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What do we know about the function of viruses in the microbiome?

Human ViromeThe human virome (representing human viral communities) presents greater technical challenges (1) for identification and enumeration compared to the microbiome.Technical difficulties with characterizing the human viromeWe identify bacteria in the human microbiome using conserved genomic sequences (16S rRNA). Lacking such conserved genomic regions, viral genomic sequences from human samples are compared to known virus reference sequence databases. Drawback is such databases don't include sequences from novel viruses (2) while the human virome likely harbors as-yet-undiscovered viruses and viral relics.Viruses have small genomes, and are proportionally fewer compared to bacteria. Thus, viral nucleic acids are proportionally minuscule in the total derived from human microbial communities. To detect them, we need to enrich viral nucleic acids before sequence analysis. In turn, enrichment methods could be unwittingly selective, bias against certain viruses, and lead to loss of low-abundance viruses (3).From 4The human virome constitutes viral communities all over the human body. They run the gamut from viral relics such as HERVs (Human Endogenous Retroviruses), retroviral genes internalized millions of years ago during evolution, to tissue-resident viruses such as CMV (Cytomegalovirus) in the respiratory tract. Contribution of these viral communities also runs the gamut from most essential such as HERV-W genes, necessary for placental development, to HERV-K, the most recent integrant, implicated in neurological diseases such as schizophrenia, cancers such as breast and prostate, and autoimmune diseases such as MS (multiple sclerosis), RA (rheumatoid arthritis) and SLE (systemic lupus erythematosus).Figure 1 from 5HERVs (Human Endogenous Retroviruses)Viral genetic material is either DNA or RNA. Retroviruses have RNA but use it to produce DNA, the reverse, 'retro', of the norm. When inserted into host DNA, this viral DNA replicates every time host DNA replicates. When retroviruses infect germline (eggs and sperm) cells, they acquire a vastly greater capacity to replicate. Now endogenous retroviruses (ERV), they are present not just in each and every cell of that host but also get passed on to each and every cell of the host's descendants.ERVs represent 8% of the human genome (6).How do we know we harbor such retroviral relics? By their striking structural genomic similarity consisting of gag, pro, pol and env genes flanked by two identical-at-integration non-coding long terminal repeats (LTRs), which contain the signal for transcription initiation and regulation.Over evolutionary time (~35 million years), ERVs accumulated mutations (insertions, deletions, substitutions) and/or epigenetic modifications (for e.g., DNA methylation) at the same rate as the host genome (7, 8, 9, 10), rendering them non-functional, i.e. unable to produce infectious viral particles.Recombinations between the two flanking LTRs removed the internal coding region leaving a single LTR and inactivating ERVs, which are 10–100 times more numerous than their full length counterparts (11), and many of these insertions are fixed in the host population.To date, no active ERVs have been discovered in humans. The human genome has ~100,000 ERV loci resulting from proliferations of ~50 independent invasions of the genome from free-living (exogenous) retroviruses (12, 13).Figure 2 from 14HERV classification is still a work-in-progress. Magiorkinis et al (15) classify HERV families as the typical, HERV-T; the old, HERV-L; the abundant, HERV-H; the indispensable, HERV-W; the last but not the least, HERV-K.HERV-K(HML2) or HK2, the most recent, is the only ERV lineage to still replicate in the human population within the last few million years.~1,000 HK2 loci in the human reference genome, apparently integrated over the last ~35 million years. Continuously replicating over this long period, most full-length integrated ERV loci (proviruses) converted to relics by recombination. Remainder acquired premature stop codons and/or frameshifts. All reference genome HK2 loci are therefore replication defective, and only 24 loci retain full-length open reading frames (ORFs) in at least one of their genes (16).RNA transcription and protein expression of HK2 and other ERVs are elevated in many cancers, some autoimmune/inflammatory diseases, and HIV infection, leading to a long and unresolved search for a causal role in disease (17, 18, 19). More recently, disease-associated elevation of HERV protein expression has driven research into their potential as immunotherapy targets for cancer and HIV treatment (20).HERV-W, the indispensable HERVs in the Placenta: Genes Syncytins 1 and 2The emergence of placentation during evolution is fundamental to human evolution.Indispensable for human fetus growth, the placenta is composed of multiple unique cell types called extravillous and villous trophoblasts. The latter differentiate into multinucleated cells called syncytiotrophoblasts, which secrete human chorionic gonadotropin (hCG) and human placental lactogen (hPL), products that help optimize mother-fetus nutrient and hormone exchange.Viral relics in the form of specific HERVs are essential for placental development (14, 21, 22).Viruses were long suspected present in placenta with virus-like particles observed in human placenta (23, 24, 25, 26). These observations faded from memory until the discovery of the Syncytin genes in the late 1990s.Two Env proteins, Syncytin-1 and Syncytin-2 proteins, encoded by two different ERV loci, i.e., ERVW-1 and ERVFRD-1, located on chromosome 7 and 6, respectively, are expressed in the placenta. Independently co-opted numerous times among placental mammals and expressed in the placenta, these genes play a crucial role in the formation of the syncytiotrophoblast, a key function that sustains the highly dynamic and metabolically demanding placenta (27, 28, 29, 30, 31, 32, 33, 34, 35).Figure 1 from 36.- Viral genes like these may actually have been central in the emergence of placental mammals from egg-laying animals (29, 37, 38, 39, 40).Box from 36.In vitro studies (41) and reduced expression in pre-eclampsia (42, 43, 44, 45, 46, 47, 48, 49) suggest these retroviral-origin genes are important in human placentation. Pre-eclampsia, 'toxemia of pregnancy', includes hypertension, liver and kidney toxicity, and if untreated, can lead to eclampsia, i.e. seizures, threatening the life of mother and child. These multiple, independent studies thus suggest that human placental syncytin expression is crucial for normal placental function and ensuing normal pregnancy.Mouse syncytin gene knockouts provide more definitive proof. Syncytin-1 knockout mouse: growth retardation, altered placental strcuture, death in utero (50). Syncytin-2 knockout mouse: impaired syncytiotrophoblasts (51).Serving a similar purpose in placentation of eutherian mammals, syncytin genes are thus a most extreme and powerful example of convergent evolution, having evolved independently multiple times through co-option of HERV genes.HERVs in the brain: No definitive proof of disease causation. Lot of correlative data for neurological diseases,Table 1 from 52.especially for schizophrenia.Tables 1 and 2 from 53HERVs and cancerHow to be sure something causes cancer? Likely causes are so numerous ranging from genetic predisposition to numerous environmental factors that pinning one or few down as causative agents is akin to the proverbial needle in a haystack. In 1965 Austin Bradford Hill proposed the famous Hill's criteria (54), essential in helping ascribe causality, as in the link between smoking and lung cancer. How does that pan out with HERVs (55, 56, 57)?Consistency of association: HERVs consistently expressed in many tumors (breast, ovarian, lymphoma, melanoma, sarcoma, bladder, prostate).Strength of association: HERVs rarely expressed in normal tissues.Temporal association: Environmental factors as in exogenous such as chemicals, UV radiation, smoking, viruses, and endogenous as in hormones and cytokines help drive HERV expression.Biological plausibility: no clear evidence yet.Experimental evidence: no clear evidence yet in humans (some mouse model data exists).Clearly work-in-progress.HERV-Breast Cancer link: 58, 59; HERV-Melanoma link: 60; HERV-prostate cancer link: 61.HERVs and autoimmunity (62, 63): MS (multiple sclerosis; 64, 65), RA (rheumatoid arthritis: 66, 67), SLE (systemic lupus erythematosus: 68), Sjogren's syndrome, Graves Disease.Association data; no causal data yet.Certain HERVs and herpes viruses associated with MS.Circulating anti-HERV antibodies present in >50% of SLE in some studies.Those with anti-HERV antibodies more likely to have active clinical SLE.Location-wise identity of Viruses in Human bodyHuman StoolStable over time (69), unsurprisingly healthy gut virome is influenced by diet (70).Abundance of food-related (plant) viruses (71).Eneteropathogenic viruses (72) found in both healthy and in those with GI tract illnesses (73).Novel bacteriophages encode genes for antibiotic resistance and bacterial metabolic pathways (69, 70, 74). More diverse in adults, much less so in a 1-week old infant stool sample (75). Clearly, we dynamically acquire a gut bacteriophage community over time.Novel viruses. Viruses from the new genus Gyrovirus in the Circoviridae family (76) are found in both chicken meat and human samples. Open questions: Do they replicate in humans, i.e. capable of cross-species transmission, or are they harmless?Diarrhea was associated with novel viruses such as astrovirus (77), cosavirus and bocavirus (78).Human SkinPersistent colonization by papillloma, polyoma, and circoviruses(79, 80). Innocuous for the most part. Exception is Merkel cell polyomavirus associated with severe skin carcinoma (81).Human circulatory systemAnelloviridae are ubiquitous in human populations (82, 83).An intriguing heart and lung transplant study (84) tracked circulating plasma virome months post-transplant, and found circulating virome changed with post-transplant treatment. Low dose of anti-viral (valganciclovir) and immunosuppressant (tacrolimus): Herpesvirales and Caudovirales dominate; high dose, Anelloviridae dominate.Graphical Abstract from 84.LiverFlavivirus GBVC (or Hepatitis virus G), a surprising partner in human health, delays HIV disease progression (85).LungInfluenza (flu), Corona and other less well-characterized viruses (86).Bocavirus found in both healthy and in those with respiratory tract illnesses (87).Bacteriophages: Cystic Fibrosis (CF) patients have bacteriophages similar to each other while those in healthy adults are unique to each individual (88). In this study, spouse of one CF patient and an asthmatic control shared some viral genomes found in CF patients. This suggests environment strongly influences human viral genome since shared environment was associated with shared viruses between spouses, and chronic pathologies that are very different, as CF and asthma are, could still lead to establishment of similar viral communities, perhaps because they both cause impaired airway clearance of microbes.CMV (Cytomegalovirus)CMV, a herpes virus, infects majority of the world’s population.In the US, ~60% prevalence in >6 years of age and ~>90% in >80 years of age in the years 1988-1994 (89).It's usually, but not always, benign (90).Associated with immunosenescence (immune aging) in the elderly (91).CMV-schizophrenia link: In a study of >1000 subjects, 15% carried a particular benign variant of a gene involved in the stabilization of neuronal connections and in synaptic plasticity, essential to learning and memory. Carriers of this gene variant had fivefold increased probability of developing schizophrenia following maternal CMV infection (92).CMV-Flu link: CMV could help body fight off flu: CMV-seropositive young adults make stronger anti-flu antibody responses (93). Seropositive means they were likely exposed to CMV and generated an anti-CMV immune response, as revealed by presence of circulating anti-CMV antibodies. Relevance of this type of finding? The well-adjusted human super-organism is one where their mammalian and microbial components work in harmony to keep pathogens at bay.FluFlu-HERV link: The influenza virus may re-activate HERVs that are associated with neuroinflammation, and white matter and myelin degeneration (94).Such HERVs have been implicated in Bipolar disorder and Schizophrenia (95, 96).Virome BibliographyCanuti, M. "About Viruses, the Importance of Being Earnest." Austin Virol and Retrovirology 1.1 (2014): 2. ME, Howey R, Gaunt E, Reilly L, Chase-Topping M, Savill N. Temporal trends in the discovery of human viruses. Proc Biol Sci 2008;275:2111–5.Thurber RV, Haynes M, Breitbart M, Wegley L, Rohwer F. Laboratory procedures to generate viral metagenomes. Nat Protoc 2009;4:470–83.Delwart, Eric. "A roadmap to the human virome." PLoS pathogens 9.2 (2013): e1003146. A Roadmap to the Human ViromeWylie, Kristine M., George M. Weinstock, and Gregory A. Storch. "Emerging view of the human virome." Translational Research 160.4 (2012): 283-290. Page on els-cdn.comLander ES, Linton LM, Birren B, Nusbaum C, Zody MC, et al. (2001) Initial sequencing and analysis of the human genome. Nature 409: 860–921.Blikstad V, Benachenhou F, Sperber GO, Blomberg J (2008) Evolution of human endogenous retroviral sequences: a conceptual account. Cellular and Molecular Life Sciences 65: 3348–3365.Dewannieux, M.; Heidmann, T. Endogenous retroviruses: Acquisition, amplification and taming of genome invaders. Curr. Opin. Virol. 2013, 3, 646–656.Stoye, J.P. Studies of endogenous retroviruses reveal a continuing evolutionary saga. Nat. Rev. Microbiol. 2012, 10, 395–406.Magiorkinis, G.; Gifford, R.J.; Katzourakis, A.; de Ranter, J.; Belshaw, R. Env-less endogenous retroviruses are genomic superspreaders. Proc. Natl. Acad. Sci. USA 2012, 109, 7385–7390.Stoye JP (2001) Endogenous retroviruses: still active after all these years? Curr Biol 11: R914–916.Belshaw R, Pereira V, Katzourakis A, Talbot G, Pa?es J, Burt A, Tristem M. 2004. Long-term reinfection of the human genome by endogenous retroviruses. Proc. Natl. Acad. Sci. U. S. A. 101:4894 – 4899.Mayer J, Blomberg J, Seal RL. 2011. A revised nomenclature for transcribed human endogenous retroviral loci. Mobile DNA 2:7.Young, George R., Jonathan P. Stoye, and George Kassiotis. "Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis." Bioessays 35.9 (2013): 794-803. Are human endogenous retroviruses pathogenic? An approach to testing the hypothesisMagiorkinis, Gkikas, Robert Belshaw, and Aris Katzourakis. "‘There and back again’: revisiting the pathophysiological roles of human endogenous retroviruses in the post-genomic era." Philosophical Transactions of the Royal Society B: Biological Sciences 368.1626 (2013): 20120504. revisiting the pathophysiological roles of human endogenous retroviruses in the post-genomic eraSubramanian RP, Wildschutte JH, Russo C, Coffin JM. 2011. Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology 8:90.Voisset C, Weiss RA, Griffiths DJ. 2008. Human RNA “rumor” viruses: the search for novel human retroviruses in chronic disease. Microbiol. Mol. Biol. Rev. 72:157–196.Young GR, Stoye JP, Kassiotis G. 2013. Are human endogenous retro- viruses pathogenic? An approach to testing the hypothesis. Bioessays 35: 794 – 803.Jern P, Coffin JM. 2008. Effects of retroviruses on host genome function. Annu. Rev. Genet. 42:709 –732.Marchi, Emanuele, et al. "Unfixed endogenous retroviral insertions in the human population." Journal of virology 88.17 (2014): 9529-9537. Unfixed Endogenous Retroviral Insertions in the Human PopulationMangeney M, Renard M, Schlecht-Louf G, Bouallaga I, et al. 2007. Placental syncytins: genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins. Proc Natl Acad Sci USA 104: 20534–9.Dupressoir A, Lavialle C, Heidmann T. 2012. From ancestral infectious retroviruses to bona fide cellular genes: role of the captured syncytins in placentation. Placenta 33: 663–71.Kalter SS, Helmke RJ, Heberling RL, Panigel M, et al. 1973. Brief communication: C-type particles in normal human placentas. J Natl Cancer Inst 50: 1081–4.Vernon ML, McMahon JM, Hackett JJ. 1974. Additional evidence of type-C particles in human placentas. J Natl Cancer Inst 52: 987–9.Kalter SS, Heberling RL, Helmke RJ, Panigel M, Smith GC, Kraemer DC, Hellman A, Fowler AK, Strickland JE (1975) A comparative study on the presence of C-type viral particles in placentas from primates and other animals. Bibl Haematol 1975(40):391–40.Dirksen ER, Levy JA. 1977. Virus-like particles in placentas from normal individuals and patients with systemic lupus erythematosus. J Natl Cancer Inst 59: 1187–92.Blond, J.L.; Beseme, F.; Duret, L.; Bouton, O.; Bedin, F.; Perron, H.; Mandrand, B.; Mallet, F. Molecular characterization and placental expression of herv-w, a new human endogenous retrovirus family. J. Virol. 1999, 73, 1175–1185.Blond, J.L.; Lavillette, D.; Cheynet, V.; Bouton, O.; Oriol, G.; Chapel-Fernandes, S.; Mandrand, B.; Mallet, F.; Cosset, F.L. An envelope glycoprotein of the human endogenous retrovirus herv-w is expressed in the human placenta and fuses cells expressing the type d mammalian retrovirus receptor. J. Virol. 2000, 74, 3321–3329.Mi, S.; Lee, X.; Li, X.; Veldman, G.M.; Finnerty, H.; Racie, L.; LaVallie, E.; Tang, X.Y.; Edouard, P.; Howes, S.; et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 2000, 403, 785–789.Frendo, J.L.; Olivier, D.; Cheynet, V.; Blond, J.L.; Bouton, O.; Vidaud, M.; Rabreau, M.; Evain-Brion, D.; Mallet, F. Direct involvement of herv-w env glycoprotein in human trophoblast cell fusion and differentiation. Mol. Cell. Biol. 2003, 23, 3566–3574.Blaise, S.; de Parseval, N.; Benit, L.; Heidmann, T. Genomewide screening for fusogenic human endogenous retrovirus envelopes identifies syncytin 2, a gene conserved on primate evolution. Proc. Natl. Acad. Sci. USA 2003, 100, 13013–13018.Malassine, A.; Dupressoir A, Marceau G, Vernochet C, Benit L, Kanellopoulos C, Sapin V, Heidmann T. 2005 Syncytin-A and syncytin-B, two fusogenic placenta- specific murine envelope genes of retroviral origin conserved in Muridae. Proc. Natl Acad. Sci. USA 102, 725 – 730.Handschuh, K.; Tsatsaris, V.; Gerbaud, P.; Cheynet, V.; Oriol, G.; Mallet, F.; Evain-Brion, D. Expression of herv-w env glycoprotein (syncytin) in the extravillous trophoblast of first trimester human placenta. Placenta 2005, 26, 556–562.Muir, A.; Lever, A.M.; Moffett, A. Human endogenous retrovirus-w envelope (syncytin) is expressed in both villous and extravillous trophoblast populations. J. Gen. Virol. 2006, 87, 2067–2071.Hayward, M.D.; Potgens, A.J.; Drewlo, S.; Kaufmann, P.; Rasko, J.E. Distribution of human endogenous retrovirus type w receptor in normal human villous placenta. Pathology 2007, 39, 406–412.Cornelis, Guillaume, et al. "Retroviral envelope gene captures and syncytin exaptation for placentation in marsupials." Proceedings of the National Academy of Sciences (2015): 201417000.Heidmann O, Vernochet C, Dupressoir A, Heidmann T. 2009 Identification of an endogenous retroviral envelope gene with fusogenic activity and placenta- specific expression in the rabbit: a new “syncytin” in a third order of mammals. Retrovirology 6, 107.Cornelis G, Heidmann O, Bernard-Stoecklin S, Reynaud K, Veron G, Mulot B, Dupressoir A, Heidmann T. 2012 Ancestral capture of syncytin- Car1, a fusogenic endogenous retroviral envelope gene involved in placentation and conserved in Carnivora. Proc. Natl Acad. Sci. USA 109, E432 – E441.Lavialle, C., Cornelis, G., Dupressoir, A., Esnault, C., Heidmann, O., Vernochet, C., & Heidmann, T. (2013). Paleovirology of 'syncytins', retroviral env genes exapted for a role in placentation. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 368(1626), 1471-2970.Lokossou, Adjimon Gatien, Caroline Toudic, and Benoit Barbeau. "Implication of Human Endogenous Retrovirus Envelope Proteins in Placental Functions." Viruses 6.11 (2014): 4609-4627. Implication of Human Endogenous Retrovirus Envelope Proteins in Placental FunctionsVargas, Amandine, et al. "Syncytin-2 plays an important role in the fusion of human trophoblast cells." Journal of molecular biology 392.2 (2009): 301-318. Syncytin-2 Plays an Important Role in the Fusion of Human Trophoblast CellsLee, X., Keith Jr., J.C., Stumm, N., Moutsatsos, I., McCoy, J.M., Crum, C.P., Genest, D., Chin, D., Ehrenfels, C., Pijnenborg, R., van Assche, F.A., Mi, S., 2001. Downregulation of placental syncytin expression and abnormal protein localization in pre- eclampsia. Placenta 22, 808–812.Keith Jr., J.C., Pijnenborg, R., Van Assche, F.A., 2002. Placental syncytin expression in normal and preeclamptic pregnancies. Am. J. Obstet. Gynecol. 187, 1122–1123 author reply 1123–1124.Knerr, I., Beinder, E., Rascher, W., 2002. Syncytin, a novel human endogenous retroviral gene in human placenta: evidence for its dysregulation in preeclampsia and HELLP syndrome. Am. J. Obstet. Gynecol. 186, 210–213.Chen, C.P., Wang, K.G., Chen, C.Y., Yu, C., Chuang, H.C., Chen, H., 2006. Altered placental syncytin and its receptor ASCT2 expression in placental development and pre- eclampsia. BJOG 113, 152–158.Chen, C.P., Chen, L.F., Yang, S.R., Chen, C.Y., Ko, C.C., Chang, G.D., Chen, H., 2008. Functional characterization of the human placental fusogenic membrane protein syncytin 2. Biol. Reprod. 79, 815–823.Kudaka, W., Oda, T., Jinno, Y., Yoshimi, N., Aoki, Y., 2008. Cellular localization of placenta-specific human endogenous retrovirus (HERV) transcripts and their possible implication in pregnancy-induced hypertension. Placenta 29, 282–289.Langbein, M., Strick, R., Strissel, P.L., Vogt, N., Parsch, H., Beckmann, M.W., Schild, R.L., 2008. Impaired cytotrophoblast cell–cell fusion is associated with reduced Syncytin and increased apoptosis in patients with placental dysfunction. Mol. Reprod. Dev. 75, 175–183.Vargas, A., Toufaily, C., Lebellego, F., Rassart, E., Lafond, J., Barbeau, B., 2011. Reduced expression of both Syncytin 1 and Syncytin 2 correlates with severity of pre-eclampsia. Reprod. Sci. 18, 1085–1091.Dupressoir, Anne, et al. "Syncytin-A knockout mice demonstrate the critical role in placentation of a fusogenic, endogenous retrovirus-derived, envelope gene." Proceedings of the National Academy of Sciences 106.29 (2009): 12127-12132. A, Vernochet C, Harper F, Guegan J, Dessen P, Pierron G, Heidmann T (2011) A pair of co-opted retroviral envelope syncytin genes is required for formation of the two-layered murine placental syncytiotrophoblast. Proc Natl Acad Sci USA 108:E1164–E1173.Manghera, Mamneet, Jennifer Ferguson, and Renée Douville. "Endogenous retrovirus-K and nervous system diseases." Current neurology and neuroscience reports 14.10 (2014): 1-10.Raúl, Alelú-Paz, and Iturrieta-Zuazo Ignacio. "Human endogenous retroviruses: Their possible role in the molecular etiology of the schizophrenia." Open Journal of Genetics 2012 (2012). Their possible role in the molecular etiology of the schizophreniaHill, Austin Bradford. "The environment and disease: association or causation?." Proceedings of the Royal Society of Medicine 58.5 (1965): 295. The Environment and Disease: Association or Causation?Cegolon, Luca, et al. "Human endogenous retroviruses and cancer prevention: evidence and prospects." BMC cancer 13.1 (2013): 4. Page on, Ronan F., et al. "Human endogenous retrovirus K and cancer: innocent bystander or tumorigenic accomplice?." International Journal of Cancer (2014). Page on wiley.comKassiotis, George. "Endogenous retroviruses and the development of cancer." The Journal of Immunology 192.4 (2014): 1343-1349. Endogenous Retroviruses and the Development of CancerSalmons, Brian, James S. Lawson, and Walter H. Günzburg. "Recent developments linking retroviruses to human breast cancer: infectious agent, enemy within or both?." Journal of General Virology Page on 12 (2014): 2589-2593.Fimereli, Danai, et al. "No significant viral transcription detected in whole breast cancer transcriptomes." BMC cancer 15.1 (2015): 147. Page on biomedcentral.comRincon, Liliana, et al. "K-type human endogenous retroviral elements in human melanoma." Advances in Genomics & Genetics 4 (2014). Page on dovepress.comWallace, Tiffany A., et al. "Elevated HERV-K mRNA expression in PBMC is associated with a prostate cancer diagnosis particularly in older men and smokers." Carcinogenesis (2014): bgu114.Balada, Eva, Miquel Vilardell-Tarrés, and Josep Ordi-Ros. "Implication of human endogenous retroviruses in the development of autoimmune diseases." International reviews of immunology 29.4 (2010): 351-370.Fierabracci, A. "Unravelling the role of infectious agents in the pathogenesis of human autoimmunity: the hypothesis of the retroviral involvement revisited." Current molecular medicine 9.9 (2009): 1024-1033. Page on researchgate.netKrone, Bernd, and John M. Grange. "Paradigms in multiple sclerosis: time for a change, time for a unifying concept." Inflammopharmacology 19.4 (2011): 187-195. Paradigms in multiple sclerosis: time for a change, time for a unifying concept.Antony, Joseph M., et al. "Human endogenous retroviruses and multiple sclerosis: innocent bystanders or disease determinants?." Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1812.2 (2011): 162-176. Innocent bystanders or disease determinants?Tugnet, Nicola, et al. "Human endogenous retroviruses (HERVs) and autoimmune rheumatic disease: Is there a link?." The open rheumatology journal 7 (2013): 13. Human Endogenous Retroviruses (HERVs) and Autoimmune Rheumatic Disease: Is There a Link?.Nelson, Paul N., et al. "Rheumatoid Arthritis is Associated with IgG Antibodies to Human Endogenous Retrovirus Gag Matrix: A Potential Pathogenic Mechanism of Disease?." The Journal of rheumatology 41.10 (2014): 1952-1960.Nelson, P., et al. "Viruses as potential pathogenic agents in systemic lupus erythematosus." Lupus 23.6 (2014): 596-605. Wu, Zhouwei, et al. "DNA methylation modulates HERV-E expression in CD4+ T cells from systemic lupus erythematosus patients." Journal of dermatological science (2015).Reyes, A., Haynes, M., Hanson, N., Angly, F.E., Heath, A.C., Rohwer, F., and Gordon, J.I. (2010). Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature 466, 334–338.Minot, S., Sinha, R., Chen, J., Li, H., Keilbaugh, S.A., Wu, G.D., Lewis, J.D., and Bushman, F.D. (2011). The human gut virome: inter-individual variation and dynamic response to diet. Genome Res. 21, 1616–1625.Zhang T, Breitbart M, Lee WH, Run JQ, Wei CL, Soh SW, et al. 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Transfusion transmission of highly prevalent commensal human viruses. Transfusion. 2010; 50: 2474- 2483.De Vlaminck, Iwijn, et al. "Temporal response of the human virome to immunosuppression and antiviral therapy." Cell 155.5 (2013): 1178-1187. Page on els-cdn.comSchwarze-Zander C, Blackard JT, Rockstroh JK. Role of GB virus C in modulating HIV disease. Expert Rev Anti Infect Ther. 2012; 10: 563-572.Mahony JB. Detection of respiratory viruses by molecular methods. Clin Microbiol Rev. 2008; 21: 716-747.Schildgen O, Müller A, Allander T, Mackay IM, Völz S, Kupfer B, et al. Human bocavirus: passenger or pathogen in acute respiratory tract infections? Clin Microbiol Rev. 2008; 21: 291-304.Willner D, Furlan M, Haynes M, Schmieder R, Angly FE, Silva J, et al. Metagenomic analysis of respiratory tract DNA viral communities in cystic fibrosis and non-cystic fibrosis individuals. PLoS One. 2009; 4: e7370.Staras, Stephanie AS, et al. "Seroprevalence of cytomegalovirus infection in the United States, 1988–1994." Clinical Infectious Diseases 43.9 (2006): 1143-1151. Seroprevalence of Cytomegalovirus Infection in the United States, 1988-1994Simanek, Amanda M., et al. "Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States." PloS one 6.2 (2011): e16103.Fülöp, T., Anis Larbi, and Graham Pawelec. "Human T cell aging and the impact of persistent viral infections." Frontiers in immunology 4 (2013). Human T Cell Aging and the Impact of Persistent Viral InfectionsBørglum, A. D., et al. "Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci." Molecular psychiatry 19.3 (2014): 325-333. Page on nature.comCytomegalovirus infection enhances the immune response to influenza; A Virus In Your Mouth Helps Fight The FluNellåker, Christoffer, et al. "Transactivation of elements in the human endogenous retrovirus W family by viral infection." Retrovirology 3.1 (2006): 44. Page on retrovirology.comPerron, Hervé, et al. "Molecular characteristics of Human Endogenous Retrovirus type-W in schizophrenia and bipolar disorder." Translational psychiatry 2.12 (2012): e201. Page on, Marion, et al. "Human endogenous retrovirus type W (HERV-W) in schizophrenia: A new avenue of research at the gene-environment interface." The World Journal of Biological Psychiatry 14.2 (2013): 80-90.Thanks for the A2A, Matt Chanoff. I'll answer about the human mycobiome (fungal communities of the human body) separately.

What is collaborative filtering in layman's terms?

Mr. X loves talking about movies. Everyone he meets, he strikes a conversation about movies or lets just say he asks what movies the person liked and to what extent. Once he has some ratings for the movies he tries to suggest some movies which the person might enjoy. Now, Mr. X has a perfect recall and he also is good with maths. He remembers all his conversations and what rating it got from different people. He stores this users-movie table with each cell corresponding to rating of the movie given by the users. It looks something like thisMovie1 Movie2 Movie3User1 5User2 1 4.1User3 3.3Let's call this the rating matrix. Now, as I said Mr. X is really good with maths and he could easily do some mathematical jugglery and find from which two matrices this matrix can be constructed. This can be tricky because he does not know all the rating.So, he gets two matrices which are factors of this matrix. Now, if he recomposes the rating matrix from the one obtained from decomposition, he gets some guesses for unknown values also. The new rating matrix looks like this.Movie1 Movie2 Movie3User1 4.9 2.8 4.7User2 3.8 1.1 4.0User3 4.4 3.2 4.9So, now he can easily suggest that User1 will like Movie3. Note that User1 told Mr. X he likes Movie1.So, what Mr. X is doing is basically try to draw conclusions from the general taste of movies.More Formally,Recommendation systems try to recommend items (movies, music, webpages, products, etc) to interested potential customers, based on the information available about user, product and user preferences or ratings. Recommendation systems can be further segmented into two classes - content based systems and collaborative filtering based systems. Content-based approaches analyze the content (e.g., texts, meta-data, features) of the items to identify related items, while collaborative filtering uses the overall behaviour or taste of a large number of users to suggest relevant items to specific users.Most good systems use a hybrid approach. One great example of using the CF algorithm on the netflix data can be found on this blog (old but neatly explained): Try This at Home It explains the dataset and the problem with possible issues.Open Source ImplementationsAs far the implementation is concerned, Apache Mahaout has a really cool CF algorithm implemented you can check out the algorithms here: Algorithms - Apache Mahout - Apache Software Foundation and it is quite easy to use, a great introduction can be found here: Page on Ibm .You can also find some good implementations in other software also, like the one here : question might be interesting. Some topics that come up regularly is the approximate decomposition of the Rating matrix in user preference and item matrix. This is dome mostly using SVD Singular value decomposition. Many algorithms are proposed for collaborative filtering (CF). The availability of netflix database [3] and the netflix prize accelerated development of CF algorithms. Some of the known methods which use Alternating-Least-Squares (ALS) are [1][4][5]. Another important category of algorithms use Singular Value Decomposition (SVD) in modified forms [2][6]. Stochastic gradient descent (SGD) based algorithms can also be found in literature [7][8].[1] Michael P. Holmes, Alexander G. Gray and Charles Lee Isbell, Jr. QUIC-SVD: Fast SVD Using Cosine Trees[2] Yunhong Zhou, Dennis Wilkinson, Robert Schreiber and Rong Pan. Large-Scale Parallel Collaborative Filtering for the Netflix Prize. Proceedings of the 4th international conference on Algorithmic Aspects in Information and Management. Shanghai, China pp. 337-348, 2008.[3] Netflix CineMatch. Watch TV Shows Online, Watch Movies Online[4] Collaborative Filtering for Implicit Feedback Datasets Hu, Y.; Koren, Y.; Volinsky, C. IEEE International Conference on Data Mining (ICDM 2008), IEEE (2008).D. Needell, J. A. Tropp CoSaMP: Iterative signal recovery from incomplete and inaccurate samples Applied and Computational Harmonic Analysis, Vol. 26, No. 3. (17 Apr 2008), pp. 301-321.[5] Xi Chen, Yanjun Qi, Bing Bai, Qihang Lin and Jaime Carbonell. Sparse Latent Semantic Analysis. In SIAM International Conference on Data Mining (SDM), 2011.[6] Y. Koren. Factorization Meets the Neighborhood: a Multifaceted Collaborative Filtering Model. In ACM KDD 2008.[7] Matrix Factorization Techniques for Recommender Systems Yehuda Koren, Robert Bell, Chris Volinsky In IEEE Computer, Vol. 42, No. 8. (07 August 2009), pp. 30-37.Takács, G, Pilászy, I., Németh, B. and Tikk, D. (2009). Scalable Collaborative Filtering Approaches for Large Recommender Systems. Journal of Machine Learning Research, 10, 623-656.[8] Y. Koren. Factorization Meets the Neighborhood: a Multifaceted Collaborative Filtering Model. In ACM KDD 2008. Equation (5).

Is there any scientific evidence that suggests exoskeleton systems (e.g. Rewalk, Cyberdyne) regenerate neurons to help stroke or paralysis victims regain control of extremities?

Is there any scientific evidence that suggests exoskeleton systems (e.g. Rewalk, Cyberdyne) regenerate neurons to help stroke or paralysis victims regain control of extremities?To date, there are no studies that address the direct effect of robotic exoskeleton systems on neurogenesis. But, if what is really being asked is whether robotic exoskeleton systems influence neural repair and remodeling (where neurogenesis is just one component) then there is at least one indirect evidence (read further).I. Neural repair and remodeling after brain injury.Self-repair after brain injury, such as stroke (brain infarction), is an inherent property of brain tissue. Post-stroke neural repair mechanisms include regeneration of neurons (neurogenesis), regeneration of neuronal elements (axonal sprouting, synaptogenesis), regeneration of glial cells (gliogenesis), and regeneration of blood vessels (angiogenesis) [1]. With more time—and with repetitive stimulation of neural circuits—brain remodeling takes place with restoration or improvement of function .Post-stroke neurogenesis has only been recognized recently. Multipotent stem cells located in the subventricular zone proliferate after a stroke and differentiate into immature neurons (neuroblasts). Angiogenic vessels release chemokines and growth factors that simulate neuroblasts to migrate to injured areas adjacent to the infarct where they differentiate into mature neurons with local synaptic connections and long-distance projections [2-4]. Ablation of newly derived immature neurons after stroke causes reduced recovery [5]. Post-stroke neurogenesis has been reported in human stroke, by utilizing tissue staining for protein markers of immature neurons in autopsy material [6-8].Post-stroke gliogenesis is much more well established than neurogenesis. Stem cells differentiate into oligodendrocyte progenitor cells which divide adjacent to the lesion [9,10]. However, these progenitor cells do not appear to differentiate into fully mature oligodendrocytes after stroke (unlike in multiple sclerosis). Damage to myelinated fiber tracts after white matter stroke is worse in aged animals [11]. Stroke induces proliferation of astrocytes adjacent to the lesion, [12,13] and a large number of new astrocytes are generated from progenitor cells that migrate from the subventricular zone [14,15] Reactive gliosis, the response of astrocytes to brain injury, may be a defensive reaction for limiting tissue damage and restoring homeostasis but it may also inhibit adaptive neuroplasticity mechanisms underlying recovery of function [1].Neuroplasticity is the ability of neurons to produce stable and lasting changes in synaptic and non-synaptic function in response to activation by extrinsic or intrinsic stimuli [16]. It is the basis of memory, learning, and brain remodeling—both during development and after brain injury (e.g. stroke). Our understanding of synaptic plasticity, motor learning, and functional recovery after brain injury has grown significantly in recent years. Brain plasticity is crucial for neural repair and remodeling which can lead to partial or complete recovery of function.Post-stroke remodeling involves reorganization of surviving brain areas, reconnection of disrupted circuits, and/or creation of new compensatory circuits. The mechanisms underlying remodeling are regeneration, growth, migration, and neuroplasticity. In adult humans, post-stroke cortical remodeling of neural circuits may result in any of the following: (1) change in interhemispheric lateralization, (2) alteration in the activity of brain regions (e.g. association cortices) that are linked to the injured zones, (3) reorganization of cortical representational maps, and/or (4) adoption of a bilateral function by the intact contralateral hemisphere [17]. Brain remodeling involves both regenerative changes in gray matter (neurogenesis, gliogenesis, synaptogenesis) and white matter (axonal sprouting, oligodendrogenesis, and remyelination).Brain remodeling can be adaptive or maladaptive. In a perfect world, remodeling results in complete restoration of lost networks and complete recovery of lost function. More often than not, remodeling is incomplete with partial sensorimotor, cognitive and behavioral recovery. Remodeling may also result in maladaptive function when aberrant connections are formed. For example, maladaptive remodeling after a thalamic stroke may result in overactive pain pathways (thalamic pain syndrome) and maladaptive motor remodeling may result in aberrant circuits which, when activated, produce movements that do not fit the repertoire (motor dyssynergia).II. Motor rehabilitation after brain injuryThe goals of post-stroke rehabilitation are functional recovery and functional adaptation. Functional recovery aims to maximize return of lost function, minimize the functional deficits from the stroke, and prevent further functional loss from secondary complications (e.g. contractures can lead to more functional impairment). This goal tends to be emphasized a lot. Thus, rehabilitative strategies are often evaluated on how fast they speed up functional recovery. Functional adaptation emphasizes strategies and techniques that help the person adapt to the impaired function and to develop new skills to compensate for the deficits incurred from the stroke; e.g. learning to use the unaffected hand to carry out two-handed tasks in a single-handed fashion. Good adaptive techniques and equipment do not only minimize the physical impact of the deficits—they also protect against the adverse psychological and social effects of the deficits. The ultimate goal of rehabilitation is improving the quality of life of the handicapped person.Motor rehabilitation influences neuroplasticity and remodeling in animals. Research in animals showed that rehabilitation (via exercise and training) modifies and boost neuroplasticity in animals. Motor learning and cortical stimulation alter intracortical inhibitory circuits and induce cortical remodeling [18-22]. Some researchers demonstrated increased protein synthesis, gene activation, and synaptogenesis in the lesioned hemisphere with motor practice of the paretic limb [21-24] .Motor rehabilitation influences neuroplasticity and remodeling in humans. Studies showed that individuals with better functional recovery of their upper extremity activate primarily the lesioned hemisphere when using the paretic arm [25-29] supporting the argument that targeted upper extremity therapy post-stroke can facilitate engagement of the lesioned hemisphere during movements of the paretic arm. Evidence that rehabilitation enhances neuroplasticity and brain remodeling in humans is indirect at best and is, by and large, based on neuroimaging and neurophysiological studies. A meta-analysis of motor rehabilitation targeting the paretic upper extremity in humans who suffered a stroke showed increased recruitment or engagement in the sensorimotor cortex of the affected hemisphere. There is an expansion in the area of the brain subserving the movements of the paretic arm and an enhancement in TMS, fMRI, PET, or SPECT signal intensity of the particular brain region [30]. Inspired by the concept of post-stroke neuroplasticity, new techniques continue to emerge. A meta-analysis was performed on 66 studies of upper limb rehabilitation in stroke patients. The main therapeutic strategies employed in the studies are: (1) activation of the ipsilesional motor cortex, (2) inhibition of the contralesional motor cortex, and (3) modulation of the sensory afferents by distal cutaneous electrostimulation, anesthesia of the healthy limb, mirror therapy, or virtual reality. The authors found that intensified rehabilitation(by increasing the total hours rehabilitating the paretic limb via repetitive movements and proprioceptive stimulation) improved the arm function significantly when performed in the subacute period (< 6 months post-stroke) [31]. Interestingly, the studies employed different techniques for intense rehabilitation including robots inactive-assisted mode, neuromuscular electrostimulation, and bilateral task training. Another interesting finding is the improvement of the paretic hand dexterity with contralesional neurostimulation or anesthesia of the healthy hand. This has been attributed to a decrease of transcallosal inhibition. Another review focused on the use of cortical stimulation in animals and humans with stroke-related hemiplegia. EMG-controlled electrical muscle stimulation was found to improve the motor function of the hemiparetic arm and hand. Near-infrared spectroscopy (NIRS) studies found that the cerebral blood flow in the injured sensory-motor cortex area is greatest during EMG-controlled functional electrical stimulation(FES). The authors argued that optimal rehabilitation requires timing of interventions to coincide with defined plastic time windows [17].III. Robotic exoskeleton for motor rehabilitationDo robotic exoskeleton systems work? In a recent review of 43 robotic systems for lower-limb rehabilitation [32], the authors concluded that: (1) more than half have not yet been marketed and some systems available in the market are not yet ready for home application because of expense, lack of clinical evidence, therapy protocol, or assessment criteria, and because some systems intended for mobile use are bulky and have short battery life, (2) the robotic systems allows precise measurement of movement parameters which can be used for assessing patient recovery and progress but there are no standardized protocols for reliable assessment of data, (3) clinical studies conducted show little evidence for superior effectiveness of robotic systems compared to manually assisted training for locomotor recovery and (4) the robotic systems have a clear benefit in terms of reduced therapist effort, time, and costs [32].REX-FES hybrid systems. Hybrid exoskeletons were first introduced in 1978 [33], though actual physical construction and preliminary results were not reported until 1989 [34]. In a recent review of hybrid exoskeletons [35]—robotic exoskeleton (REX) with functional electrical stimulation (FES)—to restore gait following spinal cord injury(SCI), the authors recognized the following: (1) FES advantage—natural muscles are the actuators of gait provide functional and psychological benefits, (2) FES disadvantages—early appearance of muscle fatigue and control of joint trajectories, (3) REX advantage—provides joint movement compensation or substitution to the body during walking, and (4) REX disadvantage—technology is not mature yet because of many limitations related to physical and cognitive interaction, portability, and energy-management issues, (5) REX-FES hybrid technology brings together technologies, methods,and rehabilitation principles that can overcome the drawbacks of each individual approach, and (6) studies are difficult to interpret and generalize due to subject variability (e.g. the location of the muscles affected, muscular atrophy in the chronic phase of the injury, impaired sensation and decreased physical capacity are different and require specific clinical evaluation in patients with SCI), lack of data on the testing method [36-38], insufficient number of subjects [34, 39-43], and the considerable variability in the metrics used to evaluate hybrid exoskeletons. Although the hybrid systems are functional there are no criteria regarding the optimum balance between the exoskeleton and muscle joint torque [35].Do robotic exoskeleton systems influence neuroplasticity and remodeling? Intuitively—yes! By definition, neuroplasticity and remodeling are driven by sensory activation. Movement is always sensory and motor—not only motor. Every time you move,proprioceptive information from the muscles and joints are sent to the brain.Every time the foot touches the ground or the hands manipulate an object proprioceptive and tactile information are sent to the brainstem, to the thalamus, to the cerebral cortex, and to the motor control circuits of the cerebellum and basal ganglia. All of these structures are involved with neuroplasticity and remodeling. Activating the appropriate circuits regularly and frequently (as in intensified rehabilitation; see above) guarantees neuroplasticity and remodeling. But there’s one caveat: the ingredients for achieving this should be available. If the part of the brain damaged is large then neuroplasticity and remodeling cannot occur in that big hole filled with CSF (called encephalomalacia). However, other parts can still compensate and participate in remodeling.Almost all studies on robotic exoskeleton (discussed earlier) address measurable effects on function (e.g. gait), optimal technical parameters, and safety issues but not neuroplasticity or brain modeling. For example, a recent paper reports that H2 robotic exoskeleton for gait rehabilitation after stroke is a robust and safe system for assisting a stroke patient perform an overground walking task [44].Only a few studies directly address the effect of robot-mediated therapy on neuroplasticity. In a review of spinal plasticity in robot-mediated therapy for the lower limbs, the authors found essentially no evidence for the mechanisms underlying functional improvements in humans (particularly in terms of neuroplasticity or remodeling in the spinal cord) and they ended up proposing methods for measuring spinal plasticity using robotic devices [45]. Thus far, the only article linking hybrid assistive limb (HAL) exoskeleton training to neuroplasticity and cortical reorganization is based on indirect evidence—changes in somatosensory evoked potentials (SEP) [46]. Based on the previous reports of reorganization in the sensorimotor cortex accompanied by increased excitability and enlarged body representations in spinal cord injury (SCI) patients, the author hypothesized that HAL-assisted body weight supported treadmill training induces cortical reorganization and improves walking function. Paired-pulse somatosensory evoked potentials (ppSEP) was performed in 11 SCI patients by stimulation above the level of injury before and after 3 months of HAL-assisted training and the SEP amplitude ratios (amplitude following double pulses) were assessed and compared to that of 11 healthy controls. PpSEPs were significantly increased in SCI patients as compared to controls at baseline. Following training, ppSEPs were increased from baseline and no longer significantly differed from controls. Walking parameters also showed significant improvements, yet there was no significant correlation between ppSEP measures and walking parameters [46].IV. The ultimate goal of rehabilitationImprovement in the quality of life through functional recovery, functional adaptation, or both is the ultimate goal of any rehabilitation program. 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