the non-specific immunosuppressive activity in mammalian type C retrovirus env protein. Alternatively, increased expression of an ERV protein, or expression of a novel ERV protein not expressed in the thymus during acquisition of immune tolerance, may lead to its perception as a neoantigen. Paraneoplastic syndromes raise the possibility that novel ERV-encoded epitopes expressed by a tumour elicit immunity to cross-reactive epitopes in normal tissues. Recombination events between different but related ERVs, to whose products the host is immunologically

  6. RESEARCH OF ANTIGEN AND ANTIBODIES FROM RETROVIRUSES, CMV AND HBV AMONG PRISONERS OF THE PENITENTIARY COMPLEX OF THE REGION OF CAMPINAS, SP, BRAZIL

    Directory of Open Access Journals (Sweden)

    Neusa Maria OSTI

    1998-07-01

    Full Text Available Some viruses of the families Retroviridae, such as Human T Lymphotropic Virus (HTLV; Herpesviridae as the Cytomegalovirus (CMV and Hepadnaviridae such as the Hepatitis B Virus (HBV are liable to be co-transmitted with the Human Immunodeficiency Virus (HIV. Since prisoners are exposed to several and important risk factors involved in the transmission of HIV and the above mentioned viruses, male inmates from the penitentiary complex of Campinas, SP, Brazil, including HIV + and HIV - ones, were examined for the presence of HTLV-I and/or II antibodies; IgG and IgM anti-CMV antibodies, and the research of the superficial hepatitis B antigen (HBsAg. The presence of anti-HTLV-I and/or II was determined by the Western Blot (WB technique, whereas IgG and IgM anti-CMV and the search of HBsAg were carried out by the Microparticle Enzyme Immunoassay (MEIA-Abbott Lab.With regard to anti-HTLV-I and/or II, 58.3% (14/24-Number of positive reactions/number of sera examined were reactive among the anti-HIV positive sera. Conversely, only 12.5% (3/24 among the HIV- negative sera showed positive reactions to HTLV-I and/or II antibodies. When looking for IgG anti-CMV percentages of 97.7% (43/44 and 95% (38/40 were obtained for anti-HIV positive and negative sera, respectively. As to IgM anti-CMV antibodies 11.36% (5/44 and 2.5% (1/40 of reactive sera were found for anti-HIV positive and negative, respectively. The HBsAg was found in 12.8% (5/39 of the sera which were anti-HIV positive.Alguns vírus das famílias Retroviridae, tais como, o Vírus do Linfoma Humano de Células T ( HTLV; Herpesviridae, tais como o Vírus Citomegálico (CMV e da Hepatite B (HBV podem ser co-transmitidos com o Vírus da Imunodeficiência Adquirida (HIV. Uma vez que prisioneiros estão expostos a diversos fatores de risco envolvidos na transmissão do HIV e dos vírus acima mencionados, prisioneiros do sexo masculino do Complexo Penitenciário de Campinas, SP, Brasil, incluindo aqueles

  7. Structure-based in silico identification of ubiquitin-binding domains provides insights into the ALIX-V:ubiquitin complex and retrovirus budding

    Science.gov (United States)

    Keren-Kaplan, Tal; Attali, Ilan; Estrin, Michael; Kuo, Lillian S; Farkash, Efrat; Jerabek-Willemsen, Moran; Blutraich, Noa; Artzi, Shay; Peri, Aviyah; Freed, Eric O; Wolfson, Haim J; Prag, Gali

    2013-01-01

    The ubiquitylation signal promotes trafficking of endogenous and retroviral transmembrane proteins. The signal is decoded by a large set of ubiquitin (Ub) receptors that tether Ub-binding domains (UBDs) to the trafficking machinery. We developed a structure-based procedure to scan the protein data bank for hidden UBDs. The screen retrieved many of the known UBDs. Intriguingly, new potential UBDs were identified, including the ALIX-V domain. Pull-down, cross-linking and E3-independent ubiquitylation assays biochemically corroborated the in silico findings. Guided by the output model, we designed mutations at the postulated ALIX-V:Ub interface. Biophysical affinity measurements using microscale-thermophoresis of wild-type and mutant proteins revealed some of the interacting residues of the complex. ALIX-V binds mono-Ub with a Kd of 119 μM. We show that ALIX-V oligomerizes with a Hill coefficient of 5.4 and IC50 of 27.6 μM and that mono-Ub induces ALIX-V oligomerization. Moreover, we show that ALIX-V preferentially binds K63 di-Ub compared with mono-Ub and K48 di-Ub. Finally, an in vivo functionality assay demonstrates the significance of ALIX-V:Ub interaction in equine infectious anaemia virus budding. These results not only validate the new procedure, but also demonstrate that ALIX-V directly interacts with Ub in vivo and that this interaction can influence retroviral budding. PMID:23361315

  8. Structure-based in silico identification of ubiquitin-binding domains provides insights into the ALIX-V:ubiquitin complex and retrovirus budding.

    Science.gov (United States)

    Keren-Kaplan, Tal; Attali, Ilan; Estrin, Michael; Kuo, Lillian S; Farkash, Efrat; Jerabek-Willemsen, Moran; Blutraich, Noa; Artzi, Shay; Peri, Aviyah; Freed, Eric O; Wolfson, Haim J; Prag, Gali

    2013-02-20

    The ubiquitylation signal promotes trafficking of endogenous and retroviral transmembrane proteins. The signal is decoded by a large set of ubiquitin (Ub) receptors that tether Ub-binding domains (UBDs) to the trafficking machinery. We developed a structure-based procedure to scan the protein data bank for hidden UBDs. The screen retrieved many of the known UBDs. Intriguingly, new potential UBDs were identified, including the ALIX-V domain. Pull-down, cross-linking and E3-independent ubiquitylation assays biochemically corroborated the in silico findings. Guided by the output model, we designed mutations at the postulated ALIX-V:Ub interface. Biophysical affinity measurements using microscale-thermophoresis of wild-type and mutant proteins revealed some of the interacting residues of the complex. ALIX-V binds mono-Ub with a K(d) of 119 μM. We show that ALIX-V oligomerizes with a Hill coefficient of 5.4 and IC(50) of 27.6 μM and that mono-Ub induces ALIX-V oligomerization. Moreover, we show that ALIX-V preferentially binds K63 di-Ub compared with mono-Ub and K48 di-Ub. Finally, an in vivo functionality assay demonstrates the significance of ALIX-V:Ub interaction in equine infectious anaemia virus budding. These results not only validate the new procedure, but also demonstrate that ALIX-V directly interacts with Ub in vivo and that this interaction can influence retroviral budding.

  9. Innate imune response against retrovirus.

    Directory of Open Access Journals (Sweden)

    Lucia González

    2015-11-01

    Full Text Available Los retrovirus son un diverso grupo de virus que se encuentran en los vertebrados. Su importancia biomédica radica en que son capaces de infectar humanos, produciendo importantes problemas de salud. El virus de la inmunodeficiencia humana (VIH es capaz de producir un estado de inmunodeficiencia en el huésped determinando el desarrollo de enfermedades oportunistas en estadio avanzados de la enfermedad. Frente a la entrada de un retrovirus al organismo, nuestro sistema inmune presenta como primera línea de defensa a la inmunidad innata. El resultado de esta respuesta es la inducción de interferones de tipo I (IFN tipo I quienes generan un estado antiviral en la célula. Recientemente se ha ampliado la investigación sobre diferentes factores de restricción del huésped que forman parte de la inmunidad innata antiviral determinando la inhibición de la replicación de los retrovirus. En esta revisión abordaremos las distintas vías de señalización implicadas en la función de estos factores. Dentro de ellos, se mencionarán; el SAMHD1 que determina un agotamiento del pool celular de dNTP inhibiendo los pasos tempranos de la retrotranscripción en células infectadas; TREX1 que es considerado un factor de restricción del huésped antagónico ya que la ausencia del mismo resulta en la activación de una respuesta de interferón; APOBEC3 que media la restricción viral principalmente por un mecanismo de edición del DNA; TRIM5α que puede formar una estructura hexagonal por encima de la cápside, lo cual desestabilizaría el core viral; Tetherin que es capaz de bloquear la liberación de viriones de VIH.

  10. Multiple groups of endogenous epsilon-like retroviruses conserved across primates.

    Science.gov (United States)

    Brown, Katherine; Emes, Richard D; Tarlinton, Rachael E

    2014-11-01

    Several types of cancer in fish are caused by retroviruses, including those responsible for major outbreaks of disease, such as walleye dermal sarcoma virus and salmon swim bladder sarcoma virus. These viruses form a phylogenetic group often described as the epsilonretrovirus genus. Epsilon-like retroviruses have become endogenous retroviruses (ERVs) on several occasions, integrating into germ line cells to become part of the host genome, and sections of fish and amphibian genomes are derived from epsilon-like retroviruses. However, epsilon-like ERVs have been identified in very few mammals. We have developed a pipeline to screen full genomes for ERVs, and using this pipeline, we have located over 800 endogenous epsilon-like ERV fragments in primate genomes. Genomes from 32 species of mammals and birds were screened, and epsilon-like ERV fragments were found in all primate and tree shrew genomes but no others. These viruses appear to have entered the genome of a common ancestor of Old and New World monkeys between 42 million and 65 million years ago. Based on these results, there is an ancient evolutionary relationship between epsilon-like retroviruses and primates. Clearly, these viruses had the potential to infect the ancestors of primates and were at some point a common pathogen in these hosts. Therefore, this result raises questions about the potential of epsilonretroviruses to infect humans and other primates and about the evolutionary history of these retroviruses. Epsilonretroviruses are a group of retroviruses that cause several important diseases in fish. Retroviruses have the ability to become a permanent part of the DNA of their host by entering the germ line as endogenous retroviruses (ERVs), where they lose their infectivity over time but can be recognized as retroviruses for millions of years. Very few mammals are known to have epsilon-like ERVs; however, we have identified over 800 fragments of endogenous epsilon-like ERVs in the genomes of all major

  11. Review of the twelfth West Coast retrovirus meeting

    Directory of Open Access Journals (Sweden)

    Melar Marta

    2005-11-01

    Full Text Available Abstract Every year the Cancer Research Institute from University of California at Irvine organizes the West Coast Retrovirus Meeting where participants have a chance to discuss the latest progress in understanding the pathology of retroviruses. The 12th meeting was held at the Hyatt Regency Suites in Palm Springs, California from October 6th to October 9th 2005, with the major focus on human immunodeficiency virus (HIV pathogenesis. Philippe Gallay from The Scripps Research Institute and Thomas J. Hope from Northwestern University organized the meeting, which covered all the steps involved in the lifecycle of retroviruses with an emphasis on virus:host interactions. The trend in research appeared to be on the restriction of viral infection, both by the endogenous, cellular restriction factors, as well as by the potential antimicrobial compounds of known or unknown mechanisms. Additionally, new stories on the inevitable feedback from the host immune system were presented as well. HIV still represents a challenge that an army of motivated people has been working on for over 20 years. And yet, the field has not reached the plateau in knowledge nor enthusiasm, which was proven again in October 2005 in Palm Springs.

  12. Rapid modification of retroviruses using lipid conjugates

    International Nuclear Information System (INIS)

    Mukherjee, Nimisha G; Le Doux, Joseph M; Andrew Lyon, L

    2009-01-01

    Methods are needed to manipulate natural nanoparticles. Viruses are particularly interesting because they can act as therapeutic cellular delivery agents. Here we examine a new method for rapidly modifying retroviruses that uses lipid conjugates composed of a lipid anchor (1,2-distearoyl-sn-glycero-3-phosphoethanolamine), a polyethylene glycol chain, and biotin. The conjugates rapidly and stably modified retroviruses and enabled them to bind streptavidin. The implication of this work for modifying viruses for gene therapy and vaccination protocols is discussed.

  13. Approaching human language with complex networks

    Science.gov (United States)

    Cong, Jin; Liu, Haitao

    2014-12-01

    The interest in modeling and analyzing human language with complex networks is on the rise in recent years and a considerable body of research in this area has already been accumulated. We survey three major lines of linguistic research from the complex network approach: 1) characterization of human language as a multi-level system with complex network analysis; 2) linguistic typological research with the application of linguistic networks and their quantitative measures; and 3) relationships between the system-level complexity of human language (determined by the topology of linguistic networks) and microscopic linguistic (e.g., syntactic) features (as the traditional concern of linguistics). We show that the models and quantitative tools of complex networks, when exploited properly, can constitute an operational methodology for linguistic inquiry, which contributes to the understanding of human language and the development of linguistics. We conclude our review with suggestions for future linguistic research from the complex network approach: 1) relationships between the system-level complexity of human language and microscopic linguistic features; 2) expansion of research scope from the global properties to other levels of granularity of linguistic networks; and 3) combination of linguistic network analysis with other quantitative studies of language (such as quantitative linguistics).

  14. Mobilization of endogenous retroviruses in mice after infection with an exogenous retrovirus.

    Science.gov (United States)

    Evans, Leonard H; Alamgir, A S M; Owens, Nick; Weber, Nick; Virtaneva, Kimmo; Barbian, Kent; Babar, Amenah; Malik, Frank; Rosenke, Kyle

    2009-03-01

    Mammalian genomes harbor a large number of retroviral elements acquired as germ line insertions during evolution. Although many of the endogenous retroviruses are defective, several contain one or more intact viral genes that are expressed under certain physiological or pathological conditions. This is true of the endogenous polytropic retroviruses that generate recombinant polytropic murine leukemia viruses (MuLVs). In these recombinants the env gene sequences of exogenous ecotropic MuLVs are replaced with env gene sequences from an endogenous polytropic retrovirus. Although replication-competent endogenous polytropic retroviruses have not been observed, the recombinant polytropic viruses are capable of replicating in numerous species. Recombination occurs during reverse transcription of a virion RNA heterodimer comprised of an RNA transcript from an endogenous polytropic virus and an RNA transcript from an exogenous ecotropic MuLV RNA. It is possible that homodimers corresponding to two full-length endogenous RNA genomes are also packaged. Thus, infection by an exogenous virus may result not only in recombination with endogenous sequences, but also in the mobilization of complete endogenous retrovirus genomes via pseudotyping within exogenous retroviral virions. We report that the infection of mice with an ecotropic virus results in pseudotyping of intact endogenous viruses that have not undergone recombination. The endogenous retroviruses infect and are integrated into target cell genomes and subsequently replicate and spread as pseudotyped viruses. The mobilization of endogenous retroviruses upon infection with an exogenous retrovirus may represent a major interaction of exogenous retroviruses with endogenous retroviruses and may have profound effects on the pathogenicity of retroviral infections.

  15. Endogenous Retroviruses: With Us and Against Us

    Science.gov (United States)

    Meyer, Thomas J.; Rosenkrantz, Jimi L.; Carbone, Lucia; Chavez, Shawn L.

    2017-04-01

    Mammalian genomes are scattered with thousands of copies of endogenous retroviruses (ERVs), mobile genetic elements that are relics of ancient retroviral infections. After inserting copies into the germ line of a host, most ERVs accumulate mutations that prevent the normal assembly of infectious viral particles, becoming trapped in host genomes and unable to leave to infect other cells. While most copies of ERVs are inactive, some are transcribed and encode the proteins needed to generate new insertions at novel loci. In some cases, old copies are removed via recombination and other mechanisms. This creates a shifting landscape of ERV copies within host genomes. New insertions can disrupt normal expression of nearby genes via directly inserting into key regulatory elements or by containing regulatory motifs within their sequences. Further, the transcriptional silencing of ERVs via epigenetic modification may result in changes to the epigenetic regulation of adjacent genes. In these ways, ERVs can be potent sources of regulatory disruption as well as genetic innovation. Here, we provide a brief review of the association between ERVs and gene expression, especially as observed in pre-implantation development and placentation. Moreover, we will describe the roles ERVs may play in somatic tissues, mostly in the context of human disease, including cancer, neurodegenerative disorders, and schizophrenia. Lastly, we discuss the recent discovery that some ERVs may have been pressed into the service of their host genomes to aid in the innate immune response to exogenous viral infections.

  16. Restriction genes for retroviruses influence the risk of multiple sclerosis

    DEFF Research Database (Denmark)

    Nexø, Bjørn A; Hansen, Bettina; Nissen, Kari K

    2013-01-01

    known for a long time. Today human restriction genes for retroviruses include amongst others TRIMs, APOBEC3s, BST2 and TREXs. We have therefore looked for a role of these retroviral restriction genes in MS using genetic epidemiology. We here report that markers in two TRIMs, TRIM5 and TRIM22...... and a marker in BST2, associated statistically with the risk of getting MS, while markers in or near APOBEC3s and TREXs showed little or no effect. This indicates that the two TRIMs and BST2 influence the risk of disease and thus supports the hypothesis of a viral involvement....

  17. Real-time quantitative PCR for retrovirus-like particle quantification in CHO cell culture.

    Science.gov (United States)

    de Wit, C; Fautz, C; Xu, Y

    2000-09-01

    Chinese hamster ovary (CHO) cells have been widely used to manufacture recombinant proteins intended for human therapeutic uses. Retrovirus-like particles, which are apparently defective and non-infectious, have been detected in all CHO cells by electron microscopy (EM). To assure viral safety of CHO cell-derived biologicals, quantification of retrovirus-like particles in production cell culture and demonstration of sufficient elimination of such retrovirus-like particles by the down-stream purification process are required for product market registration worldwide. EM, with a detection limit of 1x10(6) particles/ml, is the standard retrovirus-like particle quantification method. The whole process, which requires a large amount of sample (3-6 litres), is labour intensive, time consuming, expensive, and subject to significant assay variability. In this paper, a novel real-time quantitative PCR assay (TaqMan assay) has been developed for the quantification of retrovirus-like particles. Each retrovirus particle contains two copies of the viral genomic particle RNA (pRNA) molecule. Therefore, quantification of retrovirus particles can be achieved by quantifying the pRNA copy number, i.e. every two copies of retroviral pRNA is equivalent to one retrovirus-like particle. The TaqMan assay takes advantage of the 5'-->3' exonuclease activity of Taq DNA polymerase and utilizes the PRISM 7700 Sequence Detection System of PE Applied Biosystems (Foster City, CA, U.S.A.) for automated pRNA quantification through a dual-labelled fluorogenic probe. The TaqMan quantification technique is highly comparable to the EM analysis. In addition, it offers significant advantages over the EM analysis, such as a higher sensitivity of less than 600 particles/ml, greater accuracy and reliability, higher sample throughput, more flexibility and lower cost. Therefore, the TaqMan assay should be used as a substitute for EM analysis for retrovirus-like particle quantification in CHO cell

  18. Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses.

    Science.gov (United States)

    Gao, Daxing; Wu, Jiaxi; Wu, You-Tong; Du, Fenghe; Aroh, Chukwuemika; Yan, Nan; Sun, Lijun; Chen, Zhijian J

    2013-08-23

    Retroviruses, including HIV, can activate innate immune responses, but the host sensors for retroviruses are largely unknown. Here we show that HIV infection activates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) to produce cGAMP, which binds to and activates the adaptor protein STING to induce type I interferons and other cytokines. Inhibitors of HIV reverse transcriptase, but not integrase, abrogated interferon-β induction by the virus, suggesting that the reverse-transcribed HIV DNA triggers the innate immune response. Knockout or knockdown of cGAS in mouse or human cell lines blocked cytokine induction by HIV, murine leukemia virus, and simian immunodeficiency virus. These results indicate that cGAS is an innate immune sensor of HIV and other retroviruses.

  19. Human Error Mechanisms in Complex Work Environments

    DEFF Research Database (Denmark)

    Rasmussen, Jens

    1988-01-01

    will account for most of the action errors observed. In addition, error mechanisms appear to be intimately related to the development of high skill and know-how in a complex work context. This relationship between errors and human adaptation is discussed in detail for individuals and organisations...

  20. Human error mechanisms in complex work environments

    International Nuclear Information System (INIS)

    Rasmussen, J.

    1988-01-01

    Human error taxonomies have been developed from analysis of industrial incident reports as well as from psychological experiments. In this paper the results of the two approaches are reviewed and compared. It is found, in both cases, that a fairly small number of basic psychological mechanisms will account for most of the action errors observed. In addition, error mechanisms appear to be intimately related to the development of high skill and know-how in a complex work context. This relationship between errors and human adaptation is discussed in detail for individuals and organisations. The implications for system safety and briefly mentioned, together with the implications for system design. (author)

  1. Human error mechanisms in complex work environments

    International Nuclear Information System (INIS)

    Rasmussen, Jens; Danmarks Tekniske Hoejskole, Copenhagen)

    1988-01-01

    Human error taxonomies have been developed from analysis of industrial incident reports as well as from psychological experiments. In this paper the results of the two approaches are reviewed and compared. It is found, in both cases, that a fairly small number of basic psychological mechanisms will account for most of the action errors observed. In addition, error mechanisms appear to be intimately related to the development of high skill and know-how in a complex work context. This relationship between errors and human adaptation is discussed in detail for individuals and organisations. The implications for system safety are briefly mentioned, together with the implications for system design. (author)

  2. Endogenous retrovirus sequences expressed in male mammalian ...

    African Journals Online (AJOL)

    Objectives: To review the research findings on the expression of endogenous retroviruses and retroviral-related particles in male mammalian reproductive tissues, and to discuss their possible role in normal cellular events and association with disease conditions in male reproductive tissues. Data sources: Published ...

  3. Endogenous retroviruses are associated with autoimmune diseases

    DEFF Research Database (Denmark)

    Nexø, Bjørn A; Bisgaard Jensen, Sara; Hansen, Bettina

    2016-01-01

    of transmission is called vertical. Viral variants of importance for development of disease must be more frequent among diseased persons than among healthy individuals. Multiple sclerosis, diabetes and rheumatoid arthritis are all associated with sets of endogenouos retroviruses but not the same sets. If a virus...

  4. Infection Barriers to Successful Xenotransplantation Focusing on Porcine Endogenous Retroviruses

    Science.gov (United States)

    Tönjes, Ralf R.

    2012-01-01

    Summary: Xenotransplantation may be a solution to overcome the shortage of organs for the treatment of patients with organ failure, but it may be associated with the transmission of porcine microorganisms and the development of xenozoonoses. Whereas most microorganisms may be eliminated by pathogen-free breeding of the donor animals, porcine endogenous retroviruses (PERVs) cannot be eliminated, since these are integrated into the genomes of all pigs. Human-tropic PERV-A and -B are present in all pigs and are able to infect human cells. Infection of ecotropic PERV-C is limited to pig cells. PERVs may adapt to host cells by varying the number of LTR-binding transcription factor binding sites. Like all retroviruses, they may induce tumors and/or immunodeficiencies. To date, all experimental, preclinical, and clinical xenotransplantations using pig cells, tissues, and organs have not shown transmission of PERV. Highly sensitive and specific methods have been developed to analyze the PERV status of donor pigs and to monitor recipients for PERV infection. Strategies have been developed to prevent PERV transmission, including selection of PERV-C-negative, low-producer pigs, generation of an effective vaccine, selection of effective antiretrovirals, and generation of animals transgenic for a PERV-specific short hairpin RNA inhibiting PERV expression by RNA interference. PMID:22491774

  5. The Brain Prize 2014: complex human functions.

    Science.gov (United States)

    Grigaityte, Kristina; Iacoboni, Marco

    2014-11-01

    Giacomo Rizzolatti, Stanislas Dehaene, and Trevor Robbins were recently awarded the 2014 Grete Lundbeck European Brain Research Prize for their 'pioneering research on higher brain mechanisms underpinning such complex human functions as literacy, numeracy, motivated behavior and social cognition, and for their effort to understand cognitive and behavioral disorders'. Why was their work highlighted? Is there anything that links together these seemingly disparate lines of research? Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Expression patterns of ERVWE1/Syncytin-1 and other placentally expressed human endogenous retroviruses along the malignant transformation process of hydatidiform moles.

    Science.gov (United States)

    Bolze, Pierre-Adrien; Patrier, Sophie; Cheynet, Valérie; Oriol, Guy; Massardier, Jérôme; Hajri, Touria; Guillotte, Michèle; Bossus, Marc; Sanlaville, Damien; Golfier, François; Mallet, François

    2016-03-01

    Up to 20% of hydatidiform moles are followed by malignant transformation in gestational trophoblastic neoplasia and require chemotherapy. Syncytin-1 is involved in human placental morphogenesis and is also expressed in various cancers. We assessed the predictive value of the expression of Syncytin-1 and its interactants in the malignant transformation process of hydatidiform moles. Syncytin-1 glycoprotein was localized by immunohistochemistry in hydatidiform moles, gestational trophoblastic neoplasia and control placentas. The transcription levels of its locus ERVWE1, its interaction partners (hASCT1, hASCT2, TLR4 and DC-SIGN) and two loci (ERVFRDE1 and ERV3) involved the expression of other placental envelopes were assessed by real-time PCR. Syncytin-1 glycoprotein was expressed in syncytiotrophoblast of hydatidiform moles with an apical enhancement when compared with normal placentas. Moles with further malignant transformation had a higher staining intensity of Syncytin-1 surface unit C-terminus but the transcription level of its locus ERVWE1 was not different from that of moles with further remission and normal placentas. hASCT1 and TLR4, showed lower transcription levels in complete moles when compared to normal placentas. ERVWE1, ERVFRDE1 and ERV3 transcription was down-regulated in hydatidiform moles and gestational trophoblastic neoplasia. Variations of Syncytin-1 protein localization and down-regulation of hASCT1 and TLR4 transcription are likely to reflect altered functions of Syncytin-1 in the premalignant context of complete moles. The reduced transcription in gestational trophoblastic diseases of ERVWE1, ERVFRDE1 and ERV3, which expression during normal pregnancy is differentially regulated by promoter region methylation, suggest a joint dysregulation mechanism in malignant context. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Synergistic immune responses induced by endogenous retrovirus and herpesvirus antigens result in increased production of inflammatory cytokines in multiple sclerosis patients

    DEFF Research Database (Denmark)

    Brudek, Tomasz; Christensen, Tove; Hansen, Hans Jacob

    2008-01-01

    Human endogenous retroviruses (HERV) and herpesviruses are increasingly associated with the pathogenesis of the neurological inflammatory disease multiple sclerosis (MS). Herpesviruses are capable of HERV activation and simultaneous presence of HERV and herpesvirus antigens have a synergistic...

  8. Endogenous MOV10 inhibits the retrotransposition of endogenous retroelements but not the replication of exogenous retroviruses

    Science.gov (United States)

    2012-01-01

    Background The identification of cellular factors that regulate the replication of exogenous viruses and endogenous mobile elements provides fundamental understanding of host-pathogen relationships. MOV10 is a superfamily 1 putative RNA helicase that controls the replication of several RNA viruses and whose homologs are necessary for the repression of endogenous mobile elements. Here, we employ both ectopic expression and gene knockdown approaches to analyse the role of human MOV10 in the replication of a panel of exogenous retroviruses and endogenous retroelements. Results MOV10 overexpression substantially decreased the production of infectious retrovirus particles, as well the propagation of LTR and non-LTR endogenous retroelements. Most significantly, RNAi-mediated silencing of endogenous MOV10 enhanced the replication of both LTR and non-LTR endogenous retroelements, but not the production of infectious retrovirus particles demonstrating that natural levels of MOV10 suppress retrotransposition, but have no impact on infection by exogenous retroviruses. Furthermore, functional studies showed that MOV10 is not necessary for miRNA or siRNA-mediated mRNA silencing. Conclusions We have identified novel specificity for human MOV10 in the control of retroelement replication and hypothesise that MOV10 may be a component of a cellular pathway or process that selectively regulates the replication of endogenous retroelements in somatic cells. PMID:22727223

  9. Endogenous MOV10 inhibits the retrotransposition of endogenous retroelements but not the replication of exogenous retroviruses.

    Science.gov (United States)

    Arjan-Odedra, Shetal; Swanson, Chad M; Sherer, Nathan M; Wolinsky, Steven M; Malim, Michael H

    2012-06-22

    The identification of cellular factors that regulate the replication of exogenous viruses and endogenous mobile elements provides fundamental understanding of host-pathogen relationships. MOV10 is a superfamily 1 putative RNA helicase that controls the replication of several RNA viruses and whose homologs are necessary for the repression of endogenous mobile elements. Here, we employ both ectopic expression and gene knockdown approaches to analyse the role of human MOV10 in the replication of a panel of exogenous retroviruses and endogenous retroelements. MOV10 overexpression substantially decreased the production of infectious retrovirus particles, as well the propagation of LTR and non-LTR endogenous retroelements. Most significantly, RNAi-mediated silencing of endogenous MOV10 enhanced the replication of both LTR and non-LTR endogenous retroelements, but not the production of infectious retrovirus particles demonstrating that natural levels of MOV10 suppress retrotransposition, but have no impact on infection by exogenous retroviruses. Furthermore, functional studies showed that MOV10 is not necessary for miRNA or siRNA-mediated mRNA silencing. We have identified novel specificity for human MOV10 in the control of retroelement replication and hypothesise that MOV10 may be a component of a cellular pathway or process that selectively regulates the replication of endogenous retroelements in somatic cells.

  10. Computational Complexity and Human Decision-Making.

    Science.gov (United States)

    Bossaerts, Peter; Murawski, Carsten

    2017-12-01

    The rationality principle postulates that decision-makers always choose the best action available to them. It underlies most modern theories of decision-making. The principle does not take into account the difficulty of finding the best option. Here, we propose that computational complexity theory (CCT) provides a framework for defining and quantifying the difficulty of decisions. We review evidence showing that human decision-making is affected by computational complexity. Building on this evidence, we argue that most models of decision-making, and metacognition, are intractable from a computational perspective. To be plausible, future theories of decision-making will need to take into account both the resources required for implementing the computations implied by the theory, and the resource constraints imposed on the decision-maker by biology. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. HERVd: database of human endogenous retroviruses

    Czech Academy of Sciences Publication Activity Database

    Pačes, Jan; Pavlíček, Adam; Pačes, Václav

    2002-01-01

    Roč. 30, č. 1 (2002), s. 205-206 ISSN 0305-1048 R&D Projects: GA MŠk LN00A079 Institutional research plan: CEZ:AV0Z5052915 Keywords : elements * repeats Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.051, year: 2002

  12. Endogenous retroviruses of sheep: a model system for understanding physiological adaptation to an evolving ruminant genome.

    Science.gov (United States)

    Spencer, Thomas E; Palmarini, Massimo

    2012-01-01

    Endogenous retroviruses (ERVs) are present in the genome of all vertebrates and are remnants of ancient exogenous retroviral infections of the host germline transmitted vertically from generation to generation. Sheep betaretroviruses offer a unique model system to study the complex interaction between retroviruses and their host. The sheep genome contains 27 endogenous betaretroviruses (enJSRVs) related to the exogenous and pathogenic Jaagsiekte sheep retrovirus (JSRV), the causative agent of a transmissible lung cancer in sheep. The enJSRVs can protect their host against JSRV infection by blocking early and late steps of the JSRV replication cycle. In the female reproductive tract, enJSRVs are specifically expressed in the uterine luminal and glandular epithelia as well as in the conceptus (embryo and associated extraembryonic membranes) trophectoderm and in utero loss-of-function experiments found the enJSRVs envelope (env) to be essential for conceptus elongation and trophectoderm growth and development. Collectively, available evidence in sheep and other mammals indicate that ERVs coevolved with their hosts for millions of years and were positively selected for biological roles in genome plasticity and evolution, protection of the host against infection of related pathogenic and exogenous retroviruses, and placental development.

  13. Methylated DNA Immunoprecipitation Analysis of Mammalian Endogenous Retroviruses.

    Science.gov (United States)

    Rebollo, Rita; Mager, Dixie L

    2016-01-01

    Endogenous retroviruses are repetitive sequences found abundantly in mammalian genomes which are capable of modulating host gene expression. Nevertheless, most endogenous retrovirus copies are under tight epigenetic control via histone-repressive modifications and DNA methylation. Here we describe a common method used in our laboratory to detect, quantify, and compare mammalian endogenous retrovirus DNA methylation. More specifically we describe methylated DNA immunoprecipitation (MeDIP) followed by quantitative PCR.

  14. On the general theory of the origins of retroviruses

    Directory of Open Access Journals (Sweden)

    Wayengera Misaki

    2010-02-01

    Full Text Available Abstract Background The order retroviridae comprises viruses based on ribonucleic acids (RNA. Some, such as HIV and HTLV, are human pathogens. Newly emerged human retroviruses have zoonotic origins. As far as has been established, both repeated infections (themselves possibly responsible for the evolution of viral mutations (Vm and host adaptability (Ha; along with interplay between inhibitors and promoters of cell tropism, are needed to effect retroviral cross-species transmissions. However, the exact modus operadi of intertwine between these factors at molecular level remains to be established. Knowledge of such intertwine could lead to a better understanding of retrovirology and possibly other infectious processes. This study was conducted to derive the mathematical equation of a general theory of the origins of retroviruses. Methods and results On the basis of an arbitrarily non-Euclidian geometrical "thought experiment" involving the cross-species transmission of simian foamy virus (sfv from a non-primate species Xy to Homo sapiens (Hs, initially excluding all social factors, the following was derived. At the port of exit from Xy (where the species barrier, SB, is defined by the Index of Origin, IO, sfv shedding is (1 enhanced by two transmitting tensors (Tt, (i virus-specific immunity (VSI and (ii evolutionary defenses such as APOBEC, RNA interference pathways, and (when present expedited therapeutics (denoted e2D; and (2 opposed by the five accepting scalars (At: (a genomic integration hot spots, gIHS, (b nuclear envelope transit (NMt vectors, (c virus-specific cellular biochemistry, VSCB, (d virus-specific cellular receptor repertoire, VSCR, and (e pH-mediated cell membrane transit, (↓pH CMat. Assuming As and Tt to be independent variables, IO = Tt/As. The same forces acting in an opposing manner determine SB at the port of sfv entry (defined here by the Index of Entry, IE = As/Tt. Overall, If sfv encounters no unforeseen effects on

  15. REVEALING THE HISTORY OF SHEEP DOMESTICATION USING RETROVIRUS INTEGRATIONS

    Science.gov (United States)

    Chessa, B.; Pereira, F.; Arnaud, F.; Amorim, A.; Goyache, F.; Mainland, I.; Kao, R.R.; Pemberton, J. M.; Beraldi, D.; Stear, M.; Alberti, A.; Pittau, M.; Iannuzzi, L.; Banabazi, M.H.; Kazwala, R.; Zhang, Y.-P.; Arranz, J.J.; Ali, B.A.; Wang, Z.; Uzun, M.; Dione, M.; Olsaker, I.; Holm, L.-E.; Saarma, U.; Ahmad, S.; Marzanov, N.; Eythorsdottir, E.; Holland, M.J.; Ajmone-Marsan, P.; Bruford, M.W.; Kantanen, J.; Spencer, T.E.; Palmarini, M.

    2011-01-01

    The domestication of livestock represented a crucial step in human history. By using endogenous retroviruses as genetic markers, we found that sheep differentiated on the basis of their “retrotype” and morphological traits, dispersed across Eurasia and Africa via separate migratory episodes. Relicts of the first migrations include the Mouflon, as well as breeds previously recognized as “primitive” on the basis of their morphology, such as the Orkney, Soay and the Nordic short-tailed sheep now confined to the periphery of NW Europe. A later migratory episode, involving sheep with improved production traits, shaped the vast majority of present-day breeds. The ability to differentiate genetically primitive sheep from more modern breeds provides valuable insights into the history of sheep domestication. PMID:19390051

  16. Endogenous Retrovirus 3 – History, Physiology, and Pathology

    Directory of Open Access Journals (Sweden)

    Yomara Y. Bustamante Rivera

    2018-01-01

    Full Text Available Endogenous viral elements (EVE seem to be present in all eukaryotic genomes. The composition of EVE varies between different species. The endogenous retrovirus 3 (ERV3 is one of these elements that is present only in humans and other Catarrhini. Conservation of ERV3 in most of the investigated Catarrhini and the expression pattern in normal tissues suggest a putative physiological role of ERV3. On the other hand, ERV3 has been implicated in the pathogenesis of auto-immunity and cancer. In the present review we summarize knowledge about this interesting EVE. We propose the model that expression of ERV3 (and probably other EVE loci under pathological conditions might be part of a metazoan SOS response.

  17. Generation of neutralising antibodies against porcine endogenous retroviruses (PERVs)

    International Nuclear Information System (INIS)

    Kaulitz, Danny; Fiebig, Uwe; Eschricht, Magdalena; Wurzbacher, Christian; Kurth, Reinhard; Denner, Joachim

    2011-01-01

    Antibodies neutralising porcine endogenous retroviruses (PERVs) were induced in different animal species by immunisation with the transmembrane envelope protein p15E. These antibodies recognised epitopes, designated E1, in the fusion peptide proximal region (FPPR) of p15E, and E2 in the membrane proximal external region (MPER). E2 is localised in a position similar to that of an epitope in the transmembrane envelope protein gp41 of the human immunodeficiency virus-1 (HIV-1), recognised by the monoclonal antibody 4E10 that is broadly neutralising. To detect neutralising antibodies specific for PERV, a novel assay was developed, which is based on quantification of provirus integration by real-time PCR. In addition, for the first time, highly effective neutralising antibodies were obtained by immunisation with the surface envelope protein of PERV. These data indicate that neutralising antibodies can be induced by immunisation with both envelope proteins.

  18. Endogenous Retrovirus 3 – History, Physiology, and Pathology

    Science.gov (United States)

    Bustamante Rivera, Yomara Y.; Brütting, Christine; Schmidt, Caroline; Volkmer, Ines; Staege, Martin S.

    2018-01-01

    Endogenous viral elements (EVE) seem to be present in all eukaryotic genomes. The composition of EVE varies between different species. The endogenous retrovirus 3 (ERV3) is one of these elements that is present only in humans and other Catarrhini. Conservation of ERV3 in most of the investigated Catarrhini and the expression pattern in normal tissues suggest a putative physiological role of ERV3. On the other hand, ERV3 has been implicated in the pathogenesis of auto-immunity and cancer. In the present review we summarize knowledge about this interesting EVE. We propose the model that expression of ERV3 (and probably other EVE loci) under pathological conditions might be part of a metazoan SOS response. PMID:29379485

  19. Revealing the history of sheep domestication using retrovirus integrations.

    Science.gov (United States)

    Chessa, Bernardo; Pereira, Filipe; Arnaud, Frederick; Amorim, Antonio; Goyache, Félix; Mainland, Ingrid; Kao, Rowland R; Pemberton, Josephine M; Beraldi, Dario; Stear, Michael J; Alberti, Alberto; Pittau, Marco; Iannuzzi, Leopoldo; Banabazi, Mohammad H; Kazwala, Rudovick R; Zhang, Ya-Ping; Arranz, Juan J; Ali, Bahy A; Wang, Zhiliang; Uzun, Metehan; Dione, Michel M; Olsaker, Ingrid; Holm, Lars-Erik; Saarma, Urmas; Ahmad, Sohail; Marzanov, Nurbiy; Eythorsdottir, Emma; Holland, Martin J; Ajmone-Marsan, Paolo; Bruford, Michael W; Kantanen, Juha; Spencer, Thomas E; Palmarini, Massimo

    2009-04-24

    The domestication of livestock represented a crucial step in human history. By using endogenous retroviruses as genetic markers, we found that sheep differentiated on the basis of their "retrotype" and morphological traits dispersed across Eurasia and Africa via separate migratory episodes. Relicts of the first migrations include the Mouflon, as well as breeds previously recognized as "primitive" on the basis of their morphology, such as the Orkney, Soay, and the Nordic short-tailed sheep now confined to the periphery of northwest Europe. A later migratory episode, involving sheep with improved production traits, shaped the great majority of present-day breeds. The ability to differentiate genetically primitive sheep from more modern breeds provides valuable insights into the history of sheep domestication.

  20. The ability of multimerized cyclophilin A to restrict retrovirus infection

    International Nuclear Information System (INIS)

    Javanbakht, Hassan; Diaz-Griffero, Felipe; Yuan Wen; Yeung, Darwin F.; Li Xing; Song Byeongwoon; Sodroski, Joseph

    2007-01-01

    In owl monkeys, the typical retroviral restriction factor of primates, TRIM5α, is replaced by TRIMCyp. TRIMCyp consists of the TRIM5 RING, B-box 2 and coiled-coil domains, as well as the intervening linker regions, fused with cyclophilin A. TRIMCyp restricts infection of retroviruses, such as human immunodeficiency virus (HIV-1) and feline immunodeficiency virus (FIV), with capsids that can bind cyclophilin A. The TRIM5 coiled coil promotes the trimerization of TRIMCyp. Here we show that cyclophilin A that is oligomeric as a result of fusion with a heterologous multimer exhibits substantial antiretroviral activity. The addition of the TRIM5 RING, B-box 2 and Linker 2 to oligomeric cyclophilin A generated a protein with antiretroviral activity approaching that of wild-type TRIMCyp. Multimerization increased the binding of cyclophilin A to the HIV-1 capsid, promoting accelerated uncoating of the capsid and restriction of infection

  1. Plant retroviruses: structure, evolution and future applications | Zaki ...

    African Journals Online (AJOL)

    Until recently, retroviruses were thought to be restricted to vertebrates. Plant sequencing projects revealed that plant genomes contain retroviral-like sequences. This review aims to address the structure and evolution of plant retroviruses. In addition, it proposes future applications for these important key components of plant ...

  2. Koala retrovirus: a genome invasion in real time

    OpenAIRE

    Stoye, Jonathan P

    2006-01-01

    Koalas are currently undergoing a wave of germline infections by the retrovirus KoRV. Study of this phenomenon not only provides an opportunity for understanding the processes regulating retrovirus endogenization but may also be essential to preventing the extinction of the species.

  3. Activation of endogenous retrovirus reverse transcriptase in multiple sclerosis patient lymphocytes by inactivated HSV-1, HHV-6 and VZV

    DEFF Research Database (Denmark)

    Brudek, Tomasz; Lühdorf, Pernille; Christensen, Tove

    2007-01-01

    Human endogenous retroviruses (HERVs) and herpesviruses have been associated with the development of multiple sclerosis (MS). These virus groups interact with each other and have been shown to induce synergistic immune responses. Here, we focus on the possible role of herpesviruses as contributing...

  4. Porcine Endogenous Retroviruses in Xenotransplantation—Molecular Aspects

    Directory of Open Access Journals (Sweden)

    Magdalena C. Kimsa

    2014-05-01

    Full Text Available In the context of the shortage of organs and other tissues for use in human transplantation, xenotransplantation procedures with material taken from pigs have come under increased consideration. However, there are unclear consequences of the potential transmission of porcine pathogens to humans. Of particular concern are porcine endogenous retroviruses (PERVs. Three subtypes of PERV have been identified, of which PERV-A and PERV-B have the ability to infect human cells in vitro. The PERV-C subtype does not show this ability but recombinant PERV-A/C forms have demonstrated infectivity in human cells. In view of the risk presented by these observations, the International Xenotransplantation Association recently indicated the existence of four strategies to prevent transmission of PERVs. This article focuses on the molecular aspects of PERV infection in xenotransplantation and reviews the techniques available for the detection of PERV DNA, RNA, reverse transcriptase activity and proteins, and anti-PERV antibodies to enable carrying out these recommendations. These methods could be used to evaluate the risk of PERV transmission in human recipients, enhance the effectiveness and reliability of monitoring procedures, and stimulate discussion on the development of improved, more sensitive methods for the detection of PERVs in the future.

  5. Porcine Endogenous Retroviruses in Xenotransplantation—Molecular Aspects

    Science.gov (United States)

    Kimsa, Magdalena C.; Strzalka-Mrozik, Barbara; Kimsa, Malgorzata W.; Gola, Joanna; Nicholson, Peter; Lopata, Krzysztof; Mazurek, Urszula

    2014-01-01

    In the context of the shortage of organs and other tissues for use in human transplantation, xenotransplantation procedures with material taken from pigs have come under increased consideration. However, there are unclear consequences of the potential transmission of porcine pathogens to humans. Of particular concern are porcine endogenous retroviruses (PERVs). Three subtypes of PERV have been identified, of which PERV-A and PERV-B have the ability to infect human cells in vitro. The PERV-C subtype does not show this ability but recombinant PERV-A/C forms have demonstrated infectivity in human cells. In view of the risk presented by these observations, the International Xenotransplantation Association recently indicated the existence of four strategies to prevent transmission of PERVs. This article focuses on the molecular aspects of PERV infection in xenotransplantation and reviews the techniques available for the detection of PERV DNA, RNA, reverse transcriptase activity and proteins, and anti-PERV antibodies to enable carrying out these recommendations. These methods could be used to evaluate the risk of PERV transmission in human recipients, enhance the effectiveness and reliability of monitoring procedures, and stimulate discussion on the development of improved, more sensitive methods for the detection of PERVs in the future. PMID:24828841

  6. Human reliability in complex systems: an overview

    International Nuclear Information System (INIS)

    Embrey, D.E.

    1976-07-01

    A detailed analysis is presented of the main conceptual background underlying the areas of human reliability and human error. The concept of error is examined and generalized to that of human reliability, and some of the practical and methodological difficulties of reconciling the different standpoints of the human factors specialist and the engineer discussed. Following a survey of general reviews available on human reliability, quantitative techniques for prediction of human reliability are considered. An in-depth critical analysis of the various quantitative methods is then presented, together with the data bank requirements for human reliability prediction. Reliability considerations in process control and nuclear plant, and also areas of design, maintenance, testing and emergency situations are discussed. The effects of stress on human reliability are analysed and methods of minimizing these effects discussed. Finally, a summary is presented and proposals for further research are set out. (author)

  7. Convergent evolution of ribonuclease h in LTR retrotransposons and retroviruses.

    Science.gov (United States)

    Ustyantsev, Kirill; Novikova, Olga; Blinov, Alexander; Smyshlyaev, Georgy

    2015-05-01

    Ty3/Gypsy long terminals repeat (LTR) retrotransposons are structurally and phylogenetically close to retroviruses. Two notable structural differences between these groups of genetic elements are 1) the presence in retroviruses of an additional envelope gene, env, which mediates infection, and 2) a specific dual ribonuclease H (RNH) domain encoded by the retroviral pol gene. However, similar to retroviruses, many Ty3/Gypsy LTR retrotransposons harbor additional env-like genes, promoting concepts of the infective mode of these retrotransposons. Here, we provide a further line of evidence of similarity between retroviruses and some Ty3/Gypsy LTR retrotransposons. We identify that, together with their additional genes, plant Ty3/Gypsy LTR retrotransposons of the Tat group have a second RNH, as do retroviruses. Most importantly, we show that the resulting dual RNHs of Tat LTR retrotransposons and retroviruses emerged independently, providing strong evidence for their convergent evolution. The convergent resemblance of Tat LTR retrotransposons and retroviruses may indicate similar selection pressures acting on these diverse groups of elements and reveal potential evolutionary constraints on their structure. We speculate that dual RNH is required to accelerate retrotransposon evolution through increased rates of strand transfer events and subsequent recombination events. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  8. Mycobacterium abscessus Complex Infections in Humans.

    Science.gov (United States)

    Lee, Meng-Rui; Sheng, Wang-Huei; Hung, Chien-Ching; Yu, Chong-Jen; Lee, Li-Na; Hsueh, Po-Ren

    2015-09-01

    Mycobacterium abscessus complex comprises a group of rapidly growing, multidrug-resistant, nontuberculous mycobacteria that are responsible for a wide spectrum of skin and soft tissue diseases, central nervous system infections, bacteremia, and ocular and other infections. M. abscessus complex is differentiated into 3 subspecies: M. abscessus subsp. abscessus, M. abscessus subsp. massiliense, and M. abscessus subsp. bolletii. The 2 major subspecies, M. abscessus subsp. abscessus and M. abscessus subsp. massiliense, have different erm(41) gene patterns. This gene provides intrinsic resistance to macrolides, so the different patterns lead to different treatment outcomes. M. abscessus complex outbreaks associated with cosmetic procedures and nosocomial transmissions are not uncommon. Clarithromycin, amikacin, and cefoxitin are the current antimicrobial drugs of choice for treatment. However, new treatment regimens are urgently needed, as are rapid and inexpensive identification methods and measures to contain nosocomial transmission and outbreaks.

  9. Host-virus interactions of mammalian endogenous retroviruses

    OpenAIRE

    Farkašová, Helena

    2017-01-01

    Endogenous retroviruses (ERVs) originate by germline infection and subsequent mendelian inheritance of their exogenous counterparts. With notable exceptions, all mammalian ERVs are evolutionarily old and fixed in the population of its host species. Some groups of retroviruses were believed not to be able to form endogenous copies. We discovered an additional endogenous Lentivirus and a first endogenous Deltaretrovirus. Both of these groups were previously considered unable to form endogenous ...

  10. Impact of cell culture process changes on endogenous retrovirus expression.

    Science.gov (United States)

    Brorson, Kurt; De Wit, Christina; Hamilton, Elizabeth; Mustafa, Mehnaz; Swann, Patrick G; Kiss, Robert; Taticek, Ron; Polastri, Gian; Stein, Kathryn E; Xu, Yuan

    2002-11-05

    Cell culture process changes (e.g., changes in scale, medium formulation, operational conditions) and cell line changes are common during the development life cycle of a therapeutic protein. To ensure that the impact of such process changes on product quality and safety is minimal, it is standard practice to compare critical product quality and safety attributes before and after the changes. One potential concern introduced by cell culture process improvements is the possibility of increased endogenous retrovirus expression to a level above the clearance capability of the subsequent purification process. To address this, retrovirus expression was measured in scaled down and full production scaled Chinese hamster ovary (CHO) cell cultures of four monoclonal antibodies and one recombinant protein before and after process changes. Two highly sensitive, quantitative (Q)-PCR-based assays were used to measure endogenous retroviruses. It is shown that cell culture process changes that primarily alter media components, nutrient feed volume, seed density, cell bank source (i.e., master cell bank vs. working cell bank), and vial size, or culture scale, singly or in combination, do not impact the rate of retrovirus expression to an extent greater than the variability of the Q-PCR assays (0.2-0.5 log(10)). Cell culture changes that significantly alter the metabolic state of the cells and/or rates of protein expression (e.g., pH and temperature shifts, NaButyrate addition) measurably impact the rate of retrovirus synthesis (up to 2 log(10)). The greatest degree of variation in endogenous retrovirus expression was observed between individual cell lines (up to 3 log(10)). These data support the practice of measuring endogenous retrovirus output for each new cell line introduced into manufacturing or after process changes that significantly increase product-specific productivity or alter the metabolic state, but suggest that reassessment of retrovirus expression after other

  11. Complex Human Dynamics From Mind to Societies

    CERN Document Server

    Winkowska-Nowak, Katarzyna; Brée, David

    2013-01-01

    This book, edited and authored by a closely collaborating network of social scientists and psychologists, recasts typical research topics in these fields into the language of nonlinear, dynamic and complex systems. The aim is to provide scientists with different backgrounds - physics, applied mathematics and computer sciences - with the opportunity to apply the tools of their trade to an altogether new range of possible applications. At the same time, this book will serve as a first reference for a new generation of social scientists and psychologists wishing to familiarize themselves with the new methodology and the "thinking in complexity".

  12. A novel recombinant retrovirus in the genomes of modern birds combines features of avian and mammalian retroviruses.

    Science.gov (United States)

    Henzy, Jamie E; Gifford, Robert J; Johnson, Welkin E; Coffin, John M

    2014-03-01

    Endogenous retroviruses (ERVs) represent ancestral sequences of modern retroviruses or their extinct relatives. The majority of ERVs cluster alongside exogenous retroviruses into two main groups based on phylogenetic analyses of the reverse transcriptase (RT) enzyme. Class I includes gammaretroviruses, and class II includes lentiviruses and alpha-, beta-, and deltaretroviruses. However, analyses of the transmembrane subunit (TM) of the envelope glycoprotein (env) gene result in a different topology for some retroviruses, suggesting recombination events in which heterologous env sequences have been acquired. We previously demonstrated that the TM sequences of five of the six genera of orthoretroviruses can be divided into three types, each of which infects a distinct set of vertebrate classes. Moreover, these classes do not always overlap the host range of the associated RT classes. Thus, recombination resulting in acquisition of a heterologous env gene could in theory facilitate cross-species transmissions across vertebrate classes, for example, from mammals to reptiles. Here we characterized a family of class II avian ERVs, "TgERV-F," that acquired a mammalian gammaretroviral env sequence. Although TgERV-F clusters near a sister clade to alpharetroviruses, its genome also has some features of betaretroviruses. We offer evidence that this unusual recombinant has circulated among several avian orders and may still have infectious members. In addition to documenting the infection of a nongalliform avian species by a mammalian retrovirus, TgERV-F also underscores the importance of env sequences in reconstructing phylogenies and supports a possible role for env swapping in allowing cross-species transmissions across wide taxonomic distances. Retroviruses can sometimes acquire an envelope gene (env) from a distantly related retrovirus. Since env is a key determinant of host range, such an event affects the host range of the recombinant virus and can lead to the creation

  13. Complex epidemiological approach to human mutagenesis

    International Nuclear Information System (INIS)

    Czeizel, A.

    1980-01-01

    The main characteristics of the epidemiological approach are summarised and the criteria discussed for the adoption of this approach for the detection of human mutagenesis. Mutation monitoring systems are described and results of epidemiological studies of higher risk populations are presented. (C.F.)

  14. A survey of endogenous retrovirus (ERV) sequences in the vicinity of multiple sclerosis (MS)-associated single nucleotide polymorphisms (SNPs).

    Science.gov (United States)

    Brütting, Christine; Emmer, Alexander; Kornhuber, Malte; Staege, Martin S

    2016-08-01

    Although multiple sclerosis (MS) is one of the most common central nervous system diseases in young adults, little is known about its etiology. Several human endogenous retroviruses (ERVs) are considered to play a role in MS. We are interested in which ERVs can be identified in the vicinity of MS associated genetic marker to find potential initiators of MS. We analysed the chromosomal regions surrounding 58 single nucleotide polymorphisms (SNPs) that are associated with MS identified in one of the last major genome wide association studies. We scanned these regions for putative endogenous retrovirus sequences with large open reading frames (ORFs). We observed that more retrovirus-related putative ORFs exist in the relatively close vicinity of SNP marker indices in multiple sclerosis compared to control SNPs. We found very high homologies to HERV-K, HCML-ARV, XMRV, Galidia ERV, HERV-H/env62 and XMRV-like mouse endogenous retrovirus mERV-XL. The associated genes (CYP27B1, CD6, CD58, MPV17L2, IL12RB1, CXCR5, PTGER4, TAGAP, TYK2, ICAM3, CD86, GALC, GPR65 as well as the HLA DRB1*1501) are mainly involved in the immune system, but also in vitamin D regulation. The most frequently detected ERV sequences are related to the multiple sclerosis-associated retrovirus, the human immunodeficiency virus 1, HERV-K, and the Simian foamy virus. Our data shows that there is a relation between MS associated SNPs and the number of retroviral elements compared to control. Our data identifies new ERV sequences that have not been associated with MS, so far.

  15. The human RNase MRP complex : composition, assembly and role in human disease

    NARCIS (Netherlands)

    Eenennaam, Hans van

    2002-01-01

    Not all RNA molecules in human cells are being translated into proteins. Some of them function in binding proteins, thereby forming so-called RNA-protein complexes. The RNase MRP complex is an example of such an RNA-protein complex. In this thesis two new protein components of the human RNase MRP

  16. Complex human mobility dynamics on a network

    International Nuclear Information System (INIS)

    Szell, M.

    2010-01-01

    Massive multiplayer online games provide a fascinating new way of observing hundreds of thousands of simultaneously interacting individuals engaged in virtual socio-economic activities. We have compiled a data set consisting of practically all actions of all players over a period of four years from an online game played by over 350,000 people. The universe of this online world is a lattice-like network on which players move in order to interact with other players. We focus on the mobility of human players on this network over a time-period of 500 days. We take a number of mobility measurements and compare them with measures of simulated random walkers on the same topology. Mobility of players is sub-diffusive - the mean squared displacement follows a power law with exponent 0.4 - and significantly deviates from mobility patterns of random walkers. Mean first passage times and transition counts relate via a power-law with slope -1/3. We compare our results with studies where human mobility was measured via mobile phone data and find striking similarities. (author)

  17. Clinical Aspects of Feline Retroviruses: A Review

    Directory of Open Access Journals (Sweden)

    Katrin Hartmann

    2012-10-01

    Full Text Available Feline leukemia virus (FeLV and feline immunodeficiency virus (FIV are retroviruses with global impact on the health of domestic cats. The two viruses differ in their potential to cause disease. FeLV is more pathogenic, and was long considered to be responsible for more clinical syndromes than any other agent in cats. FeLV can cause tumors (mainly lymphoma, bone marrow suppression syndromes (mainly anemia, and lead to secondary infectious diseases caused by suppressive effects of the virus on bone marrow and the immune system. Today, FeLV is less commonly diagnosed than in the previous 20 years; prevalence has been decreasing in most countries. However, FeLV importance may be underestimated as it has been shown that regressively infected cats (that are negative in routinely used FeLV tests also can develop clinical signs. FIV can cause an acquired immunodeficiency syndrome that increases the risk of opportunistic infections, neurological diseases, and tumors. In most naturally infected cats, however, FIV itself does not cause severe clinical signs, and FIV-infected cats may live many years without any health problems. This article provides a review of clinical syndromes in progressively and regressively FeLV-infected cats as well as in FIV-infected cats.

  18. Biology and evolution of the endogenous koala retrovirus.

    Science.gov (United States)

    Tarlinton, R; Meers, J; Young, P

    2008-11-01

    Although endogenous retroviruses are ubiquitous features of all mammalian genomes, the process of initial germ line invasion and subsequent inactivation from a pathogenic element has not yet been observed in a wild species. Koala retrovirus (KoRV) provides a unique opportunity to study this process of endogenisation in action as it still appears to be spreading through the koala population. Ongoing expression of the endogenous sequence and consequent high levels of viraemia have been linked to neoplasia and immunosuppression in koalas. This apparently recent invader of the koala genome shares a remarkably close sequence relationship with the pathogenic exogenous Gibbon ape leukaemia virus (GALV), and comparative analyses of KoRV and GALVare helping to shed light on how retroviruses in general adapt to a relatively benign or at least less pathogenic existence within a new host genome. (Part of a multi-author review).

  19. Small finger protein of avian and murine retroviruses has nucleic acid annealing activity and positions the replication primer tRNA onto genomic RNA.

    Science.gov (United States)

    Prats, A C; Sarih, L; Gabus, C; Litvak, S; Keith, G; Darlix, J L

    1988-06-01

    Retrovirus virions carry a diploid genome associated with a large number of small viral finger protein molecules which are required for encapsidation. Our present results show that finger protein p12 of Rous sarcoma virus (RSV) and p10 of murine leukaemia virus (MuLV) positions replication primer tRNA on the replication initiation site (PBS) at the 5' end of the RNA genome. An RSV mutant with a Val-Pro insertion in the finger motif of p12 is able to partially encapsidate genomic RNA but is not infectious because mutated p12 is incapable of positioning the replication primer, tRNATrp. Since all known replication competent retroviruses, and the plant virus CaMV, code for finger proteins analogous to RSV p12 or MuLV p10, the initial stage of reverse transcription in avian, mammalian and human retroviruses and in CaMV is probably controlled in an analogous way.

  20. Characterization of the human GARP (Golgi associated retrograde protein) complex

    International Nuclear Information System (INIS)

    Liewen, Heike; Meinhold-Heerlein, Ivo; Oliveira, Vasco; Schwarzenbacher, Robert; Luo Guorong; Wadle, Andreas; Jung, Martin; Pfreundschuh, Michael; Stenner-Liewen, Frank

    2005-01-01

    The Golgi associated retrograde protein complex (GARP) or Vps fifty-three (VFT) complex is part of cellular inter-compartmental transport systems. Here we report the identification of the VFT tethering factor complex and its interactions in mammalian cells. Subcellular fractionation shows that human Vps proteins are found in the smooth membrane/Golgi fraction but not in the cytosol. Immunostaining of human Vps proteins displays a vesicular distribution most concentrated at the perinuclear envelope. Co-staining experiments with endosomal markers imply an endosomal origin of these vesicles. Significant accumulation of VFT complex positive endosomes is found in the vicinity of the Trans Golgi Network area. This is in accordance with a putative role in Golgi associated transport processes. In Saccharomyces cerevisiae, GARP is the main effector of the small GTPase Ypt6p and interacts with the SNARE Tlg1p to facilitate membrane fusion. Accordingly, the human homologue of Ypt6p, Rab6, specifically binds hVps52. In human cells, the 'orphan' SNARE Syntaxin 10 is the genuine binding partner of GARP mediated by hVps52. This reveals a previously unknown function of human Syntaxin 10 in membrane docking and fusion events at the Golgi. Taken together, GARP shows significant conservation between various species but diversification and specialization result in important differences in human cells

  1. Koala retroviruses: characterization and impact on the life of koalas

    OpenAIRE

    Denner, Joachim; Young, Paul R

    2013-01-01

    Koala retroviruses (KoRV) have been isolated from wild and captive koalas in Australia as well as from koala populations held in zoos in other countries. They are members of the genus Gammaretrovirus, are most closely related to gibbon ape leukemia virus (GaLV), feline leukemia virus (FeLV) and porcine endogenous retrovirus (PERV) and are likely the result of a relatively recent trans-species transmission from rodents or bats. The first KoRV to be isolated, KoRV-A, is widely distributed in th...

  2. Heterogeneous pathogenicity of retroviruses: lessons from birds, primates, and rodents

    Czech Academy of Sciences Publication Activity Database

    Svoboda, Jan; Geryk, Josef; Elleder, Daniel

    2003-01-01

    Roč. 87, - (2003), s. 59-126 ISSN 0065-230X R&D Projects: GA ČR GV312/96/K205; GA ČR GA524/01/0866; GA ČR GA204/01/0632; GA ČR GA204/02/0407 Institutional research plan: CEZ:AV0Z5052915 Keywords : pathogenicity of retroviruses * heterotransmission of retroviruses Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.938, year: 2003

  3. Circular chromatin complexes in human lymphocytes high-resolution autoradiography

    International Nuclear Information System (INIS)

    Becak, M.L.; Fukuda-Pizzocaro, K.; Santos, R. de C.S. dos; Brunner, O.

    1985-01-01

    Transcriptionally active chromatin fibers were observed in chromosomes presenting the loops/scaffold configuration. The active fibers showed altered nucleosomes and presented multiforked aspects which led to the formation of ring complexes. The ribonucleoprotein transcripts (RNP) appeared as networks of 0.1 μm or multiples tandemly disposed along the fiber. It is suggested that the ring complexes belong to the human genome. The possibility that these circular structures come from a prokaryote is also considered. (author) [pt

  4. Role of nucleocytoplasmic RNA transport during the life cycle of retroviruses

    Directory of Open Access Journals (Sweden)

    Hisatoshi eShida

    2012-05-01

    Full Text Available Retroviruses have evolved mechanisms for transporting their intron-containing RNAs (including genomic and messenger RNAs, which encode virion components from the nucleus to the cytoplasm of the infected cell. Human retroviruses, such as human immunodeficiency virus (HIV and human T cell leukemia virus type 1 (HTLV-1, encode the regulatory proteins Rev and Rex, which form a bridge between the viral RNA and the export receptor CRM1. Recent studies show that these transport systems are not only involved in RNA export, but also in the encapsidation of genomic RNA; furthermore, they influence subsequent events in the cytoplasm, including the translation of the cognate mRNA, transport of Gag proteins to the plasma membrane, and the formation of virus particles. Moreover, the mode of interaction between the viral and cellular RNA transport machinery underlies the species-specific propagation of HIV-1 and HTLV-1, forming the basis for constructing animal models of infection. This review article discusses recent progress regarding these issues.

  5. The role of BST2/tetherin in infection with the feline retroviruses

    Science.gov (United States)

    Dietrich, Isabelle; Hosie, Margaret J.; Willett, Brian J.

    2014-01-01

    The recently identified host restriction factor tetherin (BST-2, CD317) potently inhibits the release of nascent retrovirus particles from infected cells. Recently, we reported the identification and characterization of tetherin as a novel feline retroviral restriction factor. Based on homology to human tetherin we identified a putative tetherin gene in the genome of the domestic cat (Felis catus) which was found to be expressed in different feline cell lines both prior to and post treatment with either type I or type II interferon (IFN). The predicted structure of feline tetherin (feTHN) was that of a type II single-pass transmembrane protein encoding an N-terminal transmembrane anchor, central predicted coiled-coil bearing extracellular domain to promote dimerization, and a C-terminal GPI-anchor, consistent with conservation of structure between human and feline tetherin. FeTHN displayed potent inhibition of feline immunodeficiency virus (FIV) and human immunodeficiency virus type 1 (HIV-1) particle release in single-cycle replication assays. Notably, feTHN activity was resistant to antagonism by HIV-1 Vpu. However, stable ectopic expression of feTHN mRNA in different feline cell lines had no inhibitory effect on the growth of diverse primary or cell culture-adapted strains of FIV. Hence, whereas feline tetherin efficiently blocks viral particle release in single-cycle replication assays, it might not prevent dissemination of feline retroviruses in vivo. PMID:21715020

  6. Characterizing novel endogenous retroviruses from genetic variation inferred from short sequence reads

    DEFF Research Database (Denmark)

    Mourier, Tobias; Mollerup, Sarah; Vinner, Lasse

    2015-01-01

    From Illumina sequencing of DNA from brain and liver tissue from the lion, Panthera leo, and tumor samples from the pike-perch, Sander lucioperca, we obtained two assembled sequence contigs with similarity to known retroviruses. Phylogenetic analyses suggest that the pike-perch retrovirus belongs...... to the epsilonretroviruses, and the lion retrovirus to the gammaretroviruses. To determine if these novel retroviral sequences originate from an endogenous retrovirus or from a recently integrated exogenous retrovirus, we assessed the genetic diversity of the parental sequences from which the short Illumina reads...

  7. The population history of endogenous retroviruses in mule deer (Odocoileus heminous)

    Science.gov (United States)

    Kamath, Pauline L.; Elleder, Daniel; Bao, Le; Cross, Paul C.; Powell, John H.; Poss, Mary

    2013-01-01

    Mobile elements are powerful agents of genomic evolution and can be exceptionally informative markers for investigating species and population-level evolutionary history. While several studies have utilized retrotransposon-based insertional polymorphisms to resolve phylogenies, few population studies exist outside of humans. Endogenous retroviruses are LTR-retrotransposons derived from retroviruses that have become stably integrated in the host genome during past infections and transmitted vertically to subsequent generations. They offer valuable insight into host-virus co-evolution and a unique perspective on host evolutionary history because they integrate into the genome at a discrete point in time. We examined the evolutionary history of a cervid endogenous gammaretrovirus (CrERVγ) in mule deer (Odocoileus hemionus). We sequenced 14 CrERV proviruses (CrERV-in1 to -in14), and examined the prevalence and distribution of 13 proviruses in 262 deer among 15 populations from Montana, Wyoming, and Utah. CrERV absence in white-tailed deer (O. virginianus), identical 5′ and 3′ long terminal repeat (LTR) sequences, insertional polymorphism, and CrERV divergence time estimates indicated that most endogenization events occurred within the last 200000 years. Population structure inferred from CrERVs (F ST = 0.008) and microsatellites (θ = 0.01) was low, but significant, with Utah, northwestern Montana, and a Helena herd being particularly differentiated. Clustering analyses indicated regional structuring, and non-contiguous clustering could often be explained by known translocations. Cluster ensemble results indicated spatial localization of viruses, specifically in deer from northeastern and western Montana. This study demonstrates the utility of endogenous retroviruses to elucidate and provide novel insight into both ERV evolutionary history and the history of contemporary host populations.

  8. The population history of endogenous retroviruses in mule deer (Odocoileus hemionus).

    Science.gov (United States)

    Kamath, Pauline L; Elleder, Daniel; Bao, Le; Cross, Paul C; Powell, John H; Poss, Mary

    2014-01-01

    Mobile elements are powerful agents of genomic evolution and can be exceptionally informative markers for investigating species and population-level evolutionary history. While several studies have utilized retrotransposon-based insertional polymorphisms to resolve phylogenies, few population studies exist outside of humans. Endogenous retroviruses are LTR-retrotransposons derived from retroviruses that have become stably integrated in the host genome during past infections and transmitted vertically to subsequent generations. They offer valuable insight into host-virus co-evolution and a unique perspective on host evolutionary history because they integrate into the genome at a discrete point in time. We examined the evolutionary history of a cervid endogenous gammaretrovirus (CrERVγ) in mule deer (Odocoileus hemionus). We sequenced 14 CrERV proviruses (CrERV-in1 to -in14), and examined the prevalence and distribution of 13 proviruses in 262 deer among 15 populations from Montana, Wyoming, and Utah. CrERV absence in white-tailed deer (O. virginianus), identical 5' and 3' long terminal repeat (LTR) sequences, insertional polymorphism, and CrERV divergence time estimates indicated that most endogenization events occurred within the last 200000 years. Population structure inferred from CrERVs (F ST = 0.008) and microsatellites (θ = 0.01) was low, but significant, with Utah, northwestern Montana, and a Helena herd being particularly differentiated. Clustering analyses indicated regional structuring, and non-contiguous clustering could often be explained by known translocations. Cluster ensemble results indicated spatial localization of viruses, specifically in deer from northeastern and western Montana. This study demonstrates the utility of endogenous retroviruses to elucidate and provide novel insight into both ERV evolutionary history and the history of contemporary host populations.

  9. Proliferation of endogenous retroviruses in the early stages of a host germ line invasion.

    Science.gov (United States)

    Ishida, Yasuko; Zhao, Kai; Greenwood, Alex D; Roca, Alfred L

    2015-01-01

    Endogenous retroviruses (ERVs) comprise 8% of the human genome and are common in all vertebrate genomes. The only retrovirus known to be currently transitioning from exogenous to endogenous form is the koala retrovirus (KoRV), making koalas (Phascolarctos cinereus) ideal for examining the early stages of retroviral endogenization. To distinguish endogenous from exogenous KoRV proviruses, we isolated koala genomic regions flanking KoRV integration sites. In three wild southern Australian koalas, there were fewer KoRV loci than in three captive Queensland koalas, consistent with reports that southern Australian koalas carry fewer KoRVs. Of 39 distinct KoRV proviral loci examined in a sire-dam-progeny triad, all proved to be vertically transmitted and endogenous; none was exogenous. Of the 39 endogenous KoRVs (enKoRVs), only one was present in the genomes of both the sire and the dam, suggesting that, at this early stage in the retroviral invasion of a host germ line, very large numbers of ERVs have proliferated at very low frequencies in the koala population. Sequence divergence between the 5'- and 3'-long terminal repeats (LTRs) of a provirus can be used as a molecular clock. Within each of ten enKoRVs, the 5'-LTR sequence was identical to the 3'-LTR sequence, suggesting a maximum age for enKoRV invasion of the koala germ line of approximately 22,200-49,900 years ago, although a much younger age is possible. Across the ten proviruses, seven LTR haplotypes were detected, indicating that at least seven different retroviral sequences had entered the koala germ line. © The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  10. Proliferation of Endogenous Retroviruses in the Early Stages of a Host Germ Line Invasion

    Science.gov (United States)

    Ishida, Yasuko; Zhao, Kai; Greenwood, Alex D.; Roca, Alfred L.

    2015-01-01

    Endogenous retroviruses (ERVs) comprise 8% of the human genome and are common in all vertebrate genomes. The only retrovirus known to be currently transitioning from exogenous to endogenous form is the koala retrovirus (KoRV), making koalas (Phascolarctos cinereus) ideal for examining the early stages of retroviral endogenization. To distinguish endogenous from exogenous KoRV proviruses, we isolated koala genomic regions flanking KoRV integration sites. In three wild southern Australian koalas, there were fewer KoRV loci than in three captive Queensland koalas, consistent with reports that southern Australian koalas carry fewer KoRVs. Of 39 distinct KoRV proviral loci examined in a sire–dam–progeny triad, all proved to be vertically transmitted and endogenous; none was exogenous. Of the 39 endogenous KoRVs (enKoRVs), only one was present in the genomes of both the sire and the dam, suggesting that, at this early stage in the retroviral invasion of a host germ line, very large numbers of ERVs have proliferated at very low frequencies in the koala population. Sequence divergence between the 5′- and 3′-long terminal repeats (LTRs) of a provirus can be used as a molecular clock. Within each of ten enKoRVs, the 5′-LTR sequence was identical to the 3′-LTR sequence, suggesting a maximum age for enKoRV invasion of the koala germ line of approximately 22,200–49,900 years ago, although a much younger age is possible. Across the ten proviruses, seven LTR haplotypes were detected, indicating that at least seven different retroviral sequences had entered the koala germ line. PMID:25261407

  11. Peak Oil and the Everyday Complexity of Human Progress Narratives

    Directory of Open Access Journals (Sweden)

    John C. Pruit

    2012-11-01

    Full Text Available The “big” story of human progress has polarizing tendencies featuring the binary options of progress or decline. I consider human progress narratives in the context of everyday life. Analysis of the “little” stories from two narrative environments focusing on peak oil offers a more complex picture of the meaning and contours of the narrative. I consider the impact of differential blog site commitments to peak oil perspectives and identify five narrative types culled from two narrative dimensions. I argue that the lived experience complicates human progress narratives, which is no longer an either/or proposition.

  12. Investigation of Endogenous Retrovirus Sequences in the Neighborhood of Genes Up-regulated in a Neuroblastoma Model after Treatment with Hypoxia-Mimetic Cobalt Chloride.

    Science.gov (United States)

    Brütting, Christine; Narasimhan, Harini; Hoffmann, Frank; Kornhuber, Malte E; Staege, Martin S; Emmer, Alexander

    2018-01-01

    Human endogenous retroviruses (ERVs) have been found to be associated with different diseases, e.g., multiple sclerosis (MS). Most human ERVs integrated in our genome are not competent to replicate and these sequences are presumably silent. However, transcription of human ERVs can be reactivated, e.g., by hypoxia. Interestingly, MS has been linked to hypoxia since decades. As some patterns of demyelination are similar to white matter ischemia, hypoxic damage is discussed. Therefore, we are interested in the association between hypoxia and ERVs. As a model, we used human SH-SY5Y neuroblastoma cells after treatment with the hypoxia-mimetic cobalt chloride and analyzed differences in the gene expression profiles in comparison to untreated cells. The vicinity of up-regulated genes was scanned for endogenous retrovirus-derived sequences. Five genes were found to be strongly up-regulated in SH-SY5Y cells after treatment with cobalt chloride: clusterin, glutathione peroxidase 3, insulin-like growth factor 2, solute carrier family 7 member 11, and neural precursor cell expressed developmentally down-regulated protein 9. In the vicinity of these genes we identified large (>1,000 bp) open reading frames (ORFs). Most of these ORFs showed only low similarities to proteins from retro-transcribing viruses. However, we found very high similarity between retrovirus envelope sequences and a sequence in the vicinity of neural precursor cell expressed developmentally down-regulated protein 9. This sequence encodes the human endogenous retrovirus group FRD member 1, the encoded protein product is called syncytin 2. Transfection of syncytin 2 into the well-characterized Ewing sarcoma cell line A673 was not able to modulate the low immunostimulatory activity of this cell line. Future research is needed to determine whether the identified genes and the human endogenous retrovirus group FRD member 1 might play a role in the etiology of MS.

  13. The dominating macromolecular complex of human gallbladder bile

    NARCIS (Netherlands)

    Verschure, J.C.M.; Mijnlieff, P.F.

    The solutes of human gall bladder bile appear to exist mainly in the form of a complex macromolecule, formed around a nucleus of lipoprotein. The existence of this macromolecule was demonstrated by paper electrophoresis1, free electrophoresis and ultracentrifuge experiments. The molecular weight of

  14. Expression and function of endogenous retroviruses in the placenta.

    Science.gov (United States)

    Denner, Joachim

    2016-01-01

    Although the expression of endogenous retroviruses in the placenta of numerous species was observed a long time ago, their physiological function during gestation was demonstrated only very recently. Expression of retroviral envelope proteins, also called syncytins, in the placenta allows generation of the multinuclear syncytiotrophoblast as an outer cellular layer of the placenta by fusion of the trophoblast cells. This fusion process is crucial for the development of the placenta and for successful pregnancy. It is still unclear whether the immunosuppressive properties of the transmembrane envelope protein of the endogenous retroviruses expressed in the placenta contribute to immunosuppression to prevent the rejection of the semiallotransplant embryo. The presence of placenta cells expressing retroviral envelope proteins surrounded by immune cells deep in the maternal tissue supports an immunosuppressive function. It is important to emphasize that during evolution different species utilized ('enslaved') different endogenous retroviruses and that two or more endogenous retroviruses are involved in placentogenesis in each species. © 2016 APMIS. Published by John Wiley & Sons Ltd.

  15. Functional hierarchy of two L domains in porcine endogenous retrovirus (PERV) that influence release and infectivity

    International Nuclear Information System (INIS)

    Marcucci, Katherine T.; Martina, Yuri; Harrison, Frank; Wilson, Carolyn A.; Salomon, Daniel R.

    2008-01-01

    The porcine endogenous retrovirus (PERV) Gag protein contains two late (L) domain motifs, PPPY and P(F/S)AP. Using viral release assays we demonstrate that PPPY is the dominant L domain involved in PERV release. PFAP represents a novel retroviral L domain variant and is defined by abnormal viral assembly phenotypes visualized by electron microscopy and attenuation of early PERV release as measured by viral genomes. PSAP is functionally dominant over PFAP in early PERV release. PSAP virions are 3.5-fold more infectious in vitro by TCID 50 and in vivo results in more RNA positive tissues and higher levels of proviral DNA using our human PERV-A receptor (HuPAR-2) transgenic mouse model [Martina, Y., Marcucci, K.T., Cherqui, S., Szabo, A., Drysdale, T., Srinivisan, U., Wilson, C.A., Patience, C., Salomon, D.R., 2006. Mice transgenic for a human porcine endogenous retrovirus receptor are susceptible to productive viral infection. J. Virol. 80 (7), 3135-3146]. The functional hierarchies displayed by PERV L domains, demonstrates that L domain selection in viral evolution exists to promote efficient viral assembly, release and infectivity in the virus-host context

  16. Wolbachia influences the maternal transmission of the gypsy endogenous retrovirus in Drosophila melanogaster.

    Science.gov (United States)

    Touret, Franck; Guiguen, François; Terzian, Christophe

    2014-09-02

    The endosymbiotic bacteria of the genus Wolbachia are present in most insects and are maternally transmitted through the germline. Moreover, these intracellular bacteria exert antiviral activity against insect RNA viruses, as in Drosophila melanogaster, which could explain the prevalence of Wolbachia bacteria in natural populations. Wolbachia is maternally transmitted in D. melanogaster through a mechanism that involves distribution at the posterior pole of mature oocytes and then incorporation into the pole cells of the embryos. In parallel, maternal transmission of several endogenous retroviruses is well documented in D. melanogaster. Notably, gypsy retrovirus is expressed in permissive follicle cells and transferred to the oocyte and then to the offspring by integrating into their genomes. Here, we show that the presence of Wolbachia wMel reduces the rate of gypsy insertion into the ovo gene. However, the presence of Wolbachia does not modify the expression levels of gypsy RNA and envelope glycoprotein from either permissive or restrictive ovaries. Moreover, Wolbachia affects the pattern of distribution of the retroviral particles and the gypsy envelope protein in permissive follicle cells. Altogether, our results enlarge the knowledge of the antiviral activity of Wolbachia to include reducing the maternal transmission of endogenous retroviruses in D. melanogaster. Animals have established complex relationships with bacteria and viruses that spread horizontally among individuals or are vertically transmitted, i.e., from parents to offspring. It is well established that members of the genus Wolbachia, maternally inherited symbiotic bacteria present mainly in arthropods, reduce the replication of several RNA viruses transmitted horizontally. Here, we demonstrate for the first time that Wolbachia diminishes the maternal transmission of gypsy, an endogenous retrovirus in Drosophila melanogaster. We hypothesize that gypsy cannot efficiently integrate into the germ

  17. Architecture of the human mTORC2 core complex.

    Science.gov (United States)

    Stuttfeld, Edward; Aylett, Christopher Hs; Imseng, Stefan; Boehringer, Daniel; Scaiola, Alain; Sauer, Evelyn; Hall, Michael N; Maier, Timm; Ban, Nenad

    2018-02-09

    The mammalian target of rapamycin (mTOR) is a key protein kinase controlling cellular metabolism and growth. It is part of the two structurally and functionally distinct multiprotein complexes mTORC1 and mTORC2. Dysregulation of mTOR occurs in diabetes, cancer and neurological disease. We report the architecture of human mTORC2 at intermediate resolution, revealing a conserved binding site for accessory proteins on mTOR and explaining the structural basis for the rapamycin insensitivity of the complex. © 2018, Stuttfeld et al.

  18. Human Health Risk Assessment of Trichloroethylene from Industrial Complex A

    OpenAIRE

    Sin, Saemi; Byeon, Sang-Hoon

    2012-01-01

    This study investigated the human health risks of trichloroethylene from Industrial Complex A. The excessive carcinogenic risks for central tendency exposure were 1.40 ? 10?5 for male and female residents in the vicinity of Industrial Complex A. The excessive cancers risk for reasonable maximum exposure were 2.88 ? 10?5 and 1.97 ? 10?5 for males and females, respectively. These values indicate that there are potential cancer risks for exposure to these concentrations. The hazard index for cen...

  19. A New Approach to Establish a Cell Line with Reduced Risk of Endogenous Retroviruses

    Science.gov (United States)

    Fukuma, Aiko; Yoshikawa, Rokusuke; Miyazawa, Takayuki; Yasuda, Jiro

    2013-01-01

    Endogenous retroviruses (ERVs) are integrated as DNA proviruses in the genomes of all mammalian species. Several ERVs are replication-competent and produced as fully infectious viruses from host cell. Thus, live-attenuated vaccines and biological substances have been prepared using the cell lines which may produce ERV. Indeed, we recently reported that several commercial live-attenuated vaccines for pets were contaminated with the infectious feline endogenous retrovirus, RD-114. In this study, to establish a cell line for vaccine manufacture with reduced risk of ERVs, we generated a cell line stably expressing human tetherin (Teth-CRFK cells). The release of infectious ERV from Teth-CRFK cells was suppressed to undetectable levels, while the production of parvovirus in Teth-CRFK cells was similar to that in parental CRFK cells. These observations suggest that Teth-CRFK cells will be useful as a cell line for the manufacture of live-attenuated vaccines or biological substances with reduced risk of ERV. PMID:23585909

  20. Computational Evaluation of the Strict Master and Random Template Models of Endogenous Retrovirus Evolution

    Science.gov (United States)

    Nascimento, Fabrícia F.; Rodrigo, Allen G.

    2016-01-01

    Transposable elements (TEs) are DNA sequences that are able to replicate and move within and between host genomes. Their mechanism of replication is also shared with endogenous retroviruses (ERVs), which are also a type of TE that represent an ancient retroviral infection within animal genomes. Two models have been proposed to explain TE proliferation in host genomes: the strict master model (SMM), and the random template (or transposon) model (TM). In SMM only a single copy of a given TE lineage is able to replicate, and all other genomic copies of TEs are derived from that master copy. In TM, any element of a given family is able to replicate in the host genome. In this paper, we simulated ERV phylogenetic trees under variations of SMM and TM. To test whether current phylogenetic programs can recover the simulated ERV phylogenies, DNA sequence alignments were simulated and maximum likelihood trees were reconstructed and compared to the simulated phylogenies. Results indicate that visual inspection of phylogenetic trees alone can be misleading. However, if a set of statistical summaries is calculated, we are able to distinguish between models with high accuracy by using a data mining algorithm that we introduce here. We also demonstrate the use of our data mining algorithm with empirical data for the porcine endogenous retrovirus (PERV), an ERV that is able to replicate in human and pig cells in vitro. PMID:27649303

  1. The aliens inside us: HERV-W endogenous retroviruses and multiple sclerosis.

    Science.gov (United States)

    Dolei, Antonina

    2018-01-01

    Two human endogenous retroviruses of the HERV-W family are proposed as multiple sclerosis (MS) co-factors: MS-associated retrovirus (MSRV) and ERVWE1, whose env proteins showed several potentially neuropathogenic features, in vitro and in animal models. Phase II clinical trials against HERV-Wenv are ongoing. HERV-W/MSRV was repeatedly found in MS patients, in striking parallel with MS stages, active/remission phases, and therapy outcome. The HERV-Wenv protein is highly expressed in active MS plaques. Early MSRV presence in spinal fluids predicted worst MS progression 10 years in advance. Effective anti-MS therapies strongly reduced MSRV/Syncytin-1/HERV-W expression. The Epstein-Barr virus (EBV) activates HERV-W/MSRV in vitro and in vivo, in patients with infectious mononucleosis and controls with high anti-EBNA1-IgG titers. Thus, the two main EBV/MS links (infectious mononucleosis and high anti-EBNA1-IgG titers) are paralleled by activation of HERV-W/MSRV. It is hypothesized that EBV may act as initial trigger of future MS, years later, by activating MSRV, which would act as direct neuropathogenic effector, before and during MS.

  2. A new approach to establish a cell line with reduced risk of endogenous retroviruses.

    Directory of Open Access Journals (Sweden)

    Aiko Fukuma

    Full Text Available Endogenous retroviruses (ERVs are integrated as DNA proviruses in the genomes of all mammalian species. Several ERVs are replication-competent and produced as fully infectious viruses from host cell. Thus, live-attenuated vaccines and biological substances have been prepared using the cell lines which may produce ERV. Indeed, we recently reported that several commercial live-attenuated vaccines for pets were contaminated with the infectious feline endogenous retrovirus, RD-114. In this study, to establish a cell line for vaccine manufacture with reduced risk of ERVs, we generated a cell line stably expressing human tetherin (Teth-CRFK cells. The release of infectious ERV from Teth-CRFK cells was suppressed to undetectable levels, while the production of parvovirus in Teth-CRFK cells was similar to that in parental CRFK cells. These observations suggest that Teth-CRFK cells will be useful as a cell line for the manufacture of live-attenuated vaccines or biological substances with reduced risk of ERV.

  3. A new approach to establish a cell line with reduced risk of endogenous retroviruses.

    Science.gov (United States)

    Fukuma, Aiko; Yoshikawa, Rokusuke; Miyazawa, Takayuki; Yasuda, Jiro

    2013-01-01

    Endogenous retroviruses (ERVs) are integrated as DNA proviruses in the genomes of all mammalian species. Several ERVs are replication-competent and produced as fully infectious viruses from host cell. Thus, live-attenuated vaccines and biological substances have been prepared using the cell lines which may produce ERV. Indeed, we recently reported that several commercial live-attenuated vaccines for pets were contaminated with the infectious feline endogenous retrovirus, RD-114. In this study, to establish a cell line for vaccine manufacture with reduced risk of ERVs, we generated a cell line stably expressing human tetherin (Teth-CRFK cells). The release of infectious ERV from Teth-CRFK cells was suppressed to undetectable levels, while the production of parvovirus in Teth-CRFK cells was similar to that in parental CRFK cells. These observations suggest that Teth-CRFK cells will be useful as a cell line for the manufacture of live-attenuated vaccines or biological substances with reduced risk of ERV.

  4. Human health risk assessment of trichloroethylene from industrial complex a.

    Science.gov (United States)

    Sin, Saemi; Byeon, Sang-Hoon

    2012-09-01

    This study investigated the human health risks of trichloroethylene from Industrial Complex A. The excessive carcinogenic risks for central tendency exposure were 1.40 × 10(?5) for male and female residents in the vicinity of Industrial Complex A. The excessive cancers risk for reasonable maximum exposure were 2.88 × 10(?5) and 1.97 × 10(?5) for males and females, respectively. These values indicate that there are potential cancer risks for exposure to these concentrations. The hazard index for central tendency exposure to trichloroethylene was 1.71 for male and female residents. The hazard indexes for reasonable maximum exposure were 3.27 and 2.41 for males and females, respectively. These values were over one, which is equivalent to the threshold value. This result showed that adverse cancer and non-cancer health effects may occur and that some risk management of trichloroethylene from Industrial Complex A was needed.

  5. Environmental layout complexity affects neural activity during navigation in humans.

    Science.gov (United States)

    Slone, Edward; Burles, Ford; Iaria, Giuseppe

    2016-05-01

    Navigating large-scale surroundings is a fundamental ability. In humans, it is commonly assumed that navigational performance is affected by individual differences, such as age, sex, and cognitive strategies adopted for orientation. We recently showed that the layout of the environment itself also influences how well people are able to find their way within it, yet it remains unclear whether differences in environmental complexity are associated with changes in brain activity during navigation. We used functional magnetic resonance imaging to investigate how the brain responds to a change in environmental complexity by asking participants to perform a navigation task in two large-scale virtual environments that differed solely in interconnection density, a measure of complexity defined as the average number of directional choices at decision points. The results showed that navigation in the simpler, less interconnected environment was faster and more accurate relative to the complex environment, and such performance was associated with increased activity in a number of brain areas (i.e. precuneus, retrosplenial cortex, and hippocampus) known to be involved in mental imagery, navigation, and memory. These findings provide novel evidence that environmental complexity not only affects navigational behaviour, but also modulates activity in brain regions that are important for successful orientation and navigation. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  6. Induction of human immunodeficiency virus neutralizing antibodies using fusion complexes.

    Science.gov (United States)

    Zipeto, Donato; Matucci, Andrea; Ripamonti, Chiara; Scarlatti, Gabriella; Rossolillo, Paola; Turci, Marco; Sartoris, Silvia; Tridente, Giuseppe; Bertazzoni, Umberto

    2006-05-01

    Human immunodeficiency virus-1 (HIV-1) infects cells by membrane fusion that is mediated by the envelope proteins gp120/gp41 and the cellular receptors CD4 and CCR5. During this process, some conserved viral epitopes are temporarily exposed and may induce a neutralizing antibody response when fixed in the fusogenic conformation. These transient structures are conserved and may be effective antigens for use in an anti-HIV-1 vaccine. In this study we tested different conditions of preparation of fusion complexes inducing neutralizing antibodies against both R5 and X4 tropic HIV-1 strains. Cell lines expressing HIV-1 gp120/gp41 and CD4-CCR5 were prepared and conditions for producing fusion complexes were tested. Complexes produced at different temperature and fixative combinations were used to immunize mice. Results indicated that (a) fusion complexes prepared at either 21 degrees C, 30 degrees C or 37 degrees C were immunogenic and induced neutralizing antibodies against both R5 and X4 HIV-1 heterologous isolates; (b) after extensive purification of antibodies there was no cytotoxic effect; (c) complexes prepared at 37 degrees C were more immunogenic and induced higher titers of neutralizing antibodies than complexes prepared at either 21 degrees C or 30 degrees C; (d) the fixative used did not affect the titer of neutralizing antibodies except for glutaraldehyde which was ineffective; (e) the neutralizing activity was retained after CD4-CCR5 antibody removal. The production of higher titers of neutralizing antibody with fusion complexes prepared at 37 degrees C, as compared to lower temperatures, may be related to the induction of antibodies against many different conformation intermediates that subsequently act synergistically at different steps in the fusion process.

  7. Susceptibility of recombinant porcine endogenous retrovirus reverse transcriptase to nucleoside and non-nucleoside inhibitors.

    Science.gov (United States)

    Wilhelm, M; Fishman, J A; Pontikis, R; Aubertin, A M; Wilhelm, F X

    2002-12-01

    Transplantation of organs, tissues or cells from pigs to humans could be a potential solution to the shortage of human organs for transplantation. Porcine endogenous retroviruses (PERVs) remain a major safety concern for porcine xenotransplantation. Thus, finding drugs that could be used as virological prophylaxis (or therapy) against PERV replication would be desirable. One of the most effective ways to block retroviral multiplication is to inhibit the enzyme reverse transcriptase (RT) which catalyzes the reverse transcription of viral RNA to proviral double-stranded DNA. We report here the cloning and expression of PERV RT and its susceptibility to several inhibitors. Our data demonstrate PERV susceptibility in vitro to the triphosphorylated nucleoside analog of zidovudine (AZT) and to ddGTP and to a lesser extent to ddTTP but almost no susceptibility to the non-nucleoside RT inhibitors tested.

  8. Dynamics of major histocompatibility complex class I association with the human peptide-loading complex.

    Science.gov (United States)

    Panter, Michaela S; Jain, Ankur; Leonhardt, Ralf M; Ha, Taekjip; Cresswell, Peter

    2012-09-07

    Although the human peptide-loading complex (PLC) is required for optimal major histocompatibility complex class I (MHC I) antigen presentation, its composition is still incompletely understood. The ratio of the transporter associated with antigen processing (TAP) and MHC I to tapasin, which is responsible for MHC I recruitment and peptide binding optimization, is particularly critical for modeling of the PLC. Here, we characterized the stoichiometry of the human PLC using both biophysical and biochemical approaches. By means of single-molecule pulldown (SiMPull), we determined a TAP/tapasin ratio of 1:2, consistent with previous studies of insect-cell microsomes, rat-human chimeric cells, and HeLa cells expressing truncated TAP subunits. We also report that the tapasin/MHC I ratio varies, with the PLC population comprising both 2:1 and 2:2 complexes, based on mutational and co-precipitation studies. The MHC I-saturated PLC may be particularly prevalent among peptide-selective alleles, such as HLA-C4. Additionally, MHC I association with the PLC increases when its peptide supply is reduced by inhibiting the proteasome or by blocking TAP-mediated peptide transport using viral inhibitors. Taken together, our results indicate that the composition of the human PLC varies under normal conditions and dynamically adapts to alterations in peptide supply that may arise during viral infection. These findings improve our understanding of the quality control of MHC I peptide loading and may aid the structural and functional modeling of the human PLC.

  9. Retroviruses as tools to study the immune system.

    Science.gov (United States)

    Lois, C; Refaeli, Y; Qin, X F; Van Parijs, L

    2001-08-01

    Retrovirus-based vectors provide an efficient means to introduce and express genes in cells of the immune system and have become a popular tool to study immune function. They are easy to manipulate and provide stable, long-term gene expression because they integrate into the genome. Current retroviral vectors do have limitations that affect their usefulness in certain applications. However, recent advances suggest a number of ways in which these vectors might be improved to extend their utility in immunological research.

  10. The human component in the safety of complex systems

    International Nuclear Information System (INIS)

    Wahlstroem, B.

    1986-02-01

    The safety of nuclear power and other complex processes requires that human actions are carried though on time and without error. Investigations indicate that human errors are the main or an important contributing cause in more than half of the incidents which occur. This makes it important to try understand the mechanisms behind the human errors and to investigate possibilities for decreasing their likelihood. The present report presents an overview of the Nordic cooperation in the field of human factors in nuclear safety, under the LIT-programme carried out 1981-1985. The work was divided into six different projects in the following fields: human reliability in test and maintenance work; safety oriented organizations and company structures; design of information and control systems; new approaches for information presentation; experimental validation of man-machine interfaces; planning and evaluation of operator training. The research topics were selected from the findings of an earlier phase of the Nordic cooperation. The results are described in more detail in separate reports

  11. Treatment of rat gliomas with recombinant retrovirus harboring Herpes simplex virus thymidine kinase suicide gene

    International Nuclear Information System (INIS)

    Hlavaty, J.; Hlubinova, K.; Altanerova, V.; Liska, J.; Altaner, C.

    1997-01-01

    The retrovirus vector containing Herpes simplex virus type 1 thymidine kinase (HSVtk) gene was constructed. The vector was transfected into the packaging cell line PG13. It was shown that individual transfected cells differ in the production of recombinant retrovirus and in their susceptibility to be killed by ganciclovir. Recombinant retrovirus with a gibbon envelope was able to transduced the HSVtk gene into rat glioma cells. In vivo studies confirmed the ability of intraperitoneal ganciclovir administration to influence subcutaneous and intracerebral tumors developed after injection of C 6 rat glioma cells with subsequent injection of HSVtk retrovirus producing cells. (author)

  12. Proposal for analysis of human talent from complex thought

    Directory of Open Access Journals (Sweden)

    Abel Del Río Cortina

    2015-12-01

    Full Text Available In this paper, it is expose a displaying scheme of the actions of the individual in the context of the productive world*, considering a series of demonstrations framed in the learning process, this, with respect to the complexity of the human development derived from the interactions of the individual, the family, the community, the labor environment, and society in general from the perspective of volitional, cognitive, and procedural dimensions. The proposed visualization, is conceived as a relational map that includes six pillars of human interaction immersed in the above dimensions, being them, know-to be, know-to know, Know-to live, Know-to create, know-to manage, and know-to communicate, being all these reflected as a synergic structure made manifest in the know-how, from the interplay of values, emotional skills or soft skills, attitudes, knowledge, and finally, ways of proceeding. All of the above, in order to generate an approach to the relational complexity of the human talent development in society. * The productive world, in this document, is conceived as the one in which people get articulated in order to live in family, community, entrepreneurial organization, a diverse kind of institutions, and society in general.

  13. Human RAD50 makes a functional DNA-binding complex.

    Science.gov (United States)

    Kinoshita, Eri; van Rossum-Fikkert, Sari; Sanchez, Humberto; Kertokalio, Aryandi; Wyman, Claire

    2015-06-01

    The MRE11-RAD50-NBS1 (MRN) complex has several distinct functions in DNA repair including important roles in both non-homologous end-joining (NHEJ) and homologous recombination (HR). The biochemical activities of MR(N) have been well characterized implying specific functional roles for the components. The arrangement of proteins in the complex implies interdependence of their biochemical activities making it difficult to separate specific functions. We obtained purified human RAD50 and observed that it binds ATP, undergoes ATP-dependent conformational changes as well as having ATPase activity. Scanning force microscopy analysis clearly showed that RAD50 binds DNA although not as oligomers. RAD50 alone was not functional in tethering DNA molecules. ATP increased formation of RAD50 multimers which were however globular lacking extended coiled coils, in contrast to the MR complex where ATP induced oligomers have obvious coiled coils protruding from a central domain. These results suggest that MRE11 is important in maintaining the structural arrangement of RAD50 in the protein complex and perhaps has a role in reinforcing proper alignment of the coiled coils in the ATP-bound state. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  14. Complex-tone pitch representations in the human auditory system

    DEFF Research Database (Denmark)

    Bianchi, Federica

    in listeners with SNHL, it is likely that HI listeners rely on the enhanced envelope cues to retrieve the pitch of unresolved harmonics. Hence, the relative importance of pitch cues may be altered in HI listeners, whereby envelope cues may be used instead of TFS cues to obtain a similar performance in pitch......Understanding how the human auditory system processes the physical properties of an acoustical stimulus to give rise to a pitch percept is a fascinating aspect of hearing research. Since most natural sounds are harmonic complex tones, this work focused on the nature of pitch-relevant cues...... that are necessary for the auditory system to retrieve the pitch of complex sounds. The existence of different pitch-coding mechanisms for low-numbered (spectrally resolved) and high-numbered (unresolved) harmonics was investigated by comparing pitch-discrimination performance across different cohorts of listeners...

  15. Human erythrocytes inhibit complement-mediated solubilization of immune complexes by human serum

    International Nuclear Information System (INIS)

    Dorval, B.L.

    1987-01-01

    The aim of this study was to develop an autologus human system to evaluate the effects of human erythrocytes on solubilization of immune complex precipitates (IC) by human serum. Incubation of IC with fresh human serum or guinea pig serum resulted in solubilization of IC. When packed erythrocytes were added to human serum or guinea pig serum binding of IC to the erythrocyte occurred and IC solubilization was inhibited significantly (p <.025). Sheep erythrocytes did not bind IC or inhibit IC solubilization. To evaluate the role of human erythrocyte complement receptor (CR1) on these findings, human erythrocytes were treated with trypsin or anti-CR1 antibodies. Both treatments abrogated IC binding to human erythrocytes but did not affect the ability of the human erythrocyte to inhibit IC solubilization. Radioimmunoassay was used to measure C3, C4 and C5 activation in human serum after incubation with IC, human erythrocytes, human erythrocytes plus IC, whole blood or in whole blood plus IC

  16. Teleconnections in complex human-Earth system models

    Science.gov (United States)

    Calvin, K. V.; Edmonds, J.

    2017-12-01

    Human systems and physical Earth systems are closely coupled and interact in complex ways that are sometimes surprising. This presentation discusses a few examples of system interactions. We consider the coupled energy-water-land-economy systems. We show how reductions in fossil fuel emissions are inversely coupled to land rents, food prices and deforestation. We discuss how water shortages in one part of the world is propagated to other distant parts of the world. We discuss the sensitivity of international trade patterns to energy and land systems technology and markets, and the potentially unanticipated results that can emerge.

  17. Understanding Complex Human Ecosystems: The Case of Ecotourism on Bonaire

    Directory of Open Access Journals (Sweden)

    Thomas Abel

    2003-12-01

    Full Text Available It is suggested that ecotourism development on the island of Bonaire can be productively understood as a perturbation of a complex human ecosystem. Inputs associated with ecotourism have fueled transformations of the island ecology and sociocultural system. The results of this study indicate that Bonaire's social and economic hierarchy is approaching a new, stable systems state following a 50-yr transition begun by government and industry that stabilized with the appearance of ecotourism development and population growth. Ecotourism can be understood to have "filled in" the middle of the production hierarchy of Bonaire. Interpreted from this perspective, population growth has completed the transformation by expanding into production niches at smaller scales in the production hierarchy. Both a consequence and a cause, ecotourism has transformed the island's social structure and demography. The theory and methods applied in this case study of interdisciplinary research in the field of human ecosystems are also presented.

  18. Human more complex than mouse at cellular level.

    Directory of Open Access Journals (Sweden)

    Alexander E Vinogradov

    Full Text Available The family of transcription factors with the C2H2 zinc finger domain is expanding in the evolution of vertebrates, reaching its highest numbers in the mammals. The question arises: whether an increased amount of these transcription factors is related to embryogenesis, nervous system, pathology or more of them are expressed in individual cells? Among mammals, the primates have a more complex anatomical structure than the rodents (e.g., brain. In this work, I show that a greater number of C2H2-ZF genes are expressed in the human cells than in the mouse cells. The effect is especially pronounced for C2H2-ZF genes accompanied with the KRAB domain. The relative difference between the numbers of C2H2-ZF(-KRAB genes in the human and mouse cellular transcriptomes even exceeds their difference in the genomes (i.e. a greater subset of existing in the genome genes is expressed in the human cellular transcriptomes compared to the mouse transcriptomes. The evolutionary turnover of C2H2-ZF(-KRAB genes acts in the direction of the revealed phenomenon, i.e. gene duplication and loss enhances the difference in the relative number of C2H2-ZF(-KRAB genes between human and mouse cellular transcriptomes. A higher amount of these genes is expressed in the brain and embryonic cells (compared with other tissues, whereas a lower amount--in the cancer cells. It is specifically the C2H2-ZF transcription factors whose repertoire is poorer in the cancer and richer in the brain (other transcription factors taken together do not show this trend. These facts suggest that increase of anatomical complexity is accompanied by a more complex intracellular regulation involving these transcription factors. Malignization is associated with simplification of this regulation. These results agree with the known fact that human cells are more resistant to oncogenic transformation than mouse cells. The list of C2H2-ZF genes whose suppression might be involved in malignization is provided.

  19. An effective method for the quantitative detection of porcine endogenous retrovirus in pig tissues.

    Science.gov (United States)

    Zhang, Peng; Yu, Ping; Wang, Wei; Zhang, Li; Li, Shengfu; Bu, Hong

    2010-05-01

    Xenotransplantation shows great promise for providing a virtually limitless supply of cells, tissues, and organs for a variety of therapeutical procedures. However, the potential of porcine endogenous retrovirus (PERV) as a human-tropic pathogen, particularly as a public health risk, is a major concern for xenotransplantation. This study focus on the detection of copy number in various tissues and organs in Banna Minipig Inbreed (BMI) from 2006 to 2007 in West China Hospital, Sichuan University. Real-time quantitative polymerase chain reaction (SYBR Green I) was performed in this study. The results showed that the pol gene had the most copy number in tissues compared with gag, envA, and envB. Our experiment will offer a rapid and accurate method for the detection of the copy number in various tissues and was especially suitable for the selection of tissues or organs in future clinical xenotransplantation.

  20. Synchronization in human musical rhythms and mutually interacting complex systems.

    Science.gov (United States)

    Hennig, Holger

    2014-09-09

    Though the music produced by an ensemble is influenced by multiple factors, including musical genre, musician skill, and individual interpretation, rhythmic synchronization is at the foundation of musical interaction. Here, we study the statistical nature of the mutual interaction between two humans synchronizing rhythms. We find that the interbeat intervals of both laypeople and professional musicians exhibit scale-free (power law) cross-correlations. Surprisingly, the next beat to be played by one person is dependent on the entire history of the other person's interbeat intervals on timescales up to several minutes. To understand this finding, we propose a general stochastic model for mutually interacting complex systems, which suggests a physiologically motivated explanation for the occurrence of scale-free cross-correlations. We show that the observed long-term memory phenomenon in rhythmic synchronization can be imitated by fractal coupling of separately recorded or synthesized audio tracks and thus applied in electronic music. Though this study provides an understanding of fundamental characteristics of timing and synchronization at the interbrain level, the mutually interacting complex systems model may also be applied to study the dynamics of other complex systems where scale-free cross-correlations have been observed, including econophysics, physiological time series, and collective behavior of animal flocks.

  1. Complex carbohydrate utilization by the healthy human microbiome.

    Directory of Open Access Journals (Sweden)

    Brandi L Cantarel

    Full Text Available The various ecological habitats in the human body provide microbes a wide array of nutrient sources and survival challenges. Advances in technology such as DNA sequencing have allowed a deeper perspective into the molecular function of the human microbiota than has been achievable in the past. Here we aimed to examine the enzymes that cleave complex carbohydrates (CAZymes in the human microbiome in order to determine (i whether the CAZyme profiles of bacterial genomes are more similar within body sites or bacterial families and (ii the sugar degradation and utilization capabilities of microbial communities inhabiting various human habitats. Upon examination of 493 bacterial references genomes from 12 human habitats, we found that sugar degradation capabilities of taxa are more similar to others in the same bacterial family than to those inhabiting the same habitat. Yet, the analysis of 520 metagenomic samples from five major body sites show that even when the community composition varies the CAZyme profiles are very similar within a body site, suggesting that the observed functional profile and microbial habitation have adapted to the local carbohydrate composition. When broad sugar utilization was compared within the five major body sites, the gastrointestinal track contained the highest potential for total sugar degradation, while dextran and peptidoglycan degradation were highest in oral and vaginal sites respectively. Our analysis suggests that the carbohydrate composition of each body site has a profound influence and probably constitutes one of the major driving forces that shapes the community composition and therefore the CAZyme profile of the local microbial communities, which in turn reflects the microbiome fitness to a body site.

  2. Social complexity parallels vocal complexity: a comparison of three non-human primate species.

    Science.gov (United States)

    Bouchet, Hélène; Blois-Heulin, Catherine; Lemasson, Alban

    2013-01-01

    Social factors play a key role in the structuring of vocal repertoires at the individual level, notably in non-human primates. Some authors suggested that, at the species level too, social life may have driven the evolution of communicative complexity, but this has rarely been empirically tested. Here, we use a comparative approach to address this issue. We investigated vocal variability, at both the call type and the repertoire levels, in three forest-dwelling species of Cercopithecinae presenting striking differences in their social systems, in terms of social organization as well as social structure. We collected female call recordings from twelve De Brazza's monkeys (Cercopithecus neglectus), six Campbell's monkeys (Cercopithecus campbelli) and seven red-capped mangabeys (Cercocebus torquatus) housed in similar conditions. First, we noted that the level of acoustic variability and individual distinctiveness found in several call types was related to their importance in social functioning. Contact calls, essential to intra-group cohesion, were the most individually distinctive regardless of the species, while threat calls were more structurally variable in mangabeys, the most "despotic" of our three species. Second, we found a parallel between the degree of complexity of the species' social structure and the size, diversity, and usage of its vocal repertoire. Mangabeys (most complex social structure) called twice as often as guenons and displayed the largest and most complex repertoire. De Brazza's monkeys (simplest social structure) displayed the smallest and simplest repertoire. Campbell's monkeys displayed an intermediate pattern. Providing evidence of higher levels of vocal variability in species presenting a more complex social system, our results are in line with the theory of a social-vocal coevolution of communicative abilities, opening new perspectives for comparative research on the evolution of communication systems in different animal taxa.

  3. The complexity of human walking: a knee osteoarthritis study.

    Directory of Open Access Journals (Sweden)

    Margarita Kotti

    Full Text Available This study proposes a framework for deconstructing complex walking patterns to create a simple principal component space before checking whether the projection to this space is suitable for identifying changes from the normality. We focus on knee osteoarthritis, the most common knee joint disease and the second leading cause of disability. Knee osteoarthritis affects over 250 million people worldwide. The motivation for projecting the highly dimensional movements to a lower dimensional and simpler space is our belief that motor behaviour can be understood by identifying a simplicity via projection to a low principal component space, which may reflect upon the underlying mechanism. To study this, we recruited 180 subjects, 47 of which reported that they had knee osteoarthritis. They were asked to walk several times along a walkway equipped with two force plates that capture their ground reaction forces along 3 axes, namely vertical, anterior-posterior, and medio-lateral, at 1000 Hz. Data when the subject does not clearly strike the force plate were excluded, leaving 1-3 gait cycles per subject. To examine the complexity of human walking, we applied dimensionality reduction via Probabilistic Principal Component Analysis. The first principal component explains 34% of the variance in the data, whereas over 80% of the variance is explained by 8 principal components or more. This proves the complexity of the underlying structure of the ground reaction forces. To examine if our musculoskeletal system generates movements that are distinguishable between normal and pathological subjects in a low dimensional principal component space, we applied a Bayes classifier. For the tested cross-validated, subject-independent experimental protocol, the classification accuracy equals 82.62%. Also, a novel complexity measure is proposed, which can be used as an objective index to facilitate clinical decision making. This measure proves that knee osteoarthritis

  4. The retrovirus MA and PreTM proteins follow immature MVL cores

    DEFF Research Database (Denmark)

    Andersen, Klaus Bahl

    2013-01-01

    Detergent can dissolve retrovirus, exept the immature core. Here we show that the Matrix protein (MA) and the Transmembrane protein in its immature form (PreTM) bind to the retrovirus core. These attachments explain the attachment in the virus particle and the dynamics of the ability to fuse with...

  5. V-cbl, an oncogene from a dual-recombinant murine retrovirus that induces early B-lineage lymphomas

    International Nuclear Information System (INIS)

    Langdon, W.Y.; Klinken, S.P.; Hartley, J.W.; Morse, H.C. III; Ruscetti, S.K.

    1989-01-01

    Cas NS-1 is an acutely transforming murine retrovirus that induces pre-B and pro-B cell lymphomas. Molecular cloning showed it was generated from the ecotropic Cas-Br-M virus by sequential recombinations with endogenous retroviral sequences and a cellular oncogene. The oncogene sequence shows no homology with known oncogenes but some similarity to the yeast transcriptional activator GCN4. A 100-kDa gag-cbl fusion protein, with no detectable kinase activity, is responsible for the cellular transformation. The cellular homologue of v-cbl, present in mouse and human DNA, is expressed in a range of hemopoietic lineages

  6. Retrovirus XMRV Is Inhibited by Host Proteins and Anti-HIV Drugs AZT, Tenofovir, and Raltegravir | Center for Cancer Research

    Science.gov (United States)

    A newly discovered retrovirus, XMRV, isolated from prostate cancer tissues for the first time in 2006, has recently been reported in patients with this cancer, as well as in patients with chronic fatigue syndrome (CFS). However, five subsequent studies could not validate these reports. Since XMRV was isolated from the T and B cells of CFS patients, Vinay Pathak and his colleagues in the HIV Drug Resistance Program sought to determine how XMRV was countering intracellular defense mechanisms that inhibit retroviral replication in human cells.

  7. Architecture of human mTOR complex 1.

    Science.gov (United States)

    Aylett, Christopher H S; Sauer, Evelyn; Imseng, Stefan; Boehringer, Daniel; Hall, Michael N; Ban, Nenad; Maier, Timm

    2016-01-01

    Target of rapamycin (TOR), a conserved protein kinase and central controller of cell growth, functions in two structurally and functionally distinct complexes: TORC1 and TORC2. Dysregulation of mammalian TOR (mTOR) signaling is implicated in pathologies that include diabetes, cancer, and neurodegeneration. We resolved the architecture of human mTORC1 (mTOR with subunits Raptor and mLST8) bound to FK506 binding protein (FKBP)-rapamycin, by combining cryo-electron microscopy at 5.9 angstrom resolution with crystallographic studies of Chaetomium thermophilum Raptor at 4.3 angstrom resolution. The structure explains how FKBP-rapamycin and architectural elements of mTORC1 limit access to the recessed active site. Consistent with a role in substrate recognition and delivery, the conserved amino-terminal domain of Raptor is juxtaposed to the kinase active site. Copyright © 2016, American Association for the Advancement of Science.

  8. Algorithmic complexity of growth hormone release in humans

    Energy Technology Data Exchange (ETDEWEB)

    Prank, K.; Wagner, M.; Brabant, G. [Medical School Hannover (Germany)

    1996-12-31

    Most hormones are secreted in an pulsatile rather than in a constant manner. This temporal pattern of pulsatile hormone release plays an important role in the regulation of cellular function and structure. In healthy humans growth hormone (GH) secretion is characterized by distinct pulses whereas patients bearing a GH producing tumor accompanied with excessive secretion (acromegaly) exhibit a highly irregular pattern of GH release. It has been hypothesized that this highly disorderly pattern of GH release in acromegaly arises from random events in the GH-producing tumor under decreased normal control of GH secretion. Using a context-free grammar complexity measure (algorithmic complexity) in conjunction with random surrogate data sets we demonstrate that the temporal pattern of GH release in acromegaly is not significantly different from a variety of stochastic processes. In contrast, normal subjects clearly exhibit deterministic structure in their temporal patterns of GH secretion. Our results support the hypothesis that GH release in acromegaly is due to random events in the GH-producing tumorous cells which might become independent from hypothalamic regulation. 17 refs., 1 fig., 2 tabs.

  9. Avian endogenous provirus (ev-3) env gene sequencing: implication for pathogenic retrovirus origination.

    Science.gov (United States)

    Tikhonenko, A T; Lomovskaya, O L

    1990-02-01

    The avian endogenous env gene product blocks the surface receptor and, as a result, cells become immune to related exogenous retroviruses. On the other hand, the same sequence can be included in the pathogenic retrovirus genome, as shown by oligonucleotide mapping. However, since the complete env gene sequence was not known, the comparison of genomic nucleotide sequences was not possible. Therefore an avian endogenous provirus with an intact env gene was cloned from a chicken gene bank and the regions coding for the C terminus of the gp85 and gp37 proteins were sequenced. Comparison of this sequence with those of other retroviruses proved that one of the pathogenic viruses associated with osteopetrosis is a cross between avian endogenous virus and Rous sarcoma virus. Retroviruses and, especially, endogenous retroviruses are traditionally of the most developed models of viral carcinogenesis. Many endogenous retroviruses are implicated in neoplastic transformation of the cell. For instance, endogenous mouse mammary tumor virus of some inbred lines appears to be the only causative agent in these mammary cancers. Other even nonpathogenic murine endogenous retroviruses are involved in the origination of MCF-type recombinant acute leukosis viruses. Some endogenous retroviruses are implicated in the transduction or activation of cellular protooncogenes. Our interest in endogenous viruses is based on their ability to make cells resistant to exogenous retroviruses. Expression of their major envelope glycoprotein leads to cellular surface receptor blockage and imparts immunity to infection by the related leukemia retroviruses. This problem is quite elaborated for chicken endogenous virus RAV-O (7-9).(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Synergistic immune responses induced by endogenous retrovirus and herpesvirus antigens result in increased production of inflammatory cytokines in multiple sclerosis patients

    DEFF Research Database (Denmark)

    Brudek, T; Christensen, T; Hansen, H J

    2008-01-01

    Human endogenous retroviruses (HERV) and herpesviruses are increasingly associated with the pathogenesis of the neurological inflammatory disease multiple sclerosis (MS). Herpesviruses are capable of HERV activation and simultaneous presence of HERV and herpesvirus antigens have a synergistic...... effect on cell-mediated immune responses, which tend to be higher in MS patients in comparison with healthy individuals. Here, we investigate whether these synergistic immune responses are reflected in changes in the production of proinflammatory cytokines. Using enzyme-linked immunosorbent assays...

  11. Complexity of human and ecosystem interactions in an agricultural landscape

    Science.gov (United States)

    Coupe, Richard H.; Barlow, Jeannie R.; Capel, Paul D.

    2012-01-01

    The complexity of human interaction in the commercial agricultural landscape and the resulting impacts on the ecosystem services of water quality and quantity is largely ignored by the current agricultural paradigm that maximizes crop production over other ecosystem services. Three examples at different spatial scales (local, regional, and global) are presented where human and ecosystem interactions in a commercial agricultural landscape adversely affect water quality and quantity in unintended ways in the Delta of northwestern Mississippi. In the first example, little to no regulation of groundwater use for irrigation has caused declines in groundwater levels resulting in loss of baseflow to streams and threatening future water supply. In the second example, federal policy which subsidizes corn for biofuel production has encouraged many producers to switch from cotton to corn, which requires more nutrients and water, counter to national efforts to reduce nutrient loads to the Gulf of Mexico and exacerbating groundwater level declines. The third example is the wholesale adoption of a system for weed control that relies on a single chemical, initially providing many benefits and ultimately leading to the widespread occurrence of glyphosate and its degradates in Delta streams and necessitating higher application rates of glyphosate as well as the use of other herbicides due to increasing weed resistance. Although these examples are specific to the Mississippi Delta, analogous situations exist throughout the world and point to the need for change in how we grow our food, fuel, and fiber, and manage our soil and water resources.

  12. Distribution of adenosine deaminase complexing protein (ADCP) in human tissues.

    Science.gov (United States)

    Dinjens, W N; ten Kate, J; van der Linden, E P; Wijnen, J T; Khan, P M; Bosman, F T

    1989-12-01

    The normal distribution of adenosine deaminase complexing protein (ADCP) in the human body was investigated quantitatively by ADCP-specific radioimmunoassay (RIA) and qualitatively by immunohistochemistry. In these studies we used a specific rabbit anti-human ADCP antiserum. In all 19 investigated tissues, except erythrocytes, ADCP was found by RIA in the soluble and membrane fractions. From all tissues the membrane fractions contained more ADCP (expressed per mg protein) than the soluble fractions. High membrane ADCP concentrations were found in skin, renal cortex, gastrointestinal tract, and prostate. Immunoperoxidase staining confirmed the predominant membrane-associated localization of the protein. In serous sweat glands, convoluted tubules of renal cortex, bile canaliculi, gastrointestinal tract, lung, pancreas, prostate gland, salivary gland, gallbladder, mammary gland, and uterus, ADCP immunoreactivity was found confined to the luminal membranes of the epithelial cells. These data demonstrate that ADCP is present predominantly in exocrine glands and absorptive epithelia. The localization of ADCP at the secretory or absorptive apex of the cells suggests that the function of ADCP is related to the secretory and/or absorptive process.

  13. Discrimination of complex human behavior by pigeons (Columba livia and humans.

    Directory of Open Access Journals (Sweden)

    Muhammad A J Qadri

    Full Text Available The cognitive and neural mechanisms for recognizing and categorizing behavior are not well understood in non-human animals. In the current experiments, pigeons and humans learned to categorize two non-repeating, complex human behaviors ("martial arts" vs. "Indian dance". Using multiple video exemplars of a digital human model, pigeons discriminated these behaviors in a go/no-go task and humans in a choice task. Experiment 1 found that pigeons already experienced with discriminating the locomotive actions of digital animals acquired the discrimination more rapidly when action information was available than when only pose information was available. Experiments 2 and 3 found this same dynamic superiority effect with naïve pigeons and human participants. Both species used the same combination of immediately available static pose information and more slowly perceived dynamic action cues to discriminate the behavioral categories. Theories based on generalized visual mechanisms, as opposed to embodied, species-specific action networks, offer a parsimonious account of how these different animals recognize behavior across and within species.

  14. Primate-specific endogenous retrovirus-driven transcription defines naive-like stem cells.

    Science.gov (United States)

    Wang, Jichang; Xie, Gangcai; Singh, Manvendra; Ghanbarian, Avazeh T; Raskó, Tamás; Szvetnik, Attila; Cai, Huiqiang; Besser, Daniel; Prigione, Alessandro; Fuchs, Nina V; Schumann, Gerald G; Chen, Wei; Lorincz, Matthew C; Ivics, Zoltán; Hurst, Laurence D; Izsvák, Zsuzsanna

    2014-12-18

    Naive embryonic stem cells hold great promise for research and therapeutics as they have broad and robust developmental potential. While such cells are readily derived from mouse blastocysts it has not been possible to isolate human equivalents easily, although human naive-like cells have been artificially generated (rather than extracted) by coercion of human primed embryonic stem cells by modifying culture conditions or through transgenic modification. Here we show that a sub-population within cultures of human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) manifests key properties of naive state cells. These naive-like cells can be genetically tagged, and are associated with elevated transcription of HERVH, a primate-specific endogenous retrovirus. HERVH elements provide functional binding sites for a combination of naive pluripotency transcription factors, including LBP9, recently recognized as relevant to naivety in mice. LBP9-HERVH drives hESC-specific alternative and chimaeric transcripts, including pluripotency-modulating long non-coding RNAs. Disruption of LBP9, HERVH and HERVH-derived transcripts compromises self-renewal. These observations define HERVH expression as a hallmark of naive-like hESCs, and establish novel primate-specific transcriptional circuitry regulating pluripotency.

  15. One Hundred Twenty Years of Koala Retrovirus Evolution Determined from Museum Skins

    OpenAIRE

    ?vila-Arcos, Mar?a C.; Ho, Simon Y.W.; Ishida, Yasuko; Nikolaidis, Nikolas; Tsangaras, Kyriakos; H?nig, Karin; Medina, Rebeca; Rasmussen, Morten; Fordyce, Sarah L.; Calvignac-Spencer, S?bastien; Willerslev, Eske; Gilbert, M. Thomas P.; Helgen, Kristofer M.; Roca, Alfred L.; Greenwood, Alex D.

    2013-01-01

    Although endogenous retroviruses are common across vertebrate genomes, the koala retrovirus (KoRV) is the only retrovirus known to be currently invading the germ line of its host. KoRV is believed to have first infected koalas in northern Australia less than two centuries ago. We examined KoRV in 28 koala museum skins collected in the late 19th and 20th centuries and deep sequenced the complete proviral envelope region from five northern Australian specimens. Strikingly, KoRV env sequences we...

  16. Characterization of Insertional Variation of Porcine Endogenous Retroviruses in Six Different Pig Breeds

    Directory of Open Access Journals (Sweden)

    W. Y. Jung

    2012-10-01

    Full Text Available Pigs may need to be exploited as xenotransplantation donors due to the shortage of human organs, tissues and cells. Porcine endogenous retroviruses (PERVs are a significant obstacle to xenotransplantation because they can infect human cells in vitro and have the potential for transmission of unexpected pathogens to humans. In this research, 101 pigs, including four commercial breeds (23 Berkshire, 13 Duroc, 22 Landrace and 14 Yorkshire pigs, one native breed (19 Korean native pigs and one miniature breed (10 NIH miniature pigs were used to investigate insertional variations for 11 PERV loci (three PERV-A, six PERV-B and two PERV-C. Over 60% of the pigs harbored one PERV-A (907F8 integration and five PERV-B (B3-3G, B3-7G, 742H1, 1155D9 and 465D1 integrations. However, two PERV-A loci (A1-6C and 1347C1 and one PERV-B locus (B3-7F were absent in Duroc pigs. Moreover, two PERV-C loci (C2-6C and C4-2G only existed in Korean native pigs and NIH miniature pigs. The results suggest that PERV insertional variations differ among pig breeds as well as among individuals within a breed. Also, the results presented here can be used for the selection of animals that do not have specific PERV integration for xenotransplantation research.

  17. Epidemiological aspects of retrovirus (HTLV infection among Indian populations in the Amazon Region of Brazil

    Directory of Open Access Journals (Sweden)

    Ricardo Ishak

    Full Text Available HTLV was initially described in association with a form of leukemia in Japan and a neurological disease in the Caribbean. It was soon shown that HTLV-II was endemic among Amerindians and particularly among Brazilian Indians. The Amazon Region of Brazil is presently the largest endemic area for this virus and has allowed several studies concerning virus biology, the search for overt disease, epidemiological data including detailed demographic data on infected individuals, clear-cut geographic distribution, definition of modes of transmission and maintenance within small, epidemiologically-closed groups, and advances in laboratory diagnosis of the infection. A new molecular subtype named HTLV-IIc was further described on the basis of genome sequencing and phylogenetic analysis. This subtype is present in other areas of Brazil, indicating that the virus is additionally both a valuable marker for tracing past human migration routes in the Americas and a probable marker for social habits of the present human population. HIV, the other human retrovirus, is still not prevalent among indigenous communities in the Brazilian Amazon, but these groups are also easy targets for the virus.

  18. Characterization of a nucleocapsid-like region and of two distinct primer tRNALys,2 binding sites in the endogenous retrovirus Gypsy.

    Science.gov (United States)

    Gabus, Caroline; Ivanyi-Nagy, Roland; Depollier, Julien; Bucheton, Alain; Pelisson, Alain; Darlix, Jean-Luc

    2006-01-01

    Mobile LTR-retroelements comprising retroviruses and LTR-retrotransposons form a large part of eukaryotic genomes. Their mode of replication and abundance favour the notion that they are major actors in eukaryote evolution. The Gypsy retroelement can spread in the germ line of the fruit fly Drosophila melanogaster via both env-independent and env-dependent processes. Thus, Gypsy is both an active retrotransposon and an infectious retrovirus resembling the gammaretrovirus MuLV. However, unlike gammaretroviruses, the Gypsy Gag structural precursor is not processed into Matrix, Capsid and Nucleocapsid (NC) proteins. In contrast, it has features in common with Gag of the ancient yeast TY1 retroelement. These characteristics of Gypsy make it a very interesting model to study replication of a retroelement at the frontier between ancient retrotransposons and retroviruses. We investigated Gypsy replication using an in vitro model system and transfection of insect cells. Results show that an unstructured domain of Gypsy Gag has all the properties of a retroviral NC. This NC-like peptide forms ribonucleoparticle-like complexes upon binding Gypsy RNA and directs the annealing of primer tRNA(Lys,2) to two distinct primer binding sites (PBS) at the genome 5' and 3' ends. Only the 5' PBS is indispensable for cDNA synthesis in vitro and in Drosophila cells.

  19. Endogenous retroviruses mobilized during friend murine leukemia virus infection.

    Science.gov (United States)

    Boi, Stefano; Rosenke, Kyle; Hansen, Ethan; Hendrick, Duncan; Malik, Frank; Evans, Leonard H

    2016-12-01

    We have demonstrated in a mouse model that infection with a retrovirus can lead not only to the generation of recombinants between exogenous and endogenous gammaretrovirus, but also to the mobilization of endogenous proviruses by pseudotyping entire polytropic proviral transcripts and facilitating their infectious spread to new cells. However, the frequency of this occurrence, the kinetics, and the identity of mobilized endogenous proviruses was unclear. Here we find that these mobilized transcripts are detected after only one day of infection. They predominate over recombinant polytropic viruses early in infection, persist throughout the course of disease and are comprised of multiple different polytropic proviruses. Other endogenous retroviral elements such as intracisternal A particles (IAPs) were not detected. The integration of the endogenous transcripts into new cells could result in loss of transcriptional control and elevated expression which may facilitate pathogenesis, perhaps by contributing to the generation of polytropic recombinant viruses. Published by Elsevier Inc.

  20. Evolution of Foamy Viruses: The Most Ancient of All Retroviruses

    Directory of Open Access Journals (Sweden)

    Jochen Bodem

    2013-09-01

    Full Text Available Recent evidence indicates that foamy viruses (FVs are the oldest retroviruses (RVs that we know and coevolved with their hosts for several hundred million years. This coevolution may have contributed to the non-pathogenicity of FVs, an important factor in development of foamy viral vectors in gene therapy. However, various questions on the molecular evolution of FVs remain still unanswered. The analysis of the spectrum of animal species infected by exogenous FVs or harboring endogenous FV elements in their genome is pivotal. Furthermore, animal studies might reveal important issues, such as the identification of the FV in vivo target cells, which than require a detailed characterization, to resolve the molecular basis of the accuracy with which FVs copy their genome. The issues of the extent of FV viremia and of the nature of the virion genome (RNA vs. DNA also need to be experimentally addressed.

  1. Koala retroviruses: characterization and impact on the life of koalas

    Science.gov (United States)

    2013-01-01

    Koala retroviruses (KoRV) have been isolated from wild and captive koalas in Australia as well as from koala populations held in zoos in other countries. They are members of the genus Gammaretrovirus, are most closely related to gibbon ape leukemia virus (GaLV), feline leukemia virus (FeLV) and porcine endogenous retrovirus (PERV) and are likely the result of a relatively recent trans-species transmission from rodents or bats. The first KoRV to be isolated, KoRV-A, is widely distributed in the koala population in both integrated endogenous and infectious exogenous forms with evidence from museum specimens older than 150 years, indicating a relatively long engagement with the koala population. More recently, additional subtypes of KoRV that are not endogenized have been identified based on sequence differences and host cell receptor specificity (KoRV-B and KoRV-J). A specific association with fatal lymphoma and leukemia has been recently suggested for KoRV-B. In addition, it has been proposed that the high viral loads found in many animals may lead to immunomodulation resulting in a higher incidence of diseases such as chlamydiosis. Although the molecular basis of this immunomodulation is still unclear, purified KoRV particles and a peptide corresponding to a highly conserved domain in the envelope protein have been shown to modulate cytokine expression in vitro, similar to that induced by other gammaretroviruses. While much is still to be learned, KoRV induced lymphoma/leukemia and opportunistic disease arising as a consequence of immunomodulation are likely to play an important role in the stability of koala populations both in the wild and in captivity. PMID:24148555

  2. Koala retroviruses: characterization and impact on the life of koalas.

    Science.gov (United States)

    Denner, Joachim; Young, Paul R

    2013-10-23

    Koala retroviruses (KoRV) have been isolated from wild and captive koalas in Australia as well as from koala populations held in zoos in other countries. They are members of the genus Gammaretrovirus, are most closely related to gibbon ape leukemia virus (GaLV), feline leukemia virus (FeLV) and porcine endogenous retrovirus (PERV) and are likely the result of a relatively recent trans-species transmission from rodents or bats. The first KoRV to be isolated, KoRV-A, is widely distributed in the koala population in both integrated endogenous and infectious exogenous forms with evidence from museum specimens older than 150 years, indicating a relatively long engagement with the koala population. More recently, additional subtypes of KoRV that are not endogenized have been identified based on sequence differences and host cell receptor specificity (KoRV-B and KoRV-J). A specific association with fatal lymphoma and leukemia has been recently suggested for KoRV-B. In addition, it has been proposed that the high viral loads found in many animals may lead to immunomodulation resulting in a higher incidence of diseases such as chlamydiosis. Although the molecular basis of this immunomodulation is still unclear, purified KoRV particles and a peptide corresponding to a highly conserved domain in the envelope protein have been shown to modulate cytokine expression in vitro, similar to that induced by other gammaretroviruses. While much is still to be learned, KoRV induced lymphoma/leukemia and opportunistic disease arising as a consequence of immunomodulation are likely to play an important role in the stability of koala populations both in the wild and in captivity.

  3. A role for Aurora C in the chromosomal passenger complex during human preimplantation embryo development

    NARCIS (Netherlands)

    Santos, Margarida Avo; van de Werken, Christine; de Vries, Marieke; Jahr, Holger; Vromans, Martijn J. M.; Laven, Joop S. E.; Fauser, Bart C.; Kops, Geert J.; Lens, Susanne M.; Baart, Esther B.

    BACKGROUND: Human embryos generated by IVF demonstrate a high incidence of chromosomal segregation errors during the cleavage divisions. To analyse underlying molecular mechanisms, we investigated the behaviour of the chromosomal passenger complex (CPC) in human oocytes and embryos. This important

  4. A review of human factors challenges of complex adaptive systems: discovering and understanding chaos in human performance.

    Science.gov (United States)

    Karwowski, Waldemar

    2012-12-01

    In this paper, the author explores a need for a greater understanding of the true nature of human-system interactions from the perspective of the theory of complex adaptive systems, including the essence of complexity, emergent properties of system behavior, nonlinear systems dynamics, and deterministic chaos. Human performance, more often than not, constitutes complex adaptive phenomena with emergent properties that exhibit nonlinear dynamical (chaotic) behaviors. The complexity challenges in the design and management of contemporary work systems, including service systems, are explored. Examples of selected applications of the concepts of nonlinear dynamics to the study of human physical performance are provided. Understanding and applications of the concepts of theory of complex adaptive and dynamical systems should significantly improve the effectiveness of human-centered design efforts of a large system of systems. Performance of many contemporary work systems and environments may be sensitive to the initial conditions and may exhibit dynamic nonlinear properties and chaotic system behaviors. Human-centered design of emergent human-system interactions requires application of the theories of nonlinear dynamics and complex adaptive system. The success of future human-systems integration efforts requires the fusion of paradigms, knowledge, design principles, and methodologies of human factors and ergonomics with those of the science of complex adaptive systems as well as modern systems engineering.

  5. The Complex Exogenous RNA Spectra in Human Plasma: An Interface with Human Gut Biota?

    Science.gov (United States)

    Wang, Kai; Li, Hong; Yuan, Yue; Etheridge, Alton; Zhou, Yong; Huang, David; Wilmes, Paul; Galas, David

    2012-01-01

    Human plasma has long been a rich source for biomarker discovery. It has recently become clear that plasma RNA molecules, such as microRNA, in addition to proteins are common and can serve as biomarkers. Surveying human plasma for microRNA biomarkers using next generation sequencing technology, we observed that a significant fraction of the circulating RNA appear to originate from exogenous species. With careful analysis of sequence error statistics and other controls, we demonstrated that there is a wide range of RNA from many different organisms, including bacteria and fungi as well as from other species. These RNAs may be associated with protein, lipid or other molecules protecting them from RNase activity in plasma. Some of these RNAs are detected in intracellular complexes and may be able to influence cellular activities under in vitro conditions. These findings raise the possibility that plasma RNAs of exogenous origin may serve as signaling molecules mediating for example the human-microbiome interaction and may affect and/or indicate the state of human health. PMID:23251414

  6. Induced prion protein controls immune-activated retroviruses in the mouse spleen.

    Directory of Open Access Journals (Sweden)

    Marius Lötscher

    Full Text Available The prion protein (PrP is crucially involved in transmissible spongiform encephalopathies (TSE, but neither its exact role in disease nor its physiological function are known. Here we show for mice, using histological, immunochemical and PCR-based methods, that stimulation of innate resistance was followed by appearance of numerous endogenous retroviruses and ensuing PrP up-regulation in germinal centers of the spleen. Subsequently, the activated retroviruses disappeared in a PrP-dependent manner. Our results reveal the regular involvement of endogenous retroviruses in murine immune responses and provide evidence for an essential function of PrP in the control of the retroviral activity. The interaction between PrP and ubiquitous endogenous retroviruses may allow new interpretations of TSE pathophysiology and explain the evolutionary conservation of PrP.

  7. Economic Complexity and Human Development: DEA performance measurement in Asia and Latin America

    OpenAIRE

    Ferraz, Diogo; Moralles, Hérick Fernando; Suarez Campoli, Jéssica; Ribeiro de Oliveira, Fabíola Cristina; do Nascimento Rebelatto, Daisy Aparecida

    2018-01-01

    Economic growth is not the unique factor to explain human development. Due to that many authors have prioritized studies to measure the Human Development Index. However, these indices do not analyze how Economic Complexity can increase Human Development. The aim of this paper is to determine the efficiency of a set of nations from Latin America and Asia, to measure a country’s performance in converting Economic Complexity into Human Development, between 2010 and 2014. The method used was Data...

  8. Exploring the potential relevance of human-specific genes to complex disease

    Directory of Open Access Journals (Sweden)

    Cooper David N

    2011-01-01

    Full Text Available Abstract Although human disease genes generally tend to be evolutionarily more ancient than non-disease genes, complex disease genes appear to be represented more frequently than Mendelian disease genes among genes of more recent evolutionary origin. It is therefore proposed that the analysis of human-specific genes might provide new insights into the genetics of complex disease. Cross-comparison with the Human Gene Mutation Database (http://www.hgmd.org revealed a number of examples of disease-causing and disease-associated mutations in putatively human-specific genes. A sizeable proportion of these were missense polymorphisms associated with complex disease. Since both human-specific genes and genes associated with complex disease have often experienced particularly rapid rates of evolutionary change, either due to weaker purifying selection or positive selection, it is proposed that a significant number of human-specific genes may play a role in complex disease.

  9. Human as the chief controller in the complex system

    International Nuclear Information System (INIS)

    Jung, Yeonsub

    2012-01-01

    Due to accuracy of measurement and improvement of control logic, human beings are freed from time consuming and repeated task. When there are situations where the control logic cannot calculate the next state of system, human beings interrupt the system and steer the system manually. The most scope of human factors is focused on this interruption, and economists are concern how to present information cognitively and reliably. Fukushima nuclear accident has considered the role of human beings again. Human beings are forced to do something without proper knowledge, procedure, and process information. Thus post Fukushima actions should include how for human beings to be trained and how to get real time information. Finally because safety culture can determine behaviors of human beings, the method to cultivate safety culture should be considered

  10. Retrovirus D/New England and its relation to Mason-Pfizer monkey virus.

    OpenAIRE

    Desrosiers, R C; Daniel, M D; Butler, C V; Schmidt, D K; Letvin, N L; Hunt, R D; King, N W; Barker, C S; Hunter, E

    1985-01-01

    Seventeen isolates of retrovirus D/New England have been obtained from three species of macaques at the New England Regional Primate Research Center. Seven of the isolates were obtained from macaques who subsequently died with the macaque immunodeficiency syndrome; other isolates were obtained from macaques with less severe or other forms of illness. Attempts to isolate type D retrovirus from peripheral lymphocytes of 97 apparently healthy macaques have not been successful. Cloned DNA was pre...

  11. Cyclic GMP-AMP Synthase is an Innate Immune Sensor of HIV and Other Retroviruses

    OpenAIRE

    Gao, Daxing; Wu, Jiaxi; Wu, You-Tong; Du, Fenghe; Aroh, Chukwuemika; Yan, Nan; Sun, Lijun; Chen, Zhijian J.

    2013-01-01

    Retroviruses, including HIV, can activate innate immune responses, but the host sensors for retroviruses are largely unknown. Here we show that HIV infection activates cyclic-GMP-AMP (cGAMP) synthase (cGAS) to produce cGAMP, which binds to and activates the adaptor protein STING to induce type-I interferons and other cytokines. Inhibitors of HIV reverse transcriptase, but not integrase, abrogated interferon-β induction by the virus, suggesting that the reverse transcribed HIV DNA triggers the...

  12. Assembly factors for the membrane arm of human complex I.

    Science.gov (United States)

    Andrews, Byron; Carroll, Joe; Ding, Shujing; Fearnley, Ian M; Walker, John E

    2013-11-19

    Mitochondrial respiratory complex I is a product of both the nuclear and mitochondrial genomes. The integration of seven subunits encoded in mitochondrial DNA into the inner membrane, their association with 14 nuclear-encoded membrane subunits, the construction of the extrinsic arm from 23 additional nuclear-encoded proteins, iron-sulfur clusters, and flavin mononucleotide cofactor require the participation of assembly factors. Some are intrinsic to the complex, whereas others participate transiently. The suppression of the expression of the NDUFA11 subunit of complex I disrupted the assembly of the complex, and subcomplexes with masses of 550 and 815 kDa accumulated. Eight of the known extrinsic assembly factors plus a hydrophobic protein, C3orf1, were associated with the subcomplexes. The characteristics of C3orf1, of another assembly factor, TMEM126B, and of NDUFA11 suggest that they all participate in constructing the membrane arm of complex I.

  13. Expression and regulation of the endogenous retrovirus 3 (ERV3 in Hodgkin’s lymphoma cells

    Directory of Open Access Journals (Sweden)

    Stefanie eKewitz

    2013-07-01

    Full Text Available Human endogenous retroviruses (ERV are an integral part of our genome. Expression of ERV is usually switched off but reactivation of ERV has been observed in varying human diseases including cancer. Recently, reactivation of ERV associated promoters in Hodgkin’s lymphoma (HL cells has been described. Despite relatively good prognosis, not all patients with HL can be cured with the established therapy and this therapy is associated with severe late side effects. Therefore, new targets are required for the development of future treatment strategies. Reactivated ERV might represent such target structures. Therefore, we asked which ERV loci are expressed in HL cells. Using DNA microarray analysis, we found no evidence for a general activation of ERV transcription in HL cells. In contrast, we observed down-regulation of ERV3, an ERV with potential tumor suppressor function, in HL cells in comparison to normal blood cells. Interestingly, ERV3 was also differentially expressed in published DNA microarray data from resting versus cycling B cells. Treatment of HL cells with the histone deacetylase inhibitor vorinostat strongly up-regulated ERV3 expression. In addition, we observed up-regulation in HL cells after treatment with hypoxia-mimetic cobalt(II chloride. Like vorinostat, cobalt(II chloride inhibited cell growth of HL cells. Our results suggest that cell cycle inhibition of HL cells is accompanied by up-regulation of ERV3.

  14. The Impact of Evolutionary Driving Forces on Human Complex Diseases: A Population Genetics Approach

    Directory of Open Access Journals (Sweden)

    Amr T. M. Saeb

    2016-01-01

    Full Text Available Investigating the molecular evolution of human genome has paved the way to understand genetic adaptation of humans to the environmental changes and corresponding complex diseases. In this review, we discussed the historical origin of genetic diversity among human populations, the evolutionary driving forces that can affect genetic diversity among populations, and the effects of human movement into new environments and gene flow on population genetic diversity. Furthermore, we presented the role of natural selection on genetic diversity and complex diseases. Then we reviewed the disadvantageous consequences of historical selection events in modern time and their relation to the development of complex diseases. In addition, we discussed the effect of consanguinity on the incidence of complex diseases in human populations. Finally, we presented the latest information about the role of ancient genes acquired from interbreeding with ancient hominids in the development of complex diseases.

  15. Humanism and nature – some reflections on a complex relationship

    Directory of Open Access Journals (Sweden)

    Jörn Rüsen

    2006-04-01

    Full Text Available The paper starts with a systematical analysis of the interrelationship of humanism and nature. It proceeds to a historical reconstruction of this relationship in the development of Western humanism from ancient Rome via Renaissance till the Enlightenment of the 18th century. In both respects the result of the analysis is the same: The Western tradition of humanism is characterised by a gap between an emphasis on the cultural quality of human life on the one hand and nature on the other one. Men are entitled to dominate and govern nature and use it for their purpose. This fits into an idea of a progressing destructive relationship between man and nature in the West. On the other the tradition of humanism has put the gap between man and nature into a harmonising cosmological or theological context. In this context a simple destructive relationship between man and nature is not possible. The humanism of today has to pick up the challenge of the ecological crisis and to refer to its tradition where man and nature are mediated into a meaningful and sense-bearing interrelationship. Instead of simply referring to the traditional cosmology a convincing idea of this mediation or even synthesis can only be made plausible by referring to the already pre-given synthesis between nature and culture, the human body.

  16. Performance in complex motor tasks deteriorates in hyperthermic humans

    DEFF Research Database (Denmark)

    Piil, Jacob Feder; Lundbye-Jensen, Jesper; Trangmar, Steven J

    2017-01-01

    -motor tracking performance was reduced by 10.7 ± 6.5% following exercise-induced hyperthermia when integrated in the multipart protocol and 4.4 ± 5.7% when tested separately (bothP 1.3% (P math tasks...... of information or decision-making prior to responding. We hypothesized that divergences could relate to task complexity and developed a protocol consisting of 1) simple motor task [TARGET_pinch], 2) complex motor task [Visuo-motor tracking], 3) simple math task [MATH_type], 4) combined motor-math task [MATH...

  17. Complex assembly, crystallization and preliminary X-ray crystallographic analysis of the human Rod–Zwilch–ZW10 (RZZ) complex

    Energy Technology Data Exchange (ETDEWEB)

    Altenfeld, Anika; Wohlgemuth, Sabine [Max Planck Institute of Molecular Physiology, Otto Hahn Strasse 11, 44227 Dortmund (Germany); Wehenkel, Annemarie [Institut Curie, CNRS UMR 3348/INSERM U1005, Bâtiment 110, Centre Universitaire, 91405 Orsay CEDEX (France); Vetter, Ingrid R. [Max Planck Institute of Molecular Physiology, Otto Hahn Strasse 11, 44227 Dortmund (Germany); Musacchio, Andrea, E-mail: andrea.musacchio@mpi-dortmund.mpg.de [Max Planck Institute of Molecular Physiology, Otto Hahn Strasse 11, 44227 Dortmund (Germany); University of Duisburg-Essen, Universitätstrasse 1, 45141 Essen (Germany)

    2015-03-20

    The 800 kDa complex of the human Rod, Zwilch and ZW10 proteins (the RZZ complex) was reconstituted in insect cells, purified, crystallized and subjected to preliminary X-ray diffraction analysis. The spindle-assembly checkpoint (SAC) monitors kinetochore–microtubule attachment during mitosis. In metazoans, the three-subunit Rod–Zwilch–ZW10 (RZZ) complex is a crucial SAC component that interacts with additional SAC-activating and SAC-silencing components, including the Mad1–Mad2 complex and cytoplasmic dynein. The RZZ complex contains two copies of each subunit and has a predicted molecular mass of ∼800 kDa. Given the low abundance of the RZZ complex in natural sources, its recombinant reconstitution was attempted by co-expression of its subunits in insect cells. The RZZ complex was purified to homogeneity and subjected to systematic crystallization attempts. Initial crystals containing the entire RZZ complex were obtained using the sitting-drop method and were subjected to optimization to improve the diffraction resolution limit. The crystals belonged to space group P3{sub 1} (No. 144) or P3{sub 2} (No. 145), with unit-cell parameters a = b = 215.45, c = 458.7 Å, α = β = 90.0, γ = 120.0°.

  18. Human resource management practices in a medical complex in the ...

    African Journals Online (AJOL)

    staff, accountability, general HR efficiency, occupation-specific dispensation adjustments and performance management and development system efficiency, and availability of HR staff. All these characteristics were judged to be poor. Conclusion. HRM practices in this Eastern Cape medical complex were inadequate and a ...

  19. The murine endogenous retrovirus MIA14 encodes an active aspartic proteinase that is functionally similar to proteinases from D-type retroviruses

    Czech Academy of Sciences Publication Activity Database

    Stříšovský, Kvido; Smrž, Daniel; Fehrmann, F.; Kräusslich, H. G.; Konvalinka, Jan

    2002-01-01

    Roč. 398, č. 2 (2002), s. 261-268 ISSN 0003-9861 Grant - others:HHMI(GB) 75195-54081 Institutional research plan: CEZ:AV0Z4055905 Keywords : endogenous retrovirus Subject RIV: CE - Biochemistry Impact factor: 2.606, year: 2002

  20. Accommodating complexity and human behaviors in decision analysis.

    Energy Technology Data Exchange (ETDEWEB)

    Backus, George A.; Siirola, John Daniel; Schoenwald, David Alan; Strip, David R.; Hirsch, Gary B.; Bastian, Mark S.; Braithwaite, Karl R.; Homer, Jack [Homer Consulting

    2007-11-01

    This is the final report for a LDRD effort to address human behavior in decision support systems. One sister LDRD effort reports the extension of this work to include actual human choices and additional simulation analyses. Another provides the background for this effort and the programmatic directions for future work. This specific effort considered the feasibility of five aspects of model development required for analysis viability. To avoid the use of classified information, healthcare decisions and the system embedding them became the illustrative example for assessment.

  1. Control of RFM strain endogenous retrovirus in RFM mouse cells

    International Nuclear Information System (INIS)

    Tennant, R.W.; Otten, J.A.; Wang, T.W.; Liou, R.S.; Brown, A.; Yang, W.K.

    1983-01-01

    RFM/Un mice express an endogenous type C retrovirus throughout their life span in many tissues; primary or established embryo fibroblast cell cultures do not express a virus but can be induced by exposure to 5-iodo-2'-deoxyuridine. All of our sources yielded a single ecotropic virus (RFV) which appeared to be related more closely to the endogenous N-tropic virus (WN1802N) of BALB/c mice than to Gross leukemia virus on the basis of two-dimensional gel electropherograms of virion proteins. No xenotropic or recombinant viruses were isolated by cocultivation techniques. RFV is N-tropic, and RFM/Un cells possess the Fv-1/sup n/ allele, as indicated by restriction of B-tropic virus and susceptibility to Gross strain N-tropic virus. However, RFM cells are highly resistant to RFV and other endogenous N-tropic viruses. This resistance is expressed by two-hit titration kinetics and by inhibition of viral linear duplex DNA formation. This is similar to the effects of the Fv-1 locus, but preliminary work has shown no apparent genetic linkage between the two restrictions. The relative strength of the restriction, the presence of a single class of ecotropic virus, and the absence of recombinant viruses suggest that in RFM mice virus is expressed only in cells in which it is induced and not by cell-to-cell transmission

  2. Unexpected Diversity and Expression of Avian Endogenous Retroviruses

    Science.gov (United States)

    Bolisetty, Mohan; Blomberg, Jonas; Benachenhou, Farid; Sperber, Göran; Beemon, Karen

    2012-01-01

    ABSTRACT Endogenous retroviruses (ERVs) were identified and characterized in three avian genomes to gain insight into early retroviral evolution. Using the computer program RetroTector to detect relatively intact ERVs, we identified 500 ERVs in the chicken genome, 150 in the turkey genome, and 1,200 in the zebra finch genome. Previous studies suggested that endogenous alpharetroviruses were present in chicken genomes. In this analysis, a small number of alpharetroviruses were seen in the chicken and turkey genomes; however, these were greatly outnumbered by beta-like, gamma-like, and alphabeta proviruses. While the avian ERVs belonged to the same major groups as mammalian ERVs, they were more heterogeneous. In particular, the beta-like viruses revealed an evolutionary continuum with the gradual acquisition and loss of betaretroviral markers and a transition from beta to alphabeta and then to alpharetroviruses. Thus, it appears that birds may resemble a melting pot for early ERV evolution. Many of the ERVs were integrated in clusters on chromosomes, often near centromeres. About 25% of the chicken ERVs were in or near cellular transcription units; this is nearly random. The majority of these integrations were in the sense orientation in introns. A higher-than-random number of integrations were >100 kb from the nearest gene. Deep-sequencing studies of chicken embryo fibroblasts revealed that about 20% of the 500 ERVs were transcribed and translated. A subset of these were also transcribed in vivo in chickens, showing tissue-specific patterns of expression. PMID:23073767

  3. Evidence of simian retrovirus type D by polymerase chain reaction.

    Science.gov (United States)

    Hwa, Christian Z R; Tsai, Sheung Pun; Yee, JoAnn L; Van Rompay, Koen K; Roberts, Jeffrey A

    2017-06-01

    Over the past few years, there have been reports of finding Simian retrovirus type D (SRV) in macaque colonies where some animals were characterized as antibody positive but virus negative raising questions about how SRV was transmitted or whether there is a variant strain detected by antibody but not polymerase chain reaction (PCR) in current use. We developed a three-round nested PCR assay using degenerate primers targeting the pol gene to detect for SRV serotypes 1-5 and applied this newly validated PCR assay to test macaque DNA samples collected in China from 2010 to 2015. Using the nested PCR assay validated in this study, we found 0.15% of the samples archived on FTA ® cards were positive. The source of SRV infection identified within domestic colonies might have originated from imported macaques. The multiplex nested PCR assay developed here may supplement the current assays for SRV. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Alteration to the SWI/SNF complex in human cancers

    Directory of Open Access Journals (Sweden)

    Vanessa S. Gordon

    2011-12-01

    Full Text Available The SWI/SNF complex is a key catalyst for gene expression and regulates a variety of pathways, many of which have anticancer roles. Its central roles in cellular growth control, DNA repair, differentiation, cell adhesion and development are often targeted, and inactivated, during cancer development and progression. In this review, we will discuss what is known about how SWI/SNF is inactivated, and describe the potential impact of abrogating this complex. BRG1 and BRM are the catalytic subunits which are essential for SWI/SNF function, and thus, it is not surprising that they are lost in a variety of cancer types. As neither gene is mutated when lost, the mechanism of suppression, as well as the impact of potential gene activity restoration, are reviewed.

  5. Suppressive effect on polyclonal B-cell activation of a synthetic peptide homologous to a transmembrane component of oncogenic retroviruses

    Energy Technology Data Exchange (ETDEWEB)

    Mitani, M.; Cianciolo, G.J.; Snyderman, R.; Yasuda, M.; Good, R.A.; Day, N.K.

    1987-01-01

    Purified feline leukemia virus, UV light-inactivated feline leukemia virus, and a synthetic peptide (CKS-17) homologous to a well-conserved region of the transmembrane components of several human and animal retroviruses were each studied for their effect on IgG production by feline peripheral blood lymphocytes. Using a reverse hemolytic plaque assay, both the viable virus and the UV-inactivated feline leukemia virus, but not the CKS-17, activated B lymphocytes to secrete IgG. When staphylococcal protein A, a polyclonal B-cell activator, was used to stimulate IgG synthesis by feline lymphocytes, the viable virus, the UV-inactivated virus, and the CKS-17 peptide each strongly suppressed IgG secretion without compromising viability of the lymphocytes. These finding suggest that the immunosuppressive influences of feline leukemia virus on immunoglobulin synthesis may reside in a conserved portion of the envelope glycoprotein that includes the region homologous to CKS-17.

  6. Suppressive effect on polyclonal B-cell activation of a synthetic peptide homologous to a transmembrane component of oncogenic retroviruses

    International Nuclear Information System (INIS)

    Mitani, M.; Cianciolo, G.J.; Snyderman, R.; Yasuda, M.; Good, R.A.; Day, N.K.

    1987-01-01

    Purified feline leukemia virus, UV light-inactivated feline leukemia virus, and a synthetic peptide (CKS-17) homologous to a well-conserved region of the transmembrane components of several human and animal retroviruses were each studied for their effect on IgG production by feline peripheral blood lymphocytes. Using a reverse hemolytic plaque assay, both the viable virus and the UV-inactivated feline leukemia virus, but not the CKS-17, activated B lymphocytes to secrete IgG. When staphylococcal protein A, a polyclonal B-cell activator, was used to stimulate IgG synthesis by feline lymphocytes, the viable virus, the UV-inactivated virus, and the CKS-17 peptide each strongly suppressed IgG secretion without compromising viability of the lymphocytes. These finding suggest that the immunosuppressive influences of feline leukemia virus on immunoglobulin synthesis may reside in a conserved portion of the envelope glycoprotein that includes the region homologous to CKS-17

  7. A recombinant endogenous retrovirus amplified in a mouse neuroblastoma is involved in tumor growth in vivo.

    Science.gov (United States)

    Pothlichet, Julien; Heidmann, Thierry; Mangeney, Marianne

    2006-08-15

    The theory of immunoediting postulates that tumor cells exhibit a reduced immunogenicity to escape eradication by the host immune system. It has been proposed that endogenous retroviruses--provided that they are active--could play a role in this process, via the immunosuppressive domain carried by their envelope protein. Here, we demonstrate that the Neuro-2a tumor cell line--originating from a spontaneous A/J mouse neuroblastoma--produces an infectious retrovirus that most probably results from a recombination event between 2 mouse endogenous retroviral elements. This Neuro-2a-associated recombinant retrovirus derives from the unique ecotropic provirus located at the Emv-1 locus, but with a gag sequence conferring B-tropism, thus allowing its high-level amplification in Neuro-2a cells. We show that knocking down -by RNA interference- this endogenous retrovirus in Neuro-2a cells has no effect on the transformed phenotype of the cells, but results in delayed tumor growth and prolonged animal survival, following engraftment of the cells into immunocompetent mice. Recombination between endogenous retroviruses, amplification of the resulting element and high-level expression of its immunosuppressive activity are therefore likely steps of an immunoediting process, leading to an invading tumor. Copyright 2006 Wiley-Liss, Inc.

  8. A novel approach to achieving modular retrovirus clearance for a parvovirus filter.

    Science.gov (United States)

    Stuckey, Juliana; Strauss, Daniel; Venkiteshwaran, Adith; Gao, Jinxin; Luo, Wen; Quertinmont, Michelle; O'Donnell, Sean; Chen, Dayue

    2014-01-01

    Viral filtration is routinely incorporated into the downstream purification processes for the production of biologics produced in mammalian cell cultures (MCC) to remove potential viral contaminants. In recent years, the use of retentive filters designed for retaining parvovirus (~20 nm) has become an industry standard in a conscious effort to further improve product safety. Since retentive filters remove viruses primarily by the size exclusion mechanism, it is expected that filters designed for parvovirus removal can effectively clear larger viruses such as retroviruses (~100 nm). In an attempt to reduce the number of viral clearance studies, we have taken a novel approach to demonstrate the feasibility of claiming modular retrovirus clearance for Asahi Planova 20N filters. Porcine parvovirus (PPV) and xenotropic murine leukemia virus (XMuLV) were co-spiked into six different feedstreams and then subjected to laboratory scale Planova 20N filtration. Our results indicate that Planova 20N filters consistently retain retroviruses and no retrovirus has ever been detected in the filtrates even when significant PPV breakthrough is observed. Based on the data from multiple in-house viral validation studies and the results from the co-spiking experiments, we have successfully claimed a modular retrovirus clearance of greater than 6 log10 reduction factors (LRF) to support clinical trial applications in both USA and Europe. © 2013 American Institute of Chemical Engineers.

  9. Endogenous Jaagsiekte Sheep Retrovirus RNA is expressed by different cell types in ovine foetus and placenta

    Directory of Open Access Journals (Sweden)

    E Sanna

    2010-01-01

    Full Text Available The endogenous retroviruses are inherited elements transmitted trough the germline of most animal species and their biological role is still controversial. Ovine Pulmonary Carcinoma (OPC represents a good model for studying the interactions of endogenous retroviruses with their exogenous counterparts. The type D exogenous retrovirus known as Jaagsiekte Sheep Retro-Virus (JSRV is necessary and sufficient to cause OPC in domestic and wild sheep, but both affected and unaffected animals host in their genome 15 to 20 copies of related endogenous retroviruses named endogenous JSRV (enJSRV. In this study we evaluated the expression of enJSRV gag sequences in ovine foetal and placental tissues. RNA in situ hybridisation was performed on tissue sections of thymi, lymph nodes and lungs from ovine foetuses and related placentas, taken at a late stage of development. Reverse transcriptase- in situ polymerase chain reactions were also carried out on placental samples to better define the involved cells. In foetal tissues, specific signals were observed in the thymus medulla, lymph nodes and, at a lesser extent, in foetal bronchiolar cells. In the placental tissues, positive areas were detected in various cell types in the sincythium-and cyto-trophoblast. These data demonstrate that en JSRV RNA is largely expressed in a broad spectrum of cells including tissues which are critical for the development of the immune system.

  10. Interaction Profiling Identifies the Human Nuclear Exosome Targeting Complex

    DEFF Research Database (Denmark)

    Lubas, Michal Szymon; Christensen, Marianne Skovgaard; Kristiansen, Maiken Søndergaard

    2011-01-01

    from nucleoli, and consistently NEXT is specifically required for the exosomal degradation of promoter upstream transcripts (PROMPTs). We also detect putative homolog TRAMP subunits hTRF4-2 (Trf4p) and ZCCHC7 (Air2p) in hRRP6 and hMTR4 precipitates. However, at least ZCCHC7 function is restricted...... to nucleoli. Our results suggest that human nuclear exosome degradation pathways comprise modules of spatially organized cofactors that diverge from the yeast model....

  11. The Complex Functioning of the Human Brain: The Two Hemispheres

    Directory of Open Access Journals (Sweden)

    Iulia Cristina Timofti

    2010-04-01

    Full Text Available The present study reveals just a glimpse of the possible functions and reactions that the human brain can have. I considered as good examples different situations characteristic both of a normal person and a split-brain one. These situations prove that the brain, although divided in two, works as a unit, as an amazing computer that has data processing as a main goal.

  12. Nucleotide excision repair : complexes and complexities : a study of global genome repair in human cells

    NARCIS (Netherlands)

    Volker, Marcel

    2006-01-01

    Of all exogenous agents that damage genomic DNA and hence threaten its integrity, the ultraviolet B (UVB) component of sunlight is highly relevant because of its abundance. UVB induces predominantly cyclobutane pyrimidine dimers and 6-4 photoproducts. In humans, these photolesions are repaired by

  13. Inhibition of human aromatase complex (CYP19) by antiepileptic drugs

    DEFF Research Database (Denmark)

    Jacobsen, Naja Wessel; Halling-Sørensen, Bent; Birkved, Franziska Maria A Kramer

    2008-01-01

    of 1.4-49.7 mM. Carbamazepine, gabapentin, primidone, topiramate and vigabatrin showed no inhibition. Additionally, binary drug combinations were tested to investigate if combination therapy could potentiate the aromatase inhibition. Additive inhibition was seen in combination experiments...... with valproate and phenobarbital. When adding carbamazepine to a range of valproate concentrations no additional inhibition was seen. The data for some of the AEDs show that side effects on steroid synthesis in humans due to inhibition of aromatase should be considered....

  14. The Cultural Historical Complexity of Human Personality Adaptation

    Directory of Open Access Journals (Sweden)

    Melissa E. Wynn

    2012-10-01

    Full Text Available Research on implicit intelligence has conceptualized students’ beliefs about the nature of intelligence as either fixed or malleable. This research has largely not included African American adolescents, a group for whom beliefs about intelligence have a cultural historical complexity related to both scientific racism and master narratives of race and intelligence. The purpose of this study was to investigate the nature of implicit theories of intelligence for 63 African American adolescents who are seventh and eighth graders in a public charter school. The two-way ANOVA revealed that these adolescents held a malleable view of intelligence, which did not vary by gender or grade. Exploratory correlation analysis showed some consistent relationships with achievement motivation variables found in other studies. These findings may be explained by African American cultural values and the personality characteristic adaptations that they make living within a racialized society.

  15. Complex Trajectories of Brain Development in the Healthy Human Fetus.

    Science.gov (United States)

    Andescavage, Nickie N; du Plessis, Adre; McCarter, Robert; Serag, Ahmed; Evangelou, Iordanis; Vezina, Gilbert; Robertson, Richard; Limperopoulos, Catherine

    2017-11-01

    This study characterizes global and hemispheric brain growth in healthy human fetuses during the second half of pregnancy using three-dimensional MRI techniques. We studied 166 healthy fetuses that underwent MRI between 18 and 39 completed weeks gestation. We created three-dimensional high-resolution reconstructions of the brain and calculated volumes for left and right cortical gray matter (CGM), fetal white matter (FWM), deep subcortical structures (DSS), and the cerebellum. We calculated the rate of growth for each tissue class according to gestational age and described patterns of hemispheric growth. Each brain region demonstrated major increases in volume during the second half of gestation, the most pronounced being the cerebellum (34-fold), followed by FWM (22-fold), CGM (21-fold), and DSS (10-fold). The left cerebellar hemisphere, CGM, and DSS had larger volumes early in gestation, but these equalized by term. It has been increasingly recognized that brain asymmetry evolves throughout the human life span. Advanced quantitative MRI provides noninvasive measurements of early structural asymmetry between the left and right fetal brain that may inform functional and behavioral laterality differences seen in children and young adulthood. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  16. Endogenous retroviruses in fish genomes: from relics of past infections to evolutionary innovations?

    Directory of Open Access Journals (Sweden)

    Magali Naville

    2016-08-01

    Full Text Available The increasing availability of fish genome sequences has allowed to gain new insights into the diversity and host distribution of retroviruses in fish and other vertebrates. This distribution can be assessed through the identification and analysis of endogenous retroviruses, which are proviral remnants of past infections integrated in genomes. Retroviral sequences are probably important for evolution through their ability to induce rearrangements and to contribute regulatory and coding sequences; they may also protect their host against new infections. We argue that the current mass of genome sequences will soon strongly improve our understanding of retrovirus diversity and evolution in aquatic animals, with the identification of new/re-emerging elements and host resistance genes that restrict their infectivity.

  17. One hundred twenty years of koala retrovirus evolution determined from museum skins

    DEFF Research Database (Denmark)

    Avila Arcos, Maria del Carmen; Ho, Simon Y. W.; Ishida, Yasuko

    2013-01-01

    Although endogenous retroviruses are common across vertebrate genomes, the koala retrovirus (KoRV) is the only retrovirus known to be currently invading the germ line of its host. KoRV is believed to have first infected koalas in northern Australia less than two centuries ago. We examined Ko......RV in 28 koala museum skins collected in the late 19th and 20th centuries and deep sequenced the complete proviral envelope region from five northern Australian specimens. Strikingly, KoRV env sequences were conserved among koalas collected over the span of a century, and two functional motifs that affect...... viral infectivity were fixed across the museum koala specimens. We detected only 20 env polymorphisms among the koalas, likely representing derived mutations subject to purifying selection. Among northern Australian koalas, KoRV was already ubiquitous by the late 19th century, suggesting that Ko...

  18. Epigenetic interplay between mouse endogenous retroviruses and host genes.

    Science.gov (United States)

    Rebollo, Rita; Miceli-Royer, Katharine; Zhang, Ying; Farivar, Sharareh; Gagnier, Liane; Mager, Dixie L

    2012-10-03

    Transposable elements are often the targets of repressive epigenetic modifications such as DNA methylation that, in theory, have the potential to spread toward nearby genes and induce epigenetic silencing. To better understand the role of DNA methylation in the relationship between transposable elements and genes, we assessed the methylation state of mouse endogenous retroviruses (ERVs) located near genes. We found that ERVs of the ETn/MusD family show decreased DNA methylation when near transcription start sites in tissues where the nearby gene is expressed. ERVs belonging to the IAP family, however, are generally heavily methylated, regardless of the genomic environment and the tissue studied. Furthermore, we found full-length ETn and IAP copies that display differential DNA methylation between their two long terminal repeats (LTRs), suggesting that the environment surrounding gene promoters can prevent methylation of the nearby LTR. Spreading from methylated ERV copies to nearby genes was rarely observed, with the regions between the ERVs and genes apparently acting as a boundary, enriched in H3K4me3 and CTCF, which possibly protects the unmethylated gene promoter. Furthermore, the flanking regions of unmethylated ERV copies harbor H3K4me3, consistent with spreading of euchromatin from the host gene toward ERV insertions. We have shown that spreading of DNA methylation from ERV copies toward active gene promoters is rare. We provide evidence that genes can be protected from ERV-induced heterochromatin spreading by either blocking the invasion of repressive marks or by spreading euchromatin toward the ERV copy.

  19. Felis Catus Gammaherpesvirus 1 DNAemia in Whole Blood from Therapeutically Immunosuppressed or Retrovirus-Infected Cats

    Directory of Open Access Journals (Sweden)

    Alicia J. McLuckie

    2017-03-01

    Full Text Available Gammaherpesviruses are major co-pathogens of human immunodeficiency virus (HIV infection, making the interactions between feline immunodeficiency virus (FIV and Felis catus gammaherpesvirus 1 (FcaGHV1 pertinent to both human and veterinary medical research. FIV-infected cats are at increased risk of FcaGHV1 DNAemia and consistently harbor higher FcaGHV1 loads than FIV-uninfected cats. Whether immune deficiencies unrelated to FIV are associated with similar risks is unknown. Using whole blood FcaGHV1 qPCR, we found no difference in the frequency of DNAemia or DNA load in therapeutically immunosuppressed (P1, n = 18 or feline leukemia virus (FeLV-infected (P2, n = 57 patients compared with age- and sex-matched controls (C1, n = 58; C2, n = 57. In contrast, FIV/FeLV-co-infected cats (P3, n = 5 were at increased risk of FcaGHV1 DNAemia compared to retrovirus uninfected controls (C3, n = 39; p = 0.0068, and had a higher median FcaGHV1 DNA load, although the latter was not significant. FIV/FeLV-co-infected cats (P3 had a similar frequency of FcaGHV1 DNAemia reported compared to FIV-infected controls (C4. In conclusion, we found no evidence that cats with therapeutic immunosuppression or FeLV infection were at greater risk of FcaGHV1 DNAemia or had higher FcaGHV1 DNA load in whole blood. The risk of DNAemia in FIV/FeLV-co-infected cats was similar to that documented previously in cats infected with FIV alone.

  20. Endogenous retrovirus induces leukemia in a xenograft mouse model for primary myelofibrosis.

    Science.gov (United States)

    Triviai, Ioanna; Ziegler, Marion; Bergholz, Ulla; Oler, Andrew J; Stübig, Thomas; Prassolov, Vladimir; Fehse, Boris; Kozak, Christine A; Kröger, Nicolaus; Stocking, Carol

    2014-06-10

    The compound immunodeficiencies in nonobese diabetic (NOD) inbred mice homozygous for the Prkdc(scid) and Il2rg(null) alleles (NSG mice) permit engraftment of a wide-range of primary human cells, enabling sophisticated modeling of human disease. In studies designed to define neoplastic stem cells of primary myelofibrosis (PMF), a myeloproliferative neoplasm characterized by profound disruption of the hematopoietic microenvironment, we observed a high frequency of acute myeloid leukemia (AML) in NSG mice. AML was of mouse origin, confined to PMF-xenografted mice, and contained multiple clonal integrations of ecotropic murine leukemia virus (E-MuLV). Significantly, MuLV replication was not only observed in diseased mice, but also in nontreated NSG controls. Furthermore, in addition to the single ecotropic endogenous retrovirus (eERV) located on chromosome 11 (Emv30) in the NOD genome, multiple de novo germ-line eERV integrations were observed in mice from each of four independent NSG mouse colonies. Analysis confirmed that E-MuLV originated from the Emv30 provirus and that recombination events were not necessary for virus replication or AML induction. Pathogenicity is thus likely attributable to PMF-mediated paracrine stimulation of mouse myeloid cells, which serve as targets for retroviral infection and transformation, as evidenced by integration into the Evi1 locus, a hotspot for retroviral-induced myeloid leukemia. This study thus corroborates a role of paracrine stimulation in PMF disease progression, underlines the importance of target cell type and numbers in MuLV-induced disease, and mandates awareness of replicating MuLV in NOD immunodeficient mice, which can significantly influence experimental results and their interpretation.

  1. Neutral Theory: From Complex Population History to Natural Selection and Sociocultural Phenomena in Human Populations.

    Science.gov (United States)

    Austerlitz, Frédéric; Heyer, Evelyne

    2018-06-01

    Here, we present a synthetic view on how Kimura's Neutral theory has helped us gaining insight on the different evolutionary forces that shape human evolution. We put this perspective in the frame of recent emerging challenges: the use of whole genome data for reconstructing population histories, natural selection on complex polygenic traits, and integrating cultural processes in human evolution.

  2. Improved methodology for the affinity isolation of human protein complexes expressed at near endogenous levels

    DEFF Research Database (Denmark)

    Domanski, Michal; Molloy, Kelly; Jiang, Hua

    2012-01-01

    An efficient and reliable procedure for the capture of affinity-tagged proteins and associated complexes from human cell lines is reported. Through multiple optimizations, high yield and low background affinity-purifications are achieved from modest quantities of human cells expressing endogenous...

  3. Skill networks and measures of complex human capital.

    Science.gov (United States)

    Anderson, Katharine A

    2017-11-28

    We propose a network-based method for measuring worker skills. We illustrate the method using data from an online freelance website. Using the tools of network analysis, we divide skills into endogenous categories based on their relationship with other skills in the market. Workers who specialize in these different areas earn dramatically different wages. We then show that, in this market, network-based measures of human capital provide additional insight into wages beyond traditional measures. In particular, we show that workers with diverse skills earn higher wages than those with more specialized skills. Moreover, we can distinguish between two different types of workers benefiting from skill diversity: jacks-of-all-trades, whose skills can be applied independently on a wide range of jobs, and synergistic workers, whose skills are useful in combination and fill a hole in the labor market. On average, workers whose skills are synergistic earn more than jacks-of-all-trades. Copyright © 2017 the Author(s). Published by PNAS.

  4. The human cumulus--oocyte complex gene-expression profile

    Science.gov (United States)

    Assou, Said; Anahory, Tal; Pantesco, Véronique; Le Carrour, Tanguy; Pellestor, Franck; Klein, Bernard; Reyftmann, Lionel; Dechaud, Hervé; De Vos, John; Hamamah, Samir

    2006-01-01

    BACKGROUND The understanding of the mechanisms regulating human oocyte maturation is still rudimentary. We have identified transcripts differentially expressed between immature and mature oocytes, and cumulus cells. METHODS Using oligonucleotides microarrays, genome wide gene expression was studied in pooled immature and mature oocytes or cumulus cells from patients who underwent IVF. RESULTS In addition to known genes such as DAZL, BMP15 or GDF9, oocytes upregulated 1514 genes. We show that PTTG3 and AURKC are respectively the securin and the Aurora kinase preferentially expressed during oocyte meiosis. Strikingly, oocytes overexpressed previously unreported growth factors such as TNFSF13/APRIL, FGF9, FGF14, and IL4, and transcription factors including OTX2, SOX15 and SOX30. Conversely, cumulus cells, in addition to known genes such as LHCGR or BMPR2, overexpressed cell-tocell signaling genes including TNFSF11/RANKL, numerous complement components, semaphorins (SEMA3A, SEMA6A, SEMA6D) and CD genes such as CD200. We also identified 52 genes progressively increasing during oocyte maturation, comprising CDC25A and SOCS7. CONCLUSION The identification of genes up and down regulated during oocyte maturation greatly improves our understanding of oocyte biology and will provide new markers that signal viable and competent oocytes. Furthermore, genes found expressed in cumulus cells are potential markers of granulosa cell tumors. PMID:16571642

  5. The human factor in operation and maintenance of complex high-reliability systems

    International Nuclear Information System (INIS)

    Ryan, T.G.

    1989-01-01

    Human factors issues in probabilistic risk assessment (PRAs) of complex high-reliability systems are addressed. These PRAs influence system operation and technical support programs such as maintainability, test, and surveillance. Using the U.S. commercial nuclear power industry as the setting, the paper addresses the manner in which PRAs currently treat human performance, the state of quantification methods and source data for analyzing human performance, and the role of human factors specialist in the analysis. The paper concludes with a presentation of TALENT, an emerging concept for fully integrating broad-based human factors expertise into the PRA process, is presented. 47 refs

  6. Expression patterns of endogenous avian retrovirus ALVE1 and its response to infection with exogenous avian tumour viruses.

    Science.gov (United States)

    Hu, Xuming; Zhu, Wenqi; Chen, Shihao; Liu, Yangyang; Sun, Zhen; Geng, Tuoyu; Song, Chengyi; Gao, Bo; Wang, Xiaoyan; Qin, Aijian; Cui, Hengmi

    2017-01-01

    Endogenous retroviruses (ERVs) are genomic elements that are present in a wide range of vertebrates and have been implicated in a variety of human diseases, including cancer. However, the characteristic expression patterns of ERVs, particularly in virus-induced tumours, is not fully clear. DNA methylation was analysed by bisulfite pyrosequencing, and gene expression was analysed by RT-qPCR. In this study, we first found that the endogenous avian retrovirus ALVE1 was highly expressed in some chicken tissues (including the heart, bursa, thymus, and spleen) at 2 days of age, but its expression was markedly decreased at 35 days of age. In contrast, the CpG methylation level of ALVE1 was significantly lower in heart and bursa at 2 days than at 35 days of age. Moreover, we found that the expression of ALVE1 was significantly inhibited in chicken embryo fibroblast cells (CEFs) and MSB1 cells infected with avian leukosis virus subgroup J (ALVJ) and reticuloendotheliosis virus (REV) at the early stages of infection. In contrast, the expression of the ALVE1 env gene was significantly induced in CEFs and MSB1 cells infected with Marek's disease virus (MDV). However, the methylation and expression levels of the ALVE1 long terminal repeat (LTR) did not show obvious alterations in response to viral infection. The present study revealed the expression patterns of ALVE1 in a variety of chicken organs and tissues and in chicken cells in response to avian tumour virus infection. These findings may be of significance for understanding the role and function of ERVs that are present in the host genome.

  7. Connectivity in the human brain dissociates entropy and complexity of auditory inputs.

    Science.gov (United States)

    Nastase, Samuel A; Iacovella, Vittorio; Davis, Ben; Hasson, Uri

    2015-03-01

    Complex systems are described according to two central dimensions: (a) the randomness of their output, quantified via entropy; and (b) their complexity, which reflects the organization of a system's generators. Whereas some approaches hold that complexity can be reduced to uncertainty or entropy, an axiom of complexity science is that signals with very high or very low entropy are generated by relatively non-complex systems, while complex systems typically generate outputs with entropy peaking between these two extremes. In understanding their environment, individuals would benefit from coding for both input entropy and complexity; entropy indexes uncertainty and can inform probabilistic coding strategies, whereas complexity reflects a concise and abstract representation of the underlying environmental configuration, which can serve independent purposes, e.g., as a template for generalization and rapid comparisons between environments. Using functional neuroimaging, we demonstrate that, in response to passively processed auditory inputs, functional integration patterns in the human brain track both the entropy and complexity of the auditory signal. Connectivity between several brain regions scaled monotonically with input entropy, suggesting sensitivity to uncertainty, whereas connectivity between other regions tracked entropy in a convex manner consistent with sensitivity to input complexity. These findings suggest that the human brain simultaneously tracks the uncertainty of sensory data and effectively models their environmental generators. Copyright © 2014. Published by Elsevier Inc.

  8. Labeling of human serum albumin with 105Rh-cysteine complexes

    International Nuclear Information System (INIS)

    Lo, J.M.; Pillai, M.R.A.; John, C.S.; Troutner, D.E.

    1990-01-01

    The conjugation of a complex formed by reacting RhCl 3 with cysteine to human serum albumin has been investigated. Approximately 50% of the rhodium (labelled with 105 Rh) was converted to the complex. Conjugation of the complex to HSA via the ECDI method resulted in yields of ∼ 40% of the total rhodium or ∼ 80% of the Rh-cysteine complex. No conjugation was observed in the absence of the ECDI. At approximately equal molar concentrations of rhodium and HSA, an average of ∼ 0.4 rhodium atoms per HSA molecule was achieved. (author)

  9. Review on porcine endogenous retrovirus detection assays—impact on quality and safety of xenotransplants

    Science.gov (United States)

    Godehardt, Antonia W; Rodrigues Costa, Michael; Tönjes, Ralf R

    2015-01-01

    Xenotransplantation of porcine organs, tissues, and cells inherits a risk for xenozoonotic infections. Viable tissues and cells intended for transplantation have to be considered as potentially contaminated non-sterile products. The demands on microbial testing, based on the regulatory requirements, are often challenging due to a restricted shelf life or the complexity of the product itself. In Europe, the regulatory framework for xenogeneic cell therapy is based on the advanced therapy medicinal products (ATMP) regulation (2007), the EMA CHMP Guideline on xenogeneic cell-based medicinal products (2009), as well as the WHO and Council of Europe recommendations. In the USA, FDA guidance for industry (2003) regulates the use of xenotransplants. To comply with the regulations, validated test methods need to be established that reveal the microbial status of a transplant within its given shelf life, complemented by strictly defined action alert limits and supported by breeding in specific pathogen-free (SPF) facilities. In this review, we focus on assays for the detection of the porcine endogenous retroviruses PERV-A/-B/-C, which exhibit highly polymorphic proviral loci in pig genomes. PERVs are transmitted vertically and cannot be completely eliminated by breeding or gene knock out technology. PERVs entail a public health concern that will persist even if no evidence of PERV infection of xenotransplant recipients in vivo has been revealed yet. Nevertheless, infectious risks must be minimized by full assessment of pigs as donors by combining different molecular screening assays for sensitive and specific detection as well as a functional analysis of the infectivity of PERV including an adequate monitoring of recipients. PMID:25641488

  10. [Elderly human being with ostomy and environments of care: reflection on the perspective of complexity].

    Science.gov (United States)

    Barros, Edaiane Joana Lima; Santos, Silvana Sidney Costa; Lunardi, Valéria Lerch; Lunardi Filho, Wilson Danilo

    2012-01-01

    This is discussion about the relationship between elderly human beings with ostomy and their environments care, under the perspective of Complexity Edgar Morin. An axis holds the reflection: environments of care for elderly humans with ostomy. In this sense, we present three types of environment that surround the context of elderly humans with ostomy: home environment, group environment and hospital environment. This brings, as a social contribution, a new look about resizing caring of elderly humans with ostomy in their environment. It is considered that the environment hosting this human being contains a diversity of feelings, emotions, experiences; it binds multiple meanings, from the Complexity perspective, about the relationship between the environment and the caring process.

  11. Inherently variable responses to glucocorticoid stress among endogenous retroviruses isolated from 23 mouse strains.

    Science.gov (United States)

    Hsu, Karen; Lee, Young-Kwan; Chew, Alex; Chiu, Sophia; Lim, Debora; Greenhalgh, David G; Cho, Kiho

    2017-10-01

    Active participation of endogenous retroviruses (ERVs) in disease processes has been exemplified by the finding that the HERV (human ERV)-W envelope protein is involved in the pathogenesis of multiple sclerosis, an autoimmune disease. We also demonstrated that injury-elicited stressors alter the expression of murine ERVs (MuERVs), both murine leukemia virus-type and mouse mammary tumor virus (MMTV)-type (MMTV-MuERV). In this study, to evaluate MMTV-MuERVs' responses to stress (e.g., injury, infection)-elicited systemic glucocorticoid (GC) levels, we examined the GC-stress response of 64 MMTV-MuERV promoters isolated from the genomes of 23 mouse strains. All 64 promoters responded to treatment with a synthetic GC, dexamethasone (DEX), at a wide range from a 0.6- to 85.7-fold increase in reporter activity compared to no treatment. An analysis of the 10 lowest and 10 highest DEX responders revealed specific promoter elements exclusively present in either the three lowest or the two highest responders. Each promoter had a unique profile of transcription regulatory elements and the glucocorticoid response element (GRE) was identified in all promoters with the number of GREs ranging from 2 to 7. The three lowest DEX responders were the only promoters with two GREs. The findings from this study suggest that certain MMTV-MuERVs are more responsive to stress-elicited systemic GC elevation compared to the others. The mouse strain-specific genomic MMTV-MuERV profiles and individual MMTV-MuERVs' differential responses to GC-stress might explain, at least in part, the variable inflammatory responses to injury and/or infection, often observed among different mouse strains. This article is part of a Special Issue entitled: Immune and Metabolic Alterations in Trauma and Sepsis edited by Dr. Raghavan Raju. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma.

    Science.gov (United States)

    Krishnamurthy, Janani; Rabinovich, Brian A; Mi, Tiejuan; Switzer, Kirsten C; Olivares, Simon; Maiti, Sourindra N; Plummer, Joshua B; Singh, Harjeet; Kumaresan, Pappanaicken R; Huls, Helen M; Wang-Johanning, Feng; Cooper, Laurence J N

    2015-07-15

    The human endogenous retrovirus (HERV-K) envelope (env) protein is a tumor-associated antigen (TAA) expressed on melanoma but not normal cells. This study was designed to engineer a chimeric antigen receptor (CAR) on T-cell surface, such that they target tumors in advanced stages of melanoma. Expression of HERV-K protein was analyzed in 220 melanoma samples (with various stages of disease) and 139 normal organ donor tissues using immunohistochemical (IHC) analysis. HERV-K env-specific CAR derived from mouse monoclonal antibody was introduced into T cells using the transposon-based Sleeping Beauty (SB) system. HERV-K env-specific CAR(+) T cells were expanded ex vivo on activating and propagating cells (AaPC) and characterized for CAR expression and specificity. This includes evaluating the HERV-K-specific CAR(+) T cells for their ability to kill A375-SM metastasized tumors in a mouse xenograft model. We detected HERV-K env protein on melanoma but not in normal tissues. After electroporation of T cells and selection on HERV-K(+) AaPC, more than 95% of genetically modified T cells expressed the CAR with an effector memory phenotype and lysed HERV-K env(+) tumor targets in an antigen-specific manner. Even though there is apparent shedding of this TAA from tumor cells that can be recognized by HERV-K env-specific CAR(+) T cells, we observed a significant antitumor effect. Adoptive cellular immunotherapy with HERV-K env-specific CAR(+) T cells represents a clinically appealing treatment strategy for advanced-stage melanoma and provides an approach for targeting this TAA on other solid tumors. ©2015 American Association for Cancer Research.

  13. Contribution of the Retrovirus Epidemiology Donor Study (REDS to research on blood transfusion safety in Brazil

    Directory of Open Access Journals (Sweden)

    Paula Loureiro

    2014-04-01

    Full Text Available The Retrovirus Epidemiology Donor Study (REDS program was established in the United States in 1989 with the purpose of increasing blood transfusion safety in the context of the HIV/AIDS and human T-lymphotropic virus epidemics. REDS and its successor, REDS-II were at first conducted in the US, then expanded in 2006 to include international partnerships with Brazil and China. In 2011, a third wave of REDS renamed the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III was launched. This seven-year research program focuses on both blood banking and transfusion medicine research in the United States of America, Brazil, China, and South Africa. The main goal of the international programs is to reduce and prevent the transmission of HIV/AIDS and other known and emerging infectious agents through transfusion, and to address research questions aimed at understanding global issues related to the availability of safe blood. This article describes the contribution of REDS-II to transfusion safety in Brazil. Articles published from 2010 to 2013 are summarized, including database analyses to characterize blood donors, deferral rates, and prevalence, incidence and residual risk of the main blood-borne infections. Specific studies were developed to understand donor motivation, the impact of the deferral questions, risk factors and molecular surveillance among HIV-positive donors, and the natural history of Chagas disease. The purpose of this review is to disseminate the acquired knowledge and briefly summarize the findings of the REDS-II studies conducted in Brazil as well as to introduce the scope of the REDS-III program that is now in progress and will continue through 2018.

  14. Reconstitution of active human core Mediator complex reveals a pivotal role of the MED14 subunit

    Science.gov (United States)

    Cevher, Murat A.; Shi, Yi; Li, Dan; Chait, Brian T.; Malik, Sohail; Roeder, Robert G.

    2014-01-01

    The evolutionarily conserved Mediator complex is a critical coactivator for RNA polymerase II (Pol II)-mediated transcription. Here, we report the reconstitution of a functional 15-subunit human core Mediator complex and its characterization by functional assays and chemical cross-linking coupled to mass spectrometry (CX-MS). Whereas the reconstituted head and middle modules can stably associate, only with incorporation of MED14 into the bi-modular complex does it acquire basal and coactivator functions. This results from a dramatically enhanced ability of MED14-containing complexes to associate with Pol II. Altogether, our analyses identify MED14 as both an architectural and a functional backbone of the Mediator complex. We further establish a conditional requirement for metazoan-specific MED26 that becomes evident in the presence of heterologous nuclear factors. This general approach paves the way for systematically dissecting the multiple layers of functionalities associated with the Mediator complex. PMID:25383669

  15. Reconstitution of active human core Mediator complex reveals a critical role of the MED14 subunit.

    Science.gov (United States)

    Cevher, Murat A; Shi, Yi; Li, Dan; Chait, Brian T; Malik, Sohail; Roeder, Robert G

    2014-12-01

    The evolutionarily conserved Mediator complex is a critical coactivator for RNA polymerase II (Pol II)-mediated transcription. Here we report the reconstitution of a functional 15-subunit human core Mediator complex and its characterization by functional assays and chemical cross-linking coupled to MS (CX-MS). Whereas the reconstituted head and middle modules can stably associate, basal and coactivator functions are acquired only after incorporation of MED14 into the bimodular complex. This results from a dramatically enhanced ability of MED14-containing complexes to associate with Pol II. Altogether, our analyses identify MED14 as both an architectural and a functional backbone of the Mediator complex. We further establish a conditional requirement for metazoan-specific MED26 that becomes evident in the presence of heterologous nuclear factors. This general approach paves the way for systematic dissection of the multiple layers of functionality associated with the Mediator complex.

  16. Human guidance of mobile robots in complex 3D environments using smart glasses

    Science.gov (United States)

    Kopinsky, Ryan; Sharma, Aneesh; Gupta, Nikhil; Ordonez, Camilo; Collins, Emmanuel; Barber, Daniel

    2016-05-01

    In order for humans to safely work alongside robots in the field, the human-robot (HR) interface, which enables bi-directional communication between human and robot, should be able to quickly and concisely express the robot's intentions and needs. While the robot operates mostly in autonomous mode, the human should be able to intervene to effectively guide the robot in complex, risky and/or highly uncertain scenarios. Using smart glasses such as Google Glass∗, we seek to develop an HR interface that aids in reducing interaction time and distractions during interaction with the robot.

  17. A role for human mitochondrial complex II in the production of reactive oxygen species in human skin

    Directory of Open Access Journals (Sweden)

    Alasdair Anderson

    2014-01-01

    Full Text Available The mitochondrial respiratory chain is a major generator of cellular oxidative stress, thought to be an underlying cause of the carcinogenic and ageing process in many tissues including skin. Previous studies of the relative contributions of the respiratory chain (RC complexes I, II and III towards production of reactive oxygen species (ROS have focussed on rat tissues and certainly not on human skin which is surprising as this tissue is regularly exposed to UVA in sunlight, a potent generator of cellular oxidative stress. In a novel approach we have used an array of established specific metabolic inhibitors and DHR123 fluorescence to study the relative roles of the mitochondrial RC complexes in cellular ROS production in 2 types of human skin cells. These include additional enhancement of ROS production by exposure to physiological levels of UVA. The effects within epidermal and dermal derived skin cells are compared to other tissue cell types as well as those harbouring a compromised mitochondrial status (Rho-zero A549. The results show that the complex II inhibitor, TTFA, was the only RC inhibitor to significantly increase UVA-induced ROS production in both skin cell types (P<0.05 suggesting that the role of human skin complex II in terms of influencing ROS production is more important than previously thought particularly in comparison to liver cells. Interestingly, two-fold greater maximal activity of complex II enzyme was observed in both skin cell types compared to liver (P<0.001. The activities of RC enzymes appear to decrease with increasing age and telomere length is correlated with ageing. Our study showed that the level of maximal complex II activity was higher in the MRC5/hTERT (human lung fibroblasts transfected with telomerase cells than the corresponding wild type cells (P=0.0012 which can be considered (in terms of telomerase activity as models of younger and older cells respectively.

  18. Interspecies radioimmunoassay for the major structural proteins of primate type-D retroviruses

    International Nuclear Information System (INIS)

    Colcher, D.; Teramoto, Y.A.; Schlom, J.

    1977-01-01

    A competition radioimmunoassay has been developed in which type-D retroviruses from three primate species compete. The assay utilizes the major structural protein (36,000 daltons) of the endogenous squirrel monkey retrovirus and antisera directed against the major structural protein (27,000 daltons) of the Mason-Pfizer monkey virus isolated from rhesus monkeys. Purified preparations of both viruses grown in heterologous cells, as well as extracts of heterologous cells infected with squirrel monkey retrovirus or Mason-Pfizer monkey virus, compete completely in the assay. Addition of an endogenous virus of the langur monkey also results in complete blocking. No blocking in the assay is observed with type-C baboon viruses, woolly monkey virus, and gibbon virus. Various other type-C and type-B viruses also showed no reactivity. An interspecies assay has thus been developed that recognizes the type-D retroviruses from both Old World monkey (rhesus and langur) and New World monkey (squirrel) species

  19. Demethylation of host-cell DNA at the site of avian retrovirus integration

    Czech Academy of Sciences Publication Activity Database

    Hejnar, Jiří; Elleder, Daniel; Hájková, P.; Walter, J.; Blažková, Jana; Svoboda, Jan

    2003-01-01

    Roč. 2003, č. 311 (2003), s. 641-648 ISSN 0006-291X Institutional research plan: CEZ:AV0Z5052915 Keywords : DNA methylation and demethylation * integration of retroviruses * gene silencing Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.836, year: 2003

  20. Single-Particle Discrimination of Retroviruses from Extracellular Vesicles by Nanoscale Flow Cytometry.

    Science.gov (United States)

    Tang, Vera A; Renner, Tyler M; Fritzsche, Anna K; Burger, Dylan; Langlois, Marc-André

    2017-12-19

    Retroviruses and small EVs overlap in size, buoyant densities, refractive indices and share many cell-derived surface markers making them virtually indistinguishable by standard biochemical methods. This poses a significant challenge when purifying retroviruses for downstream analyses or for phenotypic characterization studies of markers on individual virions given that EVs are a major contaminant of retroviral preparations. Nanoscale flow cytometry (NFC), also called flow virometry, is an adaptation of flow cytometry technology for the analysis of individual nanoparticles such as extracellular vesicles (EVs) and retroviruses. In this study we systematically optimized NFC parameters for the detection of retroviral particles in the range of 115-130 nm, including viral production, sample labeling, laser power and voltage settings. By using the retroviral envelope glycoprotein as a selection marker, and evaluating a number of fluorescent dyes and labeling methods, we demonstrate that it is possible to confidently distinguish retroviruses from small EVs by NFC. Our findings make it now possible to individually phenotype genetically modified retroviral particles that express a fluorescent envelope glycoprotein without removing EV contaminants from the sample.

  1. The role of human performance in the safety complex plants' operation

    International Nuclear Information System (INIS)

    Preda, Irina Aida; Lazar, Roxana Elena; Croitoru, Cornelia

    1999-01-01

    According to statistics, about 20-30% from the failures occurred in the plants are caused directly or indirectly by human errors. Furthermore, it was established that 10-15% of the global failures are related with the human errors. These are mainly due to the wrong actions, maintenance errors, and misinterpretation of instruments. The human performance is influenced by: professional ability, complexity and danger to the plant experience in the working place, level of skills, events in personal and/or professional life, discipline, social ambience, somatic health. The human performances' assessment in the probabilistic safety assessment offers the possibility of evaluation of human contribution to the events sequences outcome. Not all the human errors have impact on the system. A human error may be recovered before the unwanted consequences had been occurred on system. This paper presents the possibilities to use the probabilistic method (event tree, fault tree) to identify the solutions for human reliability improved in order to minimize the risk in industrial plants' operation. Also, the human error types and their causes are defined and the 'decision tree method' as technique in our analysis for human reliability assessment is presented. The exemplification of human error analysis method was achieved based on operation data for Valcea Heavy Water Pilot Plant. As initiating event for the accident state 'the steam supply interruption' event has been considered. The human errors' contribution was analysed for the accident sequence with the worst consequences. (authors)

  2. Sustaining Economic Exploitation of Complex Ecosystems in Computational Models of Coupled Human-Natural Networks

    OpenAIRE

    Martinez, Neo D.; Tonin, Perrine; Bauer, Barbara; Rael, Rosalyn C.; Singh, Rahul; Yoon, Sangyuk; Yoon, Ilmi; Dunne, Jennifer A.

    2012-01-01

    Understanding ecological complexity has stymied scientists for decades. Recent elucidation of the famously coined "devious strategies for stability in enduring natural systems" has opened up a new field of computational analyses of complex ecological networks where the nonlinear dynamics of many interacting species can be more realistically mod-eled and understood. Here, we describe the first extension of this field to include coupled human-natural systems. This extension elucidates new strat...

  3. Model-based identification and use of task complexity factors of human integrated systems

    International Nuclear Information System (INIS)

    Ham, Dong-Han; Park, Jinkyun; Jung, Wondea

    2012-01-01

    Task complexity is one of the conceptual constructs that are critical to explain and predict human performance in human integrated systems. A basic approach to evaluating the complexity of tasks is to identify task complexity factors and measure them. Although a great deal of task complexity factors have been studied, there is still a lack of conceptual frameworks for identifying and organizing them analytically, which can be generally used irrespective of the types of domains and tasks. This study proposes a model-based approach to identifying and using task complexity factors, which has two facets—the design aspects of a task and complexity dimensions. Three levels of design abstraction, which are functional, behavioral, and structural aspects of a task, characterize the design aspect of a task. The behavioral aspect is further classified into five cognitive processing activity types. The complexity dimensions explain a task complexity from different perspectives, which are size, variety, and order/organization. Twenty-one task complexity factors are identified by the combination of the attributes of each facet. Identification and evaluation of task complexity factors based on this model is believed to give insights for improving the design quality of tasks. This model for complexity factors can also be used as a referential framework for allocating tasks and designing information aids. The proposed approach is applied to procedure-based tasks of nuclear power plants (NPPs) as a case study to demonstrate its use. Last, we compare the proposed approach with other studies and then suggest some future research directions.

  4. Complex forms of mitochondrial DNA in human B cells transformed by Epstein-Barr virus (EBV)

    DEFF Research Database (Denmark)

    Christiansen, Gunna; Christiansen, C; Zeuthen, J

    1983-01-01

    Human lymphocytes and lymphoid cell lines were analyzed for the presence of complex forms of mitochondrial DNA (mtDNA) by electron microscopy. A high frequency (9%-14.5%) of catenated dimers, circular dimers, or oligomers were found in samples from Epstein-Barr-virus-(EBV) transformed lymphoblast......Human lymphocytes and lymphoid cell lines were analyzed for the presence of complex forms of mitochondrial DNA (mtDNA) by electron microscopy. A high frequency (9%-14.5%) of catenated dimers, circular dimers, or oligomers were found in samples from Epstein-Barr-virus-(EBV) transformed...

  5. [Dinitrosyl iron complexes are endogenous signaling agents in animal and human cells and tissues (a hypothesis)].

    Science.gov (United States)

    Vanin, A F

    2004-01-01

    The hypothesis was advanced that dinitrosyl iron complexes generated in animal and human cells and tissues producing nitric oxide can function as endogenous universal regulators of biochemical and physiological processes. This function is realized by the ability of dinitrosyl iron complexes to act as donors of free nitric oxide molecules interacting with the heme groups of proteins, nitrosonium ions, or Fe+(NO+)2 interacting with the thiol groups of proteins. The effect of dinitrosyl iron complexes on the activity of some enzymes and the expression of the genome at the translation and transcription levels was considered.

  6. Human reliability and human factors in complex organizations: epistemological and critical analysis - practical avenues to action

    International Nuclear Information System (INIS)

    Llory, A.

    1991-08-01

    This article starts out with comment on the existence of persistent problems inherent to probabilistic safety assessments (PSA). It first surveys existing American documents on the subject which make a certain number of criticisms on human reliability analyses, e.g. limitations due to the scant quantities of data available, lack of a basic theoretical model, non-reproducibility of analyses, etc. The article therefore examines and criticizes the epistemological bases of these analyses. One of the fundamental points stressed is that human reliability analyses do not take account of all the special features of the work situation which result in human error (so as to draw up statistical data from a sufficiently representative number of cases), and consequently lose all notion of the 'relationships' between human errors and the different aspects of the working environment. The other key points of criticism concern the collective nature of work which is not taken into account, and the frequent confusion between what operatives actually do and their formally prescribed job-tasks. The article proposes aspects to be given thought in order to overcome these difficulties, e.g. quantitative assessment of the social environment within a company, non-linear model for assessment of the accident rate, analysis of stress levels in staff on off-shore platforms. The method approaches used in these three studies are of the same type, and could be transposed to human-reliability problems. The article then goes into greater depth on thinking aimed at developing a 'positive' view of the human factor (and not just a 'negative' one, i.e. centred on human errors and organizational malfunctions), applying investigation methods developed in the occupational human sciences (occupational psychodynamics, ergonomics, occupational sociology). The importance of operatives working as actors of a team is stressed

  7. Effects of human serun albumin in some biological properties of rhodium(II complexes

    Directory of Open Access Journals (Sweden)

    Espósito Breno P.

    2000-01-01

    Full Text Available The affinities for human albumin (HSA of five rhodium(II complexes of general formula [Rh2(bridge4] (bridge = acetate, propionate, butyrate, trifluoroacetate and trifluoroacetamidate were determined by spectrophotometry. In the case of the alkylcarboxylates, an inverse correlation of affinity with their liposolubilities was observed. Diffusion of the free or protein-bound complexes into Ehrlich cells in vitro seems to be primarily governed by the hydrophobic character of the complex. The complex [Rh2(tfc4] exhibited affinity towards the protein (K = 214.1 as well as cell partition both in the absence (32.1% and presence (48.6% of HSA. The compound HSA: [Rh2(tfc4] has had its antitumoral action in tumor-bearing Balb-c mice investigated, showing that HSA can be a drug reservoir for the rhodium complex.

  8. How do precision medicine and system biology response to human body's complex adaptability?

    Science.gov (United States)

    Yuan, Bing

    2016-12-01

    In the field of life sciences, although system biology and "precision medicine" introduce some complex scientifific methods and techniques, it is still based on the "analysis-reconstruction" of reductionist theory as a whole. Adaptability of complex system increase system behaviour uncertainty as well as the difficulties of precise identifification and control. It also put systems biology research into trouble. To grasp the behaviour and characteristics of organism fundamentally, systems biology has to abandon the "analysis-reconstruction" concept. In accordance with the guidelines of complexity science, systems biology should build organism model from holistic level, just like the Chinese medicine did in dealing with human body and disease. When we study the living body from the holistic level, we will fifind the adaptability of complex system is not the obstacle that increases the diffificulty of problem solving. It is the "exceptional", "right-hand man" that helping us to deal with the complexity of life more effectively.

  9. Interactions of the human MCM-BP protein with MCM complex components and Dbf4.

    Directory of Open Access Journals (Sweden)

    Tin Nguyen

    Full Text Available MCM-BP was discovered as a protein that co-purified from human cells with MCM proteins 3 through 7; results which were recapitulated in frogs, yeast and plants. Evidence in all of these organisms supports an important role for MCM-BP in DNA replication, including contributions to MCM complex unloading. However the mechanisms by which MCM-BP functions and associates with MCM complexes are not well understood. Here we show that human MCM-BP is capable of interacting with individual MCM proteins 2 through 7 when co-expressed in insect cells and can greatly increase the recovery of some recombinant MCM proteins. Glycerol gradient sedimentation analysis indicated that MCM-BP interacts most strongly with MCM4 and MCM7. Similar gradient analyses of human cell lysates showed that only a small amount of MCM-BP overlapped with the migration of MCM complexes and that MCM complexes were disrupted by exogenous MCM-BP. In addition, large complexes containing MCM-BP and MCM proteins were detected at mid to late S phase, suggesting that the formation of specific MCM-BP complexes is cell cycle regulated. We also identified an interaction between MCM-BP and the Dbf4 regulatory component of the DDK kinase in both yeast 2-hybrid and insect cell co-expression assays, and this interaction was verified by co-immunoprecipitation of endogenous proteins from human cells. In vitro kinase assays showed that MCM-BP was not a substrate for DDK but could inhibit DDK phosphorylation of MCM4,6,7 within MCM4,6,7 or MCM2-7 complexes, with little effect on DDK phosphorylation of MCM2. Since DDK is known to activate DNA replication through phosphorylation of these MCM proteins, our results suggest that MCM-BP may affect DNA replication in part by regulating MCM phosphorylation by DDK.

  10. Interactions of the human MCM-BP protein with MCM complex components and Dbf4.

    Science.gov (United States)

    Nguyen, Tin; Jagannathan, Madhav; Shire, Kathy; Frappier, Lori

    2012-01-01

    MCM-BP was discovered as a protein that co-purified from human cells with MCM proteins 3 through 7; results which were recapitulated in frogs, yeast and plants. Evidence in all of these organisms supports an important role for MCM-BP in DNA replication, including contributions to MCM complex unloading. However the mechanisms by which MCM-BP functions and associates with MCM complexes are not well understood. Here we show that human MCM-BP is capable of interacting with individual MCM proteins 2 through 7 when co-expressed in insect cells and can greatly increase the recovery of some recombinant MCM proteins. Glycerol gradient sedimentation analysis indicated that MCM-BP interacts most strongly with MCM4 and MCM7. Similar gradient analyses of human cell lysates showed that only a small amount of MCM-BP overlapped with the migration of MCM complexes and that MCM complexes were disrupted by exogenous MCM-BP. In addition, large complexes containing MCM-BP and MCM proteins were detected at mid to late S phase, suggesting that the formation of specific MCM-BP complexes is cell cycle regulated. We also identified an interaction between MCM-BP and the Dbf4 regulatory component of the DDK kinase in both yeast 2-hybrid and insect cell co-expression assays, and this interaction was verified by co-immunoprecipitation of endogenous proteins from human cells. In vitro kinase assays showed that MCM-BP was not a substrate for DDK but could inhibit DDK phosphorylation of MCM4,6,7 within MCM4,6,7 or MCM2-7 complexes, with little effect on DDK phosphorylation of MCM2. Since DDK is known to activate DNA replication through phosphorylation of these MCM proteins, our results suggest that MCM-BP may affect DNA replication in part by regulating MCM phosphorylation by DDK.

  11. Mixed-complexity artificial grammar learning in humans and macaque monkeys: evaluating learning strategies.

    Science.gov (United States)

    Wilson, Benjamin; Smith, Kenny; Petkov, Christopher I

    2015-03-01

    Artificial grammars (AG) can be used to generate rule-based sequences of stimuli. Some of these can be used to investigate sequence-processing computations in non-human animals that might be related to, but not unique to, human language. Previous AG learning studies in non-human animals have used different AGs to separately test for specific sequence-processing abilities. However, given that natural language and certain animal communication systems (in particular, song) have multiple levels of complexity, mixed-complexity AGs are needed to simultaneously evaluate sensitivity to the different features of the AG. Here, we tested humans and Rhesus macaques using a mixed-complexity auditory AG, containing both adjacent (local) and non-adjacent (longer-distance) relationships. Following exposure to exemplary sequences generated by the AG, humans and macaques were individually tested with sequences that were either consistent with the AG or violated specific adjacent or non-adjacent relationships. We observed a considerable level of cross-species correspondence in the sensitivity of both humans and macaques to the adjacent AG relationships and to the statistical properties of the sequences. We found no significant sensitivity to the non-adjacent AG relationships in the macaques. A subset of humans was sensitive to this non-adjacent relationship, revealing interesting between- and within-species differences in AG learning strategies. The results suggest that humans and macaques are largely comparably sensitive to the adjacent AG relationships and their statistical properties. However, in the presence of multiple cues to grammaticality, the non-adjacent relationships are less salient to the macaques and many of the humans. © 2015 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  12. The role of human performance in safe operation of complex plants

    International Nuclear Information System (INIS)

    Preda, Irina Aida; Lazar, Roxana Elena; Croitoru, Cornelia

    1999-01-01

    According to statistics, about 20-30% from the failures occurring in plants are caused directly or indirectly by human errors. Furthermore, it was established that 10-15 percents of the global failures are related to the human errors. These are mainly due to the wrong actions, maintenance errors, and misinterpretation of instruments. The human performance is influenced by: professional ability, complexity and danger of the plant, experience in the same working place, level of skills, events in personal and/or professional life, discipline, social ambience and somatic health. The human performances assessment in the probabilistic safety assessment offers the possibility of evaluation for human contribution to the events sequences outcome. A human error may be recovered before the unwanted consequences had been occurred on system. This paper presents the possibilities to use the probabilistic methods (event tree, fault tree) to identify the solution for human reliability improvement in order to minimise the risk in industrial plant operation. Also, are defined the human error types and their causes and the 'decision tree method' is presented as technique in our analyses for human reliability assessment. The exemplification of human error analysis method was achieved based on operation data for Valcea heavy water pilot plant. (authors)

  13. Concordance of gene expression in human protein complexes reveals tissue specificity and pathology

    DEFF Research Database (Denmark)

    Börnigen, Daniela; Pers, Tune Hannes; Thorrez, Lieven

    2013-01-01

    Disease-causing variants in human genes usually lead to phenotypes specific to only a few tissues. Here, we present a method for predicting tissue specificity based on quantitative deregulation of protein complexes. The underlying assumption is that the degree of coordinated expression among prot...

  14. A model of the human triceps surae muscle-tendon complex applied to jumping

    NARCIS (Netherlands)

    Bobbert, Maarten F.; Huijing, Peter A.; van Ingen Schenau, Gerrit Jan

    1986-01-01

    The purpose of this study was to gain more insight into the behavior of the muscle-tendon complex of human m. triceps surae in jumping. During one-legged vertical jumps of ten subjects ground reaction forces as well as cinematographic data were registered, and electromyograms were recorded from m.

  15. Modelling of spatially complex human-ecosystem, rural-urban and rich-poor interactions

    CSIR Research Space (South Africa)

    Naude, AH

    2008-06-01

    Full Text Available The paper outlines the challenges of modelling and assessing spatially complex human-ecosystem interactions, and the need to simultaneously consider rural-urban and rich-poor interactions. The context for exploring these challenges is South Africa...

  16. Collaborative Educational Leadership: The Emergence of Human Interactional Sense-Making Process as a Complex System

    Science.gov (United States)

    Jäppinen, Aini-Kristiina

    2014-01-01

    The article aims at explicating the emergence of human interactional sense-making process within educational leadership as a complex system. The kind of leadership is understood as a holistic entity called collaborative leadership. There, sense-making emerges across interdependent domains, called attributes of collaborative leadership. The…

  17. Finding the molecular basis of complex genetic variation in humans and mice

    OpenAIRE

    Mott, Richard

    2006-01-01

    I survey the state of the art in complex trait analysis, including the use of new experimental and computational technologies and resources becoming available, and the challenges facing us. I also discuss how the prospects of rodent model systems compare with association mapping in humans.

  18. Impact of familiarity on information complexity in human-computer interfaces

    Directory of Open Access Journals (Sweden)

    Bakaev Maxim

    2016-01-01

    Full Text Available A quantitative measure of information complexity remains very much desirable in HCI field, since it may aid in optimization of user interfaces, especially in human-computer systems for controlling complex objects. Our paper is dedicated to exploration of subjective (subject-depended aspect of the complexity, conceptualized as information familiarity. Although research of familiarity in human cognition and behaviour is done in several fields, the accepted models in HCI, such as Human Processor or Hick-Hyman’s law do not generally consider this issue. In our experimental study the subjects performed search and selection of digits and letters, whose familiarity was conceptualized as frequency of occurrence in numbers and texts. The analysis showed significant effect of information familiarity on selection time and throughput in regression models, although the R2 values were somehow low. Still, we hope that our results might aid in quantification of information complexity and its further application for optimizing interaction in human-machine systems.

  19. Quantification of spatial structure of human proximal tibial bone biopsies using 3D measures of complexity

    DEFF Research Database (Denmark)

    Saparin, Peter I.; Thomsen, Jesper Skovhus; Prohaska, Steffen

    2005-01-01

    3D data sets of human tibia bone biopsies acquired by a micro-CT scanner. In order to justify the newly proposed approach, the measures of complexity of the bone architecture were compared with the results of traditional 2D bone histomorphometry. The proposed technique is able to quantify...

  20. Complexities in human herpesvirus-6A and -6B binding to host cells

    DEFF Research Database (Denmark)

    Pedersen, Simon Metz; Höllsberg, Per

    2006-01-01

    Human herpesvirus-6A and -6B uses the cellular receptor CD46 for fusion and infection of the host cell. The viral glycoprotein complex gH-gL from HHV-6A binds to the short consensus repeat 2 and 3 in CD46. Although all the major isoforms of CD46 bind the virus, certain isoforms may have higher...

  1. Multi-view 3D Human Pose Estimation in Complex Environment

    NARCIS (Netherlands)

    Hofmann, K.M.; Gavrila, D.M.

    2012-01-01

    We introduce a framework for unconstrained 3D human upper body pose estimation from multiple camera views in complex environment. Its main novelty lies in the integration of three components: single-frame pose recovery, temporal integration and model texture adaptation. Single-frame pose recovery

  2. History matching of a complex epidemiological model of human immunodeficiency virus transmission by using variance emulation.

    Science.gov (United States)

    Andrianakis, I; Vernon, I; McCreesh, N; McKinley, T J; Oakley, J E; Nsubuga, R N; Goldstein, M; White, R G

    2017-08-01

    Complex stochastic models are commonplace in epidemiology, but their utility depends on their calibration to empirical data. History matching is a (pre)calibration method that has been applied successfully to complex deterministic models. In this work, we adapt history matching to stochastic models, by emulating the variance in the model outputs, and therefore accounting for its dependence on the model's input values. The method proposed is applied to a real complex epidemiological model of human immunodeficiency virus in Uganda with 22 inputs and 18 outputs, and is found to increase the efficiency of history matching, requiring 70% of the time and 43% fewer simulator evaluations compared with a previous variant of the method. The insight gained into the structure of the human immunodeficiency virus model, and the constraints placed on it, are then discussed.

  3. Does human migration affect international trade? A complex-network perspective.

    Directory of Open Access Journals (Sweden)

    Giorgio Fagiolo

    Full Text Available This paper explores the relationships between international human migration and merchandise trade, using a complex-network approach. We firstly compare the topological structure of worldwide networks of human migration and bilateral trade over the period 1960-2000. Next, we ask whether the position of any pair of countries in the migration network affects their bilateral trade flows. We show that: (i both weighted and binary versions of the networks of international migration and trade are strongly correlated; (ii such correlations can be mostly explained by country economic/demographic size and geographical distance; and (iii pairs of countries that are more central in the international-migration network trade more. Our findings suggest that bilateral trade between any two countries is not only affected by the presence of migrants from either countries but also by their relative embeddedness in the complex web of corridors making up the network of international human migration.

  4. Does human migration affect international trade? A complex-network perspective.

    Science.gov (United States)

    Fagiolo, Giorgio; Mastrorillo, Marina

    2014-01-01

    This paper explores the relationships between international human migration and merchandise trade, using a complex-network approach. We firstly compare the topological structure of worldwide networks of human migration and bilateral trade over the period 1960-2000. Next, we ask whether the position of any pair of countries in the migration network affects their bilateral trade flows. We show that: (i) both weighted and binary versions of the networks of international migration and trade are strongly correlated; (ii) such correlations can be mostly explained by country economic/demographic size and geographical distance; and (iii) pairs of countries that are more central in the international-migration network trade more. Our findings suggest that bilateral trade between any two countries is not only affected by the presence of migrants from either countries but also by their relative embeddedness in the complex web of corridors making up the network of international human migration.

  5. Early modern human diversity suggests subdivided population structure and a complex out-of-Africa scenario

    Science.gov (United States)

    Gunz, Philipp; Bookstein, Fred L.; Mitteroecker, Philipp; Stadlmayr, Andrea; Seidler, Horst; Weber, Gerhard W.

    2009-01-01

    The interpretation of genetic evidence regarding modern human origins depends, among other things, on assessments of the structure and the variation of ancient populations. Because we lack genetic data from the time when the first anatomically modern humans appeared, between 200,000 and 60,000 years ago, instead we exploit the phenotype of neurocranial geometry to compare the variation in early modern human fossils with that in other groups of fossil Homo and recent modern humans. Variation is assessed as the mean-squared Procrustes distance from the group average shape in a representation based on several hundred neurocranial landmarks and semilandmarks. We find that the early modern group has more shape variation than any other group in our sample, which covers 1.8 million years, and that they are morphologically similar to recent modern humans of diverse geographically dispersed populations but not to archaic groups. Of the currently competing models of modern human origins, some are inconsistent with these findings. Rather than a single out-of-Africa dispersal scenario, we suggest that early modern humans were already divided into different populations in Pleistocene Africa, after which there followed a complex migration pattern. Our conclusions bear implications for the inference of ancient human demography from genetic models and emphasize the importance of focusing research on those early modern humans, in particular, in Africa. PMID:19307568

  6. Three-dimensional structure of a pre-catalytic human spliceosomal complex B.

    Science.gov (United States)

    Boehringer, Daniel; Makarov, Evgeny M; Sander, Bjoern; Makarova, Olga V; Kastner, Berthold; Lührmann, Reinhard; Stark, Holger

    2004-05-01

    Major structural changes occur in the spliceosome during its transition from the fully assembled complex B to the catalytically activated spliceosome. To understand the rearrangement, it is necessary to know the detailed three-dimensional structures of these complexes. Here, we have immunoaffinity-purified human spliceosomes (designated B Delta U1) at a stage after U4/U6.U5 tri-snRNP integration but before activation, and have determined the three-dimensional structure of B Delta U1 by single-particle electron cryomicroscopy at a resolution of approximately 40 A. The overall size of the complex is about 370 x 270 x 170 A. The three-dimensional structure features a roughly triangular body linked to a head domain in variable orientations. The body is very similar in size and shape to the isolated U4/U6.U5 tri-snRNP. This provides initial insight into the structural organization of complex B.

  7. Ontogeny of neuro-insular complexes and islets innervation in the human pancreas.

    Directory of Open Access Journals (Sweden)

    Alexandra E. Proshchina

    2014-04-01

    Full Text Available The ontogeny of the neuro-insular complexes (NIC and the islets innervation in human pancreas has not been studied in detail. Our aim was to describe the developmental dynamics and distribution of the nervous system structures in the endocrine part of human pancreas. We used doublestaining with antibodies specific to pan-neural markers (neuron-specific enolase (NSE and S100 protein and to hormones of pancreatic endocrine cells. NSE and S100-positive nerves and ganglia were identified in the human fetal pancreas from gestation week (gw 10 onwards. Later the density of S100 and NSE-positive fibers increased. In adults this network was sparse. The islets innervation started to form from gw 14. NSE-containing endocrine cells were identified from gw 12 onwards. Additionally, S100-positive cells were detected both in the periphery and within some of the islets starting at gw 14. The analysis of islets innervation has shown that the fetal pancreas contained neuro-insular complexes and the number of these complexes was reduced in adults. The highest density of neuro-insular complexes is detected during middle and late fetal periods, when the mosaic islets, typical for adults, form. The close integration between the developing pancreatic islets and the nervous system structures may play an important role not only in the hormone secretion, but also in the islets morphogenesis.

  8. The Driving Forces of Cultural Complexity : Neanderthals, Modern Humans, and the Question of Population Size.

    Science.gov (United States)

    Fogarty, Laurel; Wakano, Joe Yuichiro; Feldman, Marcus W; Aoki, Kenichi

    2017-03-01

    The forces driving cultural accumulation in human populations, both modern and ancient, are hotly debated. Did genetic, demographic, or cognitive features of behaviorally modern humans (as opposed to, say, early modern humans or Neanderthals) allow culture to accumulate to its current, unprecedented levels of complexity? Theoretical explanations for patterns of accumulation often invoke demographic factors such as population size or density, whereas statistical analyses of variation in cultural complexity often point to the importance of environmental factors such as food stability, in determining cultural complexity. Here we use both an analytical model and an agent-based simulation model to show that a full understanding of the emergence of behavioral modernity, and the cultural evolution that has followed, depends on understanding and untangling the complex relationships among culture, genetically determined cognitive ability, and demographic history. For example, we show that a small but growing population could have a different number of cultural traits from a shrinking population with the same absolute number of individuals in some circumstances.

  9. Current theoretical models fail to predict the topological complexity of the human genome

    Directory of Open Access Journals (Sweden)

    Javier eArsuaga

    2015-08-01

    Full Text Available Understanding the folding of the human genome is a key challenge of modern structural biology. The emergence of chromatin conformation capture assays ({it e.g.} Hi-C has revolutionized chromosome biology and provided new insights into the three dimensional structure of the genome. The experimental data are highly complex and need to be analyzed with quantitative tools. It has been argued that the data obtained from Hi-C assays are consistent with a fractal organization of the genome. A key characteristic textcolor{red}{of the fractal globule} is the lack of topological complexity (knotting or inter-linking. However, the absence of topological complexity contradicts results from polymer physics showing that the entanglement of long linear polymers in a confined volume increases rapidly with the length and with decreasing volume. textcolor{red}{{it In vivo} and {it in vitro} assays support this claim in some biological systems. We simulate knotted lattice polygons confined inside a sphere and demonstrate that their contact frequencies agree with the human Hi-C data.} We conclude that the topological complexity of the human genome cannot be inferred from current Hi-C data.

  10. Human practice in the life cycle of complex systems. Challenges and methods

    International Nuclear Information System (INIS)

    Nuutinen, M.; Luoma, J.

    2005-12-01

    This book describes the current and near future challenges in work and traffic environments in light of the rapid technology development. It focuses on the following domains: road and vessel traffic, nuclear power production, automatic mining, steel factory and the pulp and paper industry. Each example concerns complex technical systems where human practice and behaviour has an important role for the safety, efficiency and productivity of the system. The articles illustrate the enormous field of human-related research when considering the design, validation, implementation, operation and maintenance of complex sociotechnical systems. Nevertheless, these 14 chapters are only examples of the range of questions related to the issue. The authors of the book are VTT experts in work or traffic psychology and research, system usability, risk and safety analysis, virtual environments and they have experience in studying different domains. This book is an attempt to open up the complex world of human-technology interaction for readers facing practical problems with complex systems. It is aimed to help a technical or organisational designer, a policy-maker, an expert or 'a user', the one who works or lives within the technology. (orig.)

  11. Understanding complexities in coupled dynamics of human-water and food security

    Science.gov (United States)

    Usmani, M.; Kondal, A.; Lin, L.; Colwell, R. R.; Jutla, A.

    2017-12-01

    Traditional premise of food security is associated with satisfying human hunger by providing sufficient calories to population. Water is the key variable associated with the growth of crops, which is then used as a metric of success for abundance of food across globe. The current framework often negates complex coupled interaction between availability of food nutrients and human well-being (such as productivity, work efficiency, low birth weight, physical and mental growth). Our analysis suggests that 1 in 3 humans suffer from malnutrition across the globe. In last five decades, most of the countries have a decreasing availability trend in at least one of the twenty-three essential food nutrients required for human well-being. We argue that food security can only be achieved if information on use of water for crops and consumption of food must include availability of nutrients for humans. Here, we propose a new concept of "consumptive nutrients" that include constant feedback mechanism between water-human and societal processes- essential for growth, distribution and consumption of food nutrients. Using Ethiopia as a signature rain-fed agricultural region, we will show how decreasing precipitation has led to an increase in crop productivity, but decreased availability of nutrients for humans. This in turn has destabilizing impact on overall regional economy. We will demonstrate why inclusion of nutrients must be a part of discussion for ensuring food security to human population.

  12. Endogenous retrovirus and radiation-induced leukemia in the RMF mouse

    International Nuclear Information System (INIS)

    Tennant, R.W.; Boone, L.R.; Lalley, P.; Yang, W.K.

    1982-01-01

    The induction of myeloid leukemia in irradiated RFM/Un mice has been associated with retrovirus infection. However, two characteristics of this strain complicate efforts to define the role of the virus. This strain possesses only one inducible host range class of endogenous virus and a unique gene, in addition to the Fv-1/sup n/ locus, which specifically restricts exogenous infection by endogenous viruses. These characteristics possibly account for absence of recombinant viruses in this strain, even though virus is amply expressed during most of the animal's life span. We have examined further the distribution of retrovirus sequences and the chromosomal locus of the inducible virus in this strain. This report describes evidence for additional viral sequences in cells of a radiation-induced myeloid leukemia line and discusses the possible origin of these added copies

  13. Association of ultraviolet-induced retrovirus expression with anchorage-independent survival in rat embryo cells

    International Nuclear Information System (INIS)

    Suk, W.A.

    1985-01-01

    The authors have shown in the AI assay that the nontransforming retrovirus increases the differential in enhanced survival response in infected cultures. To more fully understand this aspect of the system, they examined the effect of UV irradiation on infected and uninfected FRE cells. In this communication the authors report that UV irradiation induces AI survival in infected and uninfected cells;in uninfected cells there is a concomitant induction of endogenous retrovirus expression. The AI survival of both cell lines was determined using a previously described procedure. Anchorage-dependent media control and solvent control cells, when suspended in medium above an agar base layer, showed a rapid decline in cell survival;however, cells that had been treated with carcinogen did not undergo the destructive process that took place in control cells, indicating specificity

  14. The human cap-binding complex is functionally connected to the nuclear RNA exosome

    DEFF Research Database (Denmark)

    Andersen, Peter Refsing; Domanski, Michal; Kristiansen, Maiken Søndergaard

    2013-01-01

    Nuclear processing and quality control of eukaryotic RNA is mediated by the RNA exosome, which is regulated by accessory factors. However, the mechanism of exosome recruitment to its ribonucleoprotein (RNP) targets remains poorly understood. Here we report a physical link between the human exosome...... and the cap-binding complex (CBC). The CBC associates with the ARS2 protein to form CBC-ARS2 (CBCA) and then further connects, together with the ZC3H18 protein, to the nuclear exosome targeting (NEXT) complex, thus forming CBC-NEXT (CBCN). RNA immunoprecipitation using CBCN factors as well as the analysis...

  15. Retrovirus-mediated in vitro gene transfer into chicken male germ line cells

    Czech Academy of Sciences Publication Activity Database

    Kalina, J.; Šenigl, Filip; Mičáková, A.; Mucksová, J.; Blažková, Jana; Haifeng, Y.; Poplštejn, M.; Hejnar, Jiří; Trefil, P.

    2007-01-01

    Roč. 134, č. 3 (2007), s. 445-453 ISSN 1470-1626 R&D Projects: GA ČR GA523/04/0569 Grant - others:GA MŠk(CZ) 1P05ME722 Institutional research plan: CEZ:AV0Z50520514 Keywords : Transgenic spermatozoa * infection of testicular cells with retrovirus * transgenesis in chicken Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.962, year: 2007

  16. Viral and cellular requirements for the budding of Feline Endogenous Retrovirus RD-114

    Directory of Open Access Journals (Sweden)

    Fukuma Aiko

    2011-12-01

    Full Text Available Abstract Background RD-114 virus is a feline endogenous retrovirus and produced as infectious viruses in some feline cell lines. Recently, we reported the contamination of an infectious RD-114 virus in a proportion of live attenuated vaccines for dogs and cats. It is very difficult to completely knock out the RD-114 proviruses from cells, as endogenous retroviruses are usually integrated multiply into the host genome. However, it may be possible to reduce the risk of contamination of RD-114 virus by regulating the viral release from cells. Results In this study, to understand the molecular mechanism of RD-114 virus budding, we attempted to identify the viral and cellular requirements for RD-114 virus budding. Analyses of RD-114 L-domain mutants showed that the PPPY sequence in the pp15 region of Gag plays a critical role in RD-114 virus release as viral L-domain. Furthermore, we investigated the cellular factors required for RD-114 virus budding. We demonstrated that RD-114 virus release was inhibited by overexpression of dominant negative mutants of Vps4A, Vps4B, and WWP2. Conclusions These results strongly suggest that RD-114 budding utilizes the cellular multivesicular body sorting pathway similar to many other retroviruses.

  17. An Evolutionarily Young Polar Bear (Ursus maritimus Endogenous Retrovirus Identified from Next Generation Sequence Data

    Directory of Open Access Journals (Sweden)

    Kyriakos Tsangaras

    2015-11-01

    Full Text Available Transcriptome analysis of polar bear (Ursus maritimus tissues identified sequences with similarity to Porcine Endogenous Retroviruses (PERV. Based on these sequences, four proviral copies and 15 solo long terminal repeats (LTRs of a newly described endogenous retrovirus were characterized from the polar bear draft genome sequence. Closely related sequences were identified by PCR analysis of brown bear (Ursus arctos and black bear (Ursus americanus but were absent in non-Ursinae bear species. The virus was therefore designated UrsusERV. Two distinct groups of LTRs were observed including a recombinant ERV that contained one LTR belonging to each group indicating that genomic invasions by at least two UrsusERV variants have recently occurred. Age estimates based on proviral LTR divergence and conservation of integration sites among ursids suggest the viral group is only a few million years old. The youngest provirus was polar bear specific, had intact open reading frames (ORFs and could potentially encode functional proteins. Phylogenetic analyses of UrsusERV consensus protein sequences suggest that it is part of a pig, gibbon and koala retrovirus clade. The young age estimates and lineage specificity of the virus suggests UrsusERV is a recent cross species transmission from an unknown reservoir and places the viral group among the youngest of ERVs identified in mammals.

  18. An Evolutionarily Young Polar Bear (Ursus maritimus) Endogenous Retrovirus Identified from Next Generation Sequence Data.

    Science.gov (United States)

    Tsangaras, Kyriakos; Mayer, Jens; Alquezar-Planas, David E; Greenwood, Alex D

    2015-11-24

    Transcriptome analysis of polar bear (Ursus maritimus) tissues identified sequences with similarity to Porcine Endogenous Retroviruses (PERV). Based on these sequences, four proviral copies and 15 solo long terminal repeats (LTRs) of a newly described endogenous retrovirus were characterized from the polar bear draft genome sequence. Closely related sequences were identified by PCR analysis of brown bear (Ursus arctos) and black bear (Ursus americanus) but were absent in non-Ursinae bear species. The virus was therefore designated UrsusERV. Two distinct groups of LTRs were observed including a recombinant ERV that contained one LTR belonging to each group indicating that genomic invasions by at least two UrsusERV variants have recently occurred. Age estimates based on proviral LTR divergence and conservation of integration sites among ursids suggest the viral group is only a few million years old. The youngest provirus was polar bear specific, had intact open reading frames (ORFs) and could potentially encode functional proteins. Phylogenetic analyses of UrsusERV consensus protein sequences suggest that it is part of a pig, gibbon and koala retrovirus clade. The young age estimates and lineage specificity of the virus suggests UrsusERV is a recent cross species transmission from an unknown reservoir and places the viral group among the youngest of ERVs identified in mammals.

  19. Hamster endogenous retrovirus (HaER) - distinct properties of structural proteins and DNA polymerase

    International Nuclear Information System (INIS)

    Goldschmied-Reouven, A.; Yaniv, A.

    1983-01-01

    The structural proteins as well as some features of the RNA-dependent DNA polymerase of the hamster endogenous retrovirus (HaER) were examined. The polypeptide pattern of this virus is substantially different from that of other known retroviruses in containing major polypeptides with molecular weights of 68000, 59000, 27000, 24000 daltons. Double antibody competitive radioimmunoassays showed that the HaER particles do not share any detectable antigenic relatedness with the murine viruses' p30, but manifest a considerable relatedness with the feline leukemia virus p27 and a slight cross-reactivity with the rat virus major protein. The RNA-dependent DNA polymerase of HaER virus has a molecular size of approximately 73000 daltons and in contrast to other mammalian retroviruses shows no significant preference for Mn 2+ over Mg 2+ . Apart from the lack of antigenic relatedness between the HaER virus proteins and the p30 protein of murine viruses, there is also no antigenic relatedness between HaER and murine viruses insofar as their DNA polymerase is concerned. (Author)

  20. An Evolutionarily Young Polar Bear (Ursus maritimus) Endogenous Retrovirus Identified from Next Generation Sequence Data

    Science.gov (United States)

    Tsangaras, Kyriakos; Mayer, Jens; Alquezar-Planas, David E.; Greenwood, Alex D.

    2015-01-01

    Transcriptome analysis of polar bear (Ursus maritimus) tissues identified sequences with similarity to Porcine Endogenous Retroviruses (PERV). Based on these sequences, four proviral copies and 15 solo long terminal repeats (LTRs) of a newly described endogenous retrovirus were characterized from the polar bear draft genome sequence. Closely related sequences were identified by PCR analysis of brown bear (Ursus arctos) and black bear (Ursus americanus) but were absent in non-Ursinae bear species. The virus was therefore designated UrsusERV. Two distinct groups of LTRs were observed including a recombinant ERV that contained one LTR belonging to each group indicating that genomic invasions by at least two UrsusERV variants have recently occurred. Age estimates based on proviral LTR divergence and conservation of integration sites among ursids suggest the viral group is only a few million years old. The youngest provirus was polar bear specific, had intact open reading frames (ORFs) and could potentially encode functional proteins. Phylogenetic analyses of UrsusERV consensus protein sequences suggest that it is part of a pig, gibbon and koala retrovirus clade. The young age estimates and lineage specificity of the virus suggests UrsusERV is a recent cross species transmission from an unknown reservoir and places the viral group among the youngest of ERVs identified in mammals. PMID:26610552

  1. The major histocompatibility complex and perfumers' descriptions of human body odors

    OpenAIRE

    Wedekind, C.; Escher, S.; Van de Waal, M.; Frei, E.

    2007-01-01

    The MHC (major histocompatibility complex) is a group of genes that play a crucial role in immune recognition and in tolerance of tissue grafting. The MHC has also been found to influence body odors, body odor preferences, and mate choice in mice and humans. Here we test whether verbal descriptions of human body odors can be linked to the MHC. We asked 45 male students to live as odor neutral as possible for two consecutive days and to wear a T-shirt during the nights. The odors of these T-sh...

  2. Distinguishing humans from computers in the game of go: A complex network approach

    Science.gov (United States)

    Coquidé, C.; Georgeot, B.; Giraud, O.

    2017-08-01

    We compare complex networks built from the game of go and obtained from databases of human-played games with those obtained from computer-played games. Our investigations show that statistical features of the human-based networks and the computer-based networks differ, and that these differences can be statistically significant on a relatively small number of games using specific estimators. We show that the deterministic or stochastic nature of the computer algorithm playing the game can also be distinguished from these quantities. This can be seen as a tool to implement a Turing-like test for go simulators.

  3. Cognitive human reliability analysis for an assessment of the safety significance of complex transients

    International Nuclear Information System (INIS)

    Amico, P.J.; Hsu, C.J.; Youngblood, R.W.; Fitzpatrick, R.G.

    1989-01-01

    This paper reports that as part of a probabilistic assessment of the safety significance of complex transients at certain PWR power plants, it was necessary to perform a cognitive human reliability analysis. To increase the confidence in the results, it was desirable to make use of actual observations of operator response which were available for the assessment. An approach was developed which incorporated these observations into the human cognitive reliability (HCR) modeling approach. The results obtained provided additional insights over what would have been found using other approaches. These insights were supported by the observations, and it is suggested that this approach be considered for use in future probabilistic safety assessments

  4. Better decision making in complex, dynamic tasks training with human-facilitated interactive learning environments

    CERN Document Server

    Qudrat-Ullah, Hassan

    2015-01-01

    This book describes interactive learning environments (ILEs) and their underlying concepts. It explains how ILEs can be used to improve the decision-making process and how these improvements can be empirically verified. The objective of this book is to enhance our understanding of and to gain insights into the process by which human facilitated ILEs are effectively designed and used in improving users’ decision making in complex, dynamic tasks. This book is divided into four major parts. Part I serves as an introduction to the importance and complexity of decision making in dynamic tasks. Part II provides background material, drawing upon relevant literature, for the development of an integrated process model on the effectiveness of human facilitated ILEs in improving decision making in dynamic tasks. Part III focuses on the design, development, and application of FishBankILE in laboratory experiments to gather empirical evidence for the validity of the process model. Finally, part IV presents a comprehensi...

  5. Cytotoxicity of Diimine Palladium (II) Complexes of Alkyldithiocarbamate Derivatives on Human Lung, Ovary and Liver Cells.

    Science.gov (United States)

    Aryanpour, Narges; Mansouri-Torshizi, Hassan; Nakhjavan, Maryam; H Shirazi, Farshad

    2012-01-01

    Three new Complexes of formula [pd(bpy)(R-NH-CSS)] Cl (where bpy is 2/2'- bipyridine, and R-NH-CSS is butylamine, hexylamine- and octyamine-dithiocabamate anion) have been synthesized by University of Sistan and Blachostan. These complexes have been characterized by spectroscopic methods such as ultraviolet-visible, infrared and (1)H-NMR as well as conductivity measurements and chemical analysis. In these complexes, each of the dithiocarbamate ligands coordinates to Pd (II) center as bidentate with two sulfur atoms. We have found a 1:1 electrolyte in water conductivity test for the above mentioned compounds. To measure the biologic activity and potential anticancer efficacy of these compounds, they have been compared with cisplatin and its palladium analogue of [Pd (NH3)2 Cl2] on three different cell lines of human hepatocarcinoma HepG2, human ovarian carcinoma OV2008, and human lung adenocarcinoma A549. Clonogenic assay has shown LD50s in the range of 0.131±0.025 to 0.934 ± 0.194 for these compounds on above cell lines. In comparison, cisplatin has shown LD50s of 0.838 ± 0.074, 2.196 ± 0.220, and 2.799 ± 0.733 on OV2008, HepG2 and A549 cell lines, respectively. As a conclusion, above three new complexes have shown higher cytotoxicities compared to cisplatin on three different human cell lines. Based on biological tests, these compounds may potentially be considered as good anticancer candidates for further pharmacological studies.

  6. Mechanical properties of the normal human cartilage-bone complex in relation to age

    DEFF Research Database (Denmark)

    Ding, Ming; Dalstra, M; Linde, F

    1998-01-01

    OBJECTIVE: This study investigates the age-related variations in the mechanical properties of the normal human tibial cartilage-bone complex and the relationships between cartilage and bone. DESIGN: A novel technique was applied to assess the mechanical properties of the cartilage and bone by mea...... that are of importance for the understanding of the etiology and pathogenesis of degenerative joint diseases, such as arthrosis....

  7. Validating cognitive support for operators of complex human-machine systems

    International Nuclear Information System (INIS)

    O'Hara, J.; Wachtel, J.

    1995-01-01

    Modem nuclear power plants (NPPs) are complex systems whose performance is the result of an intricate interaction of human and system control. A complex system may be defined as one which supports a dynamic process involving a large number of elements that interact in many different ways. Safety is addressed through defense-in-depth design and preplanning; i.e., designers consider the types of failures that are most likely to occur and those of high consequence, and design their solutions in advance. However, complex interactions and their failure modes cannot always be anticipated by the designer and may be unfamiliar to plant personnel. These situations may pose cognitive demands on plant personnel, both individually and as a crew. Other factors may contribute to the cognitive challenges of NPP operation as well, including hierarchal processes, dynamic pace, system redundancy and reliability, and conflicting objectives. These factors are discussed in this paper

  8. Saving Human Lives: What Complexity Science and Information Systems can Contribute

    Science.gov (United States)

    Helbing, Dirk; Brockmann, Dirk; Chadefaux, Thomas; Donnay, Karsten; Blanke, Ulf; Woolley-Meza, Olivia; Moussaid, Mehdi; Johansson, Anders; Krause, Jens; Schutte, Sebastian; Perc, Matjaž

    2015-02-01

    We discuss models and data of crowd disasters, crime, terrorism, war and disease spreading to show that conventional recipes, such as deterrence strategies, are often not effective and sufficient to contain them. Many common approaches do not provide a good picture of the actual system behavior, because they neglect feedback loops, instabilities and cascade effects. The complex and often counter-intuitive behavior of social systems and their macro-level collective dynamics can be better understood by means of complexity science. We highlight that a suitable system design and management can help to stop undesirable cascade effects and to enable favorable kinds of self-organization in the system. In such a way, complexity science can help to save human lives.

  9. Complexity and dynamics of switched human balance control during quiet standing.

    Science.gov (United States)

    Nema, Salam; Kowalczyk, Piotr; Loram, Ian

    2015-10-01

    In this paper, we use a combination of numerical simulations, time series analysis, and complexity measures to investigate the dynamics of switched systems with noise, which are often used as models of human balance control during quiet standing. We link the results with complexity measures found in experimental data of human sway motion during quiet standing. The control model ensuring balance, which we use, is based on an act-and-wait control concept, that is, a human controller is switched on when a certain sway angle is reached. Otherwise, there is no active control present. Given a time series data, we determine how does it look a typical pattern of control strategy in our model system. We detect the switched nonlinearity in the system using a frequency analysis method in the absence of noise. We also analyse the effect of time delay on the existence of limit cycles in the system in the absence of noise. We perform the entropy and detrended fluctuation analyses in view of linking the switchings (and the dead zone) with the occurrences of complexity in the model system in the presence of noise. Finally, we perform the entropy and detrended fluctuation analyses on experimental data and link the results with numerical findings in our model example.

  10. Human practice in the life cycle of complex systems. Challenges and methods

    Energy Technology Data Exchange (ETDEWEB)

    Nuutinen, M. (ed.) [VTT Building and Transport, Espoo (Finland); Luoma, J. (ed.) [VTT Industrial Systems, Espoo (Finland)

    2005-12-15

    This book describes the current and near future challenges in work and traffic environments in light of the rapid technology development. It focuses on the following domains: road and vessel traffic, nuclear power production, automatic mining, steel factory and the pulp and paper industry. Each example concerns complex technical systems where human practice and behaviour has an important role for the safety, efficiency and productivity of the system. The articles illustrate the enormous field of humanrelated research when considering the design, validation, implementation, operation and maintenance of complex sociotechnical systems. Nevertheless, these 14 chapters are only examples of the range of questions related to the issue. The authors of the book are VTT experts in work or traffic psychology and research, system usability, risk and safety analysis, virtual environments and they have experience in studying different domains. This book is an attempt to open up the complex world of human-technology interaction for readers facing practical problems with complex systems. It is aimed to help a technical or organisational designer, a policy- maker, an expert or a user, the one who works or lives within the technology. (orig.)

  11. Parkin Mutations Reduce the Complexity of Neuronal Processes in iPSC-derived Human Neurons

    Science.gov (United States)

    Ren, Yong; Jiang, Houbo; Hu, Zhixing; Fan, Kevin; Wang, Jun; Janoschka, Stephen; Wang, Xiaomin; Ge, Shaoyu; Feng, Jian

    2015-01-01

    Parkinson’s disease (PD) is characterized by the degeneration of nigral dopaminergic (DA) neurons and non-DA neurons in many parts of the brain. Mutations of parkin, an E3 ubiquitin ligase that strongly binds to microtubules, are the most frequent cause of recessively inherited Parkinson’s disease. The lack of robust PD phenotype in parkin knockout mice suggests a unique vulnerability of human neurons to parkin mutations. Here, we show that the complexity of neuronal processes as measured by total neurite length, number of terminals, number of branch points and Sholl analysis, was greatly reduced in induced pluripotent stem cell (iPSC)-derived TH+ or TH− neurons from PD patients with parkin mutations. Consistent with these, microtubule stability was significantly decreased by parkin mutations in iPSC-derived neurons. Overexpression of parkin, but not its PD-linked mutant nor GFP, restored the complexity of neuronal processes and the stability of microtubules. Consistent with these, the microtubule-depolymerizing agent colchicine mimicked the effect of parkin mutations by decreasing neurite length and complexity in control neurons while the microtubule-stabilizing drug taxol mimicked the effect of parkin overexpression by enhancing the morphology of parkin-deficient neurons. The results suggest that parkin maintains the morphological complexity of human neurons by stabilizing microtubules. PMID:25332110

  12. Neurochemical dynamics of acute orofacial pain in the human trigeminal brainstem nuclear complex.

    Science.gov (United States)

    de Matos, Nuno M P; Hock, Andreas; Wyss, Michael; Ettlin, Dominik A; Brügger, Mike

    2017-11-15

    The trigeminal brainstem sensory nuclear complex is the first central relay structure mediating orofacial somatosensory and nociceptive perception. Animal studies suggest a substantial involvement of neurochemical alterations at such basal CNS levels in acute and chronic pain processing. Translating this animal based knowledge to humans is challenging. Human related examining of brainstem functions are challenged by MR related peculiarities as well as applicability aspects of experimentally standardized paradigms. Based on our experience with an MR compatible human orofacial pain model, the aims of the present study were twofold: 1) from a technical perspective, the evaluation of proton magnetic resonance spectroscopy at 3 T regarding measurement accuracy of neurochemical profiles in this small brainstem nuclear complex and 2) the examination of possible neurochemical alterations induced by an experimental orofacial pain model. Data from 13 healthy volunteers aged 19-46 years were analyzed and revealed high quality spectra with significant reductions in total N-acetylaspartate (N-acetylaspartate + N-acetylaspartylglutamate) (-3.7%, p = 0.009) and GABA (-10.88%, p = 0.041) during the pain condition. These results might reflect contributions of N-acetylaspartate and N-acetylaspartylglutamate in neuronal activity-dependent physiologic processes and/or excitatory neurotransmission, whereas changes in GABA might indicate towards a reduction in tonic GABAergic functioning during nociceptive signaling. Summarized, the present study indicates the applicability of 1 H-MRS to obtain neurochemical dynamics within the human trigeminal brainstem sensory nuclear complex. Further developments are needed to pave the way towards bridging important animal based knowledge with human research to understand the neurochemistry of orofacial nociception and pain. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Biochemical reconstitution and phylogenetic comparison of human SET1 family core complexes involved in histone methylation.

    Science.gov (United States)

    Shinsky, Stephen A; Monteith, Kelsey E; Viggiano, Susan; Cosgrove, Michael S

    2015-03-06

    Mixed lineage leukemia protein-1 (MLL1) is a member of the SET1 family of histone H3 lysine 4 (H3K4) methyltransferases that are required for metazoan development. MLL1 is the best characterized human SET1 family member, which includes MLL1-4 and SETd1A/B. MLL1 assembles with WDR5, RBBP5, ASH2L, DPY-30 (WRAD) to form the MLL1 core complex, which is required for H3K4 dimethylation and transcriptional activation. Because all SET1 family proteins interact with WRAD in vivo, it is hypothesized they are regulated by similar mechanisms. However, recent evidence suggests differences among family members that may reflect unique regulatory inputs in the cell. Missing is an understanding of the intrinsic enzymatic activities of different SET1 family complexes under standard conditions. In this investigation, we reconstituted each human SET1 family core complex and compared subunit assembly and enzymatic activities. We found that in the absence of WRAD, all but one SET domain catalyzes at least weak H3K4 monomethylation. In the presence of WRAD, all SET1 family members showed stimulated monomethyltransferase activity but differed in their di- and trimethylation activities. We found that these differences are correlated with evolutionary lineage, suggesting these enzyme complexes have evolved to accomplish unique tasks within metazoan genomes. To understand the structural basis for these differences, we employed a "phylogenetic scanning mutagenesis" assay and identified a cluster of amino acid substitutions that confer a WRAD-dependent gain-of-function dimethylation activity on complexes assembled with the MLL3 or Drosophila trithorax proteins. These results form the basis for understanding how WRAD differentially regulates SET1 family complexes in vivo. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Not so bad after all: retroviruses and long terminal repeat retrotransposons as a source of new genes in vertebrates.

    Science.gov (United States)

    Naville, M; Warren, I A; Haftek-Terreau, Z; Chalopin, D; Brunet, F; Levin, P; Galiana, D; Volff, J-N

    2016-04-01

    Viruses and transposable elements, once considered as purely junk and selfish sequences, have repeatedly been used as a source of novel protein-coding genes during the evolution of most eukaryotic lineages, a phenomenon called 'molecular domestication'. This is exemplified perfectly in mammals and other vertebrates, where many genes derived from long terminal repeat (LTR) retroelements (retroviruses and LTR retrotransposons) have been identified through comparative genomics and functional analyses. In particular, genes derived from gag structural protein and envelope (env) genes, as well as from the integrase-coding and protease-coding sequences, have been identified in humans and other vertebrates. Retroelement-derived genes are involved in many important biological processes including placenta formation, cognitive functions in the brain and immunity against retroelements, as well as in cell proliferation, apoptosis and cancer. These observations support an important role of retroelement-derived genes in the evolution and diversification of the vertebrate lineage. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  15. Recombination Origin of Retrovirus XMRV | Center for Cancer Research

    Science.gov (United States)

    Xenotropic murine leukemia virus–related virus (XMRV) was first reported in samples from a human prostate tumor in 2006, and, at that time, claims were made that XMRV infection rates ranged from 6 to 27 percent of human prostate cancers.  Later research reported XMRV in the blood of 67 percent of people with chronic fatigue syndrome (CFS). When follow-up studies failed to

  16. Crystal structure of a complex of human chymase with its benzimidazole derived inhibitor

    International Nuclear Information System (INIS)

    Matsumoto, Yoshiyuki; Kakuda, Shinji; Koizumi, Masahiro; Mizuno, Tsuyoshi; Muroga, Yumiko; Kawamura, Takashi; Takimoto-Kamimura, Midori

    2013-01-01

    The crystal structure of human chymase complexed with a novel benzimidazole inhibitor, TJK002, was determined at 2.8 Å resolution. The present study shows that the benzimidazole ring of the inhibitor takes the stable stacking interaction with the protonated His57 in the catalytic domain of human chymase. The crystal structure of human chymase complexed with a novel benzimidazole inhibitor, TJK002, was determined at 2.8 Å resolution. The X-ray crystallographic study shows that the benzimidazole inhibitor forms a non-covalent interaction with the catalytic domain of human chymase. The hydrophobic fragment of the inhibitor occupies the S1 pocket. The carboxylic acid group of the inhibitor forms hydrogen bonds with the imidazole N(∊) atom of His57 and/or the O(γ) atom of Ser195 which are members of the catalytic triad. This imidazole ring of His57 induces π–π stacking to the benzene ring of the benzimidazole scaffold as P2 moiety. Fragment molecular orbital calculation of the atomic coordinates by X-ray crystallography shows that this imidazole ring of His57 could be protonated with the carboxyl group of Asp102 or hydroxyl group of Ser195 and the stacking interaction is stabilized. A new drug design strategy is proposed where the stacking to the protonated imidazole of the drug target protein with the benzimidazole scaffold inhibitor causes unpredicted potent inhibitory activity for some enzymes

  17. Aviation Safety: Modeling and Analyzing Complex Interactions between Humans and Automated Systems

    Science.gov (United States)

    Rungta, Neha; Brat, Guillaume; Clancey, William J.; Linde, Charlotte; Raimondi, Franco; Seah, Chin; Shafto, Michael

    2013-01-01

    The on-going transformation from the current US Air Traffic System (ATS) to the Next Generation Air Traffic System (NextGen) will force the introduction of new automated systems and most likely will cause automation to migrate from ground to air. This will yield new function allocations between humans and automation and therefore change the roles and responsibilities in the ATS. Yet, safety in NextGen is required to be at least as good as in the current system. We therefore need techniques to evaluate the safety of the interactions between humans and automation. We think that current human factor studies and simulation-based techniques will fall short in front of the ATS complexity, and that we need to add more automated techniques to simulations, such as model checking, which offers exhaustive coverage of the non-deterministic behaviors in nominal and off-nominal scenarios. In this work, we present a verification approach based both on simulations and on model checking for evaluating the roles and responsibilities of humans and automation. Models are created using Brahms (a multi-agent framework) and we show that the traditional Brahms simulations can be integrated with automated exploration techniques based on model checking, thus offering a complete exploration of the behavioral space of the scenario. Our formal analysis supports the notion of beliefs and probabilities to reason about human behavior. We demonstrate the technique with the Ueberligen accident since it exemplifies authority problems when receiving conflicting advices from human and automated systems.

  18. Characterization of solubilized human and rat brain US -endorphin-receptor complex

    Energy Technology Data Exchange (ETDEWEB)

    Helmeste, D.M.; Li, C.H.

    1986-01-01

    Opioid receptors have been solubilized from human striatal and rat whole-brain membranes by use of 3-((3-cholamidopropyl)dimethylammonio)-1-propanesulfonate (CHAPS). Tritiated human US -endorphin (TH-US /sub h/-EP) binding revealed high-affinity competition by morphine, naloxone, and various US -EP analogues. Lack of high-affinity competition by (+/-)-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)cyclohexyl)benzeneacetamide methanesulfonate (U50-488, Upjohn) indicated that k sites were not labeled by TH-US -/sub h/-EP under these conditions. Affinities were similar in both soluble and membrane preparations except for (Met)enkephalin, which appears to be rapidly degraded by the solubilized extract. Size differences between human and rat solubilized TH-US /sub h/-EP-receptor complexes were revealed by exclusion chromatography.

  19. Nuclear pore complex protein mediated nuclear localization of dicer protein in human cells.

    Directory of Open Access Journals (Sweden)

    Yoshinari Ando

    Full Text Available Human DICER1 protein cleaves double-stranded RNA into small sizes, a crucial step in production of single-stranded RNAs which are mediating factors of cytoplasmic RNA interference. Here, we clearly demonstrate that human DICER1 protein localizes not only to the cytoplasm but also to the nucleoplasm. We also find that human DICER1 protein associates with the NUP153 protein, one component of the nuclear pore complex. This association is detected predominantly in the cytoplasm but is also clearly distinguishable at the nuclear periphery. Additional characterization of the NUP153-DICER1 association suggests NUP153 plays a crucial role in the nuclear localization of the DICER1 protein.

  20. Prediction of Complex Human Traits Using the Genomic Best Linear Unbiased Predictor

    DEFF Research Database (Denmark)

    de los Campos, Gustavo; Vazquez, Ana I; Fernando, Rohan

    2013-01-01

    Despite important advances from Genome Wide Association Studies (GWAS), for most complex human traits and diseases, a sizable proportion of genetic variance remains unexplained and prediction accuracy (PA) is usually low. Evidence suggests that PA can be improved using Whole-Genome Regression (WGR......) models where phenotypes are regressed on hundreds of thousands of variants simultaneously. The Genomic Best Linear Unbiased Prediction G-BLUP, a ridge-regression type method) is a commonly used WGR method and has shown good predictive performance when applied to plant and animal breeding populations....... However, breeding and human populations differ greatly in a number of factors that can affect the predictive performance of G-BLUP. Using theory, simulations, and real data analysis, we study the erformance of G-BLUP when applied to data from related and unrelated human subjects. Under perfect linkage...

  1. [The evolution of human cultural behavior: notes on Darwinism and complexity].

    Science.gov (United States)

    Peric, Mikael; Murrieta, Rui Sérgio Sereni

    2015-12-01

    The article analyzes three schools that can be understood as central in studies of the evolution of human behavior within the paradigm of evolution by natural selection: human behavioral ecology (HBE), evolutionary psychology, and dual inheritance. These three streams of thought are used to depict the Darwinist landscape and pinpoint its strong suits and limitations. Theoretical gaps were identified that seem to reduce these schools' ability to account for the diversity of human evolutionary behavior. Their weak points include issues related to the concept of reproductive success, types of adaptation, and targets of selection. An interdisciplinary approach is proposed as the solution to this dilemma, where complex adaptive systems would serve as a source.

  2. The complexity of the calretinin-expressing progenitors in the human cerebral cortex

    Directory of Open Access Journals (Sweden)

    Nevena V Radonjic

    2014-08-01

    Full Text Available The complex structure and function of the cerebral cortex critically depend on the balance of excitation and inhibition provided by the pyramidal projection neurons and GABAergic interneurons, respectively. The calretinin-expressing (CalR+ cell is a subtype of GABAergic cortical interneurons that is more prevalent in humans than in rodents. In rodents, CalR+ interneurons originate in the caudal ganglionic eminence (CGE from Gsx2+ progenitors, but in humans it has been suggested that a subpopulation of CalR+ cells can also be generated in the cortical ventricular/subventricular zone (VZ/SVZ. The progenitors for cortically generated CalR+ subpopulation in primates are not yet characterized. Hence, the aim of this study was to identify patterns of expression of the transcription factors (TFs that commit cortical stem cells to the CalR fate, with a focus on Gsx2. First, we studied the expression of Gsx2 and its downstream effectors, Ascl1 and Sp8 in the cortical regions of the fetal human forebrain at midgestation. Next, we established that a subpopulation of cells expressing these TFs are proliferating in the cortical SVZ, and can be co-labeled with CalR. The presence and proliferation of Gsx2+ cells, not only in the ventral telencephalon (GE as previously reported, but also in the cerebral cortex suggests cortical origin of a subpopulation of CalR+ neurons in humans. In vitro treatment of human cortical progenitors with Sonic hedgehog (Shh, an important morphogen in the specification of interneurons, decreased levels of Ascl1 and Sp8 proteins, but did not affect Gsx2 levels. Taken together, our ex-vivo and in vitro results on human fetal brain suggest complex endogenous and exogenous regulation of TFs implied in the specification of different subtypes of CalR+ cortical interneurons.

  3. Complexities in human herpesvirus-6A and -6B binding to host cells

    International Nuclear Information System (INIS)

    Pedersen, Simon Metz; Hoellsberg, Per

    2006-01-01

    Human herpesvirus-6A and -6B uses the cellular receptor CD46 for fusion and infection of the host cell. The viral glycoprotein complex gH-gL from HHV-6A binds to the short consensus repeat 2 and 3 in CD46. Although all the major isoforms of CD46 bind the virus, certain isoforms may have higher affinity than others for the virus. Within recent years, elucidation of the viral complex has identified additional HHV-6A and -6B specific glycoproteins. Thus, gH-gL associates with a gQ1-gQ2 dimer to form a heterotetrameric complex. In addition, a novel complex consisting of gH-gL-gO has been described that does not bind CD46. Accumulating evidence suggests that an additional HHV-6A and -6B receptor exists. The previous simple picture of HHV-6A/B-host cell contact therefore includes more layers of complexities on both the viral and the host cell side of the interaction

  4. Structure of the active form of human origin recognition complex and its ATPase motor module

    Energy Technology Data Exchange (ETDEWEB)

    Tocilj, Ante; On, Kin Fan; Yuan, Zuanning; Sun, Jingchuan; Elkayam, Elad; Li, Huilin; Stillman, Bruce; Joshua-Tor, Leemor

    2017-01-23

    Binding of the Origin Recognition Complex (ORC) to origins of replication marks the first step in the initiation of replication of the genome in all eukaryotic cells. Here, we report the structure of the active form of human ORC determined by X-ray crystallography and cryo-electron microscopy. The complex is composed of an ORC1/4/5 motor module lobe in an organization reminiscent of the DNA polymerase clamp loader complexes. A second lobe contains the ORC2/3 subunits. The complex is organized as a double-layered shallow corkscrew, with the AAA+ and AAA+-like domains forming one layer, and the winged-helix domains (WHDs) forming a top layer. CDC6 fits easily between ORC1 and ORC2, completing the ring and the DNA-binding channel, forming an additional ATP hydrolysis site. Analysis of the ATPase activity of the complex provides a basis for understanding ORC activity as well as molecular defects observed in Meier-Gorlin Syndrome mutations.

  5. Crystal structure of the human 4-1BB/4-1BBL complex.

    Science.gov (United States)

    Gilbreth, Ryan N; Oganesyan, Vaheh Y; Amdouni, Hamza; Novarra, Shabazz; Grinberg, Luba; Barnes, Arnita; Baca, Manuel

    2018-05-02

    4-1BBL is a member of the TNF superfamily and is the ligand for the TNFRsuperfamily receptor, 4-1BB. 4-1BB plays an immunomodulatory role in T cells and NK cells and agonists of this receptor have garnered strong attention as potentialimmunotherapy agents. Broadly speaking, the structural features of TNF superfamilymembers, their receptors and ligand/receptor complexes are similar. However, apublished crystal structure of human 4-1BBL suggests that it may be unique in thisregard, exhibiting a three-bladed propeller-like trimer assembly that is distinctly different from that observed in other family members. This unusual structure also suggests that the human 4-1BB/4-1BBL complex may be structurally unique within the TNF/TNFR superfamily, but to date no structural data have been reported. Here we report the crystal structure of the human 4-1BB/4-1BBL complex at 2.4 Å resolution. In this structure, 4-1BBL does not adopt the unusual trimer assembly previously reported, but instead forms a canonical bell-shaped trimer typical of other TNF superfamily members. The structure of 4-1BB is also largely canonical as is the 4-1BB/4-1BBL complex. Mutational data support the 4-1BBL structure reported here as being biologically relevant, suggesting that the previously reported structure is not. Together, the data presented here offer insight into structure/function relationships in the 4-1BB/4-1BBL system and improve our structural understanding of the TNF/TNFR superfamily more broadly. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Lateral gene transfer of an ABC transporter complex between major constituents of the human gut microbiome

    Directory of Open Access Journals (Sweden)

    Meehan Conor J

    2012-11-01

    Full Text Available Abstract Background Several links have been established between the human gut microbiome and conditions such as obesity and inflammatory bowel syndrome. This highlights the importance of understanding what properties of the gut microbiome can affect the health of the human host. Studies have been undertaken to determine the species composition of this microbiome and infer functional profiles associated with such host properties. However, lateral gene transfer (LGT between community members may result in misleading taxonomic attributions for the recipient organisms, thus making species-function links difficult to establish. Results We identified a peptides/nickel transport complex whose components differed in abundance based upon levels of host obesity, and assigned the encoded proteins to members of the microbial community. Each protein was assigned to several distinct taxonomic groups, with moderate levels of agreement observed among different proteins in the complex. Phylogenetic trees of these proteins produced clusters that differed greatly from taxonomic attributions and indicated that habitat-directed LGT of this complex is likely to have occurred, though not always between the same partners. Conclusions These findings demonstrate that certain membrane transport systems may be an important factor within an obese-associated gut microbiome and that such complexes may be acquired several times by different strains of the same species. Additionally, an example of individual proteins from different organisms being transferred into one operon was observed, potentially demonstrating a functional complex despite the donors of the subunits being taxonomically disparate. Our results also highlight the potential impact of habitat-directed LGT on the resident microbiota.

  7. Multistructure index in revealing complexity of regulatory mechanisms of human cardiovascular system at rest and orthostatic stress in healthy humans

    Science.gov (United States)

    Makowiec, Danuta; Graff, Beata; Struzik, Zbigniew R.

    2017-02-01

    Biological regulation is sufficiently complex to pose an enduring challenge for characterization of both its equilibrium and transient non-equilibrium dynamics. Two univariate but coupled observables, heart rate and systolic blood pressure, are commonly characterized in the benchmark example of the human cardiovascular regulatory system. Asymmetric distributions of accelerations and decelerations of heart rate, as well as rises and falls in systolic blood pressure, recorded in humans during a head-up tilt test provide insights into the dynamics of cardiovascular response to a rapid, controlled deregulation of the system's homeostasis. The baroreflex feedback loop is assumed to be the fundamental physiological mechanism for ensuring homeostatic blood supply to distant organs at rest and during orthostatic stress, captured in a classical beat-to-beat autoregressive model of baroreflex by de Boer et al. (1987). For model corroboration, a multistructure index statistic is proposed, seamlessly evaluating the size spectrum of magnitudes of neural reflexes such as baroreflex, responsible for maintaining the homeostatic dynamics. The multistructure index exposes a distinctly different dynamics of multiscale asymmetry between results obtained from real-life signals recorded from healthy subjects and those simulated using both the classical and perturbed versions of the model. Nonlinear effects observed suggest the pronounced presence of complex mechanisms resulting from baroreflex regulation when a human is at rest, which is aggravated in the system's response to orthostatic stress. Using our methodology of multistructure index, we therefore show a marked difference between model and real-life scenarios, which we attribute to multiscale asymmetry of non-linear origin in real-life signals, which we are not reproducible by the classical model.

  8. Colloque S&T Symposium 2008: Understanding the Human Dimension in 21st Century Conflict/Warfare: The Complexities of Human-with-Human Relationships

    Science.gov (United States)

    2008-08-01

    intentionally left blank. DRDC Corporate TR [2008-004] v Executive summary Colloque S&T Symposium 2008: The Complexities of Human...mettaient en jeu notre capacité ou notre incapacité de déterminer le prochain choc radical et la manière dont la communauté y réagit. Il a aussi...iii Executive summary

  9. STARS experiential group intervention: a complex trauma treatment approach for survivors of human trafficking.

    Science.gov (United States)

    Hopper, Elizabeth K; Azar, Naomi; Bhattacharyya, Sriya; Malebranche, Dominique A; Brennan, Kelsey E

    2018-01-01

    This is the abstract that was submitted online with the paper: Despite the fact that many survivors of human trafficking have experienced complex trauma, there are no established interventions designed to specifically address these impacts. Leaders in the field of complex trauma have advocated for the need for somatic approaches to intervention. This paper presents STARS Experiential Group treatment, the first structured bodybased group intervention that has been designed to address complex trauma in survivors of human trafficking. Three pilot groups were run in residential settings with adolescent and adult survivors of sex trafficking. Two adaptations were utilized, with one focusing on application of expressive arts modalities and the other incorporating theater games. Qualitative results, using thematic analysis, identified several themes related to challenges and potential benefits of these groups. Potential benefits of the STARS groups were found in the areas of Interpersonal Relationships, Regulation, and Self/ Identity, with fourteen sub-themes further describing positive impacts. Challenges within these areas are explored, to inform the development of group interventions for trafficking survivors. The results of this paper suggest that experiential, somatically-oriented group treatment shows promise as an important element of holistic intervention with trafficking survivors.

  10. The human CTC1/STN1/TEN1 complex regulates telomere maintenance in ALT cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Chenhui; Jia, Pingping; Chastain, Megan; Shiva, Olga; Chai, Weihang, E-mail: wchai@wsu.edu

    2017-06-15

    Maintaining functional telomeres is important for long-term proliferation of cells. About 15% of cancer cells are telomerase-negative and activate the alternative-lengthening of telomeres (ALT) pathway to maintain their telomeres. Recent studies have shown that the human CTC1/STN1/TEN1 complex (CST) plays a multi-faceted role in telomere maintenance in telomerase-expressing cancer cells. However, the role of CST in telomere maintenance in ALT cells is unclear. Here, we report that human CST forms a functional complex localizing in the ALT-associated PML bodies (APBs) in ALT cells throughout the cell cycle. Suppression of CST induces telomere instabilities including telomere fragility and elevates telomeric DNA recombination, leading to telomere dysfunction. In addition, CST deficiency significantly diminishes the abundance of extrachromosomal circular telomere DNA known as C-circles and t-circles. Suppression of CST also results in multinucleation in ALT cells and impairs cell proliferation. Our findings imply that the CST complex plays an important role in regulating telomere maintenance in ALT cells. - Highlights: • CST localizes at telomeres and ALT-associated PML bodies in ALT cells throughout the cell cycle. • CST is important for promoting telomeric DNA replication in ALT cells. • CST deficiency decreases ECTR formation and increases T-SCE. • CST deficiency impairs ALT cell proliferation and results in multinucleation.

  11. Ontogeny of neuro-insular complexes and islets innervation in the human pancreas.

    Science.gov (United States)

    Proshchina, Alexandra E; Krivova, Yulia S; Barabanov, Valeriy M; Saveliev, Sergey V

    2014-01-01

    The ontogeny of the neuro-insular complexes (NIC) and the islets innervation in human pancreas has not been studied in detail. Our aim was to describe the developmental dynamics and distribution of the nervous system structures in the endocrine part of human pancreas. We used double-staining with antibodies specific to pan-neural markers [neuron-specific enolase (NSE) and S100 protein] and to hormones of pancreatic endocrine cells. NSE and S100-positive nerves and ganglia were identified in the human fetal pancreas from gestation week (gw) 10 onward. Later the density of S100 and NSE-positive fibers increased. In adults, this network was sparse. The islets innervation started to form from gw 14. NSE-containing endocrine cells were identified from gw 12 onward. Additionally, S100-positive cells were detected both in the periphery and within some of the islets starting at gw 14. The analysis of islets innervation has shown that the fetal pancreas contained NIC and the number of these complexes was reduced in adults. The highest density of NIC is detected during middle and late fetal periods, when the mosaic islets, typical for adults, form. The close integration between the developing pancreatic islets and the nervous system structures may play an important role not only in the hormone secretion, but also in the islets morphogenesis.

  12. MUC1-C activates polycomb repressive complexes and downregulates tumor suppressor genes in human cancer cells.

    Science.gov (United States)

    Rajabi, Hasan; Hiraki, Masayuki; Kufe, Donald

    2018-04-01

    The PRC2 and PRC1 complexes are aberrantly expressed in human cancers and have been linked to decreases in patient survival. MUC1-C is an oncoprotein that is also overexpressed in diverse human cancers and is associated with a poor prognosis. Recent studies have supported a previously unreported function for MUC1-C in activating PRC2 and PRC1 in cancer cells. In the regulation of PRC2, MUC1-C (i) drives transcription of the EZH2 gene, (ii) binds directly to EZH2, and (iii) enhances occupancy of EZH2 on target gene promoters with an increase in H3K27 trimethylation. Regarding PRC1, which is recruited to PRC2 sites in the hierarchical model, MUC1-C induces BMI1 transcription, forms a complex with BMI1, and promotes H2A ubiquitylation. MUC1-C thereby contributes to the integration of PRC2 and PRC1-mediated repression of tumor suppressor genes, such as CDH1, CDKN2A, PTEN and BRCA1. Like PRC2 and PRC1, MUC1-C is associated with the epithelial-mesenchymal transition (EMT) program, cancer stem cell (CSC) state, and acquisition of anticancer drug resistance. In concert with these observations, targeting MUC1-C downregulates EZH2 and BMI1, inhibits EMT and the CSC state, and reverses drug resistance. These findings emphasize the significance of MUC1-C as a therapeutic target for inhibiting aberrant PRC function and reprogramming the epigenome in human cancers.

  13. Abnormally high levels of virus-infected IFN-gamma+ CCR4+ CD4+ CD25+ T cells in a retrovirus-associated neuroinflammatory disorder.

    Directory of Open Access Journals (Sweden)

    Yoshihisa Yamano

    Full Text Available BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1 is a human retrovirus associated with both HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP, which is a chronic neuroinflammatory disease, and adult T-cell leukemia (ATL. The pathogenesis of HAM/TSP is known to be as follows: HTLV-1-infected T cells trigger a hyperimmune response leading to neuroinflammation. However, the HTLV-1-infected T cell subset that plays a major role in the accelerated immune response has not yet been identified. PRINCIPAL FINDINGS: Here, we demonstrate that CD4(+CD25(+CCR4(+ T cells are the predominant viral reservoir, and their levels are increased in HAM/TSP patients. While CCR4 is known to be selectively expressed on T helper type 2 (Th2, Th17, and regulatory T (Treg cells in healthy individuals, we demonstrate that IFN-gamma production is extraordinarily increased and IL-4, IL-10, IL-17, and Foxp3 expression is decreased in the CD4(+CD25(+CCR4(+ T cells of HAM/TSP patients as compared to those in healthy individuals, and the alteration in function is specific to this cell subtype. Notably, the frequency of IFN-gamma-producing CD4(+CD25(+CCR4(+Foxp3(- T cells is dramatically increased in HAM/TSP patients, and this was found to be correlated with disease activity and severity. CONCLUSIONS: We have defined a unique T cell subset--IFN-gamma(+CCR4(+CD4(+CD25(+ T cells--that is abnormally increased and functionally altered in this retrovirus-associated inflammatory disorder of the central nervous system.

  14. Fatigue crack propagation path across the dentinoenamel junction complex in human teeth.

    Science.gov (United States)

    Dong, X D; Ruse, N D

    2003-07-01

    The human tooth structures should be understood clearly to improve clinically used restorative materials. The dentinoenamel junction (DEJ) plays a key role in resisting crack propagation in teeth. The aim of this study was to determine the fracture toughness of the enamel-DEJ-dentin complex and to investigate the influence of the DEJ on the fatigue crack propagation path across it by characterizing fatigue-fractured enamel-DEJ-dentin complexes using optical and scanning electron microscopy. The results of this study showed that the fracture toughness of the enamel-DEJ-dentin complex was 1.50 +/- 0.28 Mpa x m(1/2). Based on the results of this investigation, it was concluded that the DEJ complex played a critical role in resisting crack propagation from enamel into dentin. The DEJ complex is, approximately, a 100 to 150 microm broad region at the interface between enamel and dentin. The toughening mechanism of the DEJ complex may be explained by the fact that crack paths were deflected as cracks propagated across it. Understanding the mechanism of crack deflection could help in improving dentin-composite as well as ceramic-cement interfacial qualities with the aim to decrease the risk of clinical failure of restorations. Both can be viewed as being composed from a layer of material of high strength and hardness bonded to a softer but tougher substratum (dentin). The bonding agent or the luting cement layer may play the critical role of the DEJ in improving the strength of these restorations in clinical situations. Copyright 2003 Wiley Periodicals, Inc.

  15. Complexity and multifractality of neuronal noise in mouse and human hippocampal epileptiform dynamics

    Science.gov (United States)

    Serletis, Demitre; Bardakjian, Berj L.; Valiante, Taufik A.; Carlen, Peter L.

    2012-10-01

    Fractal methods offer an invaluable means of investigating turbulent nonlinearity in non-stationary biomedical recordings from the brain. Here, we investigate properties of complexity (i.e. the correlation dimension, maximum Lyapunov exponent, 1/fγ noise and approximate entropy) and multifractality in background neuronal noise-like activity underlying epileptiform transitions recorded at the intracellular and local network scales from two in vitro models: the whole-intact mouse hippocampus and lesional human hippocampal slices. Our results show evidence for reduced dynamical complexity and multifractal signal features following transition to the ictal epileptiform state. These findings suggest that pathological breakdown in multifractal complexity coincides with loss of signal variability or heterogeneity, consistent with an unhealthy ictal state that is far from the equilibrium of turbulent yet healthy fractal dynamics in the brain. Thus, it appears that background noise-like activity successfully captures complex and multifractal signal features that may, at least in part, be used to classify and identify brain state transitions in the healthy and epileptic brain, offering potential promise for therapeutic neuromodulatory strategies for afflicted patients suffering from epilepsy and other related neurological disorders. This paper is based on chapter 5 of Serletis (2010 PhD Dissertation Department of Physiology, Institute of Biomaterials and Biomedical Engineering, University of Toronto).

  16. Comprehensive analysis of the transcriptional profile of the Mediator complex across human cancer types.

    Science.gov (United States)

    Syring, Isabella; Klümper, Niklas; Offermann, Anne; Braun, Martin; Deng, Mario; Boehm, Diana; Queisser, Angela; von Mässenhausen, Anne; Brägelmann, Johannes; Vogel, Wenzel; Schmidt, Doris; Majores, Michael; Schindler, Anne; Kristiansen, Glen; Müller, Stefan C; Ellinger, Jörg; Shaikhibrahim, Zaki; Perner, Sven

    2016-04-26

    The Mediator complex is a key regulator of gene transcription and several studies demonstrated altered expressions of particular subunits in diverse human diseases, especially cancer. However a systematic study deciphering the transcriptional expression of the Mediator across different cancer entities is still lacking.We therefore performed a comprehensive in silico cancer vs. benign analysis of the Mediator complex subunits (MEDs) for 20 tumor entities using Oncomine datasets. The transcriptional expression profiles across almost all cancer entities showed differentially expressed MEDs as compared to benign tissue. Differential expression of MED8 in renal cell carcinoma (RCC) and MED12 in lung cancer (LCa) were validated and further investigated by immunohistochemical staining on tissue microarrays containing large numbers of specimen. MED8 in clear cell RCC (ccRCC) associated with shorter survival and advanced TNM stage and showed higher expression in metastatic than primary tumors. In vitro, siRNA mediated MED8 knockdown significantly impaired proliferation and motility in ccRCC cell lines, hinting at a role for MED8 to serve as a novel therapeutic target in ccRCC. Taken together, our Mediator complex transcriptome proved to be a valid tool for identifying cancer-related shifts in Mediator complex composition, revealing that MEDs do exhibit cancer specific transcriptional expression profiles.

  17. Ethics in Publishing: Complexity Science and Human Factors Offer Insights to Develop a Just Culture.

    Science.gov (United States)

    Saurin, Tarcisio Abreu

    2016-12-01

    While ethics in publishing has been increasingly debated, there seems to be a lack of a theoretical framework for making sense of existing rules of behavior as well as for designing, managing and enforcing such rules. This letter argues that systems-oriented disciplines, such as complexity science and human factors, offer insights into new ways of dealing with ethics in publishing. Some examples of insights are presented. Also, a call is made for empirical studies that unveil the context and details of both retracted papers and the process of writing and publishing academic papers. This is expected to shed light on the complexity of the publication system as well as to support the development of a just culture, in which all participants are accountable.

  18. Simultaneous presence of endogenous retrovirus and herpes virus antigens has profound effect on cell-mediated immune responses: implications for multiple sclerosis

    DEFF Research Database (Denmark)

    Brudek, T.; Christensen, T.; Hansen, H.J.

    2004-01-01

    Retroviruses have been suggested as possible pathogenic factors in multiple sclerosis (MS), supported by the observation that endogenous retroviruses are activated in MS patients. Different members of the herpes family of which several are neurotropic have also been suggested as factors in MS pat...

  19. Serum Antibody Response to Koala Retrovirus Antigens Varies in Free-Ranging Koalas ( Phascolarctos cinereus ) in Australia: Implications for Vaccine Design.

    Science.gov (United States)

    Waugh, Courtney; Gillett, Amber; Polkinghorne, Adam; Timms, Peter

    2016-04-28

    Little is known about the immune response in the koala ( Phascolarctos cinereus ) to its retroviruses. Koala retroviruses (KoRVs) have been linked to neoplasia in wild and captive koalas, but there is no treatment available. We tested the KoRV-specific serum immunoglobulin G antibody response in nonimmunized and immunized koalas.

  20. Behavior of the nucleic acid ethidium complex sedimentation of human lymphocytes after gamma irradiation

    International Nuclear Information System (INIS)

    Langrock, K.

    1982-01-01

    Under standardized conditions the repair kinetic test by Fender and Hartwig demonstrates the dose dependence of the injury of the nucleic acid complex of human lymphocytes after gamma irradiation and their repair even in low dose regions. Seasonal changes with infect incubation, individual variability in the lymphocyte population and culture conditions are to be proved before clinical application of the test in radiotherapy to generalize the influence of the factors. 3.4 up to 6 μg/ml ethidium bromide should be chosen as an optimum ethidium concentration of the gradient. (author)

  1. Colour and luminance contrasts predict the human detection of natural stimuli in complex visual environments.

    Science.gov (United States)

    White, Thomas E; Rojas, Bibiana; Mappes, Johanna; Rautiala, Petri; Kemp, Darrell J

    2017-09-01

    Much of what we know about human colour perception has come from psychophysical studies conducted in tightly-controlled laboratory settings. An enduring challenge, however, lies in extrapolating this knowledge to the noisy conditions that characterize our actual visual experience. Here we combine statistical models of visual perception with empirical data to explore how chromatic (hue/saturation) and achromatic (luminant) information underpins the detection and classification of stimuli in a complex forest environment. The data best support a simple linear model of stimulus detection as an additive function of both luminance and saturation contrast. The strength of each predictor is modest yet consistent across gross variation in viewing conditions, which accords with expectation based upon general primate psychophysics. Our findings implicate simple visual cues in the guidance of perception amidst natural noise, and highlight the potential for informing human vision via a fusion between psychophysical modelling and real-world behaviour. © 2017 The Author(s).

  2. The Major Histocompatibility Complex and Perfumers' Descriptions of Human Body Odors

    Directory of Open Access Journals (Sweden)

    Claus Wedekind

    2007-04-01

    Full Text Available The MHC (major histocompatibility complex is a group of genes that play a crucial role in immune recognition and in tolerance of tissue grafting. The MHC has also been found to influence body odors, body odor preferences, and mate choice in mice and humans. Here we test whether verbal descriptions of human body odors can be linked to the MHC. We asked 45 male students to live as odor neutral as possible for two consecutive days and to wear a T-shirt during the nights. The odors of these T-shirts were then described by five evaluators: two professional perfumers and three laymen. One of the perfumers was able to describe the T-shirt odors in such a way that some of the allelic specificity of the MHC was significantly revealed (after Bonferroni correction for multiple testing. This shows that, although difficult, some people are able to describe MHC-correlated body odor components.

  3. Genomic binding profiles of functionally distinct RNA polymerase III transcription complexes in human cells.

    Science.gov (United States)

    Moqtaderi, Zarmik; Wang, Jie; Raha, Debasish; White, Robert J; Snyder, Michael; Weng, Zhiping; Struhl, Kevin

    2010-05-01

    Genome-wide occupancy profiles of five components of the RNA polymerase III (Pol III) machinery in human cells identified the expected tRNA and noncoding RNA targets and revealed many additional Pol III-associated loci, mostly near short interspersed elements (SINEs). Several genes are targets of an alternative transcription factor IIIB (TFIIIB) containing Brf2 instead of Brf1 and have extremely low levels of TFIIIC. Strikingly, expressed Pol III genes, unlike nonexpressed Pol III genes, are situated in regions with a pattern of histone modifications associated with functional Pol II promoters. TFIIIC alone associates with numerous ETC loci, via the B box or a novel motif. ETCs are often near CTCF binding sites, suggesting a potential role in chromosome organization. Our results suggest that human Pol III complexes associate preferentially with regions near functional Pol II promoters and that TFIIIC-mediated recruitment of TFIIIB is regulated in a locus-specific manner.

  4. Integrated approach to knowledge acquisition and safety management of complex plants with emphasis on human factors

    International Nuclear Information System (INIS)

    Kosmowski, K.T.

    1998-01-01

    In this paper an integrated approach to the knowledge acquisition and safety management of complex industrial plants is proposed and outlined. The plant is considered within a man-technology-environment (MTE) system. The knowledge acquisition is aimed at the consequent reliability evaluation of human factor and probabilistic modeling of the plant. Properly structured initial knowledge is updated in life-time of the plant. The data and knowledge concerning the topology of safety related systems and their functions are created in a graphical CAD system and are object oriented. Safety oriented monitoring of the plant includes abnormal situations due to external and internal disturbances, failures of hard/software components and failures of human factor. The operation and safety related evidence is accumulated in special data bases. Data/knowledge bases are designed in such a way to support effectively the reliability and safety management of the plant. (author)

  5. Functional modelling for integration of human-software-hardware in complex physical systems

    International Nuclear Information System (INIS)

    Modarres, M.

    1996-01-01

    A framework describing the properties of complex physical systems composed of human-software-hardware interactions in terms of their functions is described. It is argued that such a framework is domain-general, so that functional primitives present a language that is more general than most other modeling methods such as mathematical simulation. The characteristics and types of functional models are described. Examples of uses of the framework in modeling physical systems composed of human-software-hardware (hereby we refer to them as only physical systems) are presented. It is concluded that a function-centered model of a physical system provides a capability for generating a high-level simulation of the system for intelligent diagnostic, control or other similar applications

  6. Ubiquitous polygenicity of human complex traits: genome-wide analysis of 49 traits in Koreans.

    Directory of Open Access Journals (Sweden)

    Jian Yang

    Full Text Available Recent studies in population of European ancestry have shown that 30% ~ 50% of heritability for human complex traits such as height and body mass index, and common diseases such as schizophrenia and rheumatoid arthritis, can be captured by common SNPs and that genetic variation attributed to chromosomes are in proportion to their length. Using genome-wide estimation and partitioning approaches, we analysed 49 human quantitative traits, many of which are relevant to human diseases, in 7,170 unrelated Korean individuals genotyped on 326,262 SNPs. For 43 of the 49 traits, we estimated a nominally significant (P<0.05 proportion of variance explained by all SNPs on the Affymetrix 5.0 genotyping array ([Formula: see text]. On average across 47 of the 49 traits for which the estimate of h(G(2 is non-zero, common SNPs explain approximately one-third (range of 7.8% to 76.8% of narrow sense heritability. The estimate of h(G(2 is highly correlated with the proportion of SNPs with association P<0.031 (r(2 = 0.92. Longer genomic segments tend to explain more phenotypic variation, with a correlation of 0.78 between the estimate of variance explained by individual chromosomes and their physical length, and 1% of the genome explains approximately 1% of the genetic variance. Despite the fact that there are a few SNPs with large effects for some traits, these results suggest that polygenicity is ubiquitous for most human complex traits and that a substantial proportion of the "missing heritability" is captured by common SNPs.

  7. Cognitive engineering models: A prerequisite to the design of human-computer interaction in complex dynamic systems

    Science.gov (United States)

    Mitchell, Christine M.

    1993-01-01

    This chapter examines a class of human-computer interaction applications, specifically the design of human-computer interaction for the operators of complex systems. Such systems include space systems (e.g., manned systems such as the Shuttle or space station, and unmanned systems such as NASA scientific satellites), aviation systems (e.g., the flight deck of 'glass cockpit' airplanes or air traffic control) and industrial systems (e.g., power plants, telephone networks, and sophisticated, e.g., 'lights out,' manufacturing facilities). The main body of human-computer interaction (HCI) research complements but does not directly address the primary issues involved in human-computer interaction design for operators of complex systems. Interfaces to complex systems are somewhat special. The 'user' in such systems - i.e., the human operator responsible for safe and effective system operation - is highly skilled, someone who in human-machine systems engineering is sometimes characterized as 'well trained, well motivated'. The 'job' or task context is paramount and, thus, human-computer interaction is subordinate to human job interaction. The design of human interaction with complex systems, i.e., the design of human job interaction, is sometimes called cognitive engineering.

  8. In Vitro Culture Conditions for Maintaining a Complex Population of Human Gastrointestinal Tract Microbiota

    Directory of Open Access Journals (Sweden)

    Bong-Soo Kim

    2011-01-01

    Full Text Available A stable intestinal microbiota is important in maintaining human physiology and health. Although there have been a number of studies using in vitro and in vivo approaches to determine the impact of diet and xenobiotics on intestinal microbiota, there is no consensus for the best in vitro culture conditions for growth of the human gastrointestinal microbiota. To investigate the dynamics and activities of intestinal microbiota, it is important for the culture conditions to support the growth of a wide range of intestinal bacteria and maintain a complex microbial community representative of the human gastrointestinal tract. Here, we compared the bacterial community in three culture media: brain heart infusion broth and high- and low-carbohydrate medium with different growth supplements. The bacterial community was analyzed using denaturing gradient gel electrophoresis (DGGE, pyrosequencing and real-time PCR. Based on the molecular analysis, this study indicated that the 3% fecal inoculum in low-concentration carbohydrate medium with 1% autoclaved fecal supernatant provided enhanced growth conditions to conduct in vitro studies representative of the human intestinal microbiota.

  9. Computational and Statistical Analyses of Insertional Polymorphic Endogenous Retroviruses in a Non-Model Organism

    Directory of Open Access Journals (Sweden)

    Le Bao

    2014-11-01

    Full Text Available Endogenous retroviruses (ERVs are a class of transposable elements found in all vertebrate genomes that contribute substantially to genomic functional and structural diversity. A host species acquires an ERV when an exogenous retrovirus infects a germ cell of an individual and becomes part of the genome inherited by viable progeny. ERVs that colonized ancestral lineages are fixed in contemporary species. However, in some extant species, ERV colonization is ongoing, which results in variation in ERV frequency in the population. To study the consequences of ERV colonization of a host genome, methods are needed to assign each ERV to a location in a species’ genome and determine which individuals have acquired each ERV by descent. Because well annotated reference genomes are not widely available for all species, de novo clustering approaches provide an alternative to reference mapping that are insensitive to differences between query and reference and that are amenable to mobile element studies in both model and non-model organisms. However, there is substantial uncertainty in both identifying ERV genomic position and assigning each unique ERV integration site to individuals in a population. We present an analysis suitable for detecting ERV integration sites in species without the need for a reference genome. Our approach is based on improved de novo clustering methods and statistical models that take the uncertainty of assignment into account and yield a probability matrix of shared ERV integration sites among individuals. We demonstrate that polymorphic integrations of a recently identified endogenous retrovirus in deer reflect contemporary relationships among individuals and populations.

  10. NDUFAF5 Hydroxylates NDUFS7 at an Early Stage in the Assembly of Human Complex I*

    Science.gov (United States)

    Rhein, Virginie F.; Carroll, Joe; Ding, Shujing; Fearnley, Ian M.; Walker, John E.

    2016-01-01

    Complex I (NADH ubiquinone oxidoreductase) in mammalian mitochondria is an L-shaped assembly of 45 proteins. One arm lies in the inner membrane, and the other extends about 100 Å into the matrix of the organelle. The extrinsic arm contains binding sites for NADH, the primary electron acceptor FMN, and seven iron-sulfur clusters that form a pathway for electrons linking FMN to the terminal electron acceptor, ubiquinone, which is bound in a tunnel in the region of the junction between the arms. The membrane arm contains four antiporter-like domains, energetically coupled to the quinone site and involved in pumping protons from the matrix into the intermembrane space contributing to the proton motive force. Seven of the subunits, forming the core of the membrane arm, are translated from mitochondrial genes, and the remaining subunits, the products of nuclear genes, are imported from the cytosol. Their assembly is coordinated by at least thirteen extrinsic assembly factor proteins that are not part of the fully assembled complex. They assist in insertion of co-factors and in building up the complex from smaller sub-assemblies. One such factor, NDUFAF5, belongs to the family of seven-β-strand S-adenosylmethionine-dependent methyltransferases. However, similar to another family member, RdmB, it catalyzes the introduction of a hydroxyl group, in the case of NDUFAF5, into Arg-73 in the NDUFS7 subunit of human complex I. This modification occurs early in the pathway of assembly of complex I, before the formation of the juncture between peripheral and membrane arms. PMID:27226634

  11. NDUFAF5 Hydroxylates NDUFS7 at an Early Stage in the Assembly of Human Complex I.

    Science.gov (United States)

    Rhein, Virginie F; Carroll, Joe; Ding, Shujing; Fearnley, Ian M; Walker, John E

    2016-07-08

    Complex I (NADH ubiquinone oxidoreductase) in mammalian mitochondria is an L-shaped assembly of 45 proteins. One arm lies in the inner membrane, and the other extends about 100 Å into the matrix of the organelle. The extrinsic arm contains binding sites for NADH, the primary electron acceptor FMN, and seven iron-sulfur clusters that form a pathway for electrons linking FMN to the terminal electron acceptor, ubiquinone, which is bound in a tunnel in the region of the junction between the arms. The membrane arm contains four antiporter-like domains, energetically coupled to the quinone site and involved in pumping protons from the matrix into the intermembrane space contributing to the proton motive force. Seven of the subunits, forming the core of the membrane arm, are translated from mitochondrial genes, and the remaining subunits, the products of nuclear genes, are imported from the cytosol. Their assembly is coordinated by at least thirteen extrinsic assembly factor proteins that are not part of the fully assembled complex. They assist in insertion of co-factors and in building up the complex from smaller sub-assemblies. One such factor, NDUFAF5, belongs to the family of seven-β-strand S-adenosylmethionine-dependent methyltransferases. However, similar to another family member, RdmB, it catalyzes the introduction of a hydroxyl group, in the case of NDUFAF5, into Arg-73 in the NDUFS7 subunit of human complex I. This modification occurs early in the pathway of assembly of complex I, before the formation of the juncture between peripheral and membrane arms. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. Dysfunction of bovine endogenous retrovirus K2 envelope glycoprotein is related to unsuccessful intracellular trafficking.

    Science.gov (United States)

    Nakaya, Yuki; Miyazawa, Takayuki

    2014-06-01

    Endogenous retroviruses (ERVs) are the remnants of retroviral infection of ancestral germ cells. Mutations introduced into ERVs halt the production of infectious agents, but their effects on the function of retroviral proteins are not fully understood. Retroviral envelope glycoproteins (Envs) are utilized in membrane fusion during viral entry, and we recently identified intact coding sequences for bovine endogenous retrovirus K1 (BERV-K1) and BERV-K2 Envs. Amino acid sequences of BERV-K1 Env (also called Fematrin-1) and BERV-K2 Env are similar, and both viruses are classified in the genus Betaretrovirus. While Fematrin-1 plays an important role in cell-to-cell fusion in bovine placenta, the BERV-K2 envelope gene is marginally expressed in vivo, and its recombinant Env protein is defective in membrane fusion due to inefficient cleavage of surface (SU) and transmembrane subunits. Here, we conducted chimeric analyses of Fematrin-1 and BERV-K2 Envs and revealed that defective maturation of BERV-K2 Env contributed to failed intracellular trafficking. Fluorescence microscopy and flow cytometric analysis suggested that in contrast to Fematrin-1 Env, BERV-K2 Env could not be transported from the endoplasmic reticulum to the trans-Golgi network, where cellular proteases required for processing retroviral Envs are localized. We also identified that one of the responsive regions of this phenomenon resided within a 65-amino-acid region of BERV-K2 SU. This is the first report to identify that retroviral Env SU is involved in the regulation of intracellular trafficking, and it may help to elucidate the maturation process of Fematrin-1 and other related Envs. Retroviruses utilize envelope glycoproteins (Envs) to enter host target cells. Mature retroviral Env is a heterodimer, which consists of surface (SU) and transmembrane (TM) subunits that are generated by the cleavage of an Env precursor protein in the trans-Golgi network. SU and TM mediate the recognition of the entry

  13. Gypsy endogenous retrovirus maintains potential infectivity in several species of Drosophilids

    Directory of Open Access Journals (Sweden)

    de Frutos Rosa

    2008-10-01

    Full Text Available Abstract Background Sequences homologous to the gypsy retroelement from Drosophila melanogaster are widely distributed among drosophilids. The structure of gypsy includes an open reading frame resembling the retroviral gene env, which is responsible for the infectious properties of retroviruses. Results In this study we report molecular and phylogeny analysis of the complete env gene from ten species of the obscura group of the genus Drosophila and one species from the genus Scaptomyza. Conclusion The results indicate that in most cases env sequences could produce a functional Env protein and therefore maintain the infectious capability of gypsy in these species.

  14. Chromosome segregation regulation in human zygotes : Altered mitotic histone phosphorylation dynamics underlying centromeric targeting of the chromosomal passenger complex

    NARCIS (Netherlands)

    Van De Werken, C.; Avo Santos, M.; Laven, J. S E; Eleveld, C.; Fauser, B. C J M; Lens, S. M A; Baart, E. B.

    2015-01-01

    STUDY QUESTION Are the kinase feedback loops that regulate activation and centromeric targeting of the chromosomal passenger complex (CPC), functional during mitosis in human embryos? SUMMARY ANSWER Investigation of the regulatory kinase pathways involved in centromeric CPC targeting revealed normal

  15. High-Resolution Patterns of Meiotic Recombination across the Human Major Histocompatibility Complex

    Science.gov (United States)

    Cullen, Michael; Perfetto, Stephen P.; Klitz, William; Nelson, George; Carrington, Mary

    2002-01-01

    Definitive characteristics of meiotic recombination events over large (i.e., >1 Mb) segments of the human genome remain obscure, yet they are essential for establishing the haplotypic structure of the genome and for efficient mapping of complex traits. We present a high-resolution map of recombination at the kilobase level across a 3.3-Mb interval encompassing the major histocompatibility complex (MHC). Genotyping of 20,031 single sperm from 12 individuals resulted in the identification and fine mapping of 325 recombinant chromosomes within genomic intervals as small as 7 kb. Several principal characteristics of recombination in this region were observed: (1) rates of recombination can differ significantly between individuals; (2) intense hot spots of recombination occur at least every 0.8 Mb but are not necessarily evenly spaced; (3) distribution in the location of recombination events can differ significantly among individuals; (4) between hot spots, low levels of recombination occur fairly evenly across 100-kb segments, suggesting the presence of warm spots of recombination; and (5) specific sequence motifs associate significantly with recombination distribution. These data provide a plausible model for recombination patterns of the human genome overall. PMID:12297984

  16. Human-Chromatin-Related Protein Interactions Identify a Demethylase Complex Required for Chromosome Segregation

    Directory of Open Access Journals (Sweden)

    Edyta Marcon

    2014-07-01

    Full Text Available Chromatin regulation is driven by multicomponent protein complexes, which form functional modules. Deciphering the components of these modules and their interactions is central to understanding the molecular pathways these proteins are regulating, their functions, and their relation to both normal development and disease. We describe the use of affinity purifications of tagged human proteins coupled with mass spectrometry to generate a protein-protein interaction map encompassing known and predicted chromatin-related proteins. On the basis of 1,394 successful purifications of 293 proteins, we report a high-confidence (85% precision network involving 11,464 protein-protein interactions among 1,738 different human proteins, grouped into 164 often overlapping protein complexes with a particular focus on the family of JmjC-containing lysine demethylases, their partners, and their roles in chromatin remodeling. We show that RCCD1 is a partner of histone H3K36 demethylase KDM8 and demonstrate that both are important for cell-cycle-regulated transcriptional repression in centromeric regions and accurate mitotic division.

  17. SSFSE sequence functional MRI of the human cervical spinal cord with complex finger tapping

    International Nuclear Information System (INIS)

    Xie Chuhai; Kong Kangmei; Guan Jitian; Chen Yexi; He Jiankang; Qi Weili; Wang Xinjia; Shen Zhiwei; Wu Renhua

    2009-01-01

    Purpose: Functional MR imaging of the human cervical spinal cord was carried out on volunteers during alternated rest and a complex finger tapping task, in order to detect image intensity changes arising from neuronal activity. Methods: Functional MR imaging data using single-shot fast spin-echo sequence (SSFSE) with echo time 42.4 ms on a 1.5 T GE Clinical System were acquired in eight subjects performing a complex finger tapping task. Cervical spinal cord activation was measured both in the sagittal and transverse imaging planes. Postprocessing was performed by AFNI (Analysis of Functional Neuroimages) software system. Results: Intensity changes (5.5-7.6%) were correlated with the time course of stimulation and were consistently detected in both sagittal and transverse imaging planes of the cervical spinal cord. The activated regions localized to the ipsilateral side of the spinal cord in agreement with the neural anatomy. Conclusion: Functional MR imaging signals can be reliably detected with finger tapping activity in the human cervical spinal cord using a SSFSE sequence with 42.4 ms echo time. The anatomic location of neural activity correlates with the muscles used in the finger tapping task.

  18. α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8.

    LENUS (Irish Health Repository)

    Bergin, David A

    2010-12-01

    Hereditary deficiency of the protein α-1 antitrypsin (AAT) causes a chronic lung disease in humans that is characterized by excessive mobilization of neutrophils into the lung. However, the reason for the increased neutrophil burden has not been fully elucidated. In this study we have demonstrated using human neutrophils that serum AAT coordinates both CXCR1- and soluble immune complex (sIC) receptor-mediated chemotaxis by divergent pathways. We demonstrated that glycosylated AAT can bind to IL-8 (a ligand for CXCR1) and that AAT-IL-8 complex formation prevented IL-8 interaction with CXCR1. Second, AAT modulated neutrophil chemotaxis in response to sIC by controlling membrane expression of the glycosylphosphatidylinositol-anchored (GPI-anchored) Fc receptor FcγRIIIb. This process was mediated through inhibition of ADAM-17 enzymatic activity. Neutrophils isolated from clinically stable AAT-deficient patients were characterized by low membrane expression of FcγRIIIb and increased chemotaxis in response to IL-8 and sIC. Treatment of AAT-deficient individuals with AAT augmentation therapy resulted in increased AAT binding to IL-8, increased AAT binding to the neutrophil membrane, decreased FcγRIIIb release from the neutrophil membrane, and normalization of chemotaxis. These results provide new insight into the mechanism underlying the effect of AAT augmentation therapy in the pulmonary disease associated with AAT deficiency.

  19. Structural insights into RNA processing by the human RISC-loading complex.

    Science.gov (United States)

    Wang, Hong-Wei; Noland, Cameron; Siridechadilok, Bunpote; Taylor, David W; Ma, Enbo; Felderer, Karin; Doudna, Jennifer A; Nogales, Eva

    2009-11-01

    Targeted gene silencing by RNA interference (RNAi) requires loading of a short guide RNA (small interfering RNA (siRNA) or microRNA (miRNA)) onto an Argonaute protein to form the functional center of an RNA-induced silencing complex (RISC). In humans, Argonaute2 (AGO2) assembles with the guide RNA-generating enzyme Dicer and the RNA-binding protein TRBP to form a RISC-loading complex (RLC), which is necessary for efficient transfer of nascent siRNAs and miRNAs from Dicer to AGO2. Here, using single-particle EM analysis, we show that human Dicer has an L-shaped structure. The RLC Dicer's N-terminal DExH/D domain, located in a short 'base branch', interacts with TRBP, whereas its C-terminal catalytic domains in the main body are proximal to AGO2. A model generated by docking the available atomic structures of Dicer and Argonaute homologs into the RLC reconstruction suggests a mechanism for siRNA transfer from Dicer to AGO2.

  20. Localization of MHC class II/human cartilage glycoprotein-39 complexes in synovia of rheumatoid arthritis patients using complex-specific monoclonal antibodies

    NARCIS (Netherlands)

    Steenbakkers, Peter G. A.; Baeten, Dominique; Rovers, Eric; Veys, Eric M.; Rijnders, Antonius W. M.; Meijerink, Jan; de Keyser, Filip; Boots, Annemieke M. H.

    2003-01-01

    Recently human cartilage gp-39 (HC gp-39) was identified as a candidate autoantigen in rheumatoid arthritis (RA). To further investigate the relevance of this Ag in RA, we have generated a set of five mAbs to a combination epitope of complexes of HC gp-39(263-275) and the RA-associated DR alpha beta

  1. Microsurgical and Tractographic Anatomy of the Supplementary Motor Area Complex in Humans.

    Science.gov (United States)

    Bozkurt, Baran; Yagmurlu, Kaan; Middlebrooks, Erik H; Karadag, Ali; Ovalioglu, Talat Cem; Jagadeesan, Bharathi; Sandhu, Gauravjot; Tanriover, Necmettin; Grande, Andrew W

    2016-11-01

    To evaluate the microsurgical anatomy of the fiber tract connections of the supplementary motor area (SMA) and pre-SMA, and examine its potential functional role with reference to clinical trials in the literature. Ten postmortem formalin-fixed human brains (20 sides) and 1 cadaveric head were prepared following Klingler's method. The fiber dissection was performed in a stepwise fashion, from lateral to medial and also from medial to lateral, under an operating microscope, with 3D images captured at each stage. Our findings were supported by in vivo magnetic resonance imaging tractography in 2 healthy subjects. The connections of the SMA complex, composed of the pre-SMA and the SMA proper, are composed of short "U" association fibers and the superior longitudinal fasciculus I, cingulum, claustrocortical fibers, callosal fibers, corticospinal tract, frontal aslant tract, and frontostriatal tract. The claustrocortical fibers may play an important role in the integration of motor, language, and limbic functions of the SMA complex. The frontostriatal tract connects the pre-SMA to the putamen and caudate nucleus, and also forms parts of both the internal capsule and the dorsal external capsule. The SMA complex has numerous connections throughout the cerebrum. An understanding of these connections is important for presurgical planning for lesions in the frontal lobe and helps explain symptoms related to SMA injury. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. The CD63-Syntenin-1 Complex Controls Post-Endocytic Trafficking of Oncogenic Human Papillomaviruses.

    Science.gov (United States)

    Gräßel, Linda; Fast, Laura Aline; Scheffer, Konstanze D; Boukhallouk, Fatima; Spoden, Gilles A; Tenzer, Stefan; Boller, Klaus; Bago, Ruzica; Rajesh, Sundaresan; Overduin, Michael; Berditchevski, Fedor; Florin, Luise

    2016-08-31

    Human papillomaviruses enter host cells via a clathrin-independent endocytic pathway involving tetraspanin proteins. However, post-endocytic trafficking required for virus capsid disassembly remains unclear. Here we demonstrate that the early trafficking pathway of internalised HPV particles involves tetraspanin CD63, syntenin-1 and ESCRT-associated adaptor protein ALIX. Following internalisation, viral particles are found in CD63-positive endosomes recruiting syntenin-1, a CD63-interacting adaptor protein. Electron microscopy and immunofluorescence experiments indicate that the CD63-syntenin-1 complex controls delivery of internalised viral particles to multivesicular endosomes. Accordingly, infectivity of high-risk HPV types 16, 18 and 31 as well as disassembly and post-uncoating processing of viral particles was markedly suppressed in CD63 or syntenin-1 depleted cells. Our analyses also present the syntenin-1 interacting protein ALIX as critical for HPV infection and CD63-syntenin-1-ALIX complex formation as a prerequisite for intracellular transport enabling viral capsid disassembly. Thus, our results identify the CD63-syntenin-1-ALIX complex as a key regulatory component in post-endocytic HPV trafficking.

  3. Anatomically-specific intratubular and interstitial biominerals in the human renal medullo-papillary complex.

    Directory of Open Access Journals (Sweden)

    Ling Chen

    Full Text Available Limited information exists on the anatomically-specific early stage events leading to clinically detectable mineral aggregates in the renal papilla. In this study, quantitative multiscale correlative maps of structural, elemental and biochemical properties of whole medullo-papillary complexes from human kidneys were developed. Correlative maps of properties specific to the uriniferous and vascular tubules using high-resolution X-ray computed tomography, scanning and transmission electron microscopy, energy dispersive X-ray spectroscopy, and immunolocalization of noncollagenous proteins (NCPs along with their association with anatomy specific biominerals were obtained. Results illustrated that intratubular spherical aggregates primarily form at the proximal regions distant from the papillary tip while interstitial spherical and fibrillar aggregates are distally located near the papillary tip. Biominerals at the papillary tip were closely localized with 10 to 50 μm diameter vasa recta immunolocalized for CD31 inside the medullo-papillary complex. Abundant NCPs known to regulate bone mineralization were localized within nanoparticles, forming early pathologic mineralized regions of the complex. Based on the physical association between vascular and urothelial tubules, results from light and electron microscopy techniques suggested that these NCPs could be delivered from vasculature to prompt calcification of the interstitial regions or they might be synthesized from local vascular smooth muscle cells after transdifferentiation into osteoblast-like phenotypes. In addition, results provided insights into the plausible temporal events that link the anatomically specific intratubular mineral aggregates with the interstitial biomineralization processes within the functional unit of the kidney.

  4. Literature and Cinema from "Adaptation" to Re-creation: Coping with the Complexity of Human Recollection

    Directory of Open Access Journals (Sweden)

    Carlo Testa

    2013-01-01

    Full Text Available Early 20th-century avant-gardes put a premium on the notion of "originality" and so created a cultural context in which "adaptation" -- in particular, lit-to cinema adaptation -- later came to be construed by film theory as a kind of derivative, inferior notion. This article offers the proof, based on work on the little-known original Russian sources, that none other than Èizenshtein opined differently, so much so that he preferred to argue instead for the use of the term "re-creation"; and that later semiotic theory, especially thanks to Iurii Lotman, provides us with the tools to develop the "re-creation" concept fully. In the process of re-creation, which is always a process of cultural re-contextualization, the original literary complexity lost in the transmutation must be made up in specific cinematic ways, in order to offer a final re-created artefact worthy of recollection by human society. In times of an overburdened human ability to remember historic sufferings, re-created artefacts that lose information vis-a-vis the original will be quite justly forgotten. On this basis, the article concludes with an elaboration on contemporary Italian cinema -- especially some commercially successful noirs -- drawn from literature (or rather, books of fiction and pinpoints the nature of one of that type of cinema's recurrent shortcomings. The essential defect of such films is identified in their inability to make up by cinematic means for the loss of complexity which they endure in the transition from one medium to another. This is all the more true when, as in the case of the noirs examined here, complexity is already scant in the original books in the first place.

  5. Applying mass spectrometry-based qualitative proteomics to human amygdaloid complex

    Directory of Open Access Journals (Sweden)

    Joaquín eFernández-Irigoyen

    2014-03-01

    Full Text Available The amygdaloid complex is a key brain structure involved in the expression of behaviours and emotions such as learning, fear, and anxiety. Brain diseases including depression, epilepsy, autism, schizophrenia, and Alzheimer`s disease, have been associated with amygdala dysfunction. For several decades, neuroanatomical, neurophysiological, volumetric, and cognitive approaches have been the gold standard techniques employed to characterize the amygdala functionality. However, little attention has been focused specifically on the molecular composition of the human amygdala from the perspective of proteomics. We have performed a global proteome analysis employing protein and peptide fractionation methods followed by nano-liquid chromatography tandem mass spectrometry (nanoLC-MS/MS, detecting expression of at least 1820 protein species in human amygdala, corresponding to 1814 proteins which represent a 9-fold increase in proteome coverage with respect to previous proteomic profiling of the rat amygdala. Gene ontology analysis were used to determine biological process represented in human amygdala highlighting molecule transport, nucleotide binding, and oxidoreductase and GTPase activities. Bioinformatic analyses have revealed that nearly 4% of identified proteins have been previously associated to neurodegenerative syndromes, and 26% of amygdaloid proteins were also found to be present in cerebrospinal fluid (CSF. In particular, a subset of amygdaloid proteins was mainly involved in axon guidance, synaptic vesicle release, L1CAM interactome, and signaling pathways transduced by NGF and NCAM1. Taken together, our data contributes to the repertoire of the human brain proteome, serving as a reference library to provide basic information for understanding the neurobiology of the human amygdala.

  6. Stabilization of the soluble, cleaved, trimeric form of the envelope glycoprotein complex of human immunodeficiency virus type 1

    NARCIS (Netherlands)

    Sanders, Rogier W.; Vesanen, Mika; Schuelke, Norbert; Master, Aditi; Schiffner, Linnea; Kalyanaraman, Roopa; Paluch, Maciej; Berkhout, Ben; Maddon, Paul J.; Olson, William C.; Lu, Min; Moore, John P.

    2002-01-01

    The envelope glycoprotein (Env) complex of human immunodeficiency virus type I has evolved a structure that is minimally immunogenic while retaining its natural function of receptor-mediated virus-cell fusion. The Env complex is trimeric; its six individual subunits (three gp120 and three gp41

  7. Use of eye tracking equipment for human reliability analysis applied to complex system operations

    International Nuclear Information System (INIS)

    Pinheiro, Andre Ricardo Mendonça; Prado, Eugenio Anselmo Pessoa do; Martins, Marcelo Ramos

    2017-01-01

    This article will discuss the preliminary results of an evaluation methodology for the analysis and quantification of manual character errors (human), by monitoring cognitive parameters and skill levels in the operation of a complex control system based on parameters provided by a eye monitoring equipment (Eye Tracker). The research was conducted using a simulator (game) that plays concepts of operation of a nuclear reactor with a split sample for evaluation of aspects of learning, knowledge and standard operating within the context addressed. bridge operators were monitored using the EYE TRACKING, eliminating the presence of the analyst in the evaluation of the operation, allowing the analysis of the results by means of multivariate statistical techniques within the scope of system reliability. The experiments aim to observe state change situations such as stops and scheduled departures, incidents assumptions and common operating characteristics. Preliminary results of this research object indicate that technical and cognitive aspects can contribute to improving the reliability of the available techniques in human reliability, making them more realistic both in the context of quantitative approaches to regulatory and training purposes, as well as reduced incidence of human error. (author)

  8. Use of eye tracking equipment for human reliability analysis applied to complex system operations

    Energy Technology Data Exchange (ETDEWEB)

    Pinheiro, Andre Ricardo Mendonça; Prado, Eugenio Anselmo Pessoa do; Martins, Marcelo Ramos, E-mail: andrericardopinheiro@usp.br, E-mail: eugenio.prado@labrisco.usp.br, E-mail: mrmatins@usp.br [Universidade de Sao Paulo (LABRISCO/USP), Sao Paulo, SP (Brazil). Lab. de Análise, Avaliação e Gerenciamento de Risco

    2017-07-01

    This article will discuss the preliminary results of an evaluation methodology for the analysis and quantification of manual character errors (human), by monitoring cognitive parameters and skill levels in the operation of a complex control system based on parameters provided by a eye monitoring equipment (Eye Tracker). The research was conducted using a simulator (game) that plays concepts of operation of a nuclear reactor with a split sample for evaluation of aspects of learning, knowledge and standard operating within the context addressed. bridge operators were monitored using the EYE TRACKING, eliminating the presence of the analyst in the evaluation of the operation, allowing the analysis of the results by means of multivariate statistical techniques within the scope of system reliability. The experiments aim to observe state change situations such as stops and scheduled departures, incidents assumptions and common operating characteristics. Preliminary results of this research object indicate that technical and cognitive aspects can contribute to improving the reliability of the available techniques in human reliability, making them more realistic both in the context of quantitative approaches to regulatory and training purposes, as well as reduced incidence of human error. (author)

  9. Tracking a Subset of Skeleton Joints: An Effective Approach towards Complex Human Activity Recognition

    Directory of Open Access Journals (Sweden)

    Muhammad Latif Anjum

    2017-01-01

    Full Text Available We present a robust algorithm for complex human activity recognition for natural human-robot interaction. The algorithm is based on tracking the position of selected joints in human skeleton. For any given activity, only a few skeleton joints are involved in performing the activity, so a subset of joints contributing the most towards the activity is selected. Our approach of tracking a subset of skeleton joints (instead of tracking the whole skeleton is computationally efficient and provides better recognition accuracy. We have developed both manual and automatic approaches for the selection of these joints. The position of the selected joints is tracked for the duration of the activity and is used to construct feature vectors for each activity. Once the feature vectors have been constructed, we use a Support Vector Machines (SVM multiclass classifier for training and testing the algorithm. The algorithm has been tested on a purposely built dataset of depth videos recorded using Kinect camera. The dataset consists of 250 videos of 10 different activities being performed by different users. Experimental results show classification accuracy of 83% when tracking all skeleton joints, 95% when using manual selection of subset joints, and 89% when using automatic selection of subset joints.

  10. Genome-Wide Prediction of DNA Methylation Using DNA Composition and Sequence Complexity in Human.

    Science.gov (United States)

    Wu, Chengchao; Yao, Shixin; Li, Xinghao; Chen, Chujia; Hu, Xuehai

    2017-02-16

    DNA methylation plays a significant role in transcriptional regulation by repressing activity. Change of the DNA methylation level is an important factor affecting the expression of target genes and downstream phenotypes. Because current experimental technologies can only assay a small proportion of CpG sites in the human genome, it is urgent to develop reliable computational models for predicting genome-wide DNA methylation. Here, we proposed a novel algorithm that accurately extracted sequence complexity features (seven features) and developed a support-vector-machine-based prediction model with integration of the reported DNA composition features (trinucleotide frequency and GC content, 65 features) by utilizing the methylation profiles of embryonic stem cells in human. The prediction results from 22 human chromosomes with size-varied windows showed that the 600-bp window achieved the best average accuracy of 94.7%. Moreover, comparisons with two existing methods further showed the superiority of our model, and cross-species predictions on mouse data also demonstrated that our model has certain generalization ability. Finally, a statistical test of the experimental data and the predicted data on functional regions annotated by ChromHMM found that six out of 10 regions were consistent, which implies reliable prediction of unassayed CpG sites. Accordingly, we believe that our novel model will be useful and reliable in predicting DNA methylation.

  11. Assignment of adenosine deaminase complexing protein (ADCP) gene(s) to human chromosome 2 in rodent-human somatic cell hybrids.

    Science.gov (United States)

    Herbschleb-Voogt, E; Grzeschik, K H; Pearson, P L; Meera Khan, P

    1981-01-01

    The experiments reported in this paper indicate that the expression of human adenosine deaminase complexing protein (ADCP) in the human-rodent somatic cell hybrids is influenced by the state of confluency of the cells and the background rodent genome. Thus, the complement of the L-cell derived A9 or B82 mouse parent apparently prevents the expression of human ADCP in the interspecific somatic cell hybrids. In the a3, E36, or RAG hybrids the human ADCP expression was not prevented by the rodent genome and was found to be proportional to the degree of confluency of the cell in the culture as in the case of primary human fibroblasts. An analysis of human chromosomes, chromosome specific enzyme markers, and ADCP in a panel of rodent-human somatic cell hybrids optimally maintained and harvested at full confluency has shown that the expression of human ADCP in the mouse (RAG)-human as well as in the hamster (E36 or a3)-human hybrids is determined by a gene(s) in human chromosome 2 and that neither chromosome 6 nor any other of the chromosomes of man carry any gene(s) involved in the formation of human ADCP at least in the Chinese hamster-human hybrids. A series of rodent-human hybrid clones exhibiting a mitotic separation of IDH1 and MDH1 indicated that ADCP is most probably situated between corresponding loci in human chromosome 2.

  12. Genomic Amplification of an Endogenous Retrovirus in Zebrafish T-Cell Malignancies

    Directory of Open Access Journals (Sweden)

    J. Kimble Frazer

    2012-01-01

    Full Text Available Genomic instability plays a crucial role in oncogenesis. Somatically acquired mutations can disable some genes and inappropriately activate others. In addition, chromosomal rearrangements can amplify, delete, or even fuse genes, altering their functions and contributing to malignant phenotypes. Using array comparative genomic hybridization (aCGH, a technique to detect numeric variations between different DNA samples, we examined genomes from zebrafish (Danio rerio T-cell leukemias of three cancer-prone lines. In all malignancies tested, we identified recurring amplifications of a zebrafish endogenous retrovirus. This retrovirus, ZFERV, was first identified due to high expression of proviral transcripts in thymic tissue from larval and adult fish. We confirmed ZFERV amplifications by quantitative PCR analyses of DNA from wild-type fish tissue and normal and malignant D. rerio T cells. We also quantified ZFERV RNA expression and found that normal and neoplastic T cells both produce retrovirally encoded transcripts, but most cancers show dramatically increased transcription. In aggregate, these data imply that ZFERV amplification and transcription may be related to T-cell leukemogenesis. Based on these data and ZFERV’s phylogenetic relation to viruses of the murine-leukemia-related virus class of gammaretroviridae, we posit that ZFERV may be oncogenic via an insertional mutagenesis mechanism.

  13. Tracking the Continuous Evolutionary Processes of an Endogenous Retrovirus of the Domestic Cat: ERV-DC

    Directory of Open Access Journals (Sweden)

    Junna Kawasaki

    2018-04-01

    Full Text Available An endogenous retrovirus (ERV is a remnant of an ancient retroviral infection in the host genome. Although most ERVs have lost their viral productivity, a few ERVs retain their replication capacity. In addition, partially inactivated ERVs can present a potential risk to the host via their encoded virulence factors or the generation of novel viruses by viral recombination. ERVs can also eventually acquire a biological function, and this ability has been a driving force of host evolution. Therefore, the presence of an ERV can be harmful or beneficial to the host. Various reports about paleovirology have revealed each event in ERV evolution, but the continuous processes of ERV evolution over millions of years are mainly unknown. A unique ERV family, ERV-DC, is present in the domestic cat (Felis silvestris catus genome. ERV-DC proviruses are phylogenetically classified into three genotypes, and the specific characteristics of each genotype have been clarified: their capacity to produce infectious viruses; their recombination with other retroviruses, such as feline leukemia virus or RD-114; and their biological functions as host antiviral factors. In this review, we describe ERV-DC-related phenomena and discuss the continuous changes in the evolution of this ERV in the domestic cat.

  14. Sequence variation of koala retrovirus transmembrane protein p15E among koalas from different geographic regions

    Science.gov (United States)

    Ishida, Yasuko; McCallister, Chelsea; Nikolaidis, Nikolas; Tsangaras, Kyriakos; Helgen, Kristofer M.; Greenwood, Alex D.; Roca, Alfred L.

    2014-01-01

    The koala retrovirus (KoRV), which is transitioning from an exogenous to an endogenous form, has been associated with high mortality in koalas. For other retroviruses, the envelope protein p15E has been considered a candidate for vaccine development. We therefore examined proviral sequence variation of KoRV p15E in a captive Queensland and three wild southern Australian koalas. We generated 163 sequences with intact open reading frames, which grouped into 39 distinct haplotypes. Sixteen distinct haplotypes comprising 139 of the sequences (85%) coded for the same polypeptide. Among the remaining 23 haplotypes, 22 were detected only once among the sequences, and each had 1 or 2 non-synonymous differences from the majority sequence. Several analyses suggested that p15E was under purifying selection. Important epitopes and domains were highly conserved across the p15E sequences and in previously reported exogenous KoRVs. Overall, these results support the potential use of p15E for KoRV vaccine development. PMID:25462343

  15. Hybridization Capture Reveals Evolution and Conservation across the Entire Koala Retrovirus Genome

    Science.gov (United States)

    Ishida, Yasuko; Cui, Pin; Vielgrader, Hanna; Helgen, Kristofer M.; Roca, Alfred L.; Greenwood, Alex D.

    2014-01-01

    The koala retrovirus (KoRV) is the only retrovirus known to be in the midst of invading the germ line of its host species. Hybridization capture and next generation sequencing were used on modern and museum DNA samples of koala (Phascolarctos cinereus) to examine ca. 130 years of evolution across the full KoRV genome. Overall, the entire proviral genome appeared to be conserved across time in sequence, protein structure and transcriptional binding sites. A total of 138 polymorphisms were detected, of which 72 were found in more than one individual. At every polymorphic site in the museum koalas, one of the character states matched that of modern KoRV. Among non-synonymous polymorphisms, radical substitutions involving large physiochemical differences between amino acids were elevated in env, potentially reflecting anti-viral immune pressure or avoidance of receptor interference. Polymorphisms were not detected within two functional regions believed to affect infectivity. Host sequences flanking proviral integration sites were also captured; with few proviral loci shared among koalas. Recently described variants of KoRV, designated KoRV-B and KoRV-J, were not detected in museum samples, suggesting that these variants may be of recent origin. PMID:24752422

  16. Hybridization capture reveals evolution and conservation across the entire Koala retrovirus genome.

    Directory of Open Access Journals (Sweden)

    Kyriakos Tsangaras

    Full Text Available The koala retrovirus (KoRV is the only retrovirus known to be in the midst of invading the germ line of its host species. Hybridization capture and next generation sequencing were used on modern and museum DNA samples of koala (Phascolarctos cinereus to examine ca. 130 years of evolution across the full KoRV genome. Overall, the entire proviral genome appeared to be conserved across time in sequence, protein structure and transcriptional binding sites. A total of 138 polymorphisms were detected, of which 72 were found in more than one individual. At every polymorphic site in the museum koalas, one of the character states matched that of modern KoRV. Among non-synonymous polymorphisms, radical substitutions involving large physiochemical differences between amino acids were elevated in env, potentially reflecting anti-viral immune pressure or avoidance of receptor interference. Polymorphisms were not detected within two functional regions believed to affect infectivity. Host sequences flanking proviral integration sites were also captured; with few proviral loci shared among koalas. Recently described variants of KoRV, designated KoRV-B and KoRV-J, were not detected in museum samples, suggesting that these variants may be of recent origin.

  17. Genetic complexity in a Drosophila model of diabetes-associated misfolded human proinsulin.

    Science.gov (United States)

    Park, Soo-Young; Ludwig, Michael Z; Tamarina, Natalia A; He, Bin Z; Carl, Sarah H; Dickerson, Desiree A; Barse, Levi; Arun, Bharath; Williams, Calvin L; Miles, Cecelia M; Philipson, Louis H; Steiner, Donald F; Bell, Graeme I; Kreitman, Martin

    2014-02-01

    Drosophila melanogaster has been widely used as a model of human Mendelian disease, but its value in modeling complex disease has received little attention. Fly models of complex disease would enable high-resolution mapping of disease-modifying loci and the identification of novel targets for therapeutic intervention. Here, we describe a fly model of permanent neonatal diabetes mellitus and explore the complexity of this model. The approach involves the transgenic expression of a misfolded mutant of human preproinsulin, hINS(C96Y), which is a cause of permanent neonatal diabetes. When expressed in fly imaginal discs, hINS(C96Y) causes a reduction of adult structures, including the eye, wing, and notum. Eye imaginal discs exhibit defects in both the structure and the arrangement of ommatidia. In the wing, expression of hINS(C96Y) leads to ectopic expression of veins and mechano-sensory organs, indicating disruption of wild-type signaling processes regulating cell fates. These readily measurable "disease" phenotypes are sensitive to temperature, gene dose, and sex. Mutant (but not wild-type) proinsulin expression in the eye imaginal disc induces IRE1-mediated XBP1 alternative splicing, a signal for endoplasmic reticulum stress response activation, and produces global change in gene expression. Mutant hINS transgene tester strains, when crossed to stocks from the Drosophila Genetic Reference Panel, produce F1 adults with a continuous range of disease phenotypes and large broad-sense heritability. Surprisingly, the severity of mutant hINS-induced disease in the eye is not correlated with that in the notum in these crosses, nor with eye reduction phenotypes caused by the expression of two dominant eye mutants acting in two different eye development pathways, Drop (Dr) or Lobe (L), when crossed into the same genetic backgrounds. The tissue specificity of genetic variability for mutant hINS-induced disease has, therefore, its own distinct signature. The genetic dominance

  18. Cellular responses induced by Cu(II quinolinonato complexes in human tumor and hepatic cells

    Directory of Open Access Journals (Sweden)

    Trávníček Zdeněk

    2012-12-01

    Full Text Available Abstract Background Inspired by the unprecedented historical success of cisplatin, one of the most important research directions in bioinorganic and medicinal chemistry is dedicated to the development of new anticancer compounds with the potential to surpass it in antitumor activity, while having lower unwanted side-effects. Therefore, a series of copper(II mixed-ligand complexes of the type [Cu(qui(L]Y · xH2O (1–6, where Hqui = 2-phenyl-3-hydroxy-4(1H-quinolinone, Y = NO3 (1, 3, 5 or BF4 (2, 4, 6, and L = 1,10-phenanthroline (phen (1, 2, 5-methyl-1,10-phenanthroline (mphen (3, 4 and bathophenanthroline (bphen (5, 6, was studied for their in vitro cytotoxicity against several human cancer cell lines (A549 lung carcinoma, HeLa cervix epitheloid carcinoma, G361 melanoma cells, A2780 ovarian carcinoma, A2780cis cisplatin-resistant ovarian carcinoma, LNCaP androgen-sensitive prostate adenocarcinoma and THP-1 monocytic leukemia. Results The tested complexes displayed a stronger cytotoxic effect against all the cancer cells as compared to cisplatin. The highest cytotoxicity was found for the complexes 4 (IC50 = 0.36 ± 0.05 μM and 0.56 ± 0.15 μM, 5 (IC50 = 0.66 ± 0.07 μM and 0.73 ± 0.08 μM and 6 (IC50 = 0.57 ± 0.11 μM and 0.70 ± 0.20 μM against A2780, and A2780cis respectively, as compared with the values of 12.0 ± 0.8 μM and 27.0 ± 4.6 μM determined for cisplatin. Moreover, the tested complexes were much less cytotoxic to primary human hepatocytes than to the cancer cells. The complexes 5 and 6 exhibited significantly high ability to modulate secretion of the pro-inflammatory cytokines TNF-α (2873 ± 238 pg/mL and 3284 ± 139 pg/mL for 5, and 6 respectively and IL-1β (1177 ± 128 pg/mL and 1087 ± 101 pg/mL for 5, and 6 respectively tested on the lipopolysaccharide (LPS-stimulated THP-1 cells as compared with the values of 1173

  19. Human sex hormone-binding globulin gene expression- multiple promoters and complex alternative splicing

    Directory of Open Access Journals (Sweden)

    Rosner William

    2009-05-01

    Full Text Available Abstract Background Human sex hormone-binding globulin (SHBG regulates free sex steroid concentrations in plasma and modulates rapid, membrane based steroid signaling. SHBG is encoded by an eight exon-long transcript whose expression is regulated by a downstream promoter (PL. The SHBG gene was previously shown to express a second major transcript of unknown function, derived from an upstream promoter (PT, and two minor transcripts. Results We report that transcriptional expression of the human SHBG gene is far more complex than previously described. PL and PT direct the expression of at least six independent transcripts each, resulting from alternative splicing of exons 4, 5, 6, and/or 7. We mapped two transcriptional start sites downstream of PL and PT, and present evidence for a third SHBG gene promoter (PN within the neighboring FXR2 gene; PN regulates the expression of at least seven independent SHBG gene transcripts, each possessing a novel, 164-nt first exon (1N. Transcriptional expression patterns were generated for human prostate, breast, testis, liver, and brain, and the LNCaP, MCF-7, and HepG2 cell lines. Each expresses the SHBG transcript, albeit in varying abundance. Alternative splicing was more pronounced in the cancer cell lines. PL- PT- and PN-derived transcripts were most abundant in liver, testis, and prostate, respectively. Initial findings reveal the existence of a smaller immunoreactive SHBG species in LNCaP, MCF-7, and HepG2 cells. Conclusion These results extend our understanding of human SHBG gene transcription, and raise new and important questions regarding the role of novel alternatively spliced transcripts, their function in hormonally responsive tissues including the breast and prostate, and the role that aberrant SHBG gene expression may play in cancer.

  20. Complexity, Compassion and Self-Organisation: Human Evolution and the Vulnerable Ape Hypothesis

    Directory of Open Access Journals (Sweden)

    Nick P. Winder

    2015-06-01

    Full Text Available Humans are agents capable of helping others, learning new behaviours and forgetting old ones. The evolutionary approach to archaeological systems has therefore been hampered by the 'modern synthesis' - a gene-centred model of evolution as a process that eliminates those that cannot handle stress. The result has been a form of environmental determinism that explains human evolution in terms of heroic struggles and selective winnowing. Biologists committed to the modern synthesis have either dismissed agency as a delusion wrought in our bodies by natural selection, or imposed a sharp, Cartesian split between 'natural' and 'artificial' ecologies. We revisit the seminal literature of evolutionary biology and show that the paradigmatic fault lines of 21st century anthropology can be traced back to the 19th century and beyond. Lamarck had developed a two-factor evolutionary theory - one factor an endogenous tendency to become more advanced and complex, the other an exogenous constraint that drove organisms into conformity with environment. Darwin tried to eliminate the progressive tendency and imposed linearity constraints on evolution that Thomas Henry Huxley rejected. When experimental evidence falsified Darwin's linear hypothesis, the race began to develop a new, gene-centred model of evolution. This became the modern synthesis. The modern synthesis is now under pressure from the evidence of anthropology, sociology, palaeontology, ecology and genetics. An 'extended synthesis' is emerging. If evolution is adequately summarised by the aphorism survival of the fittest, then 'fitness' cannot always be defined in the heroic sense of 'better able to compete and reproduce'. The fittest organisms are often those that evade selective winnowing, even when their ability to compete and reproduce has been compromised by their genes. Characteristically human traits like language, abstraction, compassion and altruism may have arisen as coping strategies that

  1. The Ecology of Human-Machine Systems II: Mediating 'Direct Perception' in Complex Work Domains

    DEFF Research Database (Denmark)

    Vicente, Kim J.; Rasmussen, Jens

    1990-01-01

    Recently, a new class of artifacts has appeared in our environment: complex, high-technology work domains. An important characteristic of such systems is that their goal-relevant properties cannot be directly observed by the unaided eye. As a result, interface design is a ubiquitous problem in th...... in the design of these work environments. Nevertheless, the problem is one that has yet to be addressed in an adequate manner. An analogy to human perceptual mechanisms suggests that a smart instrument approach to interface design is needed to supplant the rote instrument (single......-sensor-single-indicator) approach that has dominated to this point. Ecological interface design (ED) is a theoretical framework in the smart instrument vein that postulates a set of general, prescriptive principles for design. The goal of E D is twofold: first, to reveal the affordances of the work domain through the interface...

  2. Hsp60 and p70S6K form a complex in human cardiomyocytes

    Directory of Open Access Journals (Sweden)

    Kroupskaya I. V.

    2011-02-01

    Full Text Available Molecular chaperon Hsp60 and protein kinase p70S6K play an important functional role in the regulation of cardiomyocytes vital function or apoptosis. Aim. To study a possibility of in vivo complex formation between Hsp60 and p70S6K in cardiomyocytes. Methods. Co-immunoprecipitation, Western-blot analysis. Results. We have identified in vivo interaction between molecular chaperone Hsp60 and two isoforms of proteinkinase p70S6K in human myocardium, normal and affected by cardiomyopathy. Conclusions. The results obtained suggest a possible participation of molecular chaperon Hsp60 in regulation of p70S6K activity in stressinduced apoptotic signaling pathway in cardiomyocytes.

  3. Computer-based diagnostic monitoring to enhance the human-machine interface of complex processes

    International Nuclear Information System (INIS)

    Kim, I.S.

    1992-02-01

    There is a growing interest in introducing an automated, on-line, diagnostic monitoring function into the human-machine interfaces (HMIs) or control rooms of complex process plants. The design of such a system should be properly integrated with other HMI systems in the control room, such as the alarms system or the Safety Parameter Display System (SPDS). This paper provides a conceptual foundation for the development of a Plant-wide Diagnostic Monitoring System (PDMS), along with functional requirements for the system and other advanced HMI systems. Insights are presented into the design of an efficient and robust PDMS, which were gained from a critical review of various methodologies developed in the nuclear power industry, the chemical process industry, and the space technological community

  4. Using virtual humans and computer animations to learn complex motor skills: a case study in karate

    Directory of Open Access Journals (Sweden)

    Spanlang Bernhard

    2011-12-01

    Full Text Available Learning motor skills is a complex task involving a lot of cognitive issues. One of the main issues consists in retrieving the relevant information from the learning environment. In a traditional learning situation, a teacher gives oral explanations and performs actions to provide the learner with visual examples. Using virtual reality (VR as a tool for learning motor tasks is promising. However, it raises questions about the type of information this kind of environments can offer. In this paper, we propose to analyze the impact of virtual humans on the perception of the learners. As a case study, we propose to apply this research problem to karate gestures. The results of this study show no significant difference on the after training performance of learners confronted to three different learning environments (traditional group, video and VR.

  5. A novel therapeutic strategy for experimental stroke using docosahexaenoic acid complexed to human albumin

    Directory of Open Access Journals (Sweden)

    Belayev Ludmila

    2016-01-01

    Full Text Available Despite tremendous efforts in ischemic stroke research and significant improvements in patient care within the last decade, therapy is still insufficient. There is a compelling, urgent need for safe and effective neuroprotective strategies to limit brain injury, facilitate brain repair, and improve functional outcome. Recently, we reported that docosahexaenoic acid (DHA; 22:6, n-3 complexed to human albumin (DHA-Alb is highly neuroprotective after temporary middle cerebral artery occlusion (MCAo in young rats. This review highlights the potency of DHA-Alb therapy in permanent MCAo and aged rats and whether protection persists with chronic survival. We discovered that a novel therapy with DHA-Alb improved behavioral outcomes accompanied by attenuation of lesion volumes even when animals were allowed to survive three weeks after experimental stroke. This treatment might provide the basis for future therapeutics for patients suffering from ischemic stroke.

  6. A New Method to Develop Human Dental Pulp Cells and Platelet-rich Fibrin Complex.

    Science.gov (United States)

    He, Xuan; Chen, Wen-Xia; Ban, Guifei; Wei, Wei; Zhou, Jun; Chen, Wen-Jin; Li, Xian-Yu

    2016-11-01

    Platelet-rich fibrin (PRF) has been used as a scaffold material in various tissue regeneration studies. In the previous methods to combine seed cells with PRF, the structure of PRF was damaged, and the manipulation time in vitro was also increased. The objective of this in vitro study was to explore an appropriate method to develop a PRF-human dental pulp cell (hDPC) complex to maintain PRF structure integrity and to find out the most efficient part of PRF. The PRF-hDPC complex was developed at 3 different time points during PRF preparation: (1) the before centrifugation (BC) group, the hDPC suspension was added to the venous blood before blood centrifugation; (2) the immediately after centrifugation (IAC) group, the hDPC suspension was added immediately after blood centrifugation; (3) the after centrifugation (AC) group, the hDPC suspension was added 10 minutes after blood centrifugation; and (4) the control group, PRF without hDPC suspension. The prepared PRF-hDPC complexes were cultured for 7 days. The samples were fixed for histologic, immunohistochemistry, and scanning electron microscopic evaluation. Real-time polymerase chain reaction was performed to evaluate messenger RNA expression of alkaline phosphatase and dentin sialophosphoprotein. Enzyme-linked immunosorbent assay quantification for growth factors was performed within the different parts of the PRF. Histologic, immunohistochemistry, and scanning electron microscopic results revealed that hDPCs were only found in the BC group and exhibited favorable proliferation. Real-time polymerase chain reaction revealed that alkaline phosphatase and dentin sialophosphoprotein expression increased in the cultured PRF-hDPC complex. The lower part of the PRF released the maximum quantity of growth factors. Our new method to develop a PRF-hDPCs complex maintained PRF structure integrity. The hDPCs were distributed in the buffy coat, which might be the most efficient part of PRF. Copyright © 2016 American

  7. Molecular characterization of full-length MLV-related endogenous retrovirus ChiRV1 from the chicken, Gallus gallus

    Czech Academy of Sciences Publication Activity Database

    Borysenko, L.; Stepanets, Volodymyr; Rynditch, A.V.

    2008-01-01

    Roč. 376, č. 1 (2008), s. 199-204 ISSN 0042-6822 Institutional research plan: CEZ:AV0Z50520514 Keywords : endogenous retrovirus * chicken * phylogeny Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.539, year: 2008

  8. Structural characterization of human heme oxygenase-1 in complex with azole-based inhibitors.

    Science.gov (United States)

    Rahman, Mona N; Vlahakis, Jason Z; Roman, Gheorghe; Vukomanovic, Dragic; Szarek, Walter A; Nakatsu, Kanji; Jia, Zongchao

    2010-03-01

    The development of inhibitors specific for heme oxygenases (HO) aims to provide powerful tools in understanding the HO system. Based on the lead structure (2S, 4S)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-[((4-aminophenyl)thio)methyl]-1,3-dioxolane (azalanstat, QC-1) we have synthesized structural modifications to develop novel and selective HO inhibitors. The structural study of human HO-1 (hHO-1) in complex with a select group of the inhibitors was initiated using X-ray crystallographic techniques. Comparison of the structures of four such compounds each in complex with hHO-1 revealed a common binding mode, despite having different structural fragments. The compounds bind to the distal side of heme through an azole "anchor" which coordinates with the heme iron. An expansion of the distal pocket, mainly due to distal helix flexibility, allows accommodation of the compounds without displacing heme or the critical Asp140 residue. Rather, binding displaces a catalytically critical water molecule and disrupts an ordered hydrogen-bond network involving Asp140. The presence of a triazole "anchor" may provide further stability via a hydrogen bond with the protein. A hydrophobic pocket acts to stabilize the region occupied by the phenyl or adamantanyl moieties of these compounds. Further, a secondary hydrophobic pocket is formed via "induced fit" to accommodate bulky substituents at the 4-position of the dioxolane ring. Copyright 2009 Elsevier Inc. All rights reserved.

  9. Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus

    DEFF Research Database (Denmark)

    Giang, Erick; Dorner, Marcus; Prentoe, Jannick C

    2012-01-01

    , and an effective vaccine should target conserved T- and B-cell epitopes of the virus. Conserved B-cell epitopes overlapping the CD81 receptor-binding site (CD81bs) on the E2 viral envelope glycoprotein have been reported previously and provide promising vaccine targets. In this study, we isolated 73 human m......Abs recognizing five distinct antigenic regions on the virus envelope glycoprotein complex E1E2 from an HCV-immune phage-display antibody library by using an exhaustive-panning strategy. Many of these mAbs were broadly neutralizing. In particular, the mAb AR4A, recognizing a discontinuous epitope outside the CD81......bs on the E1E2 complex, has an exceptionally broad neutralizing activity toward diverse HCV genotypes and protects against heterologous HCV challenge in a small animal model. The mAb panel will be useful for the design and development of vaccine candidates to elicit broadly neutralizing antibodies...

  10. The Human Nuclear Exosome Targeting Complex Is Loaded onto Newly Synthesized RNA to Direct Early Ribonucleolysis

    Directory of Open Access Journals (Sweden)

    Michal Lubas

    2015-01-01

    Full Text Available The RNA exosome complex constitutes the major nuclear eukaryotic 3′-5′ exonuclease. Outside of nucleoli, the human nucleoplasmic exosome is directed to some of its substrates by the nuclear exosome targeting (NEXT complex. How NEXT targets RNA has remained elusive. Using an in vivo crosslinking approach, we report global RNA binding sites of RBM7, a key component of NEXT. RBM7 associates broadly with RNA polymerase II-derived RNA, including pre-mRNA and short-lived exosome substrates such as promoter upstream transcripts (PROMPTs, enhancer RNAs (eRNAs, and 3′-extended products from snRNA and replication-dependent histone genes. Within pre-mRNA, RBM7 accumulates at the 3′ ends of introns, and pulse-labeling experiments demonstrate that RBM7/NEXT defines an early exosome-targeting pathway for 3′-extended snoRNAs derived from such introns. We propose that RBM7 is generally loaded onto newly synthesized RNA to accommodate exosome action in case of available unprotected RNA 3′ ends.

  11. PHB Associates with the HIRA Complex to Control an Epigenetic-Metabolic Circuit in Human ESCs.

    Science.gov (United States)

    Zhu, Zhexin; Li, Chunliang; Zeng, Yanwu; Ding, Jianyi; Qu, Zepeng; Gu, Junjie; Ge, Laixiang; Tang, Fan; Huang, Xin; Zhou, Chenlin; Wang, Ping; Zheng, Deyou; Jin, Ying

    2017-02-02

    The chromatin landscape and cellular metabolism both contribute to cell fate determination, but their interplay remains poorly understood. Using genome-wide siRNA screening, we have identified prohibitin (PHB) as an essential factor in self-renewal of human embryonic stem cells (hESCs). Mechanistically, PHB forms protein complexes with HIRA, a histone H3.3 chaperone, and stabilizes the protein levels of HIRA complex components. Like PHB, HIRA is required for hESC self-renewal. PHB and HIRA act together to control global deposition of histone H3.3 and gene expression in hESCs. Of particular note, PHB and HIRA regulate the chromatin architecture at the promoters of isocitrate dehydrogenase genes to promote transcription and, thus, production of α-ketoglutarate, a key metabolite in the regulation of ESC fate. Our study shows that PHB has an unexpected nuclear role in hESCs that is required for self-renewal and that it acts with HIRA in chromatin organization to link epigenetic organization to a metabolic circuit. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Genetic recombination within the human T-cell receptor α-chain gene complex

    International Nuclear Information System (INIS)

    Robinson, M.A.; Kindt, T.J.

    1987-01-01

    Genetic analyses of the human T-cell receptor (TCR) α-chain genes indicate that recombination events may occur frequently within this gene complex. Examination of the inheritance of restriction fragment length polymorphisms (RFLP) detected by using probes for constant or variable region gene segments made it possible to assign TCRα haplotypes to the 16 parents and 43 offspring of eight families studied. A total of six RFLP, three for the constant region and three for variable region segments, were examined in the present studies. Most enzyme and probe combinations tested revealed no polymorphism and those finally selected for the study showed limited polymorphism in that only two or, in one case, three allelic forms of the gene were seen. In spite of limited variability at this level, extensive heterogeneity was observed for the combinations of markers present in haplotypes, suggesting that frequent recombination events have occurred. Most strikingly, multiple combinations of RFLP occurring in close proximity of the TCRα constant region gene were observed in this study. A high recombination frequency for the TCRα gene complex is further supported by the observation that two children, one in each of two families, inherited recombinant TCRα haplotypes

  13. Unique cell type-specific junctional complexes in vascular endothelium of human and rat liver sinusoids.

    Directory of Open Access Journals (Sweden)

    Cyrill Géraud

    Full Text Available Liver sinusoidal endothelium is strategically positioned to control access of fluids, macromolecules and cells to the liver parenchyma and to serve clearance functions upstream of the hepatocytes. While clearance of macromolecular debris from the peripheral blood is performed by liver sinusoidal endothelial cells (LSECs using a delicate endocytic receptor system featuring stabilin-1 and -2, the mannose receptor and CD32b, vascular permeability and cell trafficking are controlled by transcellular pores, i.e. the fenestrae, and by intercellular junctional complexes. In contrast to blood vascular and lymphatic endothelial cells in other organs, the junctional complexes of LSECs have not yet been consistently characterized in molecular terms. In a comprehensive analysis, we here show that LSECs express the typical proteins found in endothelial adherens junctions (AJ, i.e. VE-cadherin as well as α-, β-, p120-catenin and plakoglobin. Tight junction (TJ transmembrane proteins typical of endothelial cells, i.e. claudin-5 and occludin, were not expressed by rat LSECs while heterogenous immunreactivity for claudin-5 was detected in human LSECs. In contrast, junctional molecules preferentially associating with TJ such as JAM-A, B and C and zonula occludens proteins ZO-1 and ZO-2 were readily detected in LSECs. Remarkably, among the JAMs JAM-C was considerably over-expressed in LSECs as compared to lung microvascular endothelial cells. In conclusion, we show here that LSECs form a special kind of mixed-type intercellular junctions characterized by co-occurrence of endothelial AJ proteins, and of ZO-1 and -2, and JAMs. The distinct molecular architecture of the intercellular junctional complexes of LSECs corroborates previous ultrastructural findings and provides the molecular basis for further analyses of the endothelial barrier function of liver sinusoids under pathologic conditions ranging from hepatic inflammation to formation of liver metastasis.

  14. Carbohydrate linked organotin(IV) complexes as human topoisomerase Iα inhibitor and their antiproliferative effects against the human carcinoma cell line.

    Science.gov (United States)

    Khan, Rais Ahmad; Yadav, Shipra; Hussain, Zahid; Arjmand, Farukh; Tabassum, Sartaj

    2014-02-14

    Dimethyltin(IV) complexes with ethanolamine (1) and biologically significant N-glycosides (2 and 3) were designed and synthesized. The structural elucidation of complexes 1-3 was done using elemental and spectroscopic methods; in addition, complex 1 was studied by single crystal X-ray diffraction studies. The in vitro DNA binding profile of complexes 2 and 3 was carried out by employing different biophysical methods to ascertain the feasibility of glycosylated complexes. Further, the cleaving ability of 2 and 3 was investigated by the agarose gel electrophoretic mobility assay with supercoiled pBR322 DNA, and demonstrated significantly good nuclease activity. Furthermore, both the complexes exhibited significant inhibitory effects on the catalytic activity of human Topo I at lower concentration than standard drugs. Computer-aided molecular docking techniques were used to ascertain the mode and mechanism of action towards the molecular target DNA and Topo I. The cytotoxicity of 2 and 3 against human hepatoma cancer cells (Huh7) was evaluated, which revealed significant regression in cancerous cells as compared with the standard drug. The antiproliferative activities of 2 and 3 were tested against human hepatoma cancer cells (Huh7), and results showed significantly good activity. Additionally, to validate the remarkable antiproliferative activity of complexes 2 and 3, specific regulatory gene expression (MMP-2 and TGF-β) was obtained by real time PCR.

  15. Crystal structure analysis of human serum albumin complexed with sodium 4-phenylbutyrate

    Directory of Open Access Journals (Sweden)

    Akito Kawai

    2018-03-01

    Full Text Available Sodium 4-phenylbutyrate (PB is an orphan drug for the treatment of urea cycle disorders. It also inhibits the development of endoplasmic reticulum stress, the action of histone deacetylases and as a regulator of the hepatocanalicular transporter. PB is generally considered to have the potential for use in the treatment of the diseases such as cancer, neurodegenerative diseases and metabolic diseases. In a previous study, we reported that PB is primarily bound to human serum albumin (HSA in plasma and its binding site is drug site 2. However, details of the binding mode of PB to HSA remain unknown. To address this issue, we examined the crystal structure of HSA with PB bound to it. The structure of the HSA–PB complex indicates that the binding mode of PB to HSA is quite similar to that for octanoate or drugs that bind to drug site 2, as opposed to that for other medium-chain length of fatty acids. These findings provide useful basic information related to drug–HSA interactions. Moreover, the information presented herein is valuable in terms of providing safe and efficient treatment and diagnosis in clinical settings. Keywords: Human serum albumin, X-ray crystallography, Sodium 4-phenylbutyrate, Drug interaction, Drug site 2

  16. MULTIPLE HUMAN TRACKING IN COMPLEX SITUATION BY DATA ASSIMILATION WITH PEDESTRIAN BEHAVIOR MODEL

    Directory of Open Access Journals (Sweden)

    W. Nakanishi

    2012-07-01

    Full Text Available A new method of multiple human tracking is proposed. The key concept is that to assume a tracking process as a data assimilation process. Despite the importance of understanding pedestrian behavior in public space with regard to achieving more sophisticated space design and flow control, automatic human tracking in complex situation is still challenging when people move close to each other or are occluded by others. For this difficulty, we stochastically combine existing tracking method by image processing with simulation models of walking behavior. We describe a system in a form of general state space model and define the components of the model according to the review on related works. Then we apply the proposed method to the data acquired at the ticket gate of the railway station. We show the high performance of the method, as well as compare the result with other model to present the advantage of integrating the behavior model to the tracking method. We also show the method's ability to acquire passenger flow information such as ticket gate choice and OD data automatically from the tracking result.

  17. Balancing Human-machine Interface (HMI) Design in Complex Supervisory Tasks

    International Nuclear Information System (INIS)

    Ha, Junsu; Kim, Arryum; Jang, Inseok; Seong, Poonghyun

    2013-01-01

    Human performance aspects such as plant performance, personnel task performance, situation awareness, cognitive workload, teamwork, and anthropomorphic/physiological factor are evaluated with the HUPESS. Even though the HUPESS provides evaluation results in each of the performance aspects for the integrated system validation (ISV), additional researches have been needed to develop methods on how to find out design deficiency leading to poor performance and give a solution for design improvement in HMI. The authors have developed a method of HMI design improvement for the monitoring and detection tasks which was named as 'DEMIS (Difficulty Evaluation Method in Information Searching)'. The DEMIS is a HMI evaluation method which bridge poor performance and design improvement. Lessons learned from the existing studies lead to a question about how to optimize the whole HMI design. Human factors principles provide the foundation for guidelines of various codes and standards in designing HMIs. Also in NPPs, a lot of guidelines directly from various codes and standard and derived from various research and development projects are available for designing MCR HMIs. In this study, a balancing principle and relevant two measures for HMI design optimization are proposed to be used in the HMI design of complex supervisory tasks in NPPs. The balancing principle is that a HMI element (e. g., an indicator or a push button) should be designed according to its importance

  18. Native gel electrophoresis of human telomerase distinguishes active complexes with or without dyskerin

    Science.gov (United States)

    Gardano, Laura; Holland, Linda; Oulton, Rena; Le Bihan, Thierry; Harrington, Lea

    2012-01-01

    Telomeres, the ends of linear chromosomes, safeguard against genome instability. The enzyme responsible for extension of the telomere 3′ terminus is the ribonucleoprotein telomerase. Whereas telomerase activity can be reconstituted in vitro with only the telomerase RNA (hTR) and telomerase reverse transcriptase (TERT), additional components are required in vivo for enzyme assembly, stability and telomere extension activity. One such associated protein, dyskerin, promotes hTR stability in vivo and is the only component to co-purify with active, endogenous human telomerase. We used oligonucleotide-based affinity purification of hTR followed by native gel electrophoresis and in-gel telomerase activity detection to query the composition of telomerase at different purification stringencies. At low salt concentrations (0.1 M NaCl), affinity-purified telomerase was ‘supershifted’ with an anti-dyskerin antibody, however the association with dyskerin was lost after purification at 0.6 M NaCl, despite the retention of telomerase activity and a comparable yield of hTR. The interaction of purified hTR and dyskerin in vitro displayed a similar salt-sensitive interaction. These results demonstrate that endogenous human telomerase, once assembled and active, does not require dyskerin for catalytic activity. Native gel electrophoresis may prove useful in the characterization of telomerase complexes under various physiological conditions. PMID:22187156

  19. Crystal structure of NL63 respiratory coronavirus receptor-binding domain complexed with its human receptor

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Kailang; Li, Weikai; Peng, Guiqing; Li, Fang; (Harvard-Med); (UMM-MED)

    2010-03-04

    NL63 coronavirus (NL63-CoV), a prevalent human respiratory virus, is the only group I coronavirus known to use angiotensin-converting enzyme 2 (ACE2) as its receptor. Incidentally, ACE2 is also used by group II SARS coronavirus (SARS-CoV). We investigated how different groups of coronaviruses recognize the same receptor, whereas homologous group I coronaviruses recognize different receptors. We determined the crystal structure of NL63-CoV spike protein receptor-binding domain (RBD) complexed with human ACE2. NL63-CoV RBD has a novel {beta}-sandwich core structure consisting of 2 layers of {beta}-sheets, presenting 3 discontinuous receptor-binding motifs (RBMs) to bind ACE2. NL63-CoV and SARS-CoV have no structural homology in RBD cores or RBMs; yet the 2 viruses recognize common ACE2 regions, largely because of a 'virus-binding hotspot' on ACE2. Among group I coronaviruses, RBD cores are conserved but RBMs are variable, explaining how these viruses recognize different receptors. These results provide a structural basis for understanding viral evolution and virus-receptor interactions.

  20. Capturing complex human behaviors in representative sports contexts with a single camera.

    Science.gov (United States)

    Duarte, Ricardo; Araújo, Duarte; Fernandes, Orlando; Fonseca, Cristina; Correia, Vanda; Gazimba, Vítor; Travassos, Bruno; Esteves, Pedro; Vilar, Luís; Lopes, José

    2010-01-01

    In the last years, several motion analysis methods have been developed without considering representative contexts for sports performance. The purpose of this paper was to explain and underscore a straightforward method to measure human behavior in these contexts. Procedures combining manual video tracking (with TACTO device) and bidimensional reconstruction (through direct linear transformation) using a single camera were used in order to capture kinematic data required to compute collective variable(s) and control parameter(s). These procedures were applied to a 1vs1 association football task as an illustrative subphase of team sports and will be presented in a tutorial fashion. Preliminary analysis of distance and velocity data identified a collective variable (difference between the distance of the attacker and the defender to a target defensive area) and two nested control parameters (interpersonal distance and relative velocity). Findings demonstrated that the complementary use of TACTO software and direct linear transformation permit to capture and reconstruct complex human actions in their context in a low dimensional space (information reduction).

  1. The Structure of the Human Centrin 2-Xeroderma Pigmentosum Group C Protein Complex

    Energy Technology Data Exchange (ETDEWEB)

    Thompson,J.; Ryan, Z.; Salisbury, J.; Kumar, R.

    2006-01-01

    Human centrin-2 plays a key role in centrosome function and stimulates nucleotide excision repair by binding to the xeroderma pigmentosum group C protein. To determine the structure of human centrin-2 and to develop an understanding of molecular interactions between centrin and xeroderma pigmentosum group C protein, we characterized the crystal structure of calcium-loaded full-length centrin-2 complexed with a xeroderma pigmentosum group C peptide. Our structure shows that the carboxyl-terminal domain of centrin-2 binds this peptide and two calcium atoms, whereas the amino-terminal lobe is in a closed conformation positioned distantly by an ordered {alpha}-helical linker. A stretch of the amino-terminal domain unique to centrins appears disordered. Two xeroderma pigmentosum group C peptides both bound to centrin-2 also interact to form an {alpha}-helical coiled-coil. The interface between centrin-2 and each peptide is predominantly nonpolar, and key hydrophobic residues of XPC have been identified that lead us to propose a novel binding motif for centrin.

  2. The Structure of the Human Centrin 2-Xeroderma Pigmentosum Group C Protein Complex

    International Nuclear Information System (INIS)

    Thompson, J.; Ryan, Z.; Salisbury, J.; Kumar, R.

    2006-01-01

    Human centrin-2 plays a key role in centrosome function and stimulates nucleotide excision repair by binding to the xeroderma pigmentosum group C protein. To determine the structure of human centrin-2 and to develop an understanding of molecular interactions between centrin and xeroderma pigmentosum group C protein, we characterized the crystal structure of calcium-loaded full-length centrin-2 complexed with a xeroderma pigmentosum group C peptide. Our structure shows that the carboxyl-terminal domain of centrin-2 binds this peptide and two calcium atoms, whereas the amino-terminal lobe is in a closed conformation positioned distantly by an ordered α-helical linker. A stretch of the amino-terminal domain unique to centrins appears disordered. Two xeroderma pigmentosum group C peptides both bound to centrin-2 also interact to form an α-helical coiled-coil. The interface between centrin-2 and each peptide is predominantly nonpolar, and key hydrophobic residues of XPC have been identified that lead us to propose a novel binding motif for centrin

  3. Balancing Human-machine Interface (HMI) Design in Complex Supervisory Tasks

    Energy Technology Data Exchange (ETDEWEB)

    Ha, Junsu [Khalifa Univ. of Science, Abu Dhabi (United Arab Emirates); Kim, Arryum; Jang, Inseok; Seong, Poonghyun [Korea Advanced Institute of Science and Technology, Daejeon (Korea, Republic of)

    2013-05-15

    Human performance aspects such as plant performance, personnel task performance, situation awareness, cognitive workload, teamwork, and anthropomorphic/physiological factor are evaluated with the HUPESS. Even though the HUPESS provides evaluation results in each of the performance aspects for the integrated system validation (ISV), additional researches have been needed to develop methods on how to find out design deficiency leading to poor performance and give a solution for design improvement in HMI. The authors have developed a method of HMI design improvement for the monitoring and detection tasks which was named as 'DEMIS (Difficulty Evaluation Method in Information Searching)'. The DEMIS is a HMI evaluation method which bridge poor performance and design improvement. Lessons learned from the existing studies lead to a question about how to optimize the whole HMI design. Human factors principles provide the foundation for guidelines of various codes and standards in designing HMIs. Also in NPPs, a lot of guidelines directly from various codes and standard and derived from various research and development projects are available for designing MCR HMIs. In this study, a balancing principle and relevant two measures for HMI design optimization are proposed to be used in the HMI design of complex supervisory tasks in NPPs. The balancing principle is that a HMI element (e. g., an indicator or a push button) should be designed according to its importance.

  4. Structure of a Human Astrovirus Capsid-Antibody Complex and Mechanistic Insights into Virus Neutralization

    Energy Technology Data Exchange (ETDEWEB)

    Bogdanoff, Walter A.; Campos, Jocelyn; Perez, Edmundo I.; Yin, Lu; Alexander, David L.; DuBois, Rebecca M. (UCSC)

    2016-11-02

    ABSTRACT

    Human astroviruses (HAstVs) are a leading cause of viral diarrhea in young children, the immunocompromised, and the elderly. There are no vaccines or antiviral therapies against HAstV disease. Several lines of evidence point to the presence of protective antibodies in healthy adults as a mechanism governing protection against reinfection by HAstV. However, development of anti-HAstV therapies is hampered by the gap in knowledge of protective antibody epitopes on the HAstV capsid surface. Here, we report the structure of the HAstV capsid spike domain bound to the neutralizing monoclonal antibody PL-2. The antibody uses all six complementarity-determining regions to bind to a quaternary epitope on each side of the dimeric capsid spike. We provide evidence that the HAstV capsid spike is a receptor-binding domain and that the antibody neutralizes HAstV by blocking virus attachment to cells. We identify patches of conserved amino acids that overlap the antibody epitope and may comprise a receptor-binding site. Our studies provide a foundation for the development of therapies to prevent and treat HAstV diarrheal disease.

    IMPORTANCEHuman astroviruses (HAstVs) infect nearly every person in the world during childhood and cause diarrhea, vomiting, and fever. Despite the prevalence of this virus, little is known about how antibodies in healthy adults protect them against reinfection. Here, we determined the crystal structure of a complex of the HAstV capsid protein and a virus-neutralizing antibody. We show that the antibody binds to the outermost spike domain of the capsid, and we provide evidence that the antibody blocks virus attachment to human cells. Importantly, our findings suggest that a subunit-based vaccine focusing the immune system on the HAstV capsid spike domain could be effective in protecting children against HAstV disease.

  5. Complex signatures of selection for the melanogenic loci TYR, TYRP1 and DCT in humans

    Directory of Open Access Journals (Sweden)

    Boyano María

    2008-02-01

    Full Text Available Abstract Background The observed correlation between ultraviolet light incidence and skin color, together with the geographical apportionment of skin reflectance among human populations, suggests an adaptive value for the pigmentation of the human skin. We have used Affymetrix U133a v2.0 gene expression microarrays to investigate the expression profiles of a total of 9 melanocyte cell lines (5 from lightly pigmented donors and 4 from darkly pigmented donors plus their respective unirradiated controls. In order to reveal signatures of selection in loci with a bearing on skin pigmentation in humans, we have resequenced between 4 to 5 kb of the proximal regulatory regions of three of the most differently expressed genes, in the expectation that variation at regulatory regions might account for intraespecific morphological diversity, as suggested elsewhere. Results Contrary to our expectations, expression profiles did not cluster the cells into unirradiated versus irradiated melanocytes, or into lightly pigmented versus darkly pigmented melanocytes. Instead, expression profiles correlated with the presence of Bovine Pituitary Extract (known to contain α-MSH in the media. This allowed us to differentiate between melanocytes that are synthesizing melanin and those that are not. TYR, TYRP1 and DCT were among the five most differently expressed genes between these two groups. Population genetic analyses of sequence haplotypes of the proximal regulatory flanking-regions included Tajima's D, HEW and DHEW neutrality tests analysis. These were complemented with EHH tests (among others in which the significance was obtained by a novel approach using extensive simulations under the coalescent model with recombination. We observe strong evidence for positive selection for TYRP1 alleles in Africans and for DCT and TYRP1 in Asians. However, the overall picture reflects a complex pattern of selection, which might include overdominance for DCT in Europeans

  6. Application of human erythrocytes to a radioimmune assay of immune complexes in serum. [Lupus erythematosus, type B hepatitis

    Energy Technology Data Exchange (ETDEWEB)

    Tsuda, F; Miyakawa, Y; Mayumi, M [Tokyo Metropolitan Lab. of Public Health (Japan)

    1979-07-01

    An immune adherence receptor exists on the surface of primate erythrocytes, and has been characterized as a receptor for the activated third component of complement (C3b). Human red blood cells (RCBs, blood group O) were applied to a sensitive determination of complement-fixing, soluble immune complexes in serum. The method involved the binding of immune complexes with RBCs in the presence of complement and the detection of cell-bound IgG molecules by radiolabelled anti-human IgG antibodies. Since the binding of RBCs with monomeric IgG was minimal, cell bound IgG molecules were taken as representing immune complexes. When aggregated human gammaglobulin (AHG) was used as a model of immune complexes, as little as 5 ..mu..g dissolved in 1 ml of normal human serum were detected. The binding of RBCs with AHG was inhibited in EDTA solution where the classical complement pathway could not be activated. The RBC radioimmune assay was successfully applied to the determination of soluble immune complexes in pathological serum samples obtained from the patients with systemic lupus erythematosus and those with fulminant Type B hepatitis. False-positive results by autoantibodies against RBCs could be excluded by a Coombs test and by comparing the binding in the presence of complement with that in EDTA solution. The ubiquitous availability of RBCs coupled with a high sensitivity would allow the RBC radioimmune assay to be used as a further method of determining immune complexes in the serum.

  7. Categorial Ontology of Complex Systems, Meta-Systems and Levels: The Emergence of Life, Human Consciousness and Society

    Directory of Open Access Journals (Sweden)

    James F. Glazebrook

    2010-06-01

    Full Text Available Relational structures of organisms and the human mind are naturally represented in terms of novel variable topology concepts, non-Abelian categories and Higher Dimensional Algebra{ relatively new concepts that would be defined in
    this tutorial paper. A unifying theme of local-to-global approaches to organismic development, evolution and human consciousness leads to novel patterns of relations that emerge in super- and ultra- complex systems in terms of compositions of local procedures [1]. The claim is defended in this paper that human consciousness is unique and should be viewed as an ultra-complex, global process of processes, at a meta-level not sub{summed by, but compatible with, human brain dynamics [2]-[5]. The emergence of consciousness and its existence
    are considered to be dependent upon an extremely complex structural and functional unit with an asymmetric network topology and connectivities{the human brain. However, the appearance of human consciousness is shown to be critically dependent upon societal co-evolution, elaborate language-symbolic communication and `virtual', higher dimensional, non{commutative processes involving separate space and time perceptions. Theories of the mind are approached from the theory of levels and ultra-complexity viewpoints that throw
    new light on previous semantic models in cognitive science. Anticipatory systems and complex causality at the top levels of reality are discussed in the context of psychology, sociology and ecology. A paradigm shift towards non-commutative, or more generally, non-Abelian theories of highly complex dynamics [6] is suggested to unfold now in physics, mathematics, life and cognitive sciences, thus leading to the realizations of higher dimensional algebras in neurosciences and psychology, as well as in human genomics, bioinformatics and interactomics. The presence of strange attractors in modern society dynamics gives rise to very serious concerns for the future

  8. A transcriptome resource for the koala (Phascolarctos cinereus): insights into koala retrovirus transcription and sequence diversity.

    Science.gov (United States)

    Hobbs, Matthew; Pavasovic, Ana; King, Andrew G; Prentis, Peter J; Eldridge, Mark D B; Chen, Zhiliang; Colgan, Donald J; Polkinghorne, Adam; Wilkins, Marc R; Flanagan, Cheyne; Gillett, Amber; Hanger, Jon; Johnson, Rebecca N; Timms, Peter

    2014-09-11

    The koala, Phascolarctos cinereus, is a biologically unique and evolutionarily distinct Australian arboreal marsupial. The goal of this study was to sequence the transcriptome from several tissues of two geographically separate koalas, and to create the first comprehensive catalog of annotated transcripts for this species, enabling detailed analysis of the unique attributes of this threatened native marsupial, including infection by the koala retrovirus. RNA-Seq data was generated from a range of tissues from one male and one female koala and assembled de novo into transcripts using Velvet-Oases. Transcript abundance in each tissue was estimated. Transcripts were searched for likely protein-coding regions and a non-redundant set of 117,563 putative protein sequences was produced. In similarity searches there were 84,907 (72%) sequences that aligned to at least one sequence in the NCBI nr protein database. The best alignments were to sequences from other marsupials. After applying a reciprocal best hit requirement of koala sequences to those from tammar wallaby, Tasmanian devil and the gray short-tailed opossum, we estimate that our transcriptome dataset represents approximately 15,000 koala genes. The marsupial alignment information was used to look for potential gene duplications and we report evidence for copy number expansion of the alpha amylase gene, and of an aldehyde reductase gene.Koala retrovirus (KoRV) transcripts were detected in the transcriptomes. These were analysed in detail and the structure of the spliced envelope gene transcript was determined. There was appreciable sequence diversity within KoRV, with 233 sites in the KoRV genome showing small insertions/deletions or single nucleotide polymorphisms. Both koalas had sequences from the KoRV-A subtype, but the male koala transcriptome has, in addition, sequences more closely related to the KoRV-B subtype. This is the first report of a KoRV-B-like sequence in a wild population. This transcriptomic

  9. An insight into the thermodynamic characteristics of human thrombopoietin complexation with TN1 antibody

    Science.gov (United States)

    Shibazaki, Chie; Adachi, Motoyasu; Honjo, Eijiro; Tamada, Taro; Maeda, Yoshitake; Tahara, Tomoyuki; Kato, Takashi; Miyazaki, Hiroshi; Blaber, Michael; Kuroki, Ryota

    2016-01-01

    Abstract Human thrombopoietin (hTPO) primarily stimulates megakaryocytopoiesis and platelet production and is neutralized by the mouse TN1 antibody. The thermodynamic characteristics of TN1 antibody–hTPO complexation were analyzed by isothermal titration calorimetry (ITC) using an antigen‐binding fragment (Fab) derived from the TN1 antibody (TN1‐Fab). To clarify the mechanism by which hTPO is recognized by TN1‐Fab the conformation of free TN1‐Fab was determined to a resolution of 2.0 Å using X‐ray crystallography and compared with the hTPO‐bound form of TN1‐Fab determined by a previous study. This structural comparison revealed that the conformation of TN1‐Fab does not substantially change after hTPO binding and a set of 15 water molecules is released from the antigen‐binding site (paratope) of TN1‐Fab upon hTPO complexation. Interestingly, the heat capacity change (ΔCp) measured by ITC (−1.52 ± 0.05 kJ mol−1 K−1) differed significantly from calculations based upon the X‐ray structure data of the hTPO‐bound and unbound forms of TN1‐Fab (−1.02 ∼ 0.25 kJ mol−1 K−1) suggesting that hTPO undergoes an induced‐fit conformational change combined with significant desolvation upon TN1‐Fab binding. The results shed light on the structural biology associated with neutralizing antibody recognition. PMID:27419667

  10. Clarifying the impact of polycomb complex component disruption in human cancers.

    Science.gov (United States)

    Yamamoto, Yukiya; Abe, Akihiro; Emi, Nobuhiko

    2014-04-01

    The dysregulation of proper transcriptional control is a major cause of developmental diseases and cancers. Polycomb proteins form chromatin-modifying complexes that transcriptionally silence genome regions in higher eukaryotes. The BCL6 corepressor (BCOR) complex comprises ring finger protein 1B (RNF2/RING1B), polycomb group ring finger 1 (PCGF1), and lysine-specific demethylase 2B (KDM2B) and is uniquely recruited to nonmethylated CpG islands, where it removes histone H3K36me2 and induces repressive histone H2A monoubiquitylation. Germline BCOR mutations have been detected in patients with oculofaciocardiodental and Lenz microphthalmia syndromes, which are inherited conditions. Recently, several variants of BCOR and BCOR-like 1 (BCORL1) chimeric fusion transcripts were reported in human cancers, including acute promyelocytic leukemia, bone sarcoma, and hepatocellular carcinoma. In addition, massively parallel sequencing has identified inactivating somatic BCOR and BCORL1 mutations in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia, medulloblastoma, and retinoblastoma. More importantly, patients with AML and MDS with BCOR mutations exhibit poor prognosis. This perspective highlights the detection of BCOR mutations and fusion transcripts of BCOR and BCORL1 and discusses their importance for diagnosing cancer subtypes and estimating the treatment responses of patients. Furthermore, this perspective proposes the need for additional functional studies to clarify the oncogenic mechanism by which BCOR and BCORL1 are disrupted in cancers, and how this may lead to the development of novel therapeutics. Mol Cancer Res; 12(4); 479-84. ©2014 AACR.

  11. Crystal Structure of the Human Symplekin-Ssu72-CTD Phosphopeptide Complex

    Energy Technology Data Exchange (ETDEWEB)

    K Xiang; T Nigaike; S Xiang; T Kilic; M Beh; J Manley; L Tong

    2011-12-31

    Symplekin (Pta1 in yeast) is a scaffold in the large protein complex that is required for 3'-end cleavage and polyadenylation of eukaryotic messenger RNA precursors (pre-mRNAs); it also participates in transcription initiation and termination by RNA polymerase II (Pol II). Symplekin mediates interactions between many different proteins in this machinery, although the molecular basis for its function is not known. Here we report the crystal structure at 2.4 {angstrom} resolution of the amino-terminal domain (residues 30-340) of human symplekin in a ternary complex with the Pol II carboxy-terminal domain (CTD) Ser5 phosphatase Ssu72 and a CTD Ser5 phosphopeptide. The N-terminal domain of symplekin has the ARM or HEAT fold, with seven pairs of antiparallel {alpha}-helices arranged in the shape of an arc. The structure of Ssu72 has some similarity to that of low-molecular-mass phosphotyrosine protein phosphatase, although Ssu72 has a unique active-site landscape as well as extra structural features at the C terminus that are important for interaction with symplekin. Ssu72 is bound to the concave face of symplekin, and engineered mutations in this interface can abolish interactions between the two proteins. The CTD peptide is bound in the active site of Ssu72, with the pSer5-Pro6 peptide bond in the cis configuration, which contrasts with all other known CTD peptide conformations. Although the active site of Ssu72 is about 25 {angstrom} from the interface with symplekin, we found that the symplekin N-terminal domain stimulates Ssu72 CTD phosphatase activity in vitro. Furthermore, the N-terminal domain of symplekin inhibits polyadenylation in vitro, but only when coupled to transcription. Because catalytically active Ssu72 overcomes this inhibition, our results show a role for mammalian Ssu72 in transcription-coupled pre-mRNA 3'-end processing.

  12. Protein kinases responsible for the phosphorylation of the nuclear egress core complex of human cytomegalovirus.

    Science.gov (United States)

    Sonntag, Eric; Milbradt, Jens; Svrlanska, Adriana; Strojan, Hanife; Häge, Sigrun; Kraut, Alexandra; Hesse, Anne-Marie; Amin, Bushra; Sonnewald, Uwe; Couté, Yohann; Marschall, Manfred

    2017-10-01

    Nuclear egress of herpesvirus capsids is mediated by a multi-component nuclear egress complex (NEC) assembled by a heterodimer of two essential viral core egress proteins. In the case of human cytomegalovirus (HCMV), this core NEC is defined by the interaction between the membrane-anchored pUL50 and its nuclear cofactor, pUL53. NEC protein phosphorylation is considered to be an important regulatory step, so this study focused on the respective role of viral and cellular protein kinases. Multiply phosphorylated pUL50 varieties were detected by Western blot and Phos-tag analyses as resulting from both viral and cellular kinase activities. In vitro kinase analyses demonstrated that pUL50 is a substrate of both PKCα and CDK1, while pUL53 can also be moderately phosphorylated by CDK1. The use of kinase inhibitors further illustrated the importance of distinct kinases for core NEC phosphorylation. Importantly, mass spectrometry-based proteomic analyses identified five major and nine minor sites of pUL50 phosphorylation. The functional relevance of core NEC phosphorylation was confirmed by various experimental settings, including kinase knock-down/knock-out and confocal imaging, in which it was found that (i) HCMV core NEC proteins are not phosphorylated solely by viral pUL97, but also by cellular kinases; (ii) both PKC and CDK1 phosphorylation are detectable for pUL50; (iii) no impact of PKC phosphorylation on NEC functionality has been identified so far; (iv) nonetheless, CDK1-specific phosphorylation appears to be required for functional core NEC interaction. In summary, our findings provide the first evidence that the HCMV core NEC is phosphorylated by cellular kinases, and that the complex pattern of NEC phosphorylation has functional relevance.

  13. Melarsoprol cyclodextrin inclusion complexes as promising oral candidates for the treatment of human African trypanosomiasis.

    Directory of Open Access Journals (Sweden)

    Jean Rodgers

    2011-09-01

    Full Text Available Human African trypanosomiasis (HAT, or sleeping sickness, results from infection with the protozoan parasites Trypanosoma brucei (T. b. gambiense or T. b. rhodesiense and is invariably fatal if untreated. There are 60 million people at risk from the disease throughout sub-Saharan Africa. The infection progresses from the haemolymphatic stage where parasites invade the blood, lymphatics and peripheral organs, to the late encephalitic stage where they enter the central nervous system (CNS to cause serious neurological disease. The trivalent arsenical drug melarsoprol (Arsobal is the only currently available treatment for CNS-stage T. b. rhodesiense infection. However, it must be administered intravenously due to the presence of propylene glycol solvent and is associated with numerous adverse reactions. A severe post-treatment reactive encephalopathy occurs in about 10% of treated patients, half of whom die. Thus melarsoprol kills 5% of all patients receiving it. Cyclodextrins have been used to improve the solubility and reduce the toxicity of a wide variety of drugs. We therefore investigated two melarsoprol cyclodextrin inclusion complexes; melarsoprol hydroxypropyl-β-cyclodextrin and melarsoprol randomly-methylated-β-cyclodextrin. We found that these compounds retain trypanocidal properties in vitro and cure CNS-stage murine infections when delivered orally, once per day for 7-days, at a dosage of 0.05 mmol/kg. No overt signs of toxicity were detected. Parasite load within the brain was rapidly reduced following treatment onset and magnetic resonance imaging showed restoration of normal blood-brain barrier integrity on completion of chemotherapy. These findings strongly suggest that complexed melarsoprol could be employed as an oral treatment for CNS-stage HAT, delivering considerable improvements over current parenteral chemotherapy.

  14. A third component of the human cytomegalovirus terminase complex is involved in letermovir resistance.

    Science.gov (United States)

    Chou, Sunwen

    2017-12-01

    Letermovir is a human cytomegalovirus (CMV) terminase inhibitor that was clinically effective in a Phase III prevention trial. In vitro studies have shown that viral mutations conferring letermovir resistance map primarily to the UL56 component of the terminase complex and uncommonly to UL89. After serial culture of a baseline CMV laboratory strain under letermovir, mutation was observed in a third terminase component in 2 experiments, both resulting in amino acid substitution P91S in gene UL51 and adding to a pre-existing UL56 mutation. Recombinant phenotyping indicated that P91S alone conferred 2.1-fold increased letermovir resistance (EC50) over baseline, and when combined with UL56 mutation S229F or R369M, multiplied the level of resistance conferred by those mutations by 3.5-7.7-fold. Similarly a combination of UL56 mutations S229F, L254F and L257I selected in the same experiment conferred 54-fold increased letermovir EC50 over baseline, but 290-fold when combined with UL51 P91S. The P91S mutant was not perceptibly growth impaired. Although pUL51 is essential for normal function of the terminase complex, its biological significance is not well understood. Letermovir resistance mutations mapping to 3 separate genes, and their multiplier effect on the level of resistance, suggest that the terminase components interactively contribute to the structure of a letermovir antiviral target. The diagnostic importance of the UL51 P91S mutation arises from its potential to augment the letermovir resistance of some UL56 mutations at low fitness cost. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Negative regulation of retrovirus expression in embryonal carcinoma cells mediated by an intragenic domain.

    Science.gov (United States)

    Loh, T P; Sievert, L L; Scott, R W

    1988-11-01

    An intragenic region spanning the tRNA primer binding site of a Moloney murine leukemia virus recombinant retrovirus was found to restrict expression specifically in embryonal carcinoma (EC) cells. When the inhibitory domain was present, the levels of steady-state RNA synthesized from integrated recombinant templates in stable cotransformation assays were reduced 20-fold in EC cells but not in C2 myoblast cells. Transient-cotransfection assays showed that repression of a template containing the EC-specific inhibitory component was relieved by an excess of specific competitor DNA. In addition, repression mediated by the inhibitory component was orientation independent. This evidence demonstrates the presence of a saturable, trans-acting negative regulatory factor(s) in EC cells and suggests that the interaction of the factor(s) with the intragenic inhibitory component occurs at the DNA level.

  16. Detection of porcine endogenous retrovirus (PERV) using highly specific antisera against Gag and Env

    International Nuclear Information System (INIS)

    Fischer, Nicole; Krach, Ulrich; Niebert, Marcus; Toenjes, Ralf R.

    2003-01-01

    Porcine endogenous retroviruses (PERV) are considered an obstacle to the safe use of cells, tissues, and organs from pigs in the course of xenotransplantation. Thus, the detection of viral proteins and of a potential PERV infection is of major interest. Recently, we have published the generation of a highly specific antiserum directed against the nucleocapsid (p10) of PERV (Xenotransplantation 7 (2000), 221). Here we present new peptide-antisera specific to the capsid protein (p30) and the surface molecule of PERV class B (SU, gp70(B)) as well as the transmembrane moiety of the envelope protein (TM, p15E) of PERV which showed functionality in several immunological assays, such as immunoblots, immunofluorescence, and immunogold staining. Thus, these antisera can be used as tools for the identification of viral proteins in basic research as well as clinical trials

  17. LTRs of Endogenous Retroviruses as a Source of Tbx6 Binding Sites.

    Science.gov (United States)

    Yasuhiko, Yukuto; Hirabayashi, Yoko; Ono, Ryuichi

    2017-01-01

    Retrotransposons are abundant in mammalian genomes and can modulate the gene expression of surrounding genes by disrupting endogenous binding sites for transcription factors (TFs) or providing novel TFs binding sites within retrotransposon sequences. Here, we show that a (C/T)CACACCT sequence motif in ORR1A, ORR1B, ORR1C, and ORR1D, Long Terminal Repeats (LTRs) of MaLR endogenous retrovirus (ERV), is the direct target of Tbx6, an evolutionary conserved family of T-box TFs. Moreover, by comparing gene expression between control mice (Tbx6 +/-) and Tbx6-deficient mice (Tbx6 -/-), we demonstrate that at least four genes, Twist2, Pitx2, Oscp1 , and Nfxl1 , are down-regulated with Tbx6 deficiency. These results suggest that ORR1A, ORR1B, ORR1C and ORR1D may contribute to the evolution of mammalian embryogenesis.

  18. Effects of spectral complexity and sound duration on automatic complex-sound pitch processing in humans - a mismatch negativity study.

    Science.gov (United States)

    Tervaniemi, M; Schröger, E; Saher, M; Näätänen, R

    2000-08-18

    The pitch of a spectrally rich sound is known to be more easily perceived than that of a sinusoidal tone. The present study compared the importance of spectral complexity and sound duration in facilitated pitch discrimination. The mismatch negativity (MMN), which reflects automatic neural discrimination, was recorded to a 2. 5% pitch change in pure tones with only one sinusoidal frequency component (500 Hz) and in spectrally rich tones with three (500-1500 Hz) and five (500-2500 Hz) harmonic partials. During the recordings, subjects concentrated on watching a silent movie. In separate blocks, stimuli were of 100 and 250 ms in duration. The MMN amplitude was enhanced with both spectrally rich sounds when compared with pure tones. The prolonged sound duration did not significantly enhance the MMN. This suggests that increased spectral rather than temporal information facilitates pitch processing of spectrally rich sounds.

  19. Use of avidin-biotin-peroxidase complex for measurement of UV lesions in human DNA by microELISA

    Energy Technology Data Exchange (ETDEWEB)

    Leipold, B [Technischen Universitaet Muenchen (Germany, F.R.). Dermatologische Klinik; Remy, W [Max-Planck-Institut fuer Biochemie, Muenchen (Germany, F.R.)

    1984-02-10

    The avidin/biotin system was introduced into the standard enzyme-linked immunosorbent assay (ELISA) to increase its sensitivity for detecting UV lesions in human DNA. Goat anti-rabbit IgG-peroxidase used in the standard ELISA as second antibody was replaced by biotinylated goat anti-rabbit IgG plus the avidin-biotin-peroxidase complex (ABC) reagent. Sensitivity of detection of plate-fixed UV-DNA-antibody complexes was increased about 8-fold and photolesions in human DNA samples irradiated with as low a dose as 1 J/m/sup 2/ UVC or a suberythermal dose of UVB light could be detected.

  20. Retrovirus endógenos humanos: Significado biológico e implicaciones evolutivas

    Directory of Open Access Journals (Sweden)

    Sentís, Carlos

    2002-05-01

    Full Text Available El genoma humano contiene un importante número de retrovirus endógenos (HERVs, es decir, secuencias derivadas de pasadas infecciones retrovirales insertadas de forma permanente; y secuencias similares se pueden observar en prácticamente todos los organismos eucariontes. Muchos de estos HERVs se transcriben y traducen en condiciones fisiológicas normales, llegando a formar partículas virales completas, y participando en procesos tan complejos como la placentación. Por su capacidad de retrotransposición y recombinación entre ellos son una fuente importante de remodelación genómica y, junto con otros retroelementos, participan en la generación de retrogenes y retropseudogenes, que suponen un sustrato de variabilidad informacional fundamental para la aparición de nuevas estructuras y funciones. Puesto que su actividad responde también a las condiciones ambientales, los cambios genómicos generados por ellos no son graduales, sino que aparecen en oleadas, de modo que se puede producir una variedad fenotípica muy extensa en momentos evolutivos concretos, coincidiendo con situaciones ambientales críticas. La consideración de los HERVs como parte integral y consustancial de nuestro genoma obliga a replantearse la utilización de vectores retrovirales en protocolos de terapia génica, así como la utilización de órganos animales -con sus propios retrovirus endógenos- para xenotrasplantes.

  1. Novel endogenous retrovirus-derived transcript expressed in the bovine placenta is regulated by WNT signaling.

    Science.gov (United States)

    Sakurai, Toshihiro; Nakagawa, So; Bai, Hanako; Bai, Rulan; Kusama, Kazuya; Ideta, Atsushi; Aoyagi, Yoshito; Kaneko, Kazuyuki; Iga, Kosuke; Yasuda, Jiro; Miyazawa, Takayuki; Imakawa, Kazuhiko

    2017-10-10

    Endogenous retroviruses (ERVs) are involved in placentation; perhaps, the most well-known ERV s are the syncytins, actively transcribed env genes involved in cell-cell fusion and possible morphological variations. However, ERVs other than syncytins that play an important role in placental development have not been well characterized. To identify ERV genes expressed during the onset of placentation in the bovine species, we characterized the expression profiles of bovine conceptus transcripts during the peri-attachment period using RNA-seq analysis, and confirming some candidates through real-time PCR. Using in silico and PCR analyses, we identified a novel ERV proviral sequence derived from a gag region, designated bovine endogenous retroviruses (BERV)-K3, containing Gag _p10 and Gag _p24, zinc finger domain. Initial expression of this ERV in bovine conceptuses was on day 20 (day 0 = day of estrus), soon after conceptus attachment to the endometrial epithelium, and its high placental expression was maintained up to the middle of pregnancy. The BERV-K3 transcript was also found in the uterine luminal and glandular epithelia, liver, kidney, intestine, and skin. BERV-K3 is located on chromosome 7 and integrated within LOC100848658 , from which noncoding RNA could be transcribed. Furthermore, the expression of endogenous BERV-K3 in bovine trophoblast cell lines was induced by a WNT agonist, a signaling system common to genes expressed in placentas. These data support the argument that during the evolutionary process, mammals incorporated not only similar ERV sequences, but also ERV s unique to individual species. BERV-K3 is in the latter case, likely providing functions unique to ruminant gestation. © 2017 The Author(s).

  2. Complexity of Complement Resistance Factors Expressed by Acinetobacter baumannii Needed for Survival in Human Serum.

    Science.gov (United States)

    Sanchez-Larrayoz, Amaro F; Elhosseiny, Noha M; Chevrette, Marc G; Fu, Yang; Giunta, Peter; Spallanzani, Raúl G; Ravi, Keerthikka; Pier, Gerald B; Lory, Stephen; Maira-Litrán, Tomás

    2017-10-15

    Acinetobacter baumannii is a bacterial pathogen with increasing impact in healthcare settings, due in part to this organism's resistance to many antimicrobial agents, with pneumonia and bacteremia as the most common manifestations of disease. A significant proportion of clinically relevant A. baumannii strains are resistant to killing by normal human serum (NHS), an observation supported in this study by showing that 12 out of 15 genetically diverse strains of A. baumannii are resistant to NHS killing. To expand our understanding of the genetic basis of A. baumannii serum resistance, a transposon (Tn) sequencing (Tn-seq) approach was used to identify genes contributing to this trait. An ordered Tn library in strain AB5075 with insertions in every nonessential gene was subjected to selection in NHS. We identified 50 genes essential for the survival of A. baumannii in NHS, including already known serum resistance factors, and many novel genes not previously associated with serum resistance. This latter group included the maintenance of lipid asymmetry genetic pathway as a key determinant in protecting A. baumannii from the bactericidal activity of NHS via the alternative complement pathway. Follow-up studies validated the role of eight additional genes identified by Tn-seq in A. baumannii resistance to killing by NHS but not by normal mouse serum, highlighting the human species specificity of A. baumannii serum resistance. The identification of a large number of genes essential for serum resistance in A. baumannii indicates the degree of complexity needed for this phenotype, which might reflect a general pattern that pathogens rely on to cause serious infections. Copyright © 2017 by The American Association of Immunologists, Inc.

  3. Evolving hard problems: Generating human genetics datasets with a complex etiology

    Directory of Open Access Journals (Sweden)

    Himmelstein Daniel S

    2011-07-01

    Full Text Available Abstract Background A goal of human genetics is to discover genetic factors that influence individuals' susceptibility to common diseases. Most common diseases are thought to result from the joint failure of two or more interacting components instead of single component failures. This greatly complicates both the task of selecting informative genetic variants and the task of modeling interactions between them. We and others have previously developed algorithms to detect and model the relationships between these genetic factors and disease. Previously these methods have been evaluated with datasets simulated according to pre-defined genetic models. Results Here we develop and evaluate a model free evolution strategy to generate datasets which display a complex relationship between individual genotype and disease susceptibility. We show that this model free approach is capable of generating a diverse array of datasets with distinct gene-disease relationships for an arbitrary interaction order and sample size. We specifically generate eight-hundred Pareto fronts; one for each independent run of our algorithm. In each run the predictiveness of single genetic variation and pairs of genetic variants have been minimized, while the predictiveness of third, fourth, or fifth-order combinations is maximized. Two hundred runs of the algorithm are further dedicated to creating datasets with predictive four or five order interactions and minimized lower-level effects. Conclusions This method and the resulting datasets will allow the capabilities of novel methods to be tested without pre-specified genetic models. This allows researchers to evaluate which methods will succeed on human genetics problems where the model is not known in advance. We further make freely available to the community the entire Pareto-optimal front of datasets from each run so that novel methods may be rigorously evaluated. These 76,600 datasets are available from http://discovery.dartmouth.edu/model_free_data/.

  4. Structure of Human G Protein-Coupled Receptor Kinase 2 in Complex with the Kinase Inhibitor Balanol

    Energy Technology Data Exchange (ETDEWEB)

    Tesmer, John J.G.; Tesmer, Valerie M.; Lodowski, David T.; Steinhagen, Henning; Huber, Jochen (Sanofi); (Michigan); (Texas)

    2010-07-19

    G protein-coupled receptor kinase 2 (GRK2) is a pharmaceutical target for the treatment of cardiovascular diseases such as congestive heart failure, myocardial infarction, and hypertension. To better understand how nanomolar inhibition and selectivity for GRK2 might be achieved, we have determined crystal structures of human GRK2 in complex with G{beta}{gamma} in the presence and absence of the AGC kinase inhibitor balanol. The selectivity of balanol among human GRKs is assessed.

  5. Complexation of intracellular cyanide by hydroxocobalamin using a human cellular model.

    Science.gov (United States)

    Astier, A; Baud, F J

    1996-01-01

    1. The rational for administering hydroxocobalamin (OHCbl) as an antidote to cyanide poisoning is based on the high affinity of CN ion for cobalt compounds. However, only few data are available on the influence of OHCbl on the intracellular cyanide pool. 2. In human fibroblasts incubated for 10 min with 500 microM of [14C] cyanide, the accumulation ratio was 25 at 37 degrees C (10.45 +/- 1.51 mM) and 11.9 at 4 degrees C. 3. Using the monoblastic U-937 cell line, a rapid uptake of radioactive cyanide was observed with a maximum accumulation ratio of 1.97 at 5 min. 4. A linear relationship between cyanide uptake by U-937 cells and cyanide concentration in incubation medium (10-500 microM; 5 min) was found suggesting a first order process (k = 0.25 min-1). 5. After incubation of fibroblasts with 500 microM of OHCbl, a 75% decrease of intracellular cyanide was observed, with concomittant formation of intracellular cyanocobalamin CNCbl (intracellular/extracellular ratio: 158). 6. These findings suggest that OHCbl is able to penetrate into heavily cyanide loaded cells and to complex cyanide to the non-toxic CNCbl form.

  6. Age and sex effects on human mutation rates. An old problem with new complexities

    International Nuclear Information System (INIS)

    Crow, James F.

    2006-01-01

    Base substitution mutations are far more common in human males than in females, and the frequency increases with paternal age. Both can be accounted for by the greater number of pre-meiotic cell divisions in males, especially old ones. In contrast, small deletions do not show any important age effect and occur with approximately equal frequency in the two sexes. Mutations in most genes include both types, and the sex and paternal age effect depends on the proportion of the two types. A few traits, of which Apert Syndrome is best understood, are mutation hot spots with all the mutations occurring in one or two codons, usually at one nucleotide. They occur with very high frequency almost exclusively in males and the frequency increases rapidly with paternal age. It has been suggested that the mutant cells have a selective advantage in the male germ-line prior to meiosis. Evidence for this surprising, but important, hypothesis is discussed. A possible mechanism is the conversion of asymmetrical stem-cell divisions into symmetric ones. Some traits with complex etiology show a slight paternal age effect. There is also a short discussion of the high deleterious mutation rate and the role of sexual reproduction in reducing the consequent mutation load. (author)

  7. Biomolecular identification of ancient Mycobacterium tuberculosis complex DNA in human remains from Britain and continental Europe.

    Science.gov (United States)

    Müller, Romy; Roberts, Charlotte A; Brown, Terence A

    2014-02-01

    Tuberculosis is known to have afflicted humans throughout history and re-emerged towards the end of the 20th century, to an extent that it was declared a global emergency in 1993. The aim of this study was to apply a rigorous analytical regime to the detection of Mycobacterium tuberculosis complex (MTBC) DNA in 77 bone and tooth samples from 70 individuals from Britain and continental Europe, spanning the 1st-19th centuries AD. We performed the work in dedicated ancient DNA facilities designed to prevent all types of modern contamination, we checked the authenticity of all products obtained by the polymerase chain reaction, and we based our conclusions on up to four replicate experiments for each sample, some carried out in an independent laboratory. We identified 12 samples that, according to our strict criteria, gave definite evidence for the presence of MTBC DNA, and another 22 that we classified as "probable" or "possible." None of the definite samples came from vertebrae displaying lesions associated with TB. Instead, eight were from ribs displaying visceral new bone formation, one was a tooth from a skeleton with rib lesions, one was taken from a skeleton with endocranial lesions, one from an individual with lesions to the sacrum and sacroiliac joint and the last was from an individual with no lesions indicative of TB or possible TB. Our results add to information on the past temporal and geographical distribution of TB and affirm the suitability of ribs for studying ancient TB. Copyright © 2013 Wiley Periodicals, Inc.

  8. Crystal structure analysis of human serum albumin complexed with sodium 4-phenylbutyrate.

    Science.gov (United States)

    Kawai, Akito; Yamasaki, Keishi; Enokida, Taisuke; Miyamoto, Shuichi; Otagiri, Masaki

    2018-03-01

    Sodium 4-phenylbutyrate (PB) is an orphan drug for the treatment of urea cycle disorders. It also inhibits the development of endoplasmic reticulum stress, the action of histone deacetylases and as a regulator of the hepatocanalicular transporter. PB is generally considered to have the potential for use in the treatment of the diseases such as cancer, neurodegenerative diseases and metabolic diseases. In a previous study, we reported that PB is primarily bound to human serum albumin (HSA) in plasma and its binding site is drug site 2. However, details of the binding mode of PB to HSA remain unknown. To address this issue, we examined the crystal structure of HSA with PB bound to it. The structure of the HSA-PB complex indicates that the binding mode of PB to HSA is quite similar to that for octanoate or drugs that bind to drug site 2, as opposed to that for other medium-chain length of fatty acids. These findings provide useful basic information related to drug-HSA interactions. Moreover, the information presented herein is valuable in terms of providing safe and efficient treatment and diagnosis in clinical settings.

  9. Non-canonical TAF complexes regulate active promoters in human embryonic stem cells.

    Science.gov (United States)

    Maston, Glenn A; Zhu, Lihua Julie; Chamberlain, Lynn; Lin, Ling; Fang, Minggang; Green, Michael R

    2012-11-13

    The general transcription factor TFIID comprises the TATA-box-binding protein (TBP) and approximately 14 TBP-associated factors (TAFs). Here we find, unexpectedly, that undifferentiated human embryonic stem cells (hESCs) contain only six TAFs (TAFs 2, 3, 5, 6, 7 and 11), whereas following differentiation all TAFs are expressed. Directed and global chromatin immunoprecipitation analyses reveal an unprecedented promoter occupancy pattern: most active genes are bound by only TAFs 3 and 5 along with TBP, whereas the remaining active genes are bound by TBP and all six hESC TAFs. Consistent with these results, hESCs contain a previously undescribed complex comprising TAFs 2, 6, 7, 11 and TBP. Altering the composition of hESC TAFs, either by depleting TAFs that are present or ectopically expressing TAFs that are absent, results in misregulated expression of pluripotency genes and induction of differentiation. Thus, the selective expression and use of TAFs underlies the ability of hESCs to self-renew.DOI:http://dx.doi.org/10.7554/eLife.00068.001.

  10. Protein chimerism: novel source of protein diversity in humans adds complexity to bottom-up proteomics.

    Science.gov (United States)

    Casado-Vela, Juan; Lacal, Juan Carlos; Elortza, Felix

    2013-01-01

    Three main molecular mechanisms are considered to contribute expanding the repertoire and diversity of proteins present in living organisms: first, at DNA level (gene polymorphisms and single nucleotide polymorphisms); second, at messenger RNA (pre-mRNA and mRNA) level including alternative splicing (also termed differential splicing or cis-splicing); finally, at the protein level mainly driven through PTM and specific proteolytic cleavages. Chimeric mRNAs constitute an alternative source of protein diversity, which can be generated either by chromosomal translocations or by trans-splicing events. The occurrence of chimeric mRNAs and proteins is a frequent event in cells from the immune system and cancer cells, mainly as a consequence of gene rearrangements. Recent reports support that chimeric proteins may also be expressed at low levels under normal physiological circumstances, thus, representing a novel source of protein diversity. Notably, recent publications demonstrate that chimeric protein products can be successfully identified through bottom-up proteomic analyses. Several questions remain unsolved, such as the physiological role and impact of such chimeric proteins or the potential occurrence of chimeric proteins in higher eukaryotic organisms different from humans. The occurrence of chimeric proteins certainly seems to be another unforeseen source of complexity for the proteome. It may be a process to take in mind not only when performing bottom-up proteomic analyses in cancer studies but also in general bottom-up proteomics experiments. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. The role of Mycobacterium avium complex fibronectin attachment protein in adherence to the human respiratory mucosa.

    Science.gov (United States)

    Middleton, A M; Chadwick, M V; Nicholson, A G; Dewar, A; Groger, R K; Brown, E J; Wilson, R

    2000-10-01

    Mycobacterium avium complex (MAC) are opportunistic respiratory pathogens that infect non-immunocompromised patients with established lung disease, although they can also cause primary infections. The ability to bind fibronectin is conserved among many mycobacterial species. We have investigated the adherence of a sputum isolate of MAC to the mucosa of organ cultures constructed with human tissue and the contribution of M. avium fibronectin attachment protein (FAP) to the process. MAC adhered to fibrous, but not globular mucus, and to extracellular matrix (ECM) in areas of epithelial damage, but not to intact extruded cells and collagen fibres. Bacteria occasionally adhered to healthy unciliated epithelium and to cells that had degenerated exposing their contents, but never to ciliated cells. The results obtained with different respiratory tissues were similar. Two ATCC strains of MAC gave similar results. There was a significant reduction (P fibrous mucus was unchanged. Immunogold labelling demonstrated fibronectin in ECM as well as in other areas of epithelial damage, but only ECM bound FAP. A Mycobacterium smegmatis strain had the same pattern of adherence to the mucosa as MAC. When the FAP gene was deleted, the strain demonstrated reduced adherence to ECM, and adherence was restored when the strain was transfected with an M. avium FAP expression construct. We conclude that MAC adheres to ECM in areas of epithelial damage via FAP and to mucus with a fibrous appearance via another adhesin. Epithelial damage exposing ECM and poor mucus clearance will predispose to MAC airway infection.

  12. Proteomic identification of dysferlin-interacting protein complexes in human vascular endothelium

    International Nuclear Information System (INIS)

    Leung, Cleo; Utokaparch, Soraya; Sharma, Arpeeta; Yu, Carol; Abraham, Thomas; Borchers, Christoph; Bernatchez, Pascal

    2011-01-01

    Highlights: ► Bi-directional (inward and outward) movement of GFP-dysferlin in COS-7 cells. ► Dysferlin interacts with key signaling proteins for transcytosis in EC. ► Dysferlin mediates trafficking of vesicles carrying protein cargos in EC. -- Abstract: Dysferlin is a membrane-anchored protein known to facilitate membrane repair in skeletal muscles following mechanical injury. Mutations of dysferlin gene impair sarcolemma integrity, a hallmark of certain forms of muscular dystrophy in patients. Dysferlin contains seven calcium-dependent C2 binding domains, which are required to promote fusion of intracellular membrane vesicles. Emerging evidence reveal the unexpected expression of dysferlin in non-muscle, non-mechanically active tissues, such as endothelial cells, which cast doubts over the belief that ferlin proteins act exclusively as membrane repair proteins. We and others have shown that deficient trafficking of membrane bound proteins in dysferlin-deficient cells, suggesting that dysferlin might mediate trafficking of client proteins. Herein, we describe the intracellular trafficking and movement of GFP-dysferlin positive vesicles in unfixed reconstituted cells using live microscopy. By performing GST pull-down assays followed by mass spectrometry, we identified dysferlin binding protein complexes in human vascular endothelial cells. Together, our data further support the claims that dysferlin not only mediates membrane repair but also trafficking of client proteins, ultimately, help bridging dysferlinopathies to aberrant membrane signaling.

  13. Proteomic identification of dysferlin-interacting protein complexes in human vascular endothelium

    Energy Technology Data Exchange (ETDEWEB)

    Leung, Cleo; Utokaparch, Soraya; Sharma, Arpeeta; Yu, Carol; Abraham, Thomas; Borchers, Christoph [UBC James Hogg Research Centre, Institute for Heart and Lung Health, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia (Canada); University of Victoria - Genome BC Proteomics Centre, University of Victoria, Victoria, British Columbia (Canada); Bernatchez, Pascal, E-mail: pbernatc@mail.ubc.ca [UBC James Hogg Research Centre, Institute for Heart and Lung Health, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia (Canada); University of Victoria - Genome BC Proteomics Centre, University of Victoria, Victoria, British Columbia (Canada)

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer Bi-directional (inward and outward) movement of GFP-dysferlin in COS-7 cells. Black-Right-Pointing-Pointer Dysferlin interacts with key signaling proteins for transcytosis in EC. Black-Right-Pointing-Pointer Dysferlin mediates trafficking of vesicles carrying protein cargos in EC. -- Abstract: Dysferlin is a membrane-anchored protein known to facilitate membrane repair in skeletal muscles following mechanical injury. Mutations of dysferlin gene impair sarcolemma integrity, a hallmark of certain forms of muscular dystrophy in patients. Dysferlin contains seven calcium-dependent C2 binding domains, which are required to promote fusion of intracellular membrane vesicles. Emerging evidence reveal the unexpected expression of dysferlin in non-muscle, non-mechanically active tissues, such as endothelial cells, which cast doubts over the belief that ferlin proteins act exclusively as membrane repair proteins. We and others have shown that deficient trafficking of membrane bound proteins in dysferlin-deficient cells, suggesting that dysferlin might mediate trafficking of client proteins. Herein, we describe the intracellular trafficking and movement of GFP-dysferlin positive vesicles in unfixed reconstituted cells using live microscopy. By performing GST pull-down assays followed by mass spectrometry, we identified dysferlin binding protein complexes in human vascular endothelial cells. Together, our data further support the claims that dysferlin not only mediates membrane repair but also trafficking of client proteins, ultimately, help bridging dysferlinopathies to aberrant membrane signaling.

  14. Complexity of mechanisms among human proprotein convertase subtilisin-kexin type 9 variants.

    Science.gov (United States)

    Dron, Jacqueline S; Hegele, Robert A

    2017-04-01

    There are many reports of human variants in proprotein convertase subtilisin-kexin type 9 (PCSK9) that are either gain-of-function (GOF) or loss-of-function (LOF), with downstream effects on LDL cholesterol and cardiovascular disease (CVD) risk. However, data on particular mechanisms have only been minimally curated. GOF variants are individually ultrarare, affect all domains of the protein, act to reduce LDL receptor expression through several mechanisms, are a minor cause of familial hypercholesterolemia, have been reported mainly within families, have variable LDL cholesterol-raising effects, and are associated with increased CVD risk mainly through observational studies in families and small cohorts. In contrast, LOF variants can be either ultrarare mutations or relatively more common polymorphisms seen in populations, affect all domains of the protein, act to increase LDL receptor expression through several mechanisms, have variable LDL cholesterol-lowering effects, and have been associated with decreased CVD risk mainly through Mendelian randomization studies in epidemiologic populations. There is considerable complexity underlying the clinical concept of both LOF and GOF variants of PCSK9. But despite the underlying mechanistic heterogeneity, altered PCSK9 secretion or function is ultimately correlated with plasma LDL cholesterol level, which is also the driver of CVD outcomes.

  15. Structure of a retro-binding peptide inhibitor complexed with human alpha-thrombin.

    Science.gov (United States)

    Tabernero, L; Chang, C Y; Ohringer, S L; Lau, W F; Iwanowicz, E J; Han, W C; Wang, T C; Seiler, S M; Roberts, D G; Sack, J S

    1995-02-10

    The crystallographic structure of the ternary complex between human alpha-thrombin, hirugen and the peptidyl inhibitor Phe-alloThr-Phe-O-CH3, which is acylated at its N terminus with 4-guanidino butanoic acid (BMS-183507), has been determined at 2.6 A resolution. The structure reveals a unique "retro-binding" mode for this tripeptide active site inhibitor. The inhibitor binds with its alkyl-guanidine moiety in the primary specificity pocket and its two phenyl rings occupying the hydrophobic proximal and distal pockets of the thrombin active site. In this arrangement the backbone of the tripeptide forms a parallel beta-strand to the thrombin main-chain at the binding site. This is opposite to the orientation of the natural substrate, fibrinogen, and all the small active site-directed thrombin inhibitors whose bound structures have been previously reported. BMS-183507 is the first synthetic inhibitor proved to bind in a retro-binding fashion to thrombin, in a fashion similar to that of the N-terminal residues of the natural inhibitor hirudin. Furthermore, this new potent thrombin inhibitor (Ki = 17.2 nM) is selective for thrombin over other serine proteases tested and may be a template to be considered in designing hirudin-based thrombin inhibitors with interactions at the specificity pocket.

  16. Dorso-medial and ventro-lateral functional specialization of the human retrosplenial complex in spatial updating and orienting.

    Science.gov (United States)

    Burles, Ford; Slone, Edward; Iaria, Giuseppe

    2017-04-01

    The retrosplenial complex is a region within the posterior cingulate cortex implicated in spatial navigation. Here, we investigated the functional specialization of this large and anatomically heterogeneous region using fMRI and resting-state functional connectivity combined with a spatial task with distinct phases of spatial 'updating' (i.e., integrating and maintaining object locations in memory during spatial displacement) and 'orienting' (i.e., recalling unseen locations from current position in space). Both spatial 'updating' and 'orienting' produced bilateral activity in the retrosplenial complex, among other areas. However, spatial 'updating' produced slightly greater activity in ventro-lateral portions, of the retrosplenial complex, whereas spatial 'orienting' produced greater activity in a more dorsal and medial portion of it (both regions localized along the parieto-occipital fissure). At rest, both ventro-lateral and dorso-medial subregions of the retrosplenial complex were functionally connected to the hippocampus and parahippocampus, regions both involved in spatial orientation and navigation. However, the ventro-lateral subregion of the retrosplenial complex displayed more positive functional connectivity with ventral occipital and temporal object recognition regions, whereas the dorso-medial subregion activity was more correlated to dorsal activity and frontal activity, as well as negatively correlated with more ventral parietal structures. These findings provide evidence for a dorso-medial to ventro-lateral functional specialization within the human retrosplenial complex that may shed more light on the complex neural mechanisms underlying spatial orientation and navigation in humans.

  17. The application of strand invasion phenomenon, directed by peptide nucleic acid (PNA) and single-stranded DNA binding protein (SSB) for the recognition of specific sequences of human endogenous retroviral HERV-W family.

    Science.gov (United States)

    Machnik, Grzegorz; Bułdak, Łukasz; Ruczyński, Jarosław; Gąsior, Tomasz; Huzarska, Małgorzata; Belowski, Dariusz; Alenowicz, Magdalena; Mucha, Piotr; Rekowski, Piotr; Okopień, Bogusław

    2017-05-01

    The HERV-W family of human endogenous retroviruses represents a group of numerous sequences that show close similarity in genetic composition. It has been documented that some members of HERV-W-derived expression products are supposed to play significant role in humans' pathology, such as multiple sclerosis or schizophrenia. Other members of the family are necessary to orchestrate physiological processes (eg, ERVWE1 coding syncytin-1 that is engaged in syncytiotrophoblast formation). Therefore, an assay that would allow the recognition of particular form of HERV-W members is highly desirable. A peptide nucleic acid (PNA)-mediated technique for the discrimination between multiple sclerosis-associated retrovirus and ERVWE1 sequence has been developed. The assay uses a PNA probe that, being fully complementary to the ERVWE1 but not to multiple sclerosis-associated retrovirus (MSRV) template, shows high selective potential. Single-stranded DNA binding protein facilitates the PNA-mediated, sequence-specific formation of strand invasion complex and, consequently, local DNA unwinding. The target DNA may be then excluded from further analysis in any downstream process such as single-stranded DNA-specific exonuclease action. Finally, the reaction conditions have been optimized, and several PNA probes that are targeted toward distinct loci along whole HERV-W env sequences have been evaluated. We believe that PNA/single-stranded DNA binding protein-based application has the potential to selectively discriminate particular HERV-W molecules as they are at least suspected to play pathogenic role in a broad range of medical conditions, from psycho-neurologic disorders (multiple sclerosis and schizophrenia) and cancers (breast cancer) to that of an auto-immunologic background (psoriasis and lupus erythematosus). Copyright © 2016 John Wiley & Sons, Ltd.

  18. Flow cytometric assay detecting cytotoxicity against human endogenous retrovirus antigens expressed on cultured multiple sclerosis cells

    DEFF Research Database (Denmark)

    Møller-Larsen, A; Brudek, T; Petersen, T

    2013-01-01

    on their surface. Polyclonal antibodies against defined peptides in the Env- and Gag-regions of the HERVs were raised in rabbits and used in antibody-dependent cell-mediated cytotoxicity (ADCC) -assays. Rituximab® (Roche), a chimeric monoclonal antibody against CD20 expressed primarily on B cells, was used...

  19. Infection with koala retrovirus subgroup B (KoRV-B), but not KoRV-A, is associated with chlamydial disease in free-ranging koalas (Phascolarctos cinereus)

    OpenAIRE

    Waugh, Courtney A.; Hanger, Jonathan; Loader, Joanne; King, Andrew; Hobbs, Matthew; Johnson, Rebecca; Timms, Peter

    2017-01-01

    The virulence of chlamydial infection in wild koalas is highly variable between individuals. Some koalas can be infected (PCR positive) with Chlamydia for long periods but remain asymptomatic, whereas others develop clinical disease. Chlamydia in the koala has traditionally been studied without regard to coinfection with other pathogens, although koalas are usually subject to infection with koala retrovirus (KoRV). Retroviruses can be immunosuppressive, and there is evidence of an immunosuppr...

  20. Biophysical study on the interaction between two palladium(II) complexes and human serum albumin by Multispectroscopic methods

    Energy Technology Data Exchange (ETDEWEB)

    Saeidifar, Maryam, E-mail: saeidifar@merc.ac.ir [Department of Nanotechnology and Advanced Materials, Materials and Energy Research Center, Karaj (Iran, Islamic Republic of); Mansouri-Torshizi, Hassan [Department of Chemistry, University of Sistan and Baluchestan, Zahedan (Iran, Islamic Republic of); Akbar Saboury, Ali [Institute of Biochemistry and Biophysics, University of Tehran, Tehran (Iran, Islamic Republic of)

    2015-11-15

    The interaction of [Pd(bpy)(n-pr-dtc)]Br (I) and ([Pd(phen)(n-pr-dtc)]Br (II) (bpy=2,2′-bipyridine, phen=1,10-phenanthroline and n-pr-dtc=n-propyldithiocarbamate) with human serum albumin (HSA) was investigated using fluorescence, UV–vis absorption and circular dichroism (CD) spectroscopy techniques under simulative physiological conditions (pH=7.4). It was observed that the two complexes interact with HSA via static fluorescence quenching. The thermodynamic parameters indicate that the binding process was spontaneous and that hydrogen bonds and van der Waals forces play a major role in the association of the HSA–Pd(II) complexes. The activation energy (E{sub a}), binding constant (K{sub b}) and number of binding sites (n) of the HSA–Pd(II) complexes were calculated from fluorescence data at 293 K, 303 K and 311 K. The conformational alternations of protein secondary structure in the presence of Pd(II) complexes were demonstrated using synchronous fluorescence, three-dimensional fluorescence spectra, UV–vis absorption and circular dichroism techniques. Furthermore, the apparent distance between donor (HSA) and acceptor (Pd(II) complexes) was determined using fluorescence resonance energy transfer (FRET). The binding studies between these complexes and HSA give us key insights into the transportation, distribution and toxicity of newly design antitumor Pd(II) complexes in human blood. - Highlights: • The HSA binding properties of two Palladium (II) complexes were studied. • Static quenching mechanism is effective in the interaction of HSA with Pd(II) complexes. • Hydrogen bonds and van der Waals forces were involved in the Pd(II) complexes–HSA interaction. • 3D fluorescence was used to study the interaction between two complexes and HSA.

  1. Immunohistochemical Mapping of Sensory Nerve Endings in the Human Triangular Fibrocartilage Complex.

    Science.gov (United States)

    Rein, Susanne; Semisch, Manuel; Garcia-Elias, Marc; Lluch, Alex; Zwipp, Hans; Hagert, Elisabet

    2015-10-01

    The triangular fibrocartilage complex is the main stabilizer of the distal radioulnar joint. While static joint stability is constituted by osseous and ligamentous integrity, the dynamic aspects of joint stability chiefly concern proprioceptive control of the compressive and directional muscular forces acting on the joint. Therefore, an investigation of the pattern and types of sensory nerve endings gives more insight in dynamic distal radioulnar joint stability. We aimed to (1) analyze the general distribution of sensory nerve endings and blood vessels; (2) examine interstructural distribution of sensory nerve endings and blood vessels; (3) compare the number and types of mechanoreceptors in each part; and (4) analyze intrastructural distribution of nerve endings at different tissue depth. The subsheath of the extensor carpi ulnaris tendon sheath, the ulnocarpal meniscoid, the articular disc, the dorsal and volar radioulnar ligaments, and the ulnolunate and ulnotriquetral ligaments were dissected from 11 human cadaver wrists. Sensory nerve endings were counted in five levels per specimen as total cell amount/cm(2) after staining with low-affinity neurotrophin receptor p75, protein gene product 9.5, and S-100 protein and thereafter classified according to Freeman and Wyke. All types of sensory corpuscles were found in the various structures of the triangular fibrocartilage complex with the exception of the ulnolunate ligament, which contained only Golgi-like endings, free nerve endings, and unclassifiable corpuscles. The articular disc had only free nerve endings. Furthermore, free nerve endings were the predominant sensory nerve ending (median, 72.6/cm(2); range, 0-469.4/cm(2)) and more prevalent than all other types of mechanoreceptors: Ruffini (median, 0; range, 0-5.6/cm(2); difference of medians, 72.6; p fibrocartilage complex (p ≤ 0.001, respectively) except the ulnolunate ligament. More blood vessels were seen in the volar radioulnar ligament (median, 363

  2. A DYNAMIC PHYSIOLOGICALLY-BASED TOXICOKINETIC (DPBTK) MODEL FOR SIMULATION OF COMPLEX TOLUENE EXPOSURE SCENARIOS IN HUMANS

    Science.gov (United States)

    A GENERAL PHYSIOLOGICAL AND TOXICOKINETIC (GPAT) MODEL FOR SIMULATION OF COMPLEX TOLUENE EXPOSURE SCENARIOS IN HUMANS. E M Kenyon1, T Colemen2, C R Eklund1 and V A Benignus3. 1U.S. EPA, ORD, NHEERL, ETD, PKB, RTP, NC, USA; 2Biological Simulators, Inc., Jackson MS, USA, 3U.S. EP...

  3. Comparison of the convergent receptor utilization of a retargeted feline leukemia virus envelope with a naturally-occurring porcine endogenous retrovirus A.

    Science.gov (United States)

    Mazari, Peter M; Argaw, Takele; Valdivieso, Leonardo; Zhang, Xia; Marcucci, Katherine T; Salomon, Daniel R; Wilson, Carolyn A; Roth, Monica J

    2012-06-05

    In vitro screening of randomized FeLV Envelope libraries identified the CP isolate, which enters cells through HuPAR-1, one of two human receptors utilized by porcine endogenous retrovirus-A (PERV-A), a distantly related gammaretrovirus. The CP and PERV-A Envs however, share little amino acid homology. Their receptor utilization was examined to define the common receptor usage of these disparate viral Envs. We demonstrate that the receptor usage of CP extends to HuPAR-2 but not to the porcine receptor PoPAR, the cognate receptor for PERV-A. Reciprocal interference between virus expressing CP and PERV-A Envs was observed on human cells. Amino acid residues localized to within the putative second extracellular loop (ECL-2) of PAR-1 and PAR-2 are found to be critical for CP envelope function. Through a panel of receptor chimeras and point mutations, this area was also found to be responsible for the differential usage of the PoPAR receptor between CP and PERV-A. Copyright © 2012 Elsevier Inc. All rights reserved.

  4. Human sperm bioassay has potential in evaluating the quality of cumulus-oocyte complexes.

    Science.gov (United States)

    Hossain, A M; Rizk, B; Huff, C; Helvacioglu, A; Thorneycroft, I H

    1996-01-01

    Human sperm bioassay is routinely used as a quality control check for the culture media. This is one of the three bioassays chosen by the College of American Pathologists (CAP) for interlaboratory proficiency testing to assess the standards of in vitro fertilization (IVF) and andrology laboratories. This study utilized sperm bioassay to assess the quality of cumulus-oocyte complexes (COCs) retrieved in IVF procedures COCs, harvested from the female partner of IVF couples, undergoing identical ovarian stimulation protocols, were individually inseminated with the sperm of the corresponding male partner. Sperm motility in sperm-COC cocultures were compared. Cocultures were established by inseminating the 103 COCs, retrieved from 18 IVF couples with 1 x 10(5) to 2 x 10(5) sperm of the corresponding male partners of the couples. In all 18 cases, the sperm were prepared identically using the Percoll wash method. The cocultures were maintained for 48 h but the oocytes were removed immediately after the fertilization check (approximately 16 h). The motility of sperm in the cocultures and in the insemination stocks were noted and 17 of 18 sperm stocks used for insemination had similar high preinsemination motility (90.2 +/- 5.0%). At 48 h the sperm motility had significantly decreased in the cocultures compared to the insemination stocks; 52.7 +/- 19.9% versus 67.2 +/- 10.4%. There was no difference in the motility among the small, medium, and large COCs (56.4 +/- 24.6%, 52.5 +/- 17.9%, and 50.8 +/- 20.9%, respectively). In 45% of IVF cases, the motility in cocultures varied widely, falling below as well as above that of their corresponding insemination stocks. Furthermore, the sperm motility varied among the cocultures in both pregnant and nonpregnant patients but the extent of variation appears to be greater in the latter. The inter-COC coculture sperm motility variation most likely is due to the differences in the quality of cumulus-oocyte complexes.

  5. Complex interactions between human myoblasts and the surrounding 3D fibrin-based matrix.

    Directory of Open Access Journals (Sweden)

    Stéphane Chiron

    Full Text Available Anchorage of muscle cells to the extracellular matrix is crucial for a range of fundamental biological processes including migration, survival and differentiation. Three-dimensional (3D culture has been proposed to provide a more physiological in vitro model of muscle growth and differentiation than routine 2D cultures. However, muscle cell adhesion and cell-matrix interplay of engineered muscle tissue remain to be determined. We have characterized cell-matrix interactions in 3D muscle culture and analyzed their consequences on cell differentiation. Human myoblasts were embedded in a fibrin matrix cast between two posts, cultured until confluence, and then induced to differentiate. Myoblasts in 3D aligned along the longitudinal axis of the gel. They displayed actin stress fibers evenly distributed around the nucleus and a cortical mesh of thin actin filaments. Adhesion sites in 3D were smaller in size than in rigid 2D culture but expression of adhesion site proteins, including α5 integrin and vinculin, was higher in 3D compared with 2D (p<0.05. Myoblasts and myotubes in 3D exhibited thicker and ellipsoid nuclei instead of the thin disk-like shape of the nuclei in 2D (p<0.001. Differentiation kinetics were faster in 3D as demonstrated by higher mRNA concentrations of α-actinin and myosin. More important, the elastic modulus of engineered muscle tissues increased significantly from 3.5 ± 0.8 to 7.4 ± 4.7 kPa during proliferation (p<0.05 and reached 12.2 ± 6.0 kPa during differentiation (p<0.05, thus attesting the increase of matrix stiffness during proliferation and differentiation of the myocytes. In conclusion, we reported modulations of the adhesion complexes, the actin cytoskeleton and nuclear shape in 3D compared with routine 2D muscle culture. These findings point to complex interactions between muscle cells and the surrounding matrix with dynamic regulation of the cell-matrix stiffness.

  6. Issues of human resources management in the enterprises of the machine-building complex of the Tyumen region

    Directory of Open Access Journals (Sweden)

    Lez’er Victoria

    2018-01-01

    Full Text Available This article, the authors have considered theoretical-methodological and practical aspects of human resource management in the process of restructuring enterprises of the machine-building complex of the Tyumen region. Based on the study of the evolution of theories concerning the human factor in the economy, the systematization and generalization of the provisions contained therein, the system of categories in the field of human resource management is substantiated. The basic principles of such management have been identified and supplemented, the tasks facing the enterprise management have been clarified, new tools for human resource management have been proposed, to ensure the completeness, continuity and validity of the decisions made in the field of human resources management in the restructuring of industrial enterprises.

  7. Complex nature of SNP genotype effects on gene expression in primary human leucocytes

    Directory of Open Access Journals (Sweden)

    Dinesen Lotte C

    2009-01-01

    Full Text Available Abstract Background Genome wide association studies have been hugely successful in identifying disease risk variants, yet most variants do not lead to coding changes and how variants influence biological function is usually unknown. Methods We correlated gene expression and genetic variation in untouched primary leucocytes (n = 110 from individuals with celiac disease – a common condition with multiple risk variants identified. We compared our observations with an EBV-transformed HapMap B cell line dataset (n = 90, and performed a meta-analysis to increase power to detect non-tissue specific effects. Results In celiac peripheral blood, 2,315 SNP variants influenced gene expression at 765 different transcripts (cis expression quantitative trait loci, eQTLs. 135 of the detected SNP-probe effects (reflecting 51 unique probes were also detected in a HapMap B cell line published dataset, all with effects in the same allelic direction. Overall gene expression differences within the two datasets predominantly explain the limited overlap in observed cis-eQTLs. Celiac associated risk variants from two regions, containing genes IL18RAP and CCR3, showed significant cis genotype-expression correlations in the peripheral blood but not in the B cell line datasets. We identified 14 genes where a SNP affected the expression of different probes within the same gene, but in opposite allelic directions. By incorporating genetic variation in co-expression analyses, functional relationships between genes can be more significantly detected. Conclusion In conclusion, the complex nature of genotypic effects in human populations makes the use of a relevant tissue, large datasets, and analysis of different exons essential to enable the identification of the function for many genetic risk variants in common diseases.

  8. Differential association of protein subunits with the human RNase MRP and RNase P complexes.

    Science.gov (United States)

    Welting, Tim J M; Kikkert, Bastiaan J; van Venrooij, Walther J; Pruijn, Ger J M

    2006-07-01

    RNase MRP is a eukaryotic endoribonuclease involved in nucleolar and mitochondrial RNA processing events. RNase MRP is a ribonucleoprotein particle, which is structurally related to RNase P, an endoribonuclease involved in pre-tRNA processing. Most of the protein components of RNase MRP have been reported to be associated with RNase P as well. In this study we determined the association of these protein subunits with the human RNase MRP and RNase P particles by glycerol gradient sedimentation and coimmunoprecipitation. In agreement with previous studies, RNase MRP sedimented at 12S and 60-80S. In contrast, only a single major peak was observed for RNase P at 12S. The analysis of individual protein subunits revealed that hPop4 (also known as Rpp29), Rpp21, Rpp20, and Rpp25 only sedimented in 12S fractions, whereas hPop1, Rpp40, Rpp38, and Rpp30 were also found in 60-80S fractions. In agreement with their cosedimentation with RNase P RNA in the 12S peak, coimmunoprecipitation with VSV-epitope-tagged protein subunits revealed that hPop4, Rpp21, and in addition Rpp14 preferentially associate with RNase P. These data show that hPop4, Rpp21, and Rpp14 may not be associated with RNase MRP. Furthermore, Rpp20 and Rpp25 appear to be associated with only a subset of RNase MRP particles, in contrast to hPop1, Rpp40, Rpp38, and Rpp30 (and possibly also hPop5), which are probably associated with all RNase MRP complexes. Our data are consistent with a transient association of Rpp20 and Rpp25 with RNase MRP, which may be inversely correlated to its involvement in pre-rRNA processing.

  9. Complex and changing patterns of natural selection explain the evolution of the human hip.

    Science.gov (United States)

    Grabowski, Mark; Roseman, Charles C

    2015-08-01

    Causal explanations for the dramatic changes that occurred during the evolution of the human hip focus largely on selection for bipedal function and locomotor efficiency. These hypotheses rest on two critical assumptions. The first-that these anatomical changes served functional roles in bipedalism-has been supported in numerous analyses showing how postcranial changes likely affected locomotion. The second-that morphological changes that did play functional roles in bipedalism were the result of selection for that behavior-has not been previously explored and represents a major gap in our understanding of hominin hip evolution. Here we use evolutionary quantitative genetic models to test the hypothesis that strong directional selection on many individual aspects of morphology was responsible for the large differences observed across a sample of fossil hominin hips spanning the Plio-Pleistocene. Our approach uses covariance among traits and the differences between relatively complete fossils to estimate the net selection pressures that drove the major transitions in hominin hip evolution. Our findings show a complex and changing pattern of natural selection drove hominin hip evolution, and that many, but not all, traits hypothesized to play functional roles in bipedalism evolved as a direct result of natural selection. While the rate of evolutionary change for all transitions explored here does not exceed the amount expected if evolution was occurring solely through neutral processes, it was far above rates of evolution for morphological traits in other mammalian groups. Given that stasis is the norm in the mammalian fossil record, our results suggest that large shifts in the adaptive landscape drove hominin evolution. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. The human milk protein-lipid complex HAMLET sensitizes bacterial pathogens to traditional antimicrobial agents.

    Science.gov (United States)

    Marks, Laura R; Clementi, Emily A; Hakansson, Anders P

    2012-01-01

    The fight against antibiotic resistance is one of the most significant challenges to public health of our time. The inevitable development of resistance following the introduction of novel antibiotics has led to an urgent need for the development of new antibacterial drugs with new mechanisms of action that are not susceptible to existing resistance mechanisms. One such compound is HAMLET, a natural complex from human milk that kills Streptococcus pneumoniae (the pneumococcus) using a mechanism different from common antibiotics and is immune to resistance-development. In this study we show that sublethal concentrations of HAMLET potentiate the effect of common antibiotics (penicillins, macrolides, and aminoglycosides) against pneumococci. Using MIC assays and short-time killing assays we dramatically reduced the concentrations of antibiotics needed to kill pneumococci, especially for antibiotic-resistant strains that in the presence of HAMLET fell into the clinically sensitive range. Using a biofilm model in vitro and nasopharyngeal colonization in vivo, a combination of HAMLET and antibiotics completely eradicated both biofilms and colonization in mice of both antibiotic-sensitive and resistant strains, something each agent alone was unable to do. HAMLET-potentiation of antibiotics was partially due to increased accessibility of antibiotics to the bacteria, but relied more on calcium import and kinase activation, the same activation pathway HAMLET uses when killing pneumococci by itself. Finally, the sensitizing effect was not confined to species sensitive to HAMLET. The HAMLET-resistant respiratory species Acinetobacter baumanii and Moraxella catarrhalis were all sensitized to various classes of antibiotics in the presence of HAMLET, activating the same mechanism as in pneumococci. Combined these results suggest the presence of a conserved HAMLET-activated pathway that circumvents antibiotic resistance in bacteria. The ability to activate this pathway may extend

  11. Thin-plate spline analysis of allometry and sexual dimorphism in the human craniofacial complex.

    Science.gov (United States)

    Rosas, Antonio; Bastir, Markus

    2002-03-01

    The relationship between allometry and sexual dimorphism in the human craniofacial complex was analyzed using geometric morphometric methods. Thin-plate splines (TPS) analysis has been applied to investigate the lateral profile of complete adult skulls of known sex. Twenty-nine three-dimensional (3D) craniofacial and mandibular landmark coordinates were recorded from a sample of 52 adult females and 52 adult males of known age and sex. No difference in the influence of size on shape was detected between sexes. Both size and sex had significant influences on shape. As expected, the influence of centroid size on shape (allometry) revealed a shift in the proportions of the neurocranium and the viscerocranium, with a marked allometric variation of the lower face. Adjusted for centroid size, males presented a relatively larger size of the nasopharyngeal space than females. A mean-male TPS transformation revealed a larger piriform aperture, achieved by an increase of the angulation of the nasal bones and a downward rotation of the anterior nasal floor. Male pharynx expansion was also reflected by larger choanae and a more posteriorly inclined basilar part of the occipital clivus. Male muscle attachment sites appeared more pronounced. In contrast, the mean-female TPS transformation was characterized by a relatively small nasal aperture. The occipital clivus inclined anteriorly, and muscle insertion areas became smoothed. Besides these variations, both maxillary and mandibular alveolar regions became prognathic. The sex-specific TPS deformation patterns are hypothesized to be associated with sexual differences in body composition and energetic requirements. Copyright 2002 Wiley-Liss, Inc.

  12. Apoptosis-like death in bacteria induced by HAMLET, a human milk lipid-protein complex.

    Directory of Open Access Journals (Sweden)

    Anders P Hakansson

    Full Text Available BACKGROUND: Apoptosis is the primary means for eliminating unwanted cells in multicellular organisms in order to preserve tissue homeostasis and function. It is characterized by distinct changes in the morphology of the dying cell that are orchestrated by a series of discrete biochemical events. Although there is evidence of primitive forms of programmed cell death also in prokaryotes, no information is available to suggest that prokaryotic death displays mechanistic similarities to the highly regulated programmed death of eukaryotic cells. In this study we compared the characteristics of tumor and bacterial cell death induced by HAMLET, a human milk complex of alpha-lactalbumin and oleic acid. METHODOLOGY/PRINCIPAL FINDINGS: We show that HAMLET-treated bacteria undergo cell death with mechanistic and morphologic similarities to apoptotic death of tumor cells. In Jurkat cells and Streptococcus pneumoniae death was accompanied by apoptosis-like morphology such as cell shrinkage, DNA condensation, and DNA degradation into high molecular weight fragments of similar sizes, detected by field inverse gel electrophoresis. HAMLET was internalized into tumor cells and associated with mitochondria, causing a rapid depolarization of the mitochondrial membrane and bound to and induced depolarization of the pneumococcal membrane with similar kinetic and magnitude as in mitochondria. Membrane depolarization in both systems required calcium transport, and both tumor cells and bacteria were found to require serine protease activity (but not caspase activity to execute cell death. CONCLUSIONS/SIGNIFICANCE: Our results suggest that many of the morphological changes and biochemical responses associated with apoptosis are present in prokaryotes. Identifying the mechanisms of bacterial cell death has the potential to reveal novel targets for future antimicrobial therapy and to further our understanding of core activation mechanisms of cell death in eukaryote cells.

  13. Apoptosis-like death in bacteria induced by HAMLET, a human milk lipid-protein complex.

    Science.gov (United States)

    Hakansson, Anders P; Roche-Hakansson, Hazeline; Mossberg, Ann-Kristin; Svanborg, Catharina

    2011-03-10

    Apoptosis is the primary means for eliminating unwanted cells in multicellular organisms in order to preserve tissue homeostasis and function. It is characterized by distinct changes in the morphology of the dying cell that are orchestrated by a series of discrete biochemical events. Although there is evidence of primitive forms of programmed cell death also in prokaryotes, no information is available to suggest that prokaryotic death displays mechanistic similarities to the highly regulated programmed death of eukaryotic cells. In this study we compared the characteristics of tumor and bacterial cell death induced by HAMLET, a human milk complex of alpha-lactalbumin and oleic acid. We show that HAMLET-treated bacteria undergo cell death with mechanistic and morphologic similarities to apoptotic death of tumor cells. In Jurkat cells and Streptococcus pneumoniae death was accompanied by apoptosis-like morphology such as cell shrinkage, DNA condensation, and DNA degradation into high molecular weight fragments of similar sizes, detected by field inverse gel electrophoresis. HAMLET was internalized into tumor cells and associated with mitochondria, causing a rapid depolarization of the mitochondrial membrane and bound to and induced depolarization of the pneumococcal membrane with similar kinetic and magnitude as in mitochondria. Membrane depolarization in both systems required calcium transport, and both tumor cells and bacteria were found to require serine protease activity (but not caspase activity) to execute cell death. Our results suggest that many of the morphological changes and biochemical responses associated with apoptosis are present in prokaryotes. Identifying the mechanisms of bacterial cell death has the potential to reveal novel targets for future antimicrobial therapy and to further our understanding of core activation mechanisms of cell death in eukaryote cells.

  14. Proviral amplification of the Gypsy endogenous retrovirus of Drosophila melanogaster involves env-independent invasion of the female germline.

    OpenAIRE

    Chalvet, F; Teysset, L; Terzian, C; Prud'homme, N; Santamaria, P; Bucheton, A; Pélisson, A

    1999-01-01

    Gypsy is an infectious endogenous retrovirus of Drosophila melanogaster. The gypsy proviruses replicate very efficiently in the genome of the progeny of females homozygous for permissive alleles of the flamenco gene. This replicative transposition is correlated with derepression of gypsy expression, specifically in the somatic cells of the ovaries of the permissive mothers. The determinism of this amplification was studied further by making chimeric mothers containing different permissive/res...

  15. Experimental study of the occurence and properties of C-type retroviruses in radiation-induced osteosarcomas in mice

    International Nuclear Information System (INIS)

    Erfle, V.

    1981-01-01

    In the radiation induced osteosarcomas of the C 3 Hx101/F 1 -mouse C-type virus particles had been found regularly with a density of 1.16 g/cm 3 , with high molecular RNA, a reverse transcriptase and the murine group-specific antigen p 30. Osteosarcomas of the NMRI-mouse, however, had only p 30 protein and so-called intra-cisternal A-type particles. After 'in vitro' cultivation retroviruses had been liberated from the osteosarcoma cells of the C 3 Hx101/F 1 -mice as well as from the NMRI-mice type C. During the tumour latency period a virus expression of the C-type retroviruses had been found for a certain period in the first month after irradiation of the bone tissue had begun; then followed an antibody-reaction which continued to persist until the 8th month. Another virus expression was observed in the skeleton during the period when the osteosarcomas appeared. This virus expression was accompanied by a decrease in antibodies and a temporary increase of the viral p 30 protein in the serum. The viruses which had been isolated from the radiation induced osteosarcomas showed the properties which are typical for ecotropic C-type retroviruses of mice. After infection of new-born mice these viruses produced fibrosarcomas (C 3 Hx 101/F 1 -mice) or lymphomas and osteomas (NMRI-mice). The results make it obvious that the endogenetic C-type retroviruses participate in the formation of radiation-induced sarcomas in mice. (orig./MG) [de

  16. Assay of mouse-cell clones for retrovirus p30 protein by use of an automated solid-state radioimmunoassay

    International Nuclear Information System (INIS)

    Kennel, S.J.; Tnnant, R.W.

    1979-01-01

    A solid-state radioimmunoassay system has been developed that is useful for automated analysis of samples in microtiter plates. Assays for interspecies and type-specific antigenic determinants of the C-type retrovirus protein, p30, have been used to identify clones of cells producing this protein. This method allows testing of at least 1000 clones a day, making it useful for studies of frequencies of virus protein induction, defective virus production, and formation of recombinant viruses

  17. Toxicity and efficacy of 2',3'-dideoxycytidine in clinical trials of pigtailed macaques infected with simian retrovirus type 2.

    OpenAIRE

    Tsai, C C; Follis, K E; Yarnall, M; Blakley, G A

    1989-01-01

    Four dosing regimens of 2',3'-dideoxycytidine (ddC) were administered intravenously for 10 to 28 days to 18 pigtailed macaques with simian acquired immunodeficiency syndrome. Ten macaques naturally infected with simian acquired immunodeficiency syndrome retrovirus serotype 2 (SRV-2), the etiologic agent of simian acquired immunodeficiency syndrome, received ddC by continuous intravenous infusion or by a daily bolus injection for 10 to 12 days. Another eight macaques that were negative for SRV...

  18. Evidence supporting oral sensitivity to complex carbohydrates independent of sweet taste sensitivity in humans.

    Directory of Open Access Journals (Sweden)

    Julia Y Q Low

    Full Text Available Compared to simple sugars, complex carbohydrates have been assumed invisible to taste. However, two recent studies proposed that there may be a perceivable taste quality elicited by complex carbohydrates independent of sweet taste. There is precedent with behavioural studies demonstrating that rats are very attracted to complex carbohydrates, and that complex carbohydrates are preferred to simple sugars at low concentrations. This suggests that rats may have independent taste sensors for simple sugars and complex carbohydrates. The aim of this paper is to investigate oral sensitivities of two different classes of complex carbohydrates (a soluble digestible and a soluble non-digestible complex carbohydrate, and to compare these to other caloric and non-nutritive sweeteners in addition to the prototypical tastes using two commonly used psychophysical measures. There were strong correlations between the detection thresholds and mean intensity ratings for complex carbohydrates (maltodextrin, oligofructose (r = 0.94, P 0.05. However, moderate correlations were observed between perceived intensities of complex carbohydrates and sweeteners (r = 0.48-0.61, P < 0.05. These data provide evidence that complex carbohydrates can be sensed in the oral cavity over a range of concentrations independent of sweet taste sensitivity at low concentrations, but with partial overlap with sweet taste intensity at higher concentrations.

  19. The endogenous langur type D retrovirus PO-1-Lu and its exogenous counterparts in macaque and langur monkeys

    International Nuclear Information System (INIS)

    Sommerfelt, Maja A.; Harkestad, Nina; Hunter, Eric

    2003-01-01

    PO-1-Lu, the endogenous type D retrovirus of langurs (Trachypithecus obscurus) has previously been considered a progenitor to the prototype type D retrovirus, Mason Pfizer monkey virus (M-PMV/SRV-3), that became established in macaque monkeys (Macaca spp.) following a zoonosis. This study reevaluates this hypothesis to include other exogenous SRVs. New sequence information from the gp70(SU)-encoding region of PO-1-Lu shows striking similarity to the newly identified exogenous langur retrovirus, SRV-6, recently isolated from the Hanuman Langur (Semnopithecus entellus). An unrooted, bootstrapped neighbor-joining tree derived from env gene nucleotide sequences shows PO-1-Lu and SRV-6 appear more closely related genetically to SRV-2 than SRV-1 or SRV-3 (M-PMV). This is also reflected in our observations that the M-PMV envelope glycoprotein precursor gPr86 Env and gp70(SU) were antigenically distinct from PO-1-Lu, although the gp22(TM) glycoproteins were antigenically cross-reactive. The potential that SRV-6 represents an exogenous form of PO-1-Lu that has arisen following a recent zoonosis is discussed

  20. "Bird biting" mosquitoes and human disease: a review of the role of Culex pipiens complex mosquitoes in epidemiology.

    Science.gov (United States)

    Farajollahi, Ary; Fonseca, Dina M; Kramer, Laura D; Marm Kilpatrick, A

    2011-10-01

    The transmission of vector-borne pathogens is greatly influenced by the ecology of their vector, which is in turn shaped by genetic ancestry, the environment, and the hosts that are fed on. One group of vectors, the mosquitoes in the Culex pipiens complex, play key roles in the transmission of a range of pathogens including several viruses such as West Nile and St. Louis encephalitis viruses, avian malaria (Plasmodium spp.), and filarial worms. The Cx. pipiens complex includes Culex pipiens pipiens with two forms, pipiens and molestus, Culex pipiens pallens, Culex quinquefasciatus, Culex australicus, and Culex globocoxitus. While several members of the complex have limited geographic distributions, Cx. pipienspipiens and Cx. quinquefasciatus are found in all known urban and sub-urban temperate and tropical regions, respectively, across the world, where they are often principal disease vectors. In addition, hybrids are common in areas of overlap. Although gaps in our knowledge still remain, the advent of genetic tools has greatly enhanced our understanding of the history of speciation, domestication, dispersal, and hybridization. We review the taxonomy, genetics, evolution, behavior, and ecology of members of the Cx. pipiens complex and their role in the transmission of medically important pathogens. The adaptation of Cx. pipiens complex mosquitoes to human-altered environments led to their global distribution through dispersal via humans and, combined with their mixed feeding patterns on birds and mammals (including humans), increased the transmission of several avian pathogens to humans. We highlight several unanswered questions that will increase our ability to control diseases transmitted by these mosquitoes. Copyright © 2011 Elsevier B.V. All rights reserved.

  1. Metabolites from invasive pests inhibit mitochondrial complex II: A potential strategy for the treatment of human ovarian carcinoma?

    Energy Technology Data Exchange (ETDEWEB)

    Ferramosca, Alessandra, E-mail: alessandra.ferramosca@unisalento.it [Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce (Italy); Conte, Annalea; Guerra, Flora; Felline, Serena [Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce (Italy); Rimoli, Maria Grazia [Dipartimento di Farmacia, Università di Napoli Federico II, Napoli (Italy); Mollo, Ernesto [Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli (Italy); Zara, Vincenzo [Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce (Italy); Terlizzi, Antonio [Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce (Italy); Stazione Zoologica Anton Dohrn, Napoli (Italy)

    2016-05-13

    The red pigment caulerpin, a secondary metabolite from the marine invasive green algae Caulerpa cylindracea can be accumulated and transferred along the trophic chain, with detrimental consequences on biodiversity and ecosystem functioning. Despite increasing research efforts to understand how caulerpin modifies fish physiology, little is known on the effects of algal metabolites on mammalian cells. Here we report for the first time the mitochondrial targeting activity of both caulerpin, and its closely related derivative caulerpinic acid, by using as experimental model rat liver mitochondria, a system in which bioenergetics mechanisms are not altered. Mitochondrial function was tested by polarographic and spectrophotometric methods. Both compounds were found to selectively inhibit respiratory complex II activity, while complexes I, III, and IV remained functional. These results led us to hypothesize that both algal metabolites could be used as antitumor agents in cell lines with defects in mitochondrial complex I. Ovarian cancer cisplatin-resistant cells are a good example of cell lines with a defective complex I function on which these molecules seem to have a toxic effect on proliferation. This provided novel insight toward the potential use of metabolites from invasive Caulerpa species for the treatment of human ovarian carcinoma cisplatin-resistant cells. -- Highlights: •Novel insight toward the potential use of the algal metabolites for the treatment of human diseases. •Caulerpin and caulerpinic acid inhibit respiratory complex II activity. •Both algal metabolites could be used as antitumor agents in ovarian cancer cisplatin-resistant cells.

  2. Metabolites from invasive pests inhibit mitochondrial complex II: A potential strategy for the treatment of human ovarian carcinoma?

    International Nuclear Information System (INIS)

    Ferramosca, Alessandra; Conte, Annalea; Guerra, Flora; Felline, Serena; Rimoli, Maria Grazia; Mollo, Ernesto; Zara, Vincenzo; Terlizzi, Antonio

    2016-01-01

    The red pigment caulerpin, a secondary metabolite from the marine invasive green algae Caulerpa cylindracea can be accumulated and transferred along the trophic chain, with detrimental consequences on biodiversity and ecosystem functioning. Despite increasing research efforts to understand how caulerpin modifies fish physiology, little is known on the effects of algal metabolites on mammalian cells. Here we report for the first time the mitochondrial targeting activity of both caulerpin, and its closely related derivative caulerpinic acid, by using as experimental model rat liver mitochondria, a system in which bioenergetics mechanisms are not altered. Mitochondrial function was tested by polarographic and spectrophotometric methods. Both compounds were found to selectively inhibit respiratory complex II activity, while complexes I, III, and IV remained functional. These results led us to hypothesize that both algal metabolites could be used as antitumor agents in cell lines with defects in mitochondrial complex I. Ovarian cancer cisplatin-resistant cells are a good example of cell lines with a defective complex I function on which these molecules seem to have a toxic effect on proliferation. This provided novel insight toward the potential use of metabolites from invasive Caulerpa species for the treatment of human ovarian carcinoma cisplatin-resistant cells. -- Highlights: •Novel insight toward the potential use of the algal metabolites for the treatment of human diseases. •Caulerpin and caulerpinic acid inhibit respiratory complex II activity. •Both algal metabolites could be used as antitumor agents in ovarian cancer cisplatin-resistant cells.

  3. A large-scale analysis of tissue-specific pathology and gene expression of human disease genes and complexes

    DEFF Research Database (Denmark)

    Hansen, Kasper Lage; Hansen, Niclas Tue; Karlberg, Erik, Olof, Linnart

    2008-01-01

    to be overexpressed in the normal tissues where defects cause pathology. In contrast, cancer genes and complexes were not overexpressed in the tissues from which the tumors emanate. We specifically identified a complex involved in XY sex reversal that is testis-specific and down-regulated in ovaries. We also......Heritable diseases are caused by germ-line mutations that, despite tissuewide presence, often lead to tissue-specific pathology. Here, we make a systematic analysis of the link between tissue-specific gene expression and pathological manifestations in many human diseases and cancers. Diseases were...

  4. Biophysical characterization of the complex between human papillomavirus E6 protein and synapse-associated protein 97

    DEFF Research Database (Denmark)

    Chi, Celestine Ngang; Bach, Anders; Engström, Åke

    2011-01-01

    The E6 protein of human papillomavirus exhibits complex interaction patterns with several host proteins and their roles in HPV mediated oncogenesis have proved challenging to study. Here we use several biophysical techniques to explore the binding of E6 to the three PDZ domains of the tumor......, this quaternary complex has the same apparent hydrodynamic volume as the unliganded PDZ region, suggesting that a conformational change occurs in the PDZ region upon binding, a conclusion supported by kinetic experiments. Using NMR, we discovered a new mode of interaction between E6 and PDZ: a subset of residues...

  5. Whole genome analysis of selected human and animal rotaviruses identified in Uganda from 2012 to 2014 reveals complex genome reassortment events between human, bovine, caprine and porcine strains.

    Science.gov (United States)

    Bwogi, Josephine; Jere, Khuzwayo C; Karamagi, Charles; Byarugaba, Denis K; Namuwulya, Prossy; Baliraine, Frederick N; Desselberger, Ulrich; Iturriza-Gomara, Miren

    2017-01-01

    Rotaviruses of species A (RVA) are a common cause of diarrhoea in children and the young of various other mammals and birds worldwide. To investigate possible interspecies transmission of RVAs, whole genomes of 18 human and 6 domestic animal RVA strains identified in Uganda between 2012 and 2014 were sequenced using the Illumina HiSeq platform. The backbone of the human RVA strains had either a Wa- or a DS-1-like genetic constellation. One human strain was a Wa-like mono-reassortant containing a DS-1-like VP2 gene of possible animal origin. All eleven genes of one bovine RVA strain were closely related to those of human RVAs. One caprine strain had a mixed genotype backbone, suggesting that it emerged from multiple reassortment events involving different host species. The porcine RVA strains had mixed genotype backbones with possible multiple reassortant events with strains of human and bovine origin.Overall, whole genome characterisation of rotaviruses found in domestic animals in Uganda strongly suggested the presence of human-to animal RVA transmission, with concomitant circulation of multi-reassortant strains potentially derived from complex interspecies transmission events. However, whole genome data from the human RVA strains causing moderate and severe diarrhoea in under-fives in Uganda indicated that they were primarily transmitted from person-to-person.

  6. Extending network approach to language dynamics and human cognition. Comment on "Approaching human language with complex networks" by Cong and Liu

    Science.gov (United States)

    Gong, Tao; Shuai, Lan; Wu, Yicheng

    2014-12-01

    By analyzing complex networks constructed from authentic language data, Cong and Liu [1] advance linguistics research into the big data era. The network approach has revealed many intrinsic generalities and crucial differences at both the macro and micro scales between human languages. The axiom behind this research is that language is a complex adaptive system [2]. Although many lexical, semantic, or syntactic features have been discovered by means of analyzing the static and dynamic linguistic networks of world languages, available network-based language studies have not explicitly addressed the evolutionary dynamics of language systems and the correlations between language and human cognition. This commentary aims to provide some insights on how to use the network approach to study these issues.

  7. Linguistic complex networks as a young field of quantitative linguistics. Comment on "Approaching human language with complex networks" by J. Cong and H. Liu

    Science.gov (United States)

    Köhler, Reinhard

    2014-12-01

    We have long been used to the domination of qualitative methods in modern linguistics. Indeed, qualitative methods have advantages such as ease of use and wide applicability to many types of linguistic phenomena. However, this shall not overshadow the fact that a great part of human language is amenable to quantification. Moreover, qualitative methods may lead to over-simplification by employing the rigid yes/no scale. When variability and vagueness of human language must be taken into account, qualitative methods will prove inadequate and give way to quantitative methods [1, p. 11]. In addition to such advantages as exactness and precision, quantitative concepts and methods make it possible to find laws of human language which are just like those in natural sciences. These laws are fundamental elements of linguistic theories in the spirit of the philosophy of science [2,3]. Theorization effort of this type is what quantitative linguistics [1,4,5] is devoted to. The review of Cong and Liu [6] has provided an informative and insightful survey of linguistic complex networks as a young field of quantitative linguistics, including the basic concepts and measures, the major lines of research with linguistic motivation, and suggestions for future research.

  8. Analyses of prevalence and polymorphisms of six replication-competent and chromosomally assigned porcine endogenous retroviruses in individual pigs and pig subspecies

    International Nuclear Information System (INIS)

    Niebert, Marcus; Toenjes, Ralf R.

    2003-01-01

    As porcine endogenous retroviruses (PERV) productively infect human cells in vitro, they pose a serious risk in xenotransplantation and xenogeneic cell therapies. We have analyzed the prevalence of six well-characterized full-length PERV, five of them being replication-competent and four of them being chromosomally assigned (J. Virol. 75 (2001) 5465; J. Virol. 76 (2002) 2714). These analyses revealed a heterogeneous distribution of PERV among individuals and, as no PERV is present in every pig, it seems feasible to generate pigs free of functional PERV by conventional breeding. Conversely, as PERV are polymorphic, single proviruses may have escaped detection and this kind of assay must be performed for every herd used in xenotransplantation or xenogeneic cell therapies. In addition, specific proviruses show internal point mutations which significantly affect their replicational capacities. As there are two different types of PERV LTR structures showing varying levels of transcriptional capacity (J. Virol. 75 (2001) 6933), an analysis of 21 distinct chromosomal locations revealed that PERV which harbor highly active LTRs with repeat elements in U3 are dominant

  9. Natural killer cells recognize friend retrovirus-infected erythroid progenitor cells through NKG2D-RAE-1 interactions In Vivo.

    Science.gov (United States)

    Ogawa, Tatsuya; Tsuji-Kawahara, Sachiyo; Yuasa, Takae; Kinoshita, Saori; Chikaishi, Tomomi; Takamura, Shiki; Matsumura, Haruo; Seya, Tsukasa; Saga, Toshihiko; Miyazawa, Masaaki

    2011-06-01

    Natural killer (NK) cells function as early effector cells in the innate immune defense against viral infections and also participate in the regulation of normal and malignant hematopoiesis. NK cell activities have been associated with early clearance of viremia in experimental simian immunodeficiency virus and clinical human immunodeficiency virus type 1 (HIV-1) infections. We have previously shown that NK cells function as major cytotoxic effector cells in vaccine-induced immune protection against Friend virus (FV)-induced leukemia, and NK cell depletion totally abrogates the above protective immunity. However, how NK cells recognize retrovirus-infected cells remains largely unclear. The present study demonstrates a correlation between the expression of the products of retinoic acid early transcript-1 (RAE-1) genes in target cells and their susceptibility to killing by NK cells isolated from FV-infected animals. This killing was abrogated by antibodies blocking the NKG2D receptor in vitro. Further, the expression of RAE-1 proteins on erythroblast surfaces increased early after FV inoculation, and administration of an RAE-1-blocking antibody resulted in increased spleen infectious centers and exaggerated pathology, indicating that FV-infected erythroid cells are recognized by NK cells mainly through the NKG2D-RAE-1 interactions in vivo. Enhanced retroviral replication due to host gene-targeting resulted in markedly increased RAE-1 expression in the absence of massive erythroid cell proliferation, indicating a direct role of retroviral replication in RAE-1 upregulation.

  10. Analysis of swine leukocyte antigen class I gene profiles and porcine endogenous retrovirus viremia level in a transgenic porcine herd inbred for xenotransplantation research

    Science.gov (United States)

    Sypniewski, Daniel; Gałka, Sabina; Sołtysik, Dagna; Loch, Tomasz; Nowak, Ewa; Smorąg, Zdzisław; Bednarek, Ilona

    2018-01-01

    Molecular characterization of swine leukocyte antigen (SLA) genes is important for elucidating the immune responses between swine-donor and human-recipient in xenotransplantation. Examination of associations between alleles of SLA class I genes, type of pig genetic modification, porcine endogenous retrovirus (PERV) viral titer, and PERV subtypes may shed light on the nature of xenograft acceptance or rejection and the safety of xenotransplantation. No significant difference in PERV gag RNA level between transgenic and non-transgenic pigs was noted; likewise, the type of applied transgene had no impact on PERV viremia. SLA-1 gene profile type may correspond with PERV level in blood and thereby influence infectiveness. Screening of pigs should provide selection of animals with low PERV expression and exclusion of specimens with PERV-C in the genome due to possible recombination between A and C subtypes, which may lead to autoinfection. Presence of PERV-C integrated in the genome was detected in 31.25% of specimens, but statistically significant increased viremia in specimens with PERV-C was not observed. There is a need for multidirectional molecular characterization (SLA typing, viremia estimation, and PERV subtype screening) of animals intended for xenotransplantation research in the interest of xeno-recipient safety. PMID:29366300

  11. Induction of ebolavirus cross-species immunity using retrovirus-like particles bearing the Ebola virus glycoprotein lacking the mucin-like domain.

    Science.gov (United States)

    Ou, Wu; Delisle, Josie; Jacques, Jerome; Shih, Joanna; Price, Graeme; Kuhn, Jens H; Wang, Vivian; Verthelyi, Daniela; Kaplan, Gerardo; Wilson, Carolyn A

    2012-01-25

    The genus Ebolavirus includes five distinct viruses. Four of these viruses cause hemorrhagic fever in humans. Currently there are no licensed vaccines for any of them; however, several vaccines are under development. Ebola virus envelope glycoprotein (GP1,2) is highly immunogenic, but antibodies frequently arise against its least conserved mucin-like domain (MLD). We hypothesized that immunization with MLD-deleted GP1,2 (GPΔMLD) would induce cross-species immunity by making more conserved regions accessible to the immune system. To test this hypothesis, mice were immunized with retrovirus-like particles (retroVLPs) bearing Ebola virus GPΔMLD, DNA plasmids (plasmo-retroVLP) that can produce such retroVLPs in vivo, or plasmo-retroVLP followed by retroVLPs. Cross-species neutralizing antibody and GP1,2-specific cellular immune responses were successfully induced. Our findings suggest that GPΔMLD presented through retroVLPs may provide a strategy for development of a vaccine against multiple ebolaviruses. Similar vaccination strategies may be adopted for other viruses whose envelope proteins contain highly variable regions that may mask more conserved domains from the immune system.

  12. Induction of ebolavirus cross-species immunity using retrovirus-like particles bearing the Ebola virus glycoprotein lacking the mucin-like domain

    Directory of Open Access Journals (Sweden)

    Ou Wu

    2012-01-01

    Full Text Available Abstract Background The genus Ebolavirus includes five distinct viruses. Four of these viruses cause hemorrhagic fever in humans. Currently there are no licensed vaccines for any of them; however, several vaccines are under development. Ebola virus envelope glycoprotein (GP1,2 is highly immunogenic, but antibodies frequently arise against its least conserved mucin-like domain (MLD. We hypothesized that immunization with MLD-deleted GP1,2 (GPΔMLD would induce cross-species immunity by making more conserved regions accessible to the immune system. Methods To test this hypothesis, mice were immunized with retrovirus-like particles (retroVLPs bearing Ebola virus GPΔMLD, DNA plasmids (plasmo-retroVLP that can produce such retroVLPs in vivo, or plasmo-retroVLP followed by retroVLPs. Results Cross-species neutralizing antibody and GP1,2-specific cellular immune responses were successfully induced. Conclusion Our findings suggest that GPΔMLD presented through retroVLPs may provide a strategy for development of a vaccine against multiple ebolaviruses. Similar vaccination strategies may be adopted for other viruses whose envelope proteins contain highly variable regions that may mask more conserved domains from the immune system.

  13. Influence of complex circumstances and risks related to human relibaility: case of integral circuits fabrication in sterile environment

    International Nuclear Information System (INIS)

    Doniol-Shaw, G.

    1991-08-01

    Concepts of operating the complex and risk bearing utilities tend to separate operators from potential sources of risk (automation, and remote control). Since isolation of operators from risk sources is not always possible and constant their exposure to risks during operation, the question of human errors is always an important issue. In such situations, independent of the control and failure detection systems, operators are responsible for achieving two objectives simultaneously: operation and safety. This presentation shows how human behaviour can be determined by safety conditions of a plant, in the frame of managing minor real risks that would cause minor

  14. Spectroscopic and molecular docking studies on the interaction of human serum albumin with copper(II) complexes

    Science.gov (United States)

    Guhathakurta, Bhargab; Pradhan, Ankur Bikash; Das, Suman; Bandyopadhyay, Nirmalya; Lu, Liping; Zhu, Miaoli; Naskar, Jnan Prakash

    2017-02-01

    Two osazone based ligands, butane-2,3-dione bis(2‧-pyridylhydrazone) (BDBPH) and hexane-3,4-dione bis(2‧-pyridylhydrazone) (HDBPH), were synthesized out of the 2:1 M Schiff base condensation of 2-hydrazino pyridine respectively with 2,3-butanedione and 3,4-hexanedione. The X-ray crystal structures of both the ligands have been determined. The copper(II) complex of HDBPH has also been synthesized and structurally characterized. HDBPH and its copper(II) complex have thoroughly been characterized through various spectroscopic and analytical techniques. The X-ray crystal structure of the copper complex of HDBPH shows that it is a monomeric Cu(II) complex having 'N4O2' co-ordination chromophore. Interaction of human serum albumin (HSA) with these ligands and their monomeric copper(II) complexes have been studied by various spectroscopic means. The experimental findings show that the ligands as well as their copper complexes are good HSA binders. Molecular docking investigations have also been done to unravel the mode of binding of the species with HSA.

  15. Rescuing the Rescuer: On the Protein Complex between the Human Mitochondrial Acyl Carrier Protein and ISD11.

    Science.gov (United States)

    Herrera, María Georgina; Pignataro, María Florencia; Noguera, Martín Ezequiel; Cruz, Karen Magalí; Santos, Javier

    2018-05-16

    Iron-sulfur clusters are essential cofactors in many biochemical processes. ISD11, one of the subunits of the protein complex that carries out the cluster assembly in mitochondria, is necessary for cysteine desulfurase NFS1 stability and function. Several authors have recently provided evidence showing that ISD11 interacts with the acyl carrier protein (ACP). We carried out the coexpression of human mitochondrial ACP and ISD11 in E. coli. This work shows that ACP and ISD11 form a soluble, structured, and stable complex able to bind to the human NFS1 subunit modulating its activity. Results suggest that ACP plays a key-role in ISD11 folding and stability in vitro. These findings offer the opportunity to study the mechanism of interaction between ISD11 and NFS1.

  16. Escape from R-peptide deletion in a γ-retrovirus

    International Nuclear Information System (INIS)

    Schneider, Irene C.; Eckhardt, Manon; Brynza, Julia; Collins, Mary K.; Cichutek, Klaus; Buchholz, Christian J.

    2011-01-01

    The R peptide in the cytoplasmic tail (C-tail) of γ-retroviral envelope proteins (Env) prevents membrane fusion before budding. To analyse its role in the formation of replication competent, infectious particles, we developed chimeric murine leukaemia viruses (MLV) with unmodified or R-peptide deleted Env proteins of the gibbon ape leukaemia virus (GaLV). While titres of these viruses were unaffected, R-peptide deficiency led to strongly impaired spreading. Most remarkably, we isolated an escape mutant which had restored an open reading frame for a C-terminal extension of the truncated C-tail. A reconstituted virus encoding this escape C-tail replicated in cell culture. In contrast to R-peptide deficient Env, particle incorporation of the escape Env was effective due to an enhanced protein expression and restored intracellular co-localisation with Gag proteins. Our data demonstrate that the R peptide not only regulates membrane fusion but also mediates efficient Env protein particle incorporation in γ-retrovirus infected cells.

  17. Characterization of an endogenous retrovirus class in elephants and their relatives

    Directory of Open Access Journals (Sweden)

    Englbrecht Claudia C

    2004-10-01

    Full Text Available Abstract Background Endogenous retrovirus-like elements (ERV-Ls, primed with tRNA leucine are a diverse group of reiterated sequences related to foamy viruses and widely distributed among mammals. As shown in previous investigations, in many primates and rodents this class of elements has remained transpositionally active, as reflected by increased copy number and high sequence diversity within and among taxa. Results Here we examine whether proviral-like sequences may be suitable molecular probes for investigating the phylogeny of groups known to have high element diversity. As a test we characterized ERV-Ls occurring in a sample of extant members of superorder Uranotheria (Asian and African elephants, manatees, and hyraxes. The ERV-L complement in this group is even more diverse than previously suspected, and there is sequence evidence for active expansion, particularly in elephantids. Many of the elements characterized have protein coding potential suggestive of activity. Conclusions In general, the evidence supports the hypothesis that the complement had a single origin within basal Uranotheria.

  18. The evolutionary capacitor HSP90 buffers the regulatory effects of mammalian endogenous retroviruses.

    Science.gov (United States)

    Hummel, Barbara; Hansen, Erik C; Yoveva, Aneliya; Aprile-Garcia, Fernando; Hussong, Rebecca; Sawarkar, Ritwick

    2017-03-01

    Understanding how genotypes are linked to phenotypes is important in biomedical and evolutionary studies. The chaperone heat-shock protein 90 (HSP90) buffers genetic variation by stabilizing proteins with variant sequences, thereby uncoupling phenotypes from genotypes. Here we report an unexpected role of HSP90 in buffering cis-regulatory variation affecting gene expression. By using the tripartite-motif-containing 28 (TRIM28; also known as KAP1)-mediated epigenetic pathway, HSP90 represses the regulatory influence of endogenous retroviruses (ERVs) on neighboring genes that are critical for mouse development. Our data based on natural variations in the mouse genome show that genes respond to HSP90 inhibition in a manner dependent on their genomic location with regard to strain-specific ERV-insertion sites. The evolutionary-capacitor function of HSP90 may thus have facilitated the exaptation of ERVs as key modifiers of gene expression and morphological diversification. Our findings add a new regulatory layer through which HSP90 uncouples phenotypic outcomes from individual genotypes.

  19. Endogenous retroviruses function as species-specific enhancer elements in the placenta.

    Science.gov (United States)

    Chuong, Edward B; Rumi, M A Karim; Soares, Michael J; Baker, Julie C

    2013-03-01

    The mammalian placenta is remarkably distinct between species, suggesting a history of rapid evolutionary diversification. To gain insight into the molecular drivers of placental evolution, we compared biochemically predicted enhancers in mouse and rat trophoblast stem cells (TSCs) and found that species-specific enhancers are highly enriched for endogenous retroviruses (ERVs) on a genome-wide level. One of these ERV families, RLTR13D5, contributes hundreds of mouse-specific histone H3 lysine 4 monomethylation (H3K4me1)- and histone H3 lysine 27 acetylation (H3K27ac)-defined enhancers that functionally bind Cdx2, Eomes and Elf5-core factors that define the TSC regulatory network. Furthermore, we show that RLTR13D5 is capable of driving gene expression in rat placental cells. Analysis in other tissues shows that species-specific ERV enhancer activity is generally restricted to hypomethylated tissues, suggesting that tissues permissive for ERV activity gain access to an