A Possible Mechanism of Zika Virus Associated Microcephaly: Imperative Role of Retinoic Acid Response Element (RARE) Consensus Sequence Repeats in the Viral Genome
Identifieur interne : 000858 ( Pmc/Corpus ); précédent : 000857; suivant : 000859A Possible Mechanism of Zika Virus Associated Microcephaly: Imperative Role of Retinoic Acid Response Element (RARE) Consensus Sequence Repeats in the Viral Genome
Auteurs : Ashutosh Kumar ; Himanshu N. Singh ; Vikas Pareek ; Khursheed Raza ; Subrahamanyam Dantham ; Pavan Kumar ; Sankat Mochan ; Muneeb A. FaiqSource :
- Frontiers in Human Neuroscience [ 1662-5161 ] ; 2016.
Abstract
Owing to the reports of microcephaly as a consistent outcome in the fetuses of pregnant women infected with ZIKV in Brazil, Zika virus (ZIKV)—microcephaly etiomechanistic relationship has recently been implicated. Researchers, however, are still struggling to establish an embryological basis for this interesting causal handcuff. The present study reveals robust evidence in favor of a plausible ZIKV-microcephaly cause-effect liaison. The rationale is based on: (1) sequence homology between ZIKV genome and the response element of an early neural tube developmental marker “retinoic acid” in human DNA and (2) comprehensive similarities between the details of brain defects in ZIKV-microcephaly and retinoic acid embryopathy. Retinoic acid is considered as the earliest factor for regulating anteroposterior axis of neural tube and positioning of structures in developing brain through retinoic acid response elements (RARE) consensus sequence (5′–AGGTCA–3′) in promoter regions of retinoic acid-dependent genes. We screened genomic sequences of already reported virulent ZIKV strains (including those linked to microcephaly) and other viruses available in National Institute of Health genetic sequence database (GenBank) for the RARE consensus repeats and obtained results strongly bolstering our hypothesis that ZIKV strains associated with microcephaly may act through precipitation of dysregulation in retinoic acid-dependent genes by introducing extra stretches of RARE consensus sequence repeats in the genome of developing brain cells. Additional support to our hypothesis comes from our findings that screening of other viruses for RARE consensus sequence repeats is positive only for those known to display neurotropism and cause fetal brain defects (for which maternal-fetal transmission during developing stage may be required). The numbers of RARE sequence repeats appeared to match with the virulence of screened positive viruses. Although, bioinformatic evidence and embryological features are in favor of our hypothesis, additional studies including animal models are warranted to validate our proposition. Such studies are likely to unfold ZIKV-microcephaly association and may help in devising methods to combat it.
Url:
DOI: 10.3389/fnhum.2016.00403
PubMed: 27555815
PubMed Central: 4977292
Links to Exploration step
PMC:4977292Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A Possible Mechanism of Zika Virus Associated Microcephaly: Imperative Role of Retinoic Acid Response Element (RARE) Consensus Sequence Repeats in the Viral Genome</title>
<author><name sortKey="Kumar, Ashutosh" sort="Kumar, Ashutosh" uniqKey="Kumar A" first="Ashutosh" last="Kumar">Ashutosh Kumar</name>
<affiliation><nlm:aff id="aff1"><institution>Department of Anatomy, All India Institute of Medical Sciences</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Singh, Himanshu N" sort="Singh, Himanshu N" uniqKey="Singh H" first="Himanshu N." last="Singh">Himanshu N. Singh</name>
<affiliation><nlm:aff id="aff2"><institution>Department of Biochemistry, All India Institute of Medical Sciences</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pareek, Vikas" sort="Pareek, Vikas" uniqKey="Pareek V" first="Vikas" last="Pareek">Vikas Pareek</name>
<affiliation><nlm:aff id="aff3"><institution>Computational Neuroscience and Neuroimaging Division, National Brain Research Centre</institution>
<country>Manesar, India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Raza, Khursheed" sort="Raza, Khursheed" uniqKey="Raza K" first="Khursheed" last="Raza">Khursheed Raza</name>
<affiliation><nlm:aff id="aff1"><institution>Department of Anatomy, All India Institute of Medical Sciences</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dantham, Subrahamanyam" sort="Dantham, Subrahamanyam" uniqKey="Dantham S" first="Subrahamanyam" last="Dantham">Subrahamanyam Dantham</name>
<affiliation><nlm:aff id="aff2"><institution>Department of Biochemistry, All India Institute of Medical Sciences</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kumar, Pavan" sort="Kumar, Pavan" uniqKey="Kumar P" first="Pavan" last="Kumar">Pavan Kumar</name>
<affiliation><nlm:aff id="aff1"><institution>Department of Anatomy, All India Institute of Medical Sciences</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mochan, Sankat" sort="Mochan, Sankat" uniqKey="Mochan S" first="Sankat" last="Mochan">Sankat Mochan</name>
<affiliation><nlm:aff id="aff1"><institution>Department of Anatomy, All India Institute of Medical Sciences</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Faiq, Muneeb A" sort="Faiq, Muneeb A" uniqKey="Faiq M" first="Muneeb A." last="Faiq">Muneeb A. Faiq</name>
<affiliation><nlm:aff id="aff4"><institution>Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff5"><institution>Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of medical Sciences</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff6"><institution>Medical Biotechnology Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">27555815</idno>
<idno type="pmc">4977292</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4977292</idno>
<idno type="RBID">PMC:4977292</idno>
<idno type="doi">10.3389/fnhum.2016.00403</idno>
<date when="2016">2016</date>
<idno type="wicri:Area/Pmc/Corpus">000858</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000858</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Possible Mechanism of Zika Virus Associated Microcephaly: Imperative Role of Retinoic Acid Response Element (RARE) Consensus Sequence Repeats in the Viral Genome</title>
<author><name sortKey="Kumar, Ashutosh" sort="Kumar, Ashutosh" uniqKey="Kumar A" first="Ashutosh" last="Kumar">Ashutosh Kumar</name>
<affiliation><nlm:aff id="aff1"><institution>Department of Anatomy, All India Institute of Medical Sciences</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Singh, Himanshu N" sort="Singh, Himanshu N" uniqKey="Singh H" first="Himanshu N." last="Singh">Himanshu N. Singh</name>
<affiliation><nlm:aff id="aff2"><institution>Department of Biochemistry, All India Institute of Medical Sciences</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pareek, Vikas" sort="Pareek, Vikas" uniqKey="Pareek V" first="Vikas" last="Pareek">Vikas Pareek</name>
<affiliation><nlm:aff id="aff3"><institution>Computational Neuroscience and Neuroimaging Division, National Brain Research Centre</institution>
<country>Manesar, India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Raza, Khursheed" sort="Raza, Khursheed" uniqKey="Raza K" first="Khursheed" last="Raza">Khursheed Raza</name>
<affiliation><nlm:aff id="aff1"><institution>Department of Anatomy, All India Institute of Medical Sciences</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dantham, Subrahamanyam" sort="Dantham, Subrahamanyam" uniqKey="Dantham S" first="Subrahamanyam" last="Dantham">Subrahamanyam Dantham</name>
<affiliation><nlm:aff id="aff2"><institution>Department of Biochemistry, All India Institute of Medical Sciences</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kumar, Pavan" sort="Kumar, Pavan" uniqKey="Kumar P" first="Pavan" last="Kumar">Pavan Kumar</name>
<affiliation><nlm:aff id="aff1"><institution>Department of Anatomy, All India Institute of Medical Sciences</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mochan, Sankat" sort="Mochan, Sankat" uniqKey="Mochan S" first="Sankat" last="Mochan">Sankat Mochan</name>
<affiliation><nlm:aff id="aff1"><institution>Department of Anatomy, All India Institute of Medical Sciences</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Faiq, Muneeb A" sort="Faiq, Muneeb A" uniqKey="Faiq M" first="Muneeb A." last="Faiq">Muneeb A. Faiq</name>
<affiliation><nlm:aff id="aff4"><institution>Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff5"><institution>Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of medical Sciences</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff6"><institution>Medical Biotechnology Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi</institution>
<country>New Delhi, India</country>
</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Frontiers in Human Neuroscience</title>
<idno type="eISSN">1662-5161</idno>
<imprint><date when="2016">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Owing to the reports of microcephaly as a consistent outcome in the fetuses of pregnant women infected with ZIKV in Brazil, Zika virus (ZIKV)—microcephaly etiomechanistic relationship has recently been implicated. Researchers, however, are still struggling to establish an embryological basis for this interesting causal handcuff. The present study reveals robust evidence in favor of a plausible ZIKV-microcephaly cause-effect liaison. The rationale is based on: (1) sequence homology between ZIKV genome and the response element of an early neural tube developmental marker “retinoic acid” in human DNA and (2) comprehensive similarities between the details of brain defects in ZIKV-microcephaly and retinoic acid embryopathy. Retinoic acid is considered as the earliest factor for regulating anteroposterior axis of neural tube and positioning of structures in developing brain through retinoic acid response elements (RARE) consensus sequence (5′–AGGTCA–3′) in promoter regions of retinoic acid-dependent genes. We screened genomic sequences of already reported virulent ZIKV strains (including those linked to microcephaly) and other viruses available in National Institute of Health genetic sequence database (GenBank) for the RARE consensus repeats and obtained results strongly bolstering our hypothesis that ZIKV strains associated with microcephaly may act through precipitation of dysregulation in retinoic acid-dependent genes by introducing extra stretches of RARE consensus sequence repeats in the genome of developing brain cells. Additional support to our hypothesis comes from our findings that screening of other viruses for RARE consensus sequence repeats is positive only for those known to display neurotropism and cause fetal brain defects (for which maternal-fetal transmission during developing stage may be required). The numbers of RARE sequence repeats appeared to match with the virulence of screened positive viruses. Although, bioinformatic evidence and embryological features are in favor of our hypothesis, additional studies including animal models are warranted to validate our proposition. Such studies are likely to unfold ZIKV-microcephaly association and may help in devising methods to combat it.</p>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Adams Waldorf, K M" uniqKey="Adams Waldorf K">K. M Adams Waldorf</name>
</author>
<author><name sortKey="Mcadams, R M" uniqKey="Mcadams R">R. M. McAdams</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Aragao, M" uniqKey="Aragao M">M. Aragao</name>
</author>
<author><name sortKey="De, F V" uniqKey="De F">F. V. de</name>
</author>
<author><name sortKey="Van Der Linden, V" uniqKey="Van Der Linden V">V. van der Linden</name>
</author>
<author><name sortKey="Brainer Lima, A M" uniqKey="Brainer Lima A">A. M. Brainer-Lima</name>
</author>
<author><name sortKey="Coeli, R R" uniqKey="Coeli R">R. R. Coeli</name>
</author>
<author><name sortKey="Rocha, M A" uniqKey="Rocha M">M. A. Rocha</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Balmer, J E" uniqKey="Balmer J">J. E. Balmer</name>
</author>
<author><name sortKey="Blomhoff, R" uniqKey="Blomhoff R">R. Blomhoff</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Baronti, C" uniqKey="Baronti C">C. Baronti</name>
</author>
<author><name sortKey="Piorkowski, G" uniqKey="Piorkowski G">G. Piorkowski</name>
</author>
<author><name sortKey="Charrel, R N" uniqKey="Charrel R">R. N. Charrel</name>
</author>
<author><name sortKey="Boubis, L" uniqKey="Boubis L">L. Boubis</name>
</author>
<author><name sortKey="Leparc Goffart, I" uniqKey="Leparc Goffart I">I. Leparc-Goffart</name>
</author>
<author><name sortKey="De Lamballerie, X" uniqKey="De Lamballerie X">X. de Lamballerie</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Calvet, G" uniqKey="Calvet G">G. Calvet</name>
</author>
<author><name sortKey="Aguiar, R S" uniqKey="Aguiar R">R. S. Aguiar</name>
</author>
<author><name sortKey="Melo, A S" uniqKey="Melo A">A. S. Melo</name>
</author>
<author><name sortKey="Sampaio, S A" uniqKey="Sampaio S">S. A. Sampaio</name>
</author>
<author><name sortKey="De Filippis, I" uniqKey="De Filippis I">I. de Filippis</name>
</author>
<author><name sortKey="Fabri, A" uniqKey="Fabri A">A. Fabri</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Carty, M" uniqKey="Carty M">M. Carty</name>
</author>
<author><name sortKey="Reinert, L" uniqKey="Reinert L">L. Reinert</name>
</author>
<author><name sortKey="Paludan, S R" uniqKey="Paludan S">S. R. Paludan</name>
</author>
<author><name sortKey="Bowie, A G" uniqKey="Bowie A">A. G. Bowie</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Cipriano, R" uniqKey="Cipriano R">R. Cipriano</name>
</author>
<author><name sortKey="Monteiro, C C" uniqKey="Monteiro C">C. C. Monteiro</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Civitello, L" uniqKey="Civitello L">L. Civitello</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Crandall, J E" uniqKey="Crandall J">J. E. Crandall</name>
</author>
<author><name sortKey="Goodman, T" uniqKey="Goodman T">T. Goodman</name>
</author>
<author><name sortKey="Mccarthy, D M" uniqKey="Mccarthy D">D. M. McCarthy</name>
</author>
<author><name sortKey="Duester, G" uniqKey="Duester G">G. Duester</name>
</author>
<author><name sortKey="Bhide, P G" uniqKey="Bhide P">P. G. Bhide</name>
</author>
<author><name sortKey="Dr Ger, U C" uniqKey="Dr Ger U">U. C. Dräger</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Dang, J" uniqKey="Dang J">J. Dang</name>
</author>
<author><name sortKey="Tiwari, S K" uniqKey="Tiwari S">S. K. Tiwari</name>
</author>
<author><name sortKey="Lichinchi, G" uniqKey="Lichinchi G">G. Lichinchi</name>
</author>
<author><name sortKey="Qin, Y" uniqKey="Qin Y">Y. Qin</name>
</author>
<author><name sortKey="Patil, V S" uniqKey="Patil V">V. S. Patil</name>
</author>
<author><name sortKey="Eroshkin, A M" uniqKey="Eroshkin A">A. M. Eroshkin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="De Paula Freitas, B" uniqKey="De Paula Freitas B">B. de Paula Freitas</name>
</author>
<author><name sortKey="De Oliveira Dias, J R" uniqKey="De Oliveira Dias J">J. R. de Oliveira Dias</name>
</author>
<author><name sortKey="Prazeres, J" uniqKey="Prazeres J">J. Prazeres</name>
</author>
<author><name sortKey="Sacramento, G A" uniqKey="Sacramento G">G. A. Sacramento</name>
</author>
<author><name sortKey="Ko, A I" uniqKey="Ko A">A. I. Ko</name>
</author>
<author><name sortKey="Maia, M" uniqKey="Maia M">M. Maia</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Durston, A J" uniqKey="Durston A">A. J. Durston</name>
</author>
<author><name sortKey="Timmermans, J P" uniqKey="Timmermans J">J. P. Timmermans</name>
</author>
<author><name sortKey="Hage, W J" uniqKey="Hage W">W. J. Hage</name>
</author>
<author><name sortKey="Hendriks, H F" uniqKey="Hendriks H">H. F. Hendriks</name>
</author>
<author><name sortKey="De Vries, N J" uniqKey="De Vries N">N. J. de Vries</name>
</author>
<author><name sortKey="Heideveld, M" uniqKey="Heideveld M">M. Heideveld</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Findlay, G" uniqKey="Findlay G">G. Findlay</name>
</author>
<author><name sortKey="Stern, R O" uniqKey="Stern R">R. O. Stern</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Forton, D M" uniqKey="Forton D">D. M. Forton</name>
</author>
<author><name sortKey="Allsop, J M" uniqKey="Allsop J">J. M. Allsop</name>
</author>
<author><name sortKey="Main, J" uniqKey="Main J">J. Main</name>
</author>
<author><name sortKey="Foster, G R" uniqKey="Foster G">G. R. Foster</name>
</author>
<author><name sortKey="Thomas, H C" uniqKey="Thomas H">H. C. Thomas</name>
</author>
<author><name sortKey="Taylor Robinson, S D" uniqKey="Taylor Robinson S">S. D. Taylor-Robinson</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Fritel, X" uniqKey="Fritel X">X. Fritel</name>
</author>
<author><name sortKey="Rollot, O" uniqKey="Rollot O">O. Rollot</name>
</author>
<author><name sortKey="Gerardin, P" uniqKey="Gerardin P">P. Gérardin</name>
</author>
<author><name sortKey="Gauzere, B A" uniqKey="Gauzere B">B. A. Gauzere</name>
</author>
<author><name sortKey="Bideault, J" uniqKey="Bideault J">J. Bideault</name>
</author>
<author><name sortKey="Lagarde, L" uniqKey="Lagarde L">L. Lagarde</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Furr, S R" uniqKey="Furr S">S. R. Furr</name>
</author>
<author><name sortKey="Marriott, I" uniqKey="Marriott I">I. Marriott</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Garcez, P P" uniqKey="Garcez P">P. P. Garcez</name>
</author>
<author><name sortKey="Loiola, E C" uniqKey="Loiola E">E. C. Loiola</name>
</author>
<author><name sortKey="Madeiro Da Costa, R" uniqKey="Madeiro Da Costa R">R Madeiro da Costa</name>
</author>
<author><name sortKey="Higa, L M" uniqKey="Higa L">L. M. Higa</name>
</author>
<author><name sortKey="Trindade, P" uniqKey="Trindade P">P. Trindade</name>
</author>
<author><name sortKey="Delvecchio, R" uniqKey="Delvecchio R">R. Delvecchio</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gerardin, P" uniqKey="Gerardin P">P. Gérardin</name>
</author>
<author><name sortKey="Barau, G" uniqKey="Barau G">G. Barau</name>
</author>
<author><name sortKey="Michault, A" uniqKey="Michault A">A. Michault</name>
</author>
<author><name sortKey="Bintner, M" uniqKey="Bintner M">M. Bintner</name>
</author>
<author><name sortKey="Randrianaivo, H" uniqKey="Randrianaivo H">H. Randrianaivo</name>
</author>
<author><name sortKey="Choker, G" uniqKey="Choker G">G. Choker</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gerardin, P" uniqKey="Gerardin P">P. Gérardin</name>
</author>
<author><name sortKey="Samperiz, S" uniqKey="Samperiz S">S. Sampériz</name>
</author>
<author><name sortKey="Ramful, D" uniqKey="Ramful D">D. Ramful</name>
</author>
<author><name sortKey="Boumahni, B" uniqKey="Boumahni B">B. Boumahni</name>
</author>
<author><name sortKey="Bintner, M" uniqKey="Bintner M">M. Bintner</name>
</author>
<author><name sortKey="Alessandri, J L" uniqKey="Alessandri J">J.-L. Alessandri</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Grapin Botton, A" uniqKey="Grapin Botton A">A. Grapin-Botton</name>
</author>
<author><name sortKey="Bonnin, M A" uniqKey="Bonnin M">M. A. Bonnin</name>
</author>
<author><name sortKey="Sieweke, M" uniqKey="Sieweke M">M. Sieweke</name>
</author>
<author><name sortKey="Le Douarin, N M" uniqKey="Le Douarin N">N. M. Le Douarin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Grover, V P" uniqKey="Grover V">V. P. Grover</name>
</author>
<author><name sortKey="Pavese, N" uniqKey="Pavese N">N. Pavese</name>
</author>
<author><name sortKey="Koh, S B" uniqKey="Koh S">S. B. Koh</name>
</author>
<author><name sortKey="Wylezinska, M" uniqKey="Wylezinska M">M. Wylezinska</name>
</author>
<author><name sortKey="Saxby, B K" uniqKey="Saxby B">B. K. Saxby</name>
</author>
<author><name sortKey="Gerhard, A" uniqKey="Gerhard A">A. Gerhard</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Guimard, T" uniqKey="Guimard T">T. Guimard</name>
</author>
<author><name sortKey="Minjolle, S" uniqKey="Minjolle S">S. Minjolle</name>
</author>
<author><name sortKey="Polard, E" uniqKey="Polard E">E. Polard</name>
</author>
<author><name sortKey="Fily, F" uniqKey="Fily F">F. Fily</name>
</author>
<author><name sortKey="Zeller, H" uniqKey="Zeller H">H. Zeller</name>
</author>
<author><name sortKey="Michelet, C" uniqKey="Michelet C">C. Michelet</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gupta, S" uniqKey="Gupta S">S. Gupta</name>
</author>
<author><name sortKey="Sen, J" uniqKey="Sen J">J. Sen</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Halilagic, A" uniqKey="Halilagic A">A. Halilagic</name>
</author>
<author><name sortKey="Ribes, V" uniqKey="Ribes V">V. Ribes</name>
</author>
<author><name sortKey="Ghyselinck, N B" uniqKey="Ghyselinck N">N. B. Ghyselinck</name>
</author>
<author><name sortKey="Zile, M H" uniqKey="Zile M">M. H. Zile</name>
</author>
<author><name sortKey="Dolle, P" uniqKey="Dolle P">P. Dollé</name>
</author>
<author><name sortKey="Studer, M" uniqKey="Studer M">M. Studer</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Harrison Uy, S J" uniqKey="Harrison Uy S">S. J. Harrison-Uy</name>
</author>
<author><name sortKey="Siegenthaler, J A" uniqKey="Siegenthaler J">J. A. Siegenthaler</name>
</author>
<author><name sortKey="Faedo, A" uniqKey="Faedo A">A. Faedo</name>
</author>
<author><name sortKey="Rubenstein, J L" uniqKey="Rubenstein J">J. L. Rubenstein</name>
</author>
<author><name sortKey="Pleasure, S J" uniqKey="Pleasure S">S. J. Pleasure</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hazin, A N" uniqKey="Hazin A">A. N. Hazin</name>
</author>
<author><name sortKey="Poretti, A" uniqKey="Poretti A">A. Poretti</name>
</author>
<author><name sortKey="Di Cavalcanti Souza Cruz, D" uniqKey="Di Cavalcanti Souza Cruz D">D. Di Cavalcanti Souza Cruz</name>
</author>
<author><name sortKey="Tenorio, M" uniqKey="Tenorio M">M. Tenorio</name>
</author>
<author><name sortKey="Van Der Linden, A" uniqKey="Van Der Linden A">A. van der Linden</name>
</author>
<author><name sortKey="Pena, L J" uniqKey="Pena L">L. J. Pena</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Huang, J K" uniqKey="Huang J">J. K. Huang</name>
</author>
<author><name sortKey="Jarjour, A A" uniqKey="Jarjour A">A. A. Jarjour</name>
</author>
<author><name sortKey="Nait Oumesmar, B" uniqKey="Nait Oumesmar B">B Nait Oumesmar</name>
</author>
<author><name sortKey="Kerninon, C" uniqKey="Kerninon C">C. Kerninon</name>
</author>
<author><name sortKey="Williams, A" uniqKey="Williams A">A. Williams</name>
</author>
<author><name sortKey="Krezel, W" uniqKey="Krezel W">W. Krezel</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Irving, D W" uniqKey="Irving D">D. W. Irving</name>
</author>
<author><name sortKey="Willhite, C C" uniqKey="Willhite C">C. C. Willhite</name>
</author>
<author><name sortKey="Burk, D T" uniqKey="Burk D">D. T. Burk</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Jain, S" uniqKey="Jain S">S. Jain</name>
</author>
<author><name sortKey="Kim, H G" uniqKey="Kim H">H.-G. Kim</name>
</author>
<author><name sortKey="Lacbawan, F" uniqKey="Lacbawan F">F. Lacbawan</name>
</author>
<author><name sortKey="Meliciani, I" uniqKey="Meliciani I">I. Meliciani</name>
</author>
<author><name sortKey="Wenzel, W" uniqKey="Wenzel W">W. Wenzel</name>
</author>
<author><name sortKey="Kurth, I" uniqKey="Kurth I">I. Kurth</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kam, R K T" uniqKey="Kam R">R. K. T. Kam</name>
</author>
<author><name sortKey="Deng, Y" uniqKey="Deng Y">Y. Deng</name>
</author>
<author><name sortKey="Chen, Y" uniqKey="Chen Y">Y. Chen</name>
</author>
<author><name sortKey="Zhao, H" uniqKey="Zhao H">H. Zhao</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kimura Kuroda, J" uniqKey="Kimura Kuroda J">J. Kimura-Kuroda</name>
</author>
<author><name sortKey="Ichikawa, M" uniqKey="Ichikawa M">M. Ichikawa</name>
</author>
<author><name sortKey="Ogata, A" uniqKey="Ogata A">A. Ogata</name>
</author>
<author><name sortKey="Nagashima, K" uniqKey="Nagashima K">K. Nagashima</name>
</author>
<author><name sortKey="Yasui, K" uniqKey="Yasui K">K. Yasui</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Konig, R" uniqKey="Konig R">R. König</name>
</author>
<author><name sortKey="Stillfried, M" uniqKey="Stillfried M">M. Stillfried</name>
</author>
<author><name sortKey="Aperdannier, P" uniqKey="Aperdannier P">P. Aperdannier</name>
</author>
<author><name sortKey="Clarner, T" uniqKey="Clarner T">T. Clarner</name>
</author>
<author><name sortKey="Beyer, C" uniqKey="Beyer C">C. Beyer</name>
</author>
<author><name sortKey="Kipp, M" uniqKey="Kipp M">M. Kipp</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kot Leibovich, H" uniqKey="Kot Leibovich H">H. Kot-Leibovich</name>
</author>
<author><name sortKey="Fainsod, A" uniqKey="Fainsod A">A. Fainsod</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Koyuncu, O O" uniqKey="Koyuncu O">O. O. Koyuncu</name>
</author>
<author><name sortKey="Hogue, I B" uniqKey="Hogue I">I. B. Hogue</name>
</author>
<author><name sortKey="Enquist, L W" uniqKey="Enquist L">L. W. Enquist</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lammer, E J" uniqKey="Lammer E">E. J. Lammer</name>
</author>
<author><name sortKey="Chen, D T" uniqKey="Chen D">D. T. Chen</name>
</author>
<author><name sortKey="Hoar, R M" uniqKey="Hoar R">R. M. Hoar</name>
</author>
<author><name sortKey="Agnish, N D" uniqKey="Agnish N">N. D. Agnish</name>
</author>
<author><name sortKey="Benke, P J" uniqKey="Benke P">P. J. Benke</name>
</author>
<author><name sortKey="Braun, J T" uniqKey="Braun J">J. T. Braun</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lau, S K" uniqKey="Lau S">S. K. Lau</name>
</author>
<author><name sortKey="Woo, P C" uniqKey="Woo P">P. C. Woo</name>
</author>
<author><name sortKey="Yip, C C" uniqKey="Yip C">C. C. Yip</name>
</author>
<author><name sortKey="Tse, H" uniqKey="Tse H">H. Tse</name>
</author>
<author><name sortKey="Tsoi, H W" uniqKey="Tsoi H">H. W. Tsoi</name>
</author>
<author><name sortKey="Cheng, V C" uniqKey="Cheng V">V. C. Cheng</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Liu, P" uniqKey="Liu P">P. Liu</name>
</author>
<author><name sortKey="Jamaluddin, M" uniqKey="Jamaluddin M">M. Jamaluddin</name>
</author>
<author><name sortKey="Li, K" uniqKey="Li K">K. Li</name>
</author>
<author><name sortKey="Garofalo, R P" uniqKey="Garofalo R">R. P. Garofalo</name>
</author>
<author><name sortKey="Casola, A" uniqKey="Casola A">A. Casola</name>
</author>
<author><name sortKey="Brasier, A R" uniqKey="Brasier A">A. R. Brasier</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ludlow, M" uniqKey="Ludlow M">M. Ludlow</name>
</author>
<author><name sortKey="Kortekaas, J" uniqKey="Kortekaas J">J. Kortekaas</name>
</author>
<author><name sortKey="Herden, C" uniqKey="Herden C">C. Herden</name>
</author>
<author><name sortKey="Hoffmann, B" uniqKey="Hoffmann B">B. Hoffmann</name>
</author>
<author><name sortKey="Tappe, D" uniqKey="Tappe D">D. Tappe</name>
</author>
<author><name sortKey="Trebst, C" uniqKey="Trebst C">C. Trebst</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Martinez Morales, P L" uniqKey="Martinez Morales P">P. L. Martínez-Morales</name>
</author>
<author><name sortKey="Del Corral, R D" uniqKey="Del Corral R">R. D. del Corral</name>
</author>
<author><name sortKey="Olivera Martinez, I" uniqKey="Olivera Martinez I">I. Olivera-Martínez</name>
</author>
<author><name sortKey="Quiroga, A C" uniqKey="Quiroga A">A. C. Quiroga</name>
</author>
<author><name sortKey="Das, R M" uniqKey="Das R">R. M. Das</name>
</author>
<author><name sortKey="Barbas, J A" uniqKey="Barbas J">J. A. Barbas</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mic, F A" uniqKey="Mic F">F. A. Mic</name>
</author>
<author><name sortKey="Molotkov, A" uniqKey="Molotkov A">A. Molotkov</name>
</author>
<author><name sortKey="Molotkova, N" uniqKey="Molotkova N">N. Molotkova</name>
</author>
<author><name sortKey="Duester, G" uniqKey="Duester G">G. Duester</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Micucci, J A" uniqKey="Micucci J">J. A. Micucci</name>
</author>
<author><name sortKey="Layman, W S" uniqKey="Layman W">W. S. Layman</name>
</author>
<author><name sortKey="Hurd, E A" uniqKey="Hurd E">E. A. Hurd</name>
</author>
<author><name sortKey="Sperry, E D" uniqKey="Sperry E">E. D. Sperry</name>
</author>
<author><name sortKey="Frank, S F" uniqKey="Frank S">S. F. Frank</name>
</author>
<author><name sortKey="Durham, M A" uniqKey="Durham M">M. A. Durham</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mlakar, J" uniqKey="Mlakar J">J. Mlakar</name>
</author>
<author><name sortKey="Korva, M" uniqKey="Korva M">M. Korva</name>
</author>
<author><name sortKey="Tul, N" uniqKey="Tul N">N. Tul</name>
</author>
<author><name sortKey="Popovi, M" uniqKey="Popovi M">M. Popović</name>
</author>
<author><name sortKey="Poljsak Prijatelj, M" uniqKey="Poljsak Prijatelj M">M. Poljšak-Prijatelj</name>
</author>
<author><name sortKey="Mraz, J" uniqKey="Mraz J">J. Mraz</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mochida, G H" uniqKey="Mochida G">G. H. Mochida</name>
</author>
<author><name sortKey="Walsh, C A" uniqKey="Walsh C">C. A. Walsh</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mupapa, K" uniqKey="Mupapa K">K. Mupapa</name>
</author>
<author><name sortKey="Mukundu, W" uniqKey="Mukundu W">W. Mukundu</name>
</author>
<author><name sortKey="Bwaka, M A" uniqKey="Bwaka M">M. A. Bwaka</name>
</author>
<author><name sortKey="Kipasa, M" uniqKey="Kipasa M">M. Kipasa</name>
</author>
<author><name sortKey="Roo, A D" uniqKey="Roo A">A. D. Roo</name>
</author>
<author><name sortKey="Kuvula, K" uniqKey="Kuvula K">K. Kuvula</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Okuda, D T" uniqKey="Okuda D">D. T. Okuda</name>
</author>
<author><name sortKey="Prados, M D" uniqKey="Prados M">M. D. Prados</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Paganelli, A" uniqKey="Paganelli A">A. Paganelli</name>
</author>
<author><name sortKey="Gnazzo, V" uniqKey="Gnazzo V">V. Gnazzo</name>
</author>
<author><name sortKey="Acosta, H" uniqKey="Acosta H">H. Acosta</name>
</author>
<author><name sortKey="L Pez, S L" uniqKey="L Pez S">S. L. López</name>
</author>
<author><name sortKey="Carrasco, A E" uniqKey="Carrasco A">A. E. Carrasco</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Rajaii, F" uniqKey="Rajaii F">F. Rajaii</name>
</author>
<author><name sortKey="Bitzer, Z T" uniqKey="Bitzer Z">Z. T. Bitzer</name>
</author>
<author><name sortKey="Xu, Q" uniqKey="Xu Q">Q. Xu</name>
</author>
<author><name sortKey="Sockanathan, S" uniqKey="Sockanathan S">S. Sockanathan</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Rasmussen, S A" uniqKey="Rasmussen S">S. A. Rasmussen</name>
</author>
<author><name sortKey="Jamieson, D J" uniqKey="Jamieson D">D. J. Jamieson</name>
</author>
<author><name sortKey="Honein, M A" uniqKey="Honein M">M. A. Honein</name>
</author>
<author><name sortKey="Petersen, L R" uniqKey="Petersen L">L. R. Petersen</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Rhinn, M" uniqKey="Rhinn M">M. Rhinn</name>
</author>
<author><name sortKey="Dolle, P" uniqKey="Dolle P">P. Dollé</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Rubin, S A" uniqKey="Rubin S">S. A. Rubin</name>
</author>
<author><name sortKey="Amexis, G" uniqKey="Amexis G">G. Amexis</name>
</author>
<author><name sortKey="Pletnikov, M" uniqKey="Pletnikov M">M. Pletnikov</name>
</author>
<author><name sortKey="Vanderzanden, J" uniqKey="Vanderzanden J">J. Vanderzanden</name>
</author>
<author><name sortKey="Mauldin, J" uniqKey="Mauldin J">J. Mauldin</name>
</author>
<author><name sortKey="Sauder, C" uniqKey="Sauder C">C. Sauder</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Salazar, M I" uniqKey="Salazar M">M. I. Salazar</name>
</author>
<author><name sortKey="Perez Garcia, M" uniqKey="Perez Garcia M">M. Pérez-García</name>
</author>
<author><name sortKey="Terreros Tinoco, M" uniqKey="Terreros Tinoco M">M. Terreros-Tinoco</name>
</author>
<author><name sortKey="Castro Mussot, M E" uniqKey="Castro Mussot M">M. E. Castro-Mussot</name>
</author>
<author><name sortKey="Diegoperez Ramirez, J" uniqKey="Diegoperez Ramirez J">J. Diegopérez-Ramírez</name>
</author>
<author><name sortKey="Ramirez Reyes, A G" uniqKey="Ramirez Reyes A">A. G. Ramírez-Reyes</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Samarasekera, U" uniqKey="Samarasekera U">U. Samarasekera</name>
</author>
<author><name sortKey="Triunfol, M" uniqKey="Triunfol M">M. Triunfol</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Samuel, M A" uniqKey="Samuel M">M. A. Samuel</name>
</author>
<author><name sortKey="Wang, H" uniqKey="Wang H">H. Wang</name>
</author>
<author><name sortKey="Siddharthan, V" uniqKey="Siddharthan V">V. Siddharthan</name>
</author>
<author><name sortKey="Morrey, J D" uniqKey="Morrey J">J. D. Morrey</name>
</author>
<author><name sortKey="Diamond, M S" uniqKey="Diamond M">M. S. Diamond</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sauerbrei, A" uniqKey="Sauerbrei A">A. Sauerbrei</name>
</author>
<author><name sortKey="Wutzler, P" uniqKey="Wutzler P">P. Wutzler</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Scheffer, I E" uniqKey="Scheffer I">I. E. Scheffer</name>
</author>
<author><name sortKey="Baraitser, M" uniqKey="Baraitser M">M. Baraitser</name>
</author>
<author><name sortKey="Brett, E M" uniqKey="Brett E">E. M. Brett</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Schuler Faccini, L" uniqKey="Schuler Faccini L">L. Schuler-Faccini</name>
</author>
<author><name sortKey="Ribeiro, E M" uniqKey="Ribeiro E">E. M. Ribeiro</name>
</author>
<author><name sortKey="Feitosa, I M L" uniqKey="Feitosa I">I. M. L. Feitosa</name>
</author>
<author><name sortKey="Horovitz, D D G" uniqKey="Horovitz D">D. D. G. Horovitz</name>
</author>
<author><name sortKey="Cavalcanti, D P" uniqKey="Cavalcanti D">D. P. Cavalcanti</name>
</author>
<author><name sortKey="Pessoa, A" uniqKey="Pessoa A">A. Pessoa</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Shimozono, S" uniqKey="Shimozono S">S. Shimozono</name>
</author>
<author><name sortKey="Iimura, T" uniqKey="Iimura T">T. Iimura</name>
</author>
<author><name sortKey="Kitaguchi, T" uniqKey="Kitaguchi T">T. Kitaguchi</name>
</author>
<author><name sortKey="Higashijima, S" uniqKey="Higashijima S">S. Higashijima</name>
</author>
<author><name sortKey="Miyawaki, A" uniqKey="Miyawaki A">A. Miyawaki</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Siegenthaler, J A" uniqKey="Siegenthaler J">J. A. Siegenthaler</name>
</author>
<author><name sortKey="Ashique, A M" uniqKey="Ashique A">A. M. Ashique</name>
</author>
<author><name sortKey="Zarbalis, K" uniqKey="Zarbalis K">K. Zarbalis</name>
</author>
<author><name sortKey="Patterson, K P" uniqKey="Patterson K">K. P. Patterson</name>
</author>
<author><name sortKey="Hecht, J H" uniqKey="Hecht J">J. H. Hecht</name>
</author>
<author><name sortKey="Kane, M A" uniqKey="Kane M">M. A. Kane</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Slater, L" uniqKey="Slater L">L. Slater</name>
</author>
<author><name sortKey="Bartlett, N W" uniqKey="Bartlett N">N. W. Bartlett</name>
</author>
<author><name sortKey="Haas, J J" uniqKey="Haas J">J. J. Haas</name>
</author>
<author><name sortKey="Zhu, J" uniqKey="Zhu J">J. Zhu</name>
</author>
<author><name sortKey="Message, S D" uniqKey="Message S">S. D Message</name>
</author>
<author><name sortKey="Walton, R P" uniqKey="Walton R">R. P. Walton</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Straface, G" uniqKey="Straface G">G. Straface</name>
</author>
<author><name sortKey="Selmin, A" uniqKey="Selmin A">A. Selmin</name>
</author>
<author><name sortKey="Zanardo, V" uniqKey="Zanardo V">V. Zanardo</name>
</author>
<author><name sortKey="De Santis, M" uniqKey="De Santis M">M. De Santis</name>
</author>
<author><name sortKey="Ercoli, A" uniqKey="Ercoli A">A. Ercoli</name>
</author>
<author><name sortKey="Scambia, G" uniqKey="Scambia G">G. Scambia</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Takano, T" uniqKey="Takano T">T. Takano</name>
</author>
<author><name sortKey="Takikita, S" uniqKey="Takikita S">S. Takikita</name>
</author>
<author><name sortKey="Shimada, M" uniqKey="Shimada M">M. Shimada</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Teissier, N" uniqKey="Teissier N">N. Teissier</name>
</author>
<author><name sortKey="Fallet Bianco, C" uniqKey="Fallet Bianco C">C. Fallet-Bianco</name>
</author>
<author><name sortKey="Delezoide, A L" uniqKey="Delezoide A">A.-L. Delezoide</name>
</author>
<author><name sortKey="Laquerriere, A" uniqKey="Laquerriere A">A. Laquerrière</name>
</author>
<author><name sortKey="Marcorelles, P" uniqKey="Marcorelles P">P. Marcorelles</name>
</author>
<author><name sortKey="Khung Savatovsky, S" uniqKey="Khung Savatovsky S">S. Khung-Savatovsky</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Tsiang, H" uniqKey="Tsiang H">H. Tsiang</name>
</author>
<author><name sortKey="Koulakoff, A" uniqKey="Koulakoff A">A. Koulakoff</name>
</author>
<author><name sortKey="Bizzini, B" uniqKey="Bizzini B">B. Bizzini</name>
</author>
<author><name sortKey="Berwald Netter, Y" uniqKey="Berwald Netter Y">Y. Berwald-Netter</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Tuiskunen, A" uniqKey="Tuiskunen A">A. Tuiskunen</name>
</author>
<author><name sortKey="Wahlstrom, M" uniqKey="Wahlstrom M">M. Wahlström</name>
</author>
<author><name sortKey="Bergstrom, J" uniqKey="Bergstrom J">J. Bergström</name>
</author>
<author><name sortKey="Buchy, P" uniqKey="Buchy P">P. Buchy</name>
</author>
<author><name sortKey="Leparc Goffart, I" uniqKey="Leparc Goffart I">I. Leparc-Goffart</name>
</author>
<author><name sortKey="Lundkvist, " uniqKey="Lundkvist ">Å. Lundkvist</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Vansant, G" uniqKey="Vansant G">G. Vansant</name>
</author>
<author><name sortKey="Reynolds, W F" uniqKey="Reynolds W">W. F. Reynolds</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ventura, C V" uniqKey="Ventura C">C. V. Ventura</name>
</author>
<author><name sortKey="Maia, M" uniqKey="Maia M">M. Maia</name>
</author>
<author><name sortKey="Bravo Filho, V" uniqKey="Bravo Filho V">V. Bravo-Filho</name>
</author>
<author><name sortKey="G Is, A L" uniqKey="G Is A">A. L. Góis</name>
</author>
<author><name sortKey="Belfort, R" uniqKey="Belfort R">R. Belfort</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Wilson, L J" uniqKey="Wilson L">L. J. Wilson</name>
</author>
<author><name sortKey="Myat, A" uniqKey="Myat A">A. Myat</name>
</author>
<author><name sortKey="Sharma, A" uniqKey="Sharma A">A. Sharma</name>
</author>
<author><name sortKey="Maden, M" uniqKey="Maden M">M. Maden</name>
</author>
<author><name sortKey="Wingate, R J" uniqKey="Wingate R">R. J. Wingate</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Wood, B R" uniqKey="Wood B">B. R. Wood</name>
</author>
<author><name sortKey="Klein, J P" uniqKey="Klein J">J. P. Klein</name>
</author>
<author><name sortKey="Lyons, J L" uniqKey="Lyons J">J. L. Lyons</name>
</author>
<author><name sortKey="Milner, D A" uniqKey="Milner D">D. A. Milner</name>
</author>
<author><name sortKey="Phillips, R E" uniqKey="Phillips R">R. E. Phillips</name>
</author>
<author><name sortKey="Schutten, M" uniqKey="Schutten M">M. Schutten</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Xu, J" uniqKey="Xu J">J. Xu</name>
</author>
<author><name sortKey="Zhong, S" uniqKey="Zhong S">S. Zhong</name>
</author>
<author><name sortKey="Liu, J" uniqKey="Liu J">J. Liu</name>
</author>
<author><name sortKey="Li, L" uniqKey="Li L">L. Li</name>
</author>
<author><name sortKey="Li, Y" uniqKey="Li Y">Y. Li</name>
</author>
<author><name sortKey="Wu, X" uniqKey="Wu X">X. Wu</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Yamamoto, M" uniqKey="Yamamoto M">M. Yamamoto</name>
</author>
<author><name sortKey="Zhang, J" uniqKey="Zhang J">J. Zhang</name>
</author>
<author><name sortKey="Smith, D" uniqKey="Smith D">D. Smith</name>
</author>
<author><name sortKey="Hayakawa, Y" uniqKey="Hayakawa Y">Y. Hayakawa</name>
</author>
<author><name sortKey="Mccaffery, P" uniqKey="Mccaffery P">P. McCaffery</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Yazigi, A" uniqKey="Yazigi A">A. Yazigi</name>
</author>
<author><name sortKey="De Pecoulas, A E" uniqKey="De Pecoulas A">A. E. De Pecoulas</name>
</author>
<author><name sortKey="Vauloup Fellous, C" uniqKey="Vauloup Fellous C">C. Vauloup-Fellous</name>
</author>
<author><name sortKey="Grangeot Keros, L" uniqKey="Grangeot Keros L">L. Grangeot-Keros</name>
</author>
<author><name sortKey="Ayoubi, J M" uniqKey="Ayoubi J">J.-M. Ayoubi</name>
</author>
<author><name sortKey="Picone, O" uniqKey="Picone O">O. Picone</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Front Hum Neurosci</journal-id>
<journal-id journal-id-type="iso-abbrev">Front Hum Neurosci</journal-id>
<journal-id journal-id-type="publisher-id">Front. Hum. Neurosci.</journal-id>
<journal-title-group><journal-title>Frontiers in Human Neuroscience</journal-title>
</journal-title-group>
<issn pub-type="epub">1662-5161</issn>
<publisher><publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">27555815</article-id>
<article-id pub-id-type="pmc">4977292</article-id>
<article-id pub-id-type="doi">10.3389/fnhum.2016.00403</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Neuroscience</subject>
<subj-group><subject>Hypothesis and Theory</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>A Possible Mechanism of Zika Virus Associated Microcephaly: Imperative Role of Retinoic Acid Response Element (RARE) Consensus Sequence Repeats in the Viral Genome</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Kumar</surname>
<given-names>Ashutosh</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/242424/overview"></uri>
</contrib>
<contrib contrib-type="author"><name><surname>Singh</surname>
<given-names>Himanshu N.</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/351023/overview"></uri>
</contrib>
<contrib contrib-type="author"><name><surname>Pareek</surname>
<given-names>Vikas</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/357998/overview"></uri>
</contrib>
<contrib contrib-type="author"><name><surname>Raza</surname>
<given-names>Khursheed</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/364356/overview"></uri>
</contrib>
<contrib contrib-type="author"><name><surname>Dantham</surname>
<given-names>Subrahamanyam</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/351149/overview"></uri>
</contrib>
<contrib contrib-type="author"><name><surname>Kumar</surname>
<given-names>Pavan</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/366101/overview"></uri>
</contrib>
<contrib contrib-type="author"><name><surname>Mochan</surname>
<given-names>Sankat</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/364569/overview"></uri>
</contrib>
<contrib contrib-type="author"><name><surname>Faiq</surname>
<given-names>Muneeb A.</given-names>
</name>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
<xref ref-type="aff" rid="aff5"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="aff6"><sup>6</sup>
</xref>
<xref ref-type="author-notes" rid="fn001"><sup>*</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/332643/overview"></uri>
</contrib>
</contrib-group>
<aff id="aff1"><sup>1</sup>
<institution>Department of Anatomy, All India Institute of Medical Sciences</institution>
<country>New Delhi, India</country>
</aff>
<aff id="aff2"><sup>2</sup>
<institution>Department of Biochemistry, All India Institute of Medical Sciences</institution>
<country>New Delhi, India</country>
</aff>
<aff id="aff3"><sup>3</sup>
<institution>Computational Neuroscience and Neuroimaging Division, National Brain Research Centre</institution>
<country>Manesar, India</country>
</aff>
<aff id="aff4"><sup>4</sup>
<institution>Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences</institution>
<country>New Delhi, India</country>
</aff>
<aff id="aff5"><sup>5</sup>
<institution>Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of medical Sciences</institution>
<country>New Delhi, India</country>
</aff>
<aff id="aff6"><sup>6</sup>
<institution>Medical Biotechnology Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi</institution>
<country>New Delhi, India</country>
</aff>
<author-notes><fn fn-type="edited-by"><p>Edited by: Mikhail Lebedev, Duke University, USA</p>
</fn>
<fn fn-type="edited-by"><p>Reviewed by: Philip Julian Broser, Ostschweizer Kinderspital, Switzerland; Chrysi Bogiatzi, McMaster University, Canada</p>
</fn>
<corresp id="fn001">*Correspondence: Muneeb A. Faiq <email xlink:type="simple">muneeb1983@gmail.com</email>
</corresp>
</author-notes>
<pub-date pub-type="epub"><day>09</day>
<month>8</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="collection"><year>2016</year>
</pub-date>
<volume>10</volume>
<elocation-id>403</elocation-id>
<history><date date-type="received"><day>23</day>
<month>5</month>
<year>2016</year>
</date>
<date date-type="accepted"><day>27</day>
<month>7</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2016 Kumar, Singh, Pareek, Raza, Dantham, Kumar, Mochan and Faiq.</copyright-statement>
<copyright-year>2016</copyright-year>
<copyright-holder>Kumar, Singh, Pareek, Raza, Dantham, Kumar, Mochan and Faiq</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</license-p>
</license>
</permissions>
<abstract><p>Owing to the reports of microcephaly as a consistent outcome in the fetuses of pregnant women infected with ZIKV in Brazil, Zika virus (ZIKV)—microcephaly etiomechanistic relationship has recently been implicated. Researchers, however, are still struggling to establish an embryological basis for this interesting causal handcuff. The present study reveals robust evidence in favor of a plausible ZIKV-microcephaly cause-effect liaison. The rationale is based on: (1) sequence homology between ZIKV genome and the response element of an early neural tube developmental marker “retinoic acid” in human DNA and (2) comprehensive similarities between the details of brain defects in ZIKV-microcephaly and retinoic acid embryopathy. Retinoic acid is considered as the earliest factor for regulating anteroposterior axis of neural tube and positioning of structures in developing brain through retinoic acid response elements (RARE) consensus sequence (5′–AGGTCA–3′) in promoter regions of retinoic acid-dependent genes. We screened genomic sequences of already reported virulent ZIKV strains (including those linked to microcephaly) and other viruses available in National Institute of Health genetic sequence database (GenBank) for the RARE consensus repeats and obtained results strongly bolstering our hypothesis that ZIKV strains associated with microcephaly may act through precipitation of dysregulation in retinoic acid-dependent genes by introducing extra stretches of RARE consensus sequence repeats in the genome of developing brain cells. Additional support to our hypothesis comes from our findings that screening of other viruses for RARE consensus sequence repeats is positive only for those known to display neurotropism and cause fetal brain defects (for which maternal-fetal transmission during developing stage may be required). The numbers of RARE sequence repeats appeared to match with the virulence of screened positive viruses. Although, bioinformatic evidence and embryological features are in favor of our hypothesis, additional studies including animal models are warranted to validate our proposition. Such studies are likely to unfold ZIKV-microcephaly association and may help in devising methods to combat it.</p>
</abstract>
<kwd-group><kwd>fetal brain malformation</kwd>
<kwd>microcephaly</kwd>
<kwd>neurotropism</kwd>
<kwd>retinoic acid response element (RARE)</kwd>
<kwd>zika virus (ZIKV)</kwd>
</kwd-group>
<counts><fig-count count="2"></fig-count>
<table-count count="3"></table-count>
<equation-count count="0"></equation-count>
<ref-count count="72"></ref-count>
<page-count count="11"></page-count>
<word-count count="8017"></word-count>
</counts>
</article-meta>
</front>
<body><sec sec-type="intro" id="s1"><title>Introduction</title>
<p>ZIKV has recently been a hot topic among researchers as well as general public due to its extensive geographical distribution and perceived health related threats; though most of the cases, as of now, are being reported from Brazil (Cipriano and Monteiro, <xref rid="B7" ref-type="bibr">2016</xref>
; Samarasekera and Triunfol, <xref rid="B52" ref-type="bibr">2016</xref>
). One of the main health intimidations by ZIKV has been microcephaly in the fetuses born of the infected women. There is division of opinion among researchers regarding ZIKV-microcephaly association (Rasmussen et al., <xref rid="B48" ref-type="bibr">2016</xref>
). This is despite the fact that ZIKV has been detected in the placenta and amniotic fluid of fetuses born with microcephaly (Calvet et al., <xref rid="B5" ref-type="bibr">2016</xref>
; Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
; Schuler-Faccini et al., <xref rid="B56" ref-type="bibr">2016</xref>
). It has also been detected in the brain of a fetus died of severe brain defects. There is strong epidemiological evidence of ZIKV–microcephaly association (Schuler-Faccini et al., <xref rid="B56" ref-type="bibr">2016</xref>
; WHO | Zika situation report, <xref rid="B67" ref-type="bibr">2016</xref>
). It would, as is obvious, be hard to justify that a true cause-effect relationship exists between ZIKV and microcephaly until its neuro-embryological basis is established. The present study has made an attempt to identify and explain a plausible embryological basis of ZIKV-microcephaly association. We chose retinoic acid for exploring its involvement in ZIKV–microcephaly relationship because of the wide-ranging similarities between brain malformations caused by retinoic acid signaling dysregulation and the brain defects observed in ZIKV infected fetuses (as provided in many important reports; Aragao et al., <xref rid="B2" ref-type="bibr">2016</xref>
; Calvet et al., <xref rid="B5" ref-type="bibr">2016</xref>
; Hazin et al., <xref rid="B26" ref-type="bibr">2016</xref>
; Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
).</p>
<sec><title>Retinoic acid-mediated mechanism in neural tube formation and further brain development</title>
<p>Retinoic acid is a non-peptide small lipophilic molecule derived from retinol—an active ingredient of vitamin A. Retinol gets converted to retinal and further into retinoic acid by the action of dehydrogenases which includes CYP1B1. Retinoic acid is taken to the nucleus by the cellular retinoic acid binding protein (CRABP) where it binds to retinoic acid receptors (RAR and RXR) on the promoter regions of specific genes (Balmer and Blomhoff, <xref rid="B3" ref-type="bibr">2002</xref>
; Rhinn and Dollé, <xref rid="B49" ref-type="bibr">2012</xref>
). RAR and RXR are important transcription factors (Rhinn and Dollé, <xref rid="B49" ref-type="bibr">2012</xref>
) and actively influence RARE consensus sequences in promoter regions of a plethora of genes involved in neural tube development in addition to serving other pertinent embryological functions (Balmer and Blomhoff, <xref rid="B3" ref-type="bibr">2002</xref>
; Rhinn and Dollé, <xref rid="B49" ref-type="bibr">2012</xref>
). These genes further activate a cascade of regulatory molecules involved in neural tube formation and brain development. Any dysregulation of this intricate molecular process at any step can lead to various degrees of neural tube defects and brain malformations (Grapin-Botton et al., <xref rid="B20" ref-type="bibr">1998</xref>
; Kam et al., <xref rid="B30" ref-type="bibr">2012</xref>
; Rhinn and Dollé, <xref rid="B49" ref-type="bibr">2012</xref>
). The RARE sequence is also spread all over human genome through commonly found ALU repeats which contain RARE sequence (Vansant and Reynolds, <xref rid="B65" ref-type="bibr">1995</xref>
). Retinoic acid enjoys the stature of being the initial-most molecular factor involved in the determination of the neural axis and, is the prime determinant of the anteroposterior axis owing to its interplay with Nodal gene in developing neural tube (Durston et al., <xref rid="B12" ref-type="bibr">1989</xref>
; Kam et al., <xref rid="B30" ref-type="bibr">2012</xref>
). Together with fibroblast growth factor (FGF), it is known to set a code for establishing the anterio-posterior axis (instituted by opposing gradients of retinoic acid and FGF along the neural tube) which is followed by other molecular factors (Martínez-Morales et al., <xref rid="B39" ref-type="bibr">2011</xref>
; Shimozono et al., <xref rid="B57" ref-type="bibr">2013</xref>
).</p>
<p>Nodal, which is thought to be the master regulator gene for deciding the axes of the developing neural tube has RARE consensus sequence in its intron-1. Retinoic acid is also involved in deciding dorsoventral axis by intricate crosstalk with Nodal (Kam et al., <xref rid="B30" ref-type="bibr">2012</xref>
). A plethora of literature suggests that retinoic acid is involved in FGF8 repression during body axis extension and regulation of the homeobox (HOX) genes involved in determining the position of the neural segments (Grapin-Botton et al., <xref rid="B20" ref-type="bibr">1998</xref>
). More than deciding the axes and positioning of the neural segments at the time of neural tube formation, retinoic acid (at a later stage) also has imperative role in the development of midline, posterio-dorsal brain structures, and forebrain components in addition to corticogenesis. Disruptions in the retinoic acid signaling pathway have been implicated in ensuing brain defects in developing fetus involving all the above mentioned structures and may, arguably, present as microcephaly (Wilson et al., <xref rid="B68" ref-type="bibr">2007</xref>
; Siegenthaler et al., <xref rid="B58" ref-type="bibr">2009</xref>
; Crandall et al., <xref rid="B9" ref-type="bibr">2011</xref>
; Gupta and Sen, <xref rid="B23" ref-type="bibr">2015</xref>
). Retinoic acid is also a teratogen and can cause the neural tube defect and other brain malformations if provided in abnormal doses to developing fetus (Yamamoto et al., <xref rid="B71" ref-type="bibr">2003</xref>
).</p>
</sec>
<sec><title>Plausible mechanism of ZIKV mediated retinoic acid signaling dysregulation resulting in fetal microcephaly</title>
<p>ZIKV is a positive sense RNA Flavivirus (Baronti et al., <xref rid="B4" ref-type="bibr">2014</xref>
). When an RNA virus infects a host cell, its genetic material is reverse-transcribed into cDNA by reverse transcriptase which, in turn, synthesizes complementary sense DNA strand, and finally, the so composed DNA gets integrated into the host DNA. We proceed with an important and coherent line of arguments that in acute viremia heavy doses of viral DNA (reverse-transcribed from RNA) will be integrating into the host DNA, and if the inserted DNA sequences match the regulatory regions of certain host genes then they may influence their expressions. By the transitive property of similarities, it can then be justified that, the RARE consensus sequence repeats (if present) in the genomic sequences of ZIKV strains would be inserted into the promoter regions of RARE dependent genes of the host DNA and, therefore, may influence their expression in a way that the developing fetus manifests with brain malformation like microcephaly (Figure <xref ref-type="fig" rid="F1">1</xref>
).</p>
<fig id="F1" position="float"><label>Figure 1</label>
<caption><p><bold>Retinoic acid response element (RARE) mediated mechanism in Zika virus microcephaly association</bold>
.</p>
</caption>
<graphic xlink:href="fnhum-10-00403-g0001"></graphic>
</fig>
<p>Current understanding of the ZIKV-microcephaly association is improving as more and more relevant reports are coming up and many recent studies strongly agree to the notion that ZIKV-microcephaly may be a developmental brain malformation rather than a mere brain destruction by the virus (Hazin et al., <xref rid="B26" ref-type="bibr">2016</xref>
; Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
). So, in the light of comprehensive similarities between fetal brain defects in ZIKV infection and brain malformations caused by retinoic acid dysregulation in developing fetus, we considered it a plausible rationale to search for a possible retinoic acid-mediated mechanism involved in ZIKV-microcephaly association. We, for this important reason, searched for the RARE consensus sequence (5′–AGGTCA–3′) repeats in the genomic sequences of the ZIKV strains with a hypothesis that the virus might act through disruption of normal retinoic acid signaling mediated by incorporation of these sequences into the DNA of developing host brain cells. To validate this hypothesis robustly and to establish the cogency of our study, we also screened some other viruses (including members of the flaviviridae family and those viruses which are known to have maternal-fetal/perinatal transmission either causing congenital brain malformations or showing neurotropism) and subjected them to the same analysis.</p>
</sec>
</sec>
<sec sec-type="materials and methods" id="s2"><title>Materials and methods</title>
<p>The genome sequence information of 17 strains of ZIKV (including “Brazil ZKIV-2015” which was recently implicated in causing microcephaly in Brazilian fetuses; Calvet et al., <xref rid="B5" ref-type="bibr">2016</xref>
; Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
), and many other viruses were retrieved from the NCBI/GenBank database (<ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/genbank/">http://www.ncbi.nlm.nih.gov/genbank/</ext-link>
) (Table <xref ref-type="table" rid="T1">1</xref>
) and screened for the presence of RARE consensus sequence (5′–AGGTCA–3′). Among the viruses other than ZIKV, selection was made under four groups viz: (1) Members of the flaviviridae family other than ZIKV (to check if RARE consensus sequence repeats were essentially present in the family) (2) Viruses showing maternal-fetal/perinatal transmission and causing congenital brain malformations (3) Viruses showing neurotropism but not known to cause fetal brain defects (4) Viruses chosen randomly from the RNA/DNA viruses not fitting in any of the above three groups (to account for the selection bias and to establish coherence and validity of the screening process). To identify the enrichment of RARE sequence (5′–AGGTCA–3′) repeats present in the viruses, a Perl script was written and executed.</p>
<table-wrap id="T1" position="float"><label>Table 1</label>
<caption><p><bold>The ZIKV and other virus strains included in the study</bold>
.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th valign="top" align="left" colspan="2" style="border-bottom: thin solid #000000;" rowspan="1"><bold>Flaviviridae Family (With GenBank accession numbers)</bold>
</th>
<th valign="top" align="center" colspan="3" style="border-bottom: thin solid #000000;" rowspan="1"><bold>Other than Flaviviridae family viruses (with GenBank accession numbers)</bold>
</th>
</tr>
<tr><th valign="top" align="left" rowspan="1" colspan="1"><bold>Zika virus strains</bold>
</th>
<th valign="top" align="left" rowspan="1" colspan="1"><bold>Other Flaviviridae members</bold>
</th>
<th valign="top" align="left" rowspan="1" colspan="1"><bold>Show maternal-fetal/perinatal transmission and cause congenital brain malformations</bold>
</th>
<th valign="top" align="left" rowspan="1" colspan="1"><bold>Show neurotropism but not known to cause fetal brain defect</bold>
</th>
<th valign="top" align="left" rowspan="1" colspan="1"><bold>RNA/DNA viruses not to be fit in the other three groups</bold>
</th>
</tr>
</thead>
<tbody><tr><td valign="top" align="left" rowspan="1" colspan="1"><bold><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KU497555">KU497555</ext-link>
</bold>
(Brazil ZIKV-2015)</td>
<td valign="top" align="left" rowspan="1" colspan="1">Dengue virus (Type I–IV)</td>
<td valign="top" align="left" rowspan="1" colspan="1">Human cytomegalovirus (Human herpesvirus 5)</td>
<td valign="top" align="left" rowspan="1" colspan="1">Measles virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KJ410048.1">KJ410048.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">Hepatitis Delta virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="NC_001653.2">NC_001653.2</ext-link>
)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="EF025110.1">EF025110.1</ext-link>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="AF489932.1">AF489932.1</ext-link>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="AB214882.1">AB214882.1</ext-link>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="AY762085.1">AY762085.1</ext-link>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" style="border-top: thin solid #000000;" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="AY632535">AY632535</ext-link>
</td>
<td valign="top" align="left" style="border-top: thin solid #000000;" rowspan="1" colspan="1">Chikungunya virus<xref ref-type="table-fn" rid="TN2"><sup>**</sup>
</xref>
(<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="JX088705.1">JX088705.1</ext-link>
)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr style="border-top: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="DQ859059">DQ859059</ext-link>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">Japanese Encephalitis virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="AY303791.1">AY303791.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">HIV Type 1 (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="NC_001802.1">NC_001802.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">Mumps virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KM597072.1">KM597072.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">Hepatitis B virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="AB937799.1">AB937799.1</ext-link>
)</td>
</tr>
<tr style="border-top: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="EU545988">EU545988</ext-link>
<xref ref-type="table-fn" rid="TN1"><sup>*</sup>
</xref>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">West Nile virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="M12294.2">M12294.2</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">Rubella virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="NC_001545">NC_001545</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">Human poliovirus 2 (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KJ419277.1">KJ419277.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">Hepatitis A virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="AB279735.1">AB279735.1</ext-link>
)</td>
</tr>
<tr style="border-top: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="NC_002031.1">NC_002031.1</ext-link>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yellow fever virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="NC_002031.1">NC_002031.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">Herpes simplex virus type 1 (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="NC_001806.2">NC_001806.2</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">Ebola virus <ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="NC_001806.2">NC_001806.2</ext-link>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">Human rhinovirus 14 <ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="NC_001490.1">NC_001490.1</ext-link>
</td>
</tr>
<tr style="border-top: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="HQ234500">HQ234500</ext-link>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">Estern Equine encephalitis Virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KJ659366.1">KJ659366.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">Herpes simplex virus type 2 (strain HG52) (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="Z86099.2">Z86099.2</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">Rabies virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="EF206718.1">EF206718.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">Human Papilloma virus type 1a <ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="HPU06714">HPU06714</ext-link>
</td>
</tr>
<tr style="border-top: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="HQ234501">HQ234501</ext-link>
</td>
<td rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1">Herpes simplex virus type 3 (Varicella Zoster) (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KC112914.1">KC112914.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">Yellow fever virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="NC_002031.1">NC_002031.1</ext-link>
)</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr style="border-top: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="JN860885">JN860885</ext-link>
<xref ref-type="table-fn" rid="TN1"><sup>*</sup>
</xref>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1">Human Corona virus HKU1 (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KF430201.1">KF430201.1</ext-link>
)</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr style="border-top: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KF268948">KF268948</ext-link>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr style="border-top: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KF268949">KF268949</ext-link>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr style="border-top: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KF268950">KF268950</ext-link>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr style="border-top: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KF993678">KF993678</ext-link>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr style="border-top: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KJ634273">KJ634273</ext-link>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr style="border-top: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KJ776791">KJ776791</ext-link>
<xref ref-type="table-fn" rid="TN1"><sup>*</sup>
</xref>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr style="border-top: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KU312315">KU312315</ext-link>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr style="border-top: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="LC002520">LC002520</ext-link>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr style="border-top: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="Z1106033">Z1106033</ext-link>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="TN1"><label>*</label>
<p>Share close genomic sequence homology with <bold><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KU497555">KU497555</ext-link>
</bold>
strain (Brazil ZIKV-2015);</p>
</fn>
<fn id="TN2"><label>**</label>
<p><italic>Maternal-fetal transmission in human reported</italic>
.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<p>In order to find and count the RARE sequences from the ZIKA virus genome, a PERL script was generated entitled “<italic>RARE_Seq_finder.pl</italic>
.” The PERL script was based on the window shift algorithm. Genome sequence information of ZIKA virus isolates was downloaded from various genome databases. As input, the PERL Script requires only the list file carrying names of the genome sequence files. It searches the RARE sequences globally in the genome, and lists all genome file names along with number of RARE sequences present in the genome. A complete flow-chart with all the steps involved in the counting the RARE sequences is shown in Figure <xref ref-type="fig" rid="F2">2</xref>
. The complete PERL script for this study is available as Supplementary Material.</p>
<fig id="F2" position="float"><label>Figure 2</label>
<caption><p><bold>Flow chart for the execution of the PERL script written to search and identify the consensus RARE sequences</bold>
.</p>
</caption>
<graphic xlink:href="fnhum-10-00403-g0002"></graphic>
</fig>
</sec>
<sec id="s3"><title>Result</title>
<p>The ZIKV strains associated with microcephaly contained RARE consensus sequence repeats. The number of repeats corresponds to the virulence of each strain i.e., greater the number of RARE repeats higher the chances of microcephaly. Complete details of the number of RARE sequence repeats in each ZIKV strain are given in Table <xref ref-type="table" rid="T2">2</xref>
. For viruses other than ZIKV, the RARE consensus sequence repeats were found to be present only in those viruses known for maternal-fetal/perinatal transmission, involved in fetal brain defects and displaying neurotropism. The numbers of RARE sequence repeats was directly proportional to the virulence of screened viruses. The number of RARE consensus sequences repeats in the checked 17 strains of the ZIKV and other ZIKV viruses are provided in Tables <xref ref-type="table" rid="T2">2</xref>
, <xref ref-type="table" rid="T3">3</xref>
respectively.</p>
<table-wrap id="T2" position="float"><label>Table 2</label>
<caption><p><bold>Number of RARE consensus sequence (5′–AGGTCA–3′) repeats in genomic sequences of ZIKV strains</bold>
.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th rowspan="1" colspan="1"></th>
<th valign="top" align="left" rowspan="1" colspan="1"><bold>ZIKV Strains</bold>
</th>
<th valign="top" align="left" rowspan="1" colspan="1"><bold>Number of RARE Sequence (5′–AGGTCA–3′) repeats</bold>
</th>
</tr>
</thead>
<tbody><tr><td valign="top" align="left" rowspan="1" colspan="1">I</td>
<td valign="top" align="left" rowspan="1" colspan="1"><bold>KU497555</bold>
(Brazil ZIKV-2015)</td>
<td valign="top" align="center" rowspan="1" colspan="1"><bold>4</bold>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Ii</td>
<td valign="top" align="left" rowspan="1" colspan="1">AY632535</td>
<td valign="top" align="center" rowspan="1" colspan="1">2</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Iii</td>
<td valign="top" align="left" rowspan="1" colspan="1">DQ859059</td>
<td valign="top" align="center" rowspan="1" colspan="1">3</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Iv</td>
<td valign="top" align="left" rowspan="1" colspan="1">EU545988</td>
<td valign="top" align="center" rowspan="1" colspan="1">4</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">V</td>
<td valign="top" align="left" rowspan="1" colspan="1">HQ234499</td>
<td valign="top" align="center" rowspan="1" colspan="1">3</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Vi</td>
<td valign="top" align="left" rowspan="1" colspan="1">HQ234500</td>
<td valign="top" align="center" rowspan="1" colspan="1">2</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Vii</td>
<td valign="top" align="left" rowspan="1" colspan="1">HQ234501</td>
<td valign="top" align="center" rowspan="1" colspan="1">3</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Viii</td>
<td valign="top" align="left" rowspan="1" colspan="1">JN860885</td>
<td valign="top" align="center" rowspan="1" colspan="1">4</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Ix</td>
<td valign="top" align="left" rowspan="1" colspan="1">KF268948</td>
<td valign="top" align="center" rowspan="1" colspan="1">3</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">X</td>
<td valign="top" align="left" rowspan="1" colspan="1">KF268949</td>
<td valign="top" align="center" rowspan="1" colspan="1">2</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Xi</td>
<td valign="top" align="left" rowspan="1" colspan="1">KF268950</td>
<td valign="top" align="center" rowspan="1" colspan="1">3</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Xii</td>
<td valign="top" align="left" rowspan="1" colspan="1">KF993678</td>
<td valign="top" align="center" rowspan="1" colspan="1">4</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Xiii</td>
<td valign="top" align="left" rowspan="1" colspan="1">KJ634273</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Xiv</td>
<td valign="top" align="left" rowspan="1" colspan="1">KJ776791</td>
<td valign="top" align="center" rowspan="1" colspan="1">4</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Xv</td>
<td valign="top" align="left" rowspan="1" colspan="1">KU312315</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Xvi</td>
<td valign="top" align="left" rowspan="1" colspan="1">LC002520</td>
<td valign="top" align="center" rowspan="1" colspan="1">2</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Xvii</td>
<td valign="top" align="left" rowspan="1" colspan="1">Z1106033</td>
<td valign="top" align="center" rowspan="1" colspan="1">4</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="T3" position="float"><label>Table 3</label>
<caption><p><bold>Number of RARE consensus sequence (5′–AGGTCA–3′) repeats in genomic sequence of other viruses</bold>
.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th valign="top" align="left" rowspan="1" colspan="1"><bold>Other Viruses Strains (GenBank accession number in brackets)</bold>
</th>
<th valign="top" align="left" rowspan="1" colspan="1"><bold>Type</bold>
</th>
<th valign="top" align="center" rowspan="1" colspan="1"><bold>Length of reading frame</bold>
</th>
<th valign="top" align="center" rowspan="1" colspan="1"><bold>Number of RARE Sequences (5′–AGGTCA–3′)</bold>
</th>
<th valign="top" align="center" rowspan="1" colspan="1"><bold>Neurotropism</bold>
</th>
<th valign="top" align="center" rowspan="1" colspan="1"><bold>Congenital Brain Defect</bold>
</th>
<th valign="top" align="left" rowspan="1" colspan="1"><bold>References</bold>
</th>
</tr>
</thead>
<tbody><tr><td valign="top" align="left" rowspan="1" colspan="1">Dengue virus (Type I–IV)</td>
<td valign="top" align="left" rowspan="1" colspan="1">(+)ssRNA, linear</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="left" rowspan="1" colspan="1">Tuiskunen et al., <xref rid="B64" ref-type="bibr">2011</xref>
; Salazar et al., <xref rid="B51" ref-type="bibr">2013</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">(<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="EF025110.1">EF025110.1</ext-link>
)</td>
<td rowspan="1" colspan="1"></td>
<td valign="top" align="center" rowspan="1" colspan="1">10735 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">Type 1–3</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">(<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="AF489932.1">AF489932.1</ext-link>
)</td>
<td rowspan="1" colspan="1"></td>
<td valign="top" align="center" rowspan="1" colspan="1">10722 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">Type 2–0</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">(<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="AB214882.1">AB214882.1</ext-link>
)</td>
<td rowspan="1" colspan="1"></td>
<td valign="top" align="center" rowspan="1" colspan="1">10707 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">Type 3–2</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">(<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="AY762085.1">AY762085.1</ext-link>
)</td>
<td rowspan="1" colspan="1"></td>
<td valign="top" align="center" rowspan="1" colspan="1">10649 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">Type 4–6</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1"><xref ref-type="table-fn" rid="TN3"><sup>*</sup>
</xref>
Chikungunya virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="JX088705.1">JX088705.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">(+)ssRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">11811 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">4</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="left" rowspan="1" colspan="1">Koyuncu et al., <xref rid="B34" ref-type="bibr">2013</xref>
; Gérardin et al., <xref rid="B19" ref-type="bibr">2014</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Japanese Encephalitis virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="AY303791.1">AY303791.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">(+)ssRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">10970 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">6</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="left" rowspan="1" colspan="1">Kimura-Kuroda et al., <xref rid="B31" ref-type="bibr">1993</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">West Nile virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="M12294.2">M12294.2</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">(+)ssRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">10962 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">2</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="left" rowspan="1" colspan="1">Samuel et al., <xref rid="B53" ref-type="bibr">2007</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Rabies virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="EF206718.1">EF206718.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">(+)ssRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">11933 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">3</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="left" rowspan="1" colspan="1">Tsiang et al., <xref rid="B63" ref-type="bibr">1983</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Yellow fever virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="NC_002031.1">NC_002031.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">(+)ssRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">10862 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">3</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="left" rowspan="1" colspan="1">Findlay and Stern, <xref rid="B13" ref-type="bibr">1935</xref>
; Guimard et al., <xref rid="B22" ref-type="bibr">2009</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Estern Equine encephalitis Virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KJ659366.1">KJ659366.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">(+)ssRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">11613 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">5</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="left" rowspan="1" colspan="1">Ludlow et al., <xref rid="B38" ref-type="bibr">2016</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1"><xref ref-type="table-fn" rid="TN3"><sup>*</sup>
</xref>
Human cytomegalovirus (Human herpesvirus 5) (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="NC_006273.2">NC_006273.2</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">ds-DNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">235646 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">40</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="left" rowspan="1" colspan="1">Teissier et al., <xref rid="B62" ref-type="bibr">2014</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1"><xref ref-type="table-fn" rid="TN3"><sup>*</sup>
</xref>
HIV Type 1 (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="NC_001802.1">NC_001802.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">(+)ssRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">9181 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">2</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="left" rowspan="1" colspan="1">Civitello, <xref rid="B8" ref-type="bibr">1991</xref>
; Koyuncu et al., <xref rid="B34" ref-type="bibr">2013</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">HIV Type 2 (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="NC_001722.1">NC_001722.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">(+)ssRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">10359 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1"><xref ref-type="table-fn" rid="TN4"><sup>**</sup>
</xref>
</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="left" rowspan="1" colspan="1">Wood et al., <xref rid="B69" ref-type="bibr">2012</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1"><xref ref-type="table-fn" rid="TN3"><sup>*</sup>
</xref>
Rubella virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="NC_001545">NC_001545</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">(+)ssRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">9762 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">3</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="left" rowspan="1" colspan="1">Koyuncu et al., <xref rid="B34" ref-type="bibr">2013</xref>
; Yazigi et al., <xref rid="B72" ref-type="bibr">2016</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Mumps virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KM597072.1">KM597072.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">(−)ssRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">15263 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">4</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="left" rowspan="1" colspan="1">Takano et al., <xref rid="B61" ref-type="bibr">1999</xref>
; Rubin et al., <xref rid="B50" ref-type="bibr">2003</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1"><xref ref-type="table-fn" rid="TN3"><sup>*</sup>
</xref>
Herpes simplex virus type 3 (Varicella Zoster) (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KC112914.1">KC112914.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">dsDNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">124884 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">8</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="left" rowspan="1" colspan="1">Scheffer et al., <xref rid="B55" ref-type="bibr">1991</xref>
; Sauerbrei and Wutzler, <xref rid="B54" ref-type="bibr">2000</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Herpes simplex virus type 1 (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="NC_001806.2">NC_001806.2</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">dsDNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">148709 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">26</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="left" rowspan="1" colspan="1">Straface et al., <xref rid="B60" ref-type="bibr">2012</xref>
; Koyuncu et al., <xref rid="B34" ref-type="bibr">2013</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1"><xref ref-type="table-fn" rid="TN3"><sup>*</sup>
</xref>
Herpes simplex virus type 2 (strain HG52) (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="Z86099.2">Z86099.2</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">ds-DNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">154746 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">20</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="left" rowspan="1" colspan="1">Straface et al., <xref rid="B60" ref-type="bibr">2012</xref>
; Koyuncu et al., <xref rid="B34" ref-type="bibr">2013</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Hepatitis C virus (subtype 1 g) <ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="AM910652">AM910652</ext-link>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">(+)ssRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">9490 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">4</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="left" rowspan="1" colspan="1">Forton et al., <xref rid="B14" ref-type="bibr">2001</xref>
; Grover et al., <xref rid="B21" ref-type="bibr">2012</xref>
; Koyuncu et al., <xref rid="B34" ref-type="bibr">2013</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Human Corona virus HKU1 <ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KF430201.1">KF430201.1</ext-link>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">(+)ssRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">29934 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">3</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="left" rowspan="1" colspan="1">Lau et al., <xref rid="B36" ref-type="bibr">2006</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">SARS Corona virus ExoN1 (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="FJ882956.1">FJ882956.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">(+)ssRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">29644 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">3</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="left" rowspan="1" colspan="1">Xu et al., <xref rid="B70" ref-type="bibr">2005</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Ebola virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KU182909.1">KU182909.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">(−)ssRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">18959 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">5</td>
<td valign="top" align="center" rowspan="1" colspan="1">+</td>
<td valign="top" align="center" rowspan="1" colspan="1">−<xref ref-type="table-fn" rid="TN5"><sup>***</sup>
</xref>
</td>
<td valign="top" align="left" rowspan="1" colspan="1">Mupapa et al., <xref rid="B44" ref-type="bibr">1999</xref>
; Koyuncu et al., <xref rid="B34" ref-type="bibr">2013</xref>
</td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Human Papilloma virus type 1a (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="HPU06714">HPU06714</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">ss-RNA, circular</td>
<td valign="top" align="center" rowspan="1" colspan="1">1682 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Hepatitis E Virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="AB220977.1">AB220977.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">(+)ssRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">7266 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Hepatitis B virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="AB937799.1">AB937799.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">ds-DNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">3213 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Hepatitis A virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="AB279735.1">AB279735.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">(+)ssRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">7478 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Human rhinovirus 14 (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="NC_001490.1">NC_001490.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">(+)ssRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">7212 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" rowspan="1" colspan="1">Adult Rota virus (<ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="NC_007553.1">NC_007553.1</ext-link>
)</td>
<td valign="top" align="left" rowspan="1" colspan="1">(+)dsRNA, linear</td>
<td valign="top" align="center" rowspan="1" colspan="1">1287 bp</td>
<td valign="top" align="center" rowspan="1" colspan="1">0</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td valign="top" align="center" rowspan="1" colspan="1">−</td>
<td rowspan="1" colspan="1"></td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="TN3"><label>*</label>
<p>Known to cause microcephaly;</p>
</fn>
<fn id="TN4"><label>**</label>
<p>Rare cases of encephalitis noted;</p>
</fn>
<fn id="TN5"><label>***</label>
<p><italic>No data available due to early fetal loss and/or non-evaluation of the dead still birth baby for brain defects</italic>
.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec sec-type="discussion" id="s4"><title>Discussion</title>
<p>The RARE consensus sequence repeats were found in most of the ZIKV strains but the frequency of the repeats varied among the strains. Surprisingly, the ZIKV strain (KU497555.1, Table <xref ref-type="table" rid="T2">2</xref>
) which was implicated in the recent cases of the microcephaly in Brazil (Calvet et al., <xref rid="B5" ref-type="bibr">2016</xref>
), and other strains which shared close homology with it contained the highest number of RARE sequence repeats (Table <xref ref-type="table" rid="T2">2</xref>
). The genomic sequence of the Brazilian ZIKV strain was found to share near 100% homology to the Polynesian strain (KJ776791, Table <xref ref-type="table" rid="T2">2</xref>
) which was taken as a reference in a recent study (Calvet et al., <xref rid="B5" ref-type="bibr">2016</xref>
). Another study (Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
) which had retrieved the virus from the brain tissue of a dead fetus with microcephaly had similar interpretation that the retrieved strain had a very close homology to the Polynesian strain (99.7%) and two other strains (EU545988-98%, JN860885-98.3%). All the three strains were amongst the highest number of RARE sequence containing strains as revealed in our study (Table <xref ref-type="table" rid="T2">2</xref>
). Although, it would still be a far-fetched conjecture to consider an association of these ZIKV strains (with the highest number of RARE sequence repeats) to microcephaly unless ZIKV-microcephaly link is well established.</p>
<p>From analysis of the data from all the viruses other than ZIKV (Table <xref ref-type="table" rid="T3">3</xref>
), it is clear that only those viruses contain the RARE consensus sequence repeats which are either known to cause fetal brain malformations or show neurotropism. Different strains of the same genus vary in the presence of these sequence repeats and it is absent altogether in some strains. A virus with comparatively higher RARE sequence repeats seems to be a more potent teratogen (in terms of causing congenital brain malformation) or displays correspondingly robust neurotropism as suggested by the analysis of Table <xref ref-type="table" rid="T3">3</xref>
. Some of these viruses are well known to cause fetal microcephaly also (Table <xref ref-type="table" rid="T3">3</xref>
, single star marked). Almost all of the viruses which contained RARE consensus sequence essentially show neurotropism of some degree (as documented in the literature) except the Dengue virus type-2 in which we found no RARE sequence repeats despite the evidence of its neurotropism in literature (Salazar et al., <xref rid="B51" ref-type="bibr">2013</xref>
). The presence of the RARE consensus sequence repeats revealed in the known neurotropic viruses (Table <xref ref-type="table" rid="T3">3</xref>
) could be an indication that retinoic acid signaling may have an important role to play in neurotropism, although we couldn't find sufficient support in literature for this claim due to paucity of research over this issue. There is, nevertheless, substantial evidence that retinoic acid inducible gene (RIG)-1 which is upregulated by retinoic acid, functions as an intra-cellular pattern recognition receptor for the known neurotrophic receptor viruses (Furr and Marriott, <xref rid="B16" ref-type="bibr">2012</xref>
; Carty et al., <xref rid="B6" ref-type="bibr">2014</xref>
). A recent study reports the involvement of a similar viral pattern recognition receptor TLR-3 in ZIKV caused growth restriction and depletion of neural stem cell progenitors in human cerebral organoids (Dang et al., <xref rid="B10" ref-type="bibr">2016</xref>
). There are additional reports suggesting a necessary RIG-1 and TLR-3 interaction to surge innate immunity in response of viral infections (Liu et al., <xref rid="B37" ref-type="bibr">2007</xref>
; Slater et al., <xref rid="B59" ref-type="bibr">2010</xref>
). These reports indicate the involvement of retinoic acid signaling in proper brain development. Further research is required to establish the nature of retinoic acid-neurotropism relationship but based on our observations on the ZIKV strains and various other viruses, it seems coherent to consider the presence of RARE consensus repeats as the reason for the obligatory neurotropic character of the ZIKV strains implicated in microcephaly (Calvet et al., <xref rid="B5" ref-type="bibr">2016</xref>
; Hazin et al., <xref rid="B26" ref-type="bibr">2016</xref>
; Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
).</p>
<p>The high frequency of RARE consensus repeats in some double stranded DNA viruses may be because of larger reading frame length and probably a RARE sequence index value (which balances number of repeats with total reading frame length of genomic sequence). This index could be an appropriate measure for representing potency of a virus for causing congenital brain malformation or neurotropism. A further detailed study on the presence of RARE consensus sequence repeats in ZIKV vs. other viruses may be desired to confirm if retinoic acid signaling dysregulation is a common mechanism used by such viruses to cause congenital brain malformations.</p>
<sec><title>Fetal brain defects in ZIKV-microcephaly closely resemble to brain malformation caused by dysregulation of retinoic acid signaling</title>
<p>Fetal microcephaly has always been known as a developmental anomaly caused by multiple etiologies (Mochida and Walsh, <xref rid="B43" ref-type="bibr">2001</xref>
). Retinoic acid signaling dysregulation has also been implicated as a common mechanism in many environmental or developmental reasons of microcephaly (Lammer et al., <xref rid="B35" ref-type="bibr">1985</xref>
; Kot-Leibovich and Fainsod, <xref rid="B33" ref-type="bibr">2009</xref>
; Paganelli et al., <xref rid="B46" ref-type="bibr">2010</xref>
). The anatomical details of the brain of the fetuses suspected of ZIKV infection in recent reports (Aragao et al., <xref rid="B2" ref-type="bibr">2016</xref>
; Calvet et al., <xref rid="B5" ref-type="bibr">2016</xref>
; Hazin et al., <xref rid="B26" ref-type="bibr">2016</xref>
; Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
) closely resemble to those caused by retinoic acid signaling dysregulation and have many features in common i.e., cerebellar and brain stem hypoplasia (Yamamoto et al., <xref rid="B71" ref-type="bibr">2003</xref>
), ventriculomegaly (Micucci et al., <xref rid="B41" ref-type="bibr">2014</xref>
), hypoplasia of forebrain derivatives like frontal or parietal lobe of the brain (Halilagic et al., <xref rid="B24" ref-type="bibr">2007</xref>
), and hypogyration of cerebral cortex (Siegenthaler et al., <xref rid="B58" ref-type="bibr">2009</xref>
). The reason behind these striking resemblances could be that the retinoic acid signaling is crucially involved in development of the dorsal brain structures (Wilson et al., <xref rid="B68" ref-type="bibr">2007</xref>
; including cerebellum and brain stem), midline forebrain structures (Gupta and Sen, <xref rid="B23" ref-type="bibr">2015</xref>
; including choroid plexus which synthesizes CSF and a malformation of it may result in hydrocephalus and in turn ventriculomegaly), and the cortex (Siegenthaler et al., <xref rid="B58" ref-type="bibr">2009</xref>
; Crandall et al., <xref rid="B9" ref-type="bibr">2011</xref>
). So it is an obviously plausible concept in the light of our hypothesis as to why retinoic acid signaling dysregulation may result in malformations similar to that noted in ZIKV caused microcephaly (Calvet et al., <xref rid="B5" ref-type="bibr">2016</xref>
; Hazin et al., <xref rid="B26" ref-type="bibr">2016</xref>
; Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
).</p>
<p>The presentation of the brain defects in retinoic acid dysregulation varies depending on the stage of embryonic development. If the signaling disruption ensues at late gastrulation or early neurulation stage, the defect should be occurring in rostrocaudal sequencing of the brain structures in the developing neural tube i.e., there may be a larger hindbrain at the expense of anterior brain structures. But if the disruption is at late developmental stages that will affect dorsalization of the brain or hindbrain structures i.e., may cause cerebellar or brain stem hypoplasia or absence of some hind brain components (Wilson et al., <xref rid="B68" ref-type="bibr">2007</xref>
).</p>
<p>The presence of microcephaly or other brain malformations in the fetuses born of the ZIKV infected mothers (similar to the other viruses causing congenital brain malformations) may also depend upon the time-point of the fetal infection during neural tube formation, and also on the total viral load (Adams Waldorf and McAdams, <xref rid="B1" ref-type="bibr">2013</xref>
). In some recent reports of the cases with ZIKV-microcephaly, pregnant women presented with clinical features of ZIKV infection at 10th week of gestation or beyond and microcephalic features were detected on ultrasound beyond 20th week (Calvet et al., <xref rid="B5" ref-type="bibr">2016</xref>
; Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
). This matches with the retinoic acid signaling dysregulation at the late developmental stages when dorsal brain structures and hindbrain brain structures are still in development and cortical gyration still in progress. A disruption at this stage would essentially result in the features typically seen in ZIKV microcephaly (Calvet et al., <xref rid="B5" ref-type="bibr">2016</xref>
; Hazin et al., <xref rid="B26" ref-type="bibr">2016</xref>
; Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
) as has been noted above.</p>
<p>Due to striking resemblance to the embryological malformations, the recent reports on ZIKV-microcephaly (Calvet et al., <xref rid="B5" ref-type="bibr">2016</xref>
; Hazin et al., <xref rid="B26" ref-type="bibr">2016</xref>
; Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
) have stressed upon considering the fetal brain damage as a developmental problem rather than the brain destruction caused by viral invasion of neuronal cells. One important study has found substantial evidence of presence of ZIKV in the neurons through immuno-histological and microbiology investigations of the fetal brain tissue died of the severe microcephaly (Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
). Interstingly, other probable infectious causes of the microcephaly were successfully ruled out in this study.</p>
</sec>
<sec><title>Justification from maternal-fetal transmission</title>
<p>On an interesting note, our data also suggests that a virus which contains RARE consensus sequence repeats also shows some degree of neurotropism but its causal handcuff to microcephaly or any other type of fetal brain defect essentially depends upon its ability for maternal-fetal transmission. Chikungunya virus ((+)ssRNA, linear, 11811 bp: Table <xref ref-type="table" rid="T3">3</xref>
) seems to be a representative example. It contains four RARE consensus sequence repeats and shows neurotropism (Koyuncu et al., <xref rid="B34" ref-type="bibr">2013</xref>
), maternal-fetal transmission in humans has also been sufficiently demonstrated for this virus (Fritel et al., <xref rid="B15" ref-type="bibr">2010</xref>
; Gérardin et al., <xref rid="B18" ref-type="bibr">2008</xref>
), and is also known to cause microcephaly and/or other fetal brain defects (Gérardin et al., <xref rid="B19" ref-type="bibr">2014</xref>
). On the other hand Japanese encephalitis virus ((+)ssRNA, linear, 10970 bp: Table <xref ref-type="table" rid="T3">3</xref>
) which has no known evidence of maternal-fetal transmission in humans, although having shorter frame length and more number of RARE consensus sequence repeats (numbering to six) is known to show neurotropism (Kimura-Kuroda et al., <xref rid="B31" ref-type="bibr">1993</xref>
) but do not cause fetal brain defect in humans. The obligatory nature of ability of maternal-fetal transmission in a virus to cause fetal brain damage is empirically coherent and further suggests that presence of RARE consensus sequence repeats in a virus genome may be limited to confer it neurovirulence only, and may require additional contributing factors toward its maternal-fetal transmission ability.</p>
</sec>
<sec><title>Further notes in support of our hypothesis concerning ZIKV-mediated microcephaly</title>
<p>Another evidence in favor of the retinoic acid signaling dysregulation as a probable mechanism in ZIKV- microcephaly is that the mouse model study of a well-known fetal anomaly syndrome called “CHARGE” (in which dysregulation of retinoic acid signaling has been implicated) reported some anomalous features very similar to that found in fetal brains suspected of ZIKV microcephaly (Calvet et al., <xref rid="B5" ref-type="bibr">2016</xref>
; Hazin et al., <xref rid="B26" ref-type="bibr">2016</xref>
; Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
) such as cerebellar hypoplasia and ventriculomegaly (Micucci et al., <xref rid="B41" ref-type="bibr">2014</xref>
). In addition to that, hydrocephalus and malformation of corpus callosum noted in some cases of ZIKV microcephaly (Aragao et al., <xref rid="B2" ref-type="bibr">2016</xref>
) are also present in “CHARGE” syndrome. Furthermore, the widespread cortical anomalies in ZIKV microcephaly get explained by an interesting study involving retinoic acid (Siegenthaler et al., <xref rid="B58" ref-type="bibr">2009</xref>
). These investigators reported cranial meninges as a source of retinoic acid to the developing cortex (radial glial cells carrying migrating progenitor cells to the upper cortical layers attach their end feet to the covering meninx, from where they get retinoic acid as a diffusible morphogen and transfer to other cells involved in corticogenesis). Retinoic acid signaling has been extensively implicated in cortical genesis (Harrison-Uy et al., <xref rid="B25" ref-type="bibr">2013</xref>
), especially in the migration of progenitor cells to the upper cortical layers riding on the radial glial cells (Siegenthaler et al., <xref rid="B58" ref-type="bibr">2009</xref>
; Crandall et al., <xref rid="B9" ref-type="bibr">2011</xref>
). Many contemporary reports have confirmed that ZIKV has detrimental effects on human cortical progenitor cells in neural stem cell cultures (Crandall et al., <xref rid="B9" ref-type="bibr">2011</xref>
) and neurospheres or brain organoids developed from human induced pluripotent cells (Garcez et al., <xref rid="B17" ref-type="bibr">2016</xref>
). ZIKV has also been shown to induce cell death and attenuate growth mediated through vast transcriptomic alterations (Crandall et al., <xref rid="B9" ref-type="bibr">2011</xref>
) involved in apoptosis (Crandall et al., <xref rid="B9" ref-type="bibr">2011</xref>
; Garcez et al., <xref rid="B17" ref-type="bibr">2016</xref>
) and cell cycle regulations (Crandall et al., <xref rid="B9" ref-type="bibr">2011</xref>
). The disruption of the normal retinoic acid signaling in developing forebrain has been shown to induce death of neural precursor cells and attenuate their growth with somewhat similar mechanisms (Rajaii et al., <xref rid="B47" ref-type="bibr">2008</xref>
), raising a possibility that ZIKV might be disrupting retinoic acid signaling pathway. Our hypothesis, hence derives support from known literature with multiple justifications. It explains many mysteries and helps in understanding the embryological basis of ZIKV mediated microcephaly.</p>
<p>Additionally, the white matter hypodensity noted in ZIKV mediated microcephaly (Hazin et al., <xref rid="B26" ref-type="bibr">2016</xref>
) can also be explained by dysregulation of retinoic acid signaling due to its noted involvement in myelination in the developing brain. To augment this, adequate retinoid receptor expression on oligodendrocyte precursor cells is necessary which later myelinate CNS (Huang et al., <xref rid="B27" ref-type="bibr">2011</xref>
). Dysregulation of retinoic acid signaling has also been implicated in some demyelinating pathologies (Okuda and Prados, <xref rid="B45" ref-type="bibr">2009</xref>
; König et al., <xref rid="B32" ref-type="bibr">2012</xref>
). Also, there is sufficient evidence that the retinal or other ophthalmic lesions, a unique finding observed in some ZIKV infected fetuses (de Paula Freitas et al., <xref rid="B11" ref-type="bibr">2016</xref>
; Ventura et al., <xref rid="B66" ref-type="bibr">2016</xref>
) may precipitate through disruption retinoic acid signaling (Mic et al., <xref rid="B40" ref-type="bibr">2004</xref>
; Micucci et al., <xref rid="B41" ref-type="bibr">2014</xref>
).</p>
<p>Our claim that ZIKV-microcephaly may involve retinoic acid signaling dysregulation is further bolstered by the fact that many of the toxins that involve retinoic acid also have microcephaly as a presenting feature (Lammer et al., <xref rid="B35" ref-type="bibr">1985</xref>
; Mochida and Walsh, <xref rid="B43" ref-type="bibr">2001</xref>
; Kot-Leibovich and Fainsod, <xref rid="B33" ref-type="bibr">2009</xref>
; Paganelli et al., <xref rid="B46" ref-type="bibr">2010</xref>
) and may share other malformations too. This is especially relevant to malformations arising in fetus with exposure of pregnant women to the isotretinoin (an analog of retinoic acid known to cause retinoic acid embryopathy). These malformations match to almost all the features described under ZIKV-microcephaly spectrum including enlarged cistern magna and calcifications in brain parenchyma (Lammer et al., <xref rid="B35" ref-type="bibr">1985</xref>
; Irving et al., <xref rid="B28" ref-type="bibr">1986</xref>
).</p>
<p>With the above-described pieces of evidence, a plausible mosaic of a justified picture comes up supporting our proposition that ZIKV interferes with retinoic acid signaling in the developing brain. In view of (1) the bioinformatic evidence of the presence of RARE sequence repeats in genome sequences of ZIKV strains and in other viruses known to cause congenital brain malformation (Table <xref ref-type="table" rid="T3">3</xref>
) and (2) confirmed role of retinoic acid in neural tube formation and further brain development mediated through RARE sequences, it is scientifically coherent to assume that a RARE sequence dependent mechanism could be the underlying mechanism of microcephaly seen in ZIKV infected fetuses. We, however stress that there is a need of confirming the proposed hypothesis on animal models or neural cell cultures.</p>
<p>Why embryonic defects are limited to the central nervous system only, and no anomaly of the other organs or limbs are reported in ZIKV if it causes an embryopathy is quite surprising. It could probably be due to strong neurotropic nature of the virus as it has been reported to be completely absent in organs other than the brain. A recent study performed the autopsy on ZIKV infected fetuses with severe microcephaly confirmed the absence of this virus in organs other than brain (Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
). ZIKV infection has also been observed to be less prevalent in human precursor cells other than the neural precursors (Crandall et al., <xref rid="B9" ref-type="bibr">2011</xref>
). Again, why did USG studies in ZIKV infected fetuses show no abnormality of brain structures almost until 20th weeks of gestation is a mystery and needs to be explained. A probable explanation for the late involvement of the brain structures has been indicated in the recent study based on immune-histological features of affected brain tissue. It indicates that time is consumed in virus invasion of the neurones and accumulation of approximate lesions capable of arresting cortical growth (Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
).</p>
<p>We chose retinoic acid for its probable role in ZIKV-mediated microcephaly but there is obvious need of exploring other molecular factors which may be involved in neural tube axis determination and its further development. Also, retinoic acid signaling dysregulation is not able to explain multifocal calcifications widespread in the basal ganglia, thalamus and cortical regions as noted in histological and radiological studies of ZIKV-microcephaly cases (Aragao et al., <xref rid="B2" ref-type="bibr">2016</xref>
; Calvet et al., <xref rid="B5" ref-type="bibr">2016</xref>
; Hazin et al., <xref rid="B26" ref-type="bibr">2016</xref>
; Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
). It is, however, important to mention that a rare presentation of an embryological anomaly syndrome (“CHARGE” syndrome, in which retinoic acid signaling dysregulation; Micucci et al., <xref rid="B41" ref-type="bibr">2014</xref>
) has been noted and reported with bilateral basal ganglia calcifications (Jain et al., <xref rid="B29" ref-type="bibr">2011</xref>
). Calcifications in brain parenchyma have also been mentioned in retinoic acid embryopathy (Lammer et al., <xref rid="B35" ref-type="bibr">1985</xref>
). As the calcifications found in the ZIKV affected fetal brain are punctiform and appear as destroyed neuronal structure on histological examination (Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
), an alternative explanation for their formation could be that calcifications are due to the deposition of the calcium compounds in the accumulations of viral invaded dead neurons (Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
) as the process of degeneration.</p>
<p>To test our hypothesis, it was is essential to ascertain that the ZIKV strains which contain either equal or less number of RARE sequences than Brazilian strain (Table <xref ref-type="table" rid="T2">2</xref>
) in their genome can also cause microcephaly or not. As we discussed above based the ZIKV strain which was recently implicated in microcephaly in Brazil has close similarity with the Polynesian and other two strains (Mlakar et al., <xref rid="B42" ref-type="bibr">2016</xref>
; Schuler-Faccini et al., <xref rid="B56" ref-type="bibr">2016</xref>
; Table <xref ref-type="table" rid="T2">2</xref>
, iv, viii, xiv), and all three contained the highest numbers of RARE consensus sequences in our study. But to make a valid claim to relate number of RARE consensus sequences with virulence of the strains, further availability of knowledge on the ZIKV strains implicated in the microcephaly is indispensable.</p>
</sec>
<sec><title>Future prospects</title>
<p>The immediate application of our study are immense. If it is established that ZIKV caused microcephaly in infected fetus is a developmental condition arising out of retinoic acid signaling dysregulation it would not only help to understand the ZIKV–microcephaly pathogenesis but also may justify retinoic acid as a therapeutic target for preventing this condition.</p>
</sec>
</sec>
<sec id="s5"><title>Author contributions</title>
<p>Conceived and designed the experiments: AK, HS, MF. Performed the experiments: AK, HS. Analyzed the data: AK, HS, MF. Wrote and revised the paper: AK, HS, VP, KR, SD, PK, SM, MF.</p>
<sec><title>Conflict of interest statement</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
</sec>
</body>
<back><sec sec-type="supplementary-material" id="s6"><title>Supplementary material</title>
<p>The Supplementary Material for this article can be found online at: <ext-link ext-link-type="uri" xlink:href="http://journal.frontiersin.org/article/10.3389/fnhum.2016.00403">http://journal.frontiersin.org/article/10.3389/fnhum.2016.00403</ext-link>
</p>
<supplementary-material content-type="local-data"><media xlink:href="DataSheet1.DOC"><caption><p>Click here for additional data file.</p>
</caption>
</media>
</supplementary-material>
</sec>
<ref-list><title>References</title>
<ref id="B1"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Adams Waldorf</surname>
<given-names>K. M</given-names>
</name>
<name><surname>McAdams</surname>
<given-names>R. M.</given-names>
</name>
</person-group>
(<year>2013</year>
). <article-title>Influence of infection during pregnancy on fetal development</article-title>
. <source>Reproduction</source>
<volume>146</volume>
, <fpage>R151</fpage>
–<lpage>R162</lpage>
. <pub-id pub-id-type="doi">10.1530/rep-13-0232</pub-id>
<pub-id pub-id-type="pmid">23884862</pub-id>
</mixed-citation>
</ref>
<ref id="B2"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Aragao</surname>
<given-names>M.</given-names>
</name>
<name><surname>de</surname>
<given-names>F. V.</given-names>
</name>
<name><surname>van der Linden</surname>
<given-names>V.</given-names>
</name>
<name><surname>Brainer-Lima</surname>
<given-names>A. M.</given-names>
</name>
<name><surname>Coeli</surname>
<given-names>R. R.</given-names>
</name>
<name><surname>Rocha</surname>
<given-names>M. A.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2016</year>
). <article-title>Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study</article-title>
. <source>BMJ</source>
<volume>353</volume>
:<fpage>i1901</fpage>
. <pub-id pub-id-type="doi">10.1136/bmj.i1901</pub-id>
<pub-id pub-id-type="pmid">27075009</pub-id>
</mixed-citation>
</ref>
<ref id="B3"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Balmer</surname>
<given-names>J. E.</given-names>
</name>
<name><surname>Blomhoff</surname>
<given-names>R.</given-names>
</name>
</person-group>
(<year>2002</year>
). <article-title>Gene expression regulation by retinoic acid</article-title>
. <source>J. Lipid Res.</source>
<volume>43</volume>
, <fpage>1773</fpage>
–<lpage>1808</lpage>
. <pub-id pub-id-type="doi">10.1194/jlr.R100015-JLR200</pub-id>
<pub-id pub-id-type="pmid">12401878</pub-id>
</mixed-citation>
</ref>
<ref id="B4"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Baronti</surname>
<given-names>C.</given-names>
</name>
<name><surname>Piorkowski</surname>
<given-names>G.</given-names>
</name>
<name><surname>Charrel</surname>
<given-names>R. N.</given-names>
</name>
<name><surname>Boubis</surname>
<given-names>L.</given-names>
</name>
<name><surname>Leparc-Goffart</surname>
<given-names>I.</given-names>
</name>
<name><surname>de Lamballerie</surname>
<given-names>X.</given-names>
</name>
</person-group>
(<year>2014</year>
). <article-title>Complete coding sequence of Zika virus from a French Polynesia outbreak in 2013</article-title>
. <source>Genome Announc.</source>
<volume>2</volume>
, <fpage>e00500</fpage>
–<lpage>e00514</lpage>
. <pub-id pub-id-type="doi">10.1128/genomeA.00500-14</pub-id>
<pub-id pub-id-type="pmid">24903869</pub-id>
</mixed-citation>
</ref>
<ref id="B5"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Calvet</surname>
<given-names>G.</given-names>
</name>
<name><surname>Aguiar</surname>
<given-names>R. S.</given-names>
</name>
<name><surname>Melo</surname>
<given-names>A. S.</given-names>
</name>
<name><surname>Sampaio</surname>
<given-names>S. A.</given-names>
</name>
<name><surname>de Filippis</surname>
<given-names>I.</given-names>
</name>
<name><surname>Fabri</surname>
<given-names>A.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2016</year>
). <article-title>Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study</article-title>
. <source>Lancet Infect. Dis.</source>
<volume>16</volume>
, <fpage>653</fpage>
–<lpage>660</lpage>
. <pub-id pub-id-type="doi">10.1016/S1473-3099(16)00095-5</pub-id>
<pub-id pub-id-type="pmid">26897108</pub-id>
</mixed-citation>
</ref>
<ref id="B6"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Carty</surname>
<given-names>M.</given-names>
</name>
<name><surname>Reinert</surname>
<given-names>L.</given-names>
</name>
<name><surname>Paludan</surname>
<given-names>S. R.</given-names>
</name>
<name><surname>Bowie</surname>
<given-names>A. G.</given-names>
</name>
</person-group>
(<year>2014</year>
). <article-title>Innate antiviral signalling in the central nervous system</article-title>
. <source>Trends Immunol.</source>
<volume>35</volume>
, <fpage>79</fpage>
–<lpage>87</lpage>
. <pub-id pub-id-type="doi">10.1016/j.it.2013.10.012</pub-id>
<pub-id pub-id-type="pmid">24316012</pub-id>
</mixed-citation>
</ref>
<ref id="B7"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cipriano</surname>
<given-names>R.</given-names>
</name>
<name><surname>Monteiro</surname>
<given-names>C. C.</given-names>
</name>
</person-group>
(<year>2016</year>
). <article-title>Reporting on Zika virus in Brazil.</article-title>
<source>Rev. Epidemiol. E Controle de Infecção</source>
<volume>6</volume>
<pub-id pub-id-type="doi">10.17058/reci.v6i1.6959</pub-id>
</mixed-citation>
</ref>
<ref id="B8"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Civitello</surname>
<given-names>L.</given-names>
</name>
</person-group>
(<year>1991</year>
). <article-title>Neurologic complications of HIV infection in children</article-title>
. <source>Pediat. Neurosurg.</source>
<volume>17</volume>
, <fpage>104</fpage>
–<lpage>112</lpage>
. <pub-id pub-id-type="doi">10.1159/000120576</pub-id>
<pub-id pub-id-type="pmid">1815729</pub-id>
</mixed-citation>
</ref>
<ref id="B9"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Crandall</surname>
<given-names>J. E.</given-names>
</name>
<name><surname>Goodman</surname>
<given-names>T.</given-names>
</name>
<name><surname>McCarthy</surname>
<given-names>D. M.</given-names>
</name>
<name><surname>Duester</surname>
<given-names>G.</given-names>
</name>
<name><surname>Bhide</surname>
<given-names>P. G.</given-names>
</name>
<name><surname>Dräger</surname>
<given-names>U. C.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2011</year>
). <article-title>Retinoic acid influences neuronal migration from the ganglionic eminence to the cerebral cortex</article-title>
. <source>J. Neurochem.</source>
<volume>119</volume>
, <fpage>723</fpage>
–<lpage>735</lpage>
. <pub-id pub-id-type="doi">10.1111/j.1471-4159.2011.07471.x</pub-id>
<pub-id pub-id-type="pmid">21895658</pub-id>
</mixed-citation>
</ref>
<ref id="B10"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dang</surname>
<given-names>J.</given-names>
</name>
<name><surname>Tiwari</surname>
<given-names>S. K.</given-names>
</name>
<name><surname>Lichinchi</surname>
<given-names>G.</given-names>
</name>
<name><surname>Qin</surname>
<given-names>Y.</given-names>
</name>
<name><surname>Patil</surname>
<given-names>V. S.</given-names>
</name>
<name><surname>Eroshkin</surname>
<given-names>A. M.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2016</year>
). <article-title>Zika virus depletes neural progenitors in human cerebral organoids through activation of the innate immune receptor TLR3</article-title>
. <source>Cell Stem Cell.</source>
<pub-id pub-id-type="doi">10.1016/j.stem.2016.04.014</pub-id>
. [Epub ahead of print].<pub-id pub-id-type="pmid">27162029</pub-id>
</mixed-citation>
</ref>
<ref id="B11"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>de Paula Freitas</surname>
<given-names>B.</given-names>
</name>
<name><surname>de Oliveira Dias</surname>
<given-names>J. R.</given-names>
</name>
<name><surname>Prazeres</surname>
<given-names>J.</given-names>
</name>
<name><surname>Sacramento</surname>
<given-names>G. A.</given-names>
</name>
<name><surname>Ko</surname>
<given-names>A. I.</given-names>
</name>
<name><surname>Maia</surname>
<given-names>M.</given-names>
</name>
<etal></etal>
</person-group>
(<year>2016</year>
). <article-title>Ocular findings in infants with microcephaly associated with presumed Zika virus congenital infection in Salvador, Brazil</article-title>
. <source>JAMA Ophthalmol.</source>
<volume>134</volume>
, <fpage>529</fpage>
–<lpage>535</lpage>
. <pub-id pub-id-type="doi">10.1001/jamaophthalmol.2016.0267</pub-id>
</mixed-citation>
</ref>
<ref id="B12"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Durston</surname>
<given-names>A. J.</given-names>
</name>
<name><surname>Timmermans</surname>
<given-names>J. P.</given-names>
</name>
<name><surname>Hage</surname>
<given-names>W. J.</given-names>
</name>
<name><surname>Hendriks</surname>
<given-names>H. F.</given-names>
</name>
<name><surname>de Vries</surname>
<given-names>N. J.</given-names>
</name>
<name><surname>Heideveld</surname>
<given-names>M.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>1989</year>
). <article-title>Retinoic acid causes an anteroposterior transformation in the developing central nervous system</article-title>
. <source>Nature</source>
<volume>340</volume>
, <fpage>140</fpage>
–<lpage>144</lpage>
. <pub-id pub-id-type="doi">10.1038/340140a0</pub-id>
<pub-id pub-id-type="pmid">2739735</pub-id>
</mixed-citation>
</ref>
<ref id="B13"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Findlay</surname>
<given-names>G.</given-names>
</name>
<name><surname>Stern</surname>
<given-names>R. O.</given-names>
</name>
</person-group>
(<year>1935</year>
). <article-title>The essential neurotropism of the yellow fever virus</article-title>
. <source>J. Pathol. Bacteriol.</source>
<volume>41</volume>
, <fpage>431</fpage>
–<lpage>438</lpage>
. <pub-id pub-id-type="doi">10.1002/path.1700410307</pub-id>
</mixed-citation>
</ref>
<ref id="B14"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Forton</surname>
<given-names>D. M.</given-names>
</name>
<name><surname>Allsop</surname>
<given-names>J. M.</given-names>
</name>
<name><surname>Main</surname>
<given-names>J.</given-names>
</name>
<name><surname>Foster</surname>
<given-names>G. R.</given-names>
</name>
<name><surname>Thomas</surname>
<given-names>H. C.</given-names>
</name>
<name><surname>Taylor-Robinson</surname>
<given-names>S. D.</given-names>
</name>
</person-group>
(<year>2001</year>
). <article-title>Evidence for a cerebral effect of the hepatitis C virus</article-title>
. <source>Lancet</source>
<volume>358</volume>
, <fpage>38</fpage>
–<lpage>39</lpage>
. <pub-id pub-id-type="doi">10.1016/S0140-6736(00)05270-3</pub-id>
<pub-id pub-id-type="pmid">11454379</pub-id>
</mixed-citation>
</ref>
<ref id="B15"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fritel</surname>
<given-names>X.</given-names>
</name>
<name><surname>Rollot</surname>
<given-names>O.</given-names>
</name>
<name><surname>Gérardin</surname>
<given-names>P.</given-names>
</name>
<name><surname>Gauzere</surname>
<given-names>B. A.</given-names>
</name>
<name><surname>Bideault</surname>
<given-names>J.</given-names>
</name>
<name><surname>Lagarde</surname>
<given-names>L.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2010</year>
). <article-title>Chikungunya virus infection during pregnancy, Reunion, France, (2006)</article-title>
. <source>Emerg. Infect. Dis.</source>
<volume>16</volume>
, <fpage>418</fpage>
–<lpage>425</lpage>
. <pub-id pub-id-type="doi">10.3201/eid1604.091403</pub-id>
<pub-id pub-id-type="pmid">20202416</pub-id>
</mixed-citation>
</ref>
<ref id="B16"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Furr</surname>
<given-names>S. R.</given-names>
</name>
<name><surname>Marriott</surname>
<given-names>I.</given-names>
</name>
</person-group>
(<year>2012</year>
). <article-title>Viral CNS infections: role of glial pattern recognition receptors in neuroinflammation</article-title>
. <source>Front. Microbiol.</source>
<volume>3</volume>
:<issue>201</issue>
. <pub-id pub-id-type="doi">10.3389/fmicb.2012.00201</pub-id>
<pub-id pub-id-type="pmid">22723794</pub-id>
</mixed-citation>
</ref>
<ref id="B17"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Garcez</surname>
<given-names>P. P.</given-names>
</name>
<name><surname>Loiola</surname>
<given-names>E. C.</given-names>
</name>
<name><surname>Madeiro da Costa</surname>
<given-names>R</given-names>
</name>
<name><surname>Higa</surname>
<given-names>L. M.</given-names>
</name>
<name><surname>Trindade</surname>
<given-names>P.</given-names>
</name>
<name><surname>Delvecchio</surname>
<given-names>R.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2016</year>
). <article-title>Zika virus impairs growth in human neurospheres and brain organoids</article-title>
. <source>Science</source>
<volume>352</volume>
, <fpage>816</fpage>
–<lpage>818</lpage>
. <pub-id pub-id-type="doi">10.1126/science.aaf6116</pub-id>
<pub-id pub-id-type="pmid">27064148</pub-id>
</mixed-citation>
</ref>
<ref id="B18"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gérardin</surname>
<given-names>P.</given-names>
</name>
<name><surname>Barau</surname>
<given-names>G.</given-names>
</name>
<name><surname>Michault</surname>
<given-names>A.</given-names>
</name>
<name><surname>Bintner</surname>
<given-names>M.</given-names>
</name>
<name><surname>Randrianaivo</surname>
<given-names>H.</given-names>
</name>
<name><surname>Choker</surname>
<given-names>G.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2008</year>
). <article-title>Multidisciplinary prospective study of mother-to-child chikungunya virus infections on the island of La Reunion</article-title>
. <source>PLoS Med.</source>
<volume>5</volume>
:<fpage>e60</fpage>
. <pub-id pub-id-type="doi">10.1371/journal.pmed.0050060</pub-id>
<pub-id pub-id-type="pmid">18351797</pub-id>
</mixed-citation>
</ref>
<ref id="B19"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gérardin</surname>
<given-names>P.</given-names>
</name>
<name><surname>Sampériz</surname>
<given-names>S.</given-names>
</name>
<name><surname>Ramful</surname>
<given-names>D.</given-names>
</name>
<name><surname>Boumahni</surname>
<given-names>B.</given-names>
</name>
<name><surname>Bintner</surname>
<given-names>M.</given-names>
</name>
<name><surname>Alessandri</surname>
<given-names>J.-L.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2014</year>
). <article-title>Neurocognitive outcome of children exposed to perinatal mother-to-child Chikungunya virus infection: the CHIMERE cohort study on Reunion Island</article-title>
. <source>PLoS Negl. Trop. Dis.</source>
<volume>8</volume>
:<fpage>e2996</fpage>
. <pub-id pub-id-type="doi">10.1371/journal.pntd.0002996</pub-id>
<pub-id pub-id-type="pmid">25033077</pub-id>
</mixed-citation>
</ref>
<ref id="B20"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Grapin-Botton</surname>
<given-names>A.</given-names>
</name>
<name><surname>Bonnin</surname>
<given-names>M. A.</given-names>
</name>
<name><surname>Sieweke</surname>
<given-names>M.</given-names>
</name>
<name><surname>Le Douarin</surname>
<given-names>N. M.</given-names>
</name>
</person-group>
(<year>1998</year>
). <article-title>Defined concentrations of a posteriorizing signal are critical for MafB/Kreisler segmental expression in the hindbrain</article-title>
. <source>Development</source>
<volume>125</volume>
, <fpage>1173</fpage>
–<lpage>1181</lpage>
. <pub-id pub-id-type="pmid">9477316</pub-id>
</mixed-citation>
</ref>
<ref id="B21"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Grover</surname>
<given-names>V. P.</given-names>
</name>
<name><surname>Pavese</surname>
<given-names>N.</given-names>
</name>
<name><surname>Koh</surname>
<given-names>S. B.</given-names>
</name>
<name><surname>Wylezinska</surname>
<given-names>M.</given-names>
</name>
<name><surname>Saxby</surname>
<given-names>B. K.</given-names>
</name>
<name><surname>Gerhard</surname>
<given-names>A.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2012</year>
). <article-title>Cerebral microglial activation in patients with hepatitis C: <italic>in vivo</italic>
evidence of neuroinflammation</article-title>
. <source>J. Viral Hepatitis</source>
<volume>19</volume>
, <fpage>e89</fpage>
–<lpage>e96</lpage>
. <pub-id pub-id-type="doi">10.1111/j.1365-2893.2011.01510.x</pub-id>
<pub-id pub-id-type="pmid">22239531</pub-id>
</mixed-citation>
</ref>
<ref id="B22"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Guimard</surname>
<given-names>T.</given-names>
</name>
<name><surname>Minjolle</surname>
<given-names>S.</given-names>
</name>
<name><surname>Polard</surname>
<given-names>E.</given-names>
</name>
<name><surname>Fily</surname>
<given-names>F.</given-names>
</name>
<name><surname>Zeller</surname>
<given-names>H.</given-names>
</name>
<name><surname>Michelet</surname>
<given-names>C.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2009</year>
). <article-title>Incidence of yellow fever vaccine-associated neurotropic disease</article-title>
. <source>Am. J. Tropic. Med. Hygiene</source>
<volume>81</volume>
, <fpage>1141</fpage>
–<lpage>1143</lpage>
. <pub-id pub-id-type="doi">10.4269/ajtmh.2009.09-0295</pub-id>
<pub-id pub-id-type="pmid">19996449</pub-id>
</mixed-citation>
</ref>
<ref id="B23"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gupta</surname>
<given-names>S.</given-names>
</name>
<name><surname>Sen</surname>
<given-names>J.</given-names>
</name>
</person-group>
(<year>2015</year>
). <article-title>Retinoic acid signaling regulates development of the dorsal forebrain midline and the choroid plexus in the chick</article-title>
. <source>Development</source>
<volume>142</volume>
, <fpage>1293</fpage>
–<lpage>1298</lpage>
. <pub-id pub-id-type="doi">10.1242/dev.122390</pub-id>
<pub-id pub-id-type="pmid">25758461</pub-id>
</mixed-citation>
</ref>
<ref id="B24"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Halilagic</surname>
<given-names>A.</given-names>
</name>
<name><surname>Ribes</surname>
<given-names>V.</given-names>
</name>
<name><surname>Ghyselinck</surname>
<given-names>N. B.</given-names>
</name>
<name><surname>Zile</surname>
<given-names>M. H.</given-names>
</name>
<name><surname>Dollé</surname>
<given-names>P.</given-names>
</name>
<name><surname>Studer</surname>
<given-names>M.</given-names>
</name>
</person-group>
(<year>2007</year>
). <article-title>Retinoids control anterior and dorsal properties in the developing forebrain</article-title>
. <source>Dev. Biol.</source>
<volume>303</volume>
, <fpage>362</fpage>
–<lpage>375</lpage>
. <pub-id pub-id-type="doi">10.1016/j.ydbio.2006.11.021</pub-id>
<pub-id pub-id-type="pmid">17184764</pub-id>
</mixed-citation>
</ref>
<ref id="B25"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Harrison-Uy</surname>
<given-names>S. J.</given-names>
</name>
<name><surname>Siegenthaler</surname>
<given-names>J. A.</given-names>
</name>
<name><surname>Faedo</surname>
<given-names>A.</given-names>
</name>
<name><surname>Rubenstein</surname>
<given-names>J. L.</given-names>
</name>
<name><surname>Pleasure</surname>
<given-names>S. J.</given-names>
</name>
</person-group>
(<year>2013</year>
). <article-title>CoupTFI interacts with retinoic acid signaling during cortical development</article-title>
. <source>PLoS ONE</source>
<volume>8</volume>
:<fpage>e58219</fpage>
. <pub-id pub-id-type="doi">10.1371/journal.pone.0058219</pub-id>
<pub-id pub-id-type="pmid">23472160</pub-id>
</mixed-citation>
</ref>
<ref id="B26"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hazin</surname>
<given-names>A. N.</given-names>
</name>
<name><surname>Poretti</surname>
<given-names>A.</given-names>
</name>
<name><surname>Di Cavalcanti Souza Cruz</surname>
<given-names>D.</given-names>
</name>
<name><surname>Tenorio</surname>
<given-names>M.</given-names>
</name>
<name><surname>van der Linden</surname>
<given-names>A.</given-names>
</name>
<name><surname>Pena</surname>
<given-names>L. J.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2016</year>
). <article-title>Computed tomographic findings in microcephaly associated with Zika virus</article-title>
. <source>New Engl. J. Med.</source>
<volume>374</volume>
, <fpage>2193</fpage>
–<lpage>2195</lpage>
. <pub-id pub-id-type="doi">10.1056/NEJMc1603617</pub-id>
<pub-id pub-id-type="pmid">27050112</pub-id>
</mixed-citation>
</ref>
<ref id="B27"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Huang</surname>
<given-names>J. K.</given-names>
</name>
<name><surname>Jarjour</surname>
<given-names>A. A.</given-names>
</name>
<name><surname>Nait Oumesmar</surname>
<given-names>B</given-names>
</name>
<name><surname>Kerninon</surname>
<given-names>C.</given-names>
</name>
<name><surname>Williams</surname>
<given-names>A.</given-names>
</name>
<name><surname>Krezel</surname>
<given-names>W.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2011</year>
). <article-title>Retinoid X receptor gamma signaling accelerates CNS remyelination</article-title>
. <source>Nat. Neurosci.</source>
<volume>14</volume>
, <fpage>45</fpage>
–<lpage>53</lpage>
. <pub-id pub-id-type="doi">10.1038/nn.2702</pub-id>
<pub-id pub-id-type="pmid">21131950</pub-id>
</mixed-citation>
</ref>
<ref id="B28"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Irving</surname>
<given-names>D. W.</given-names>
</name>
<name><surname>Willhite</surname>
<given-names>C. C.</given-names>
</name>
<name><surname>Burk</surname>
<given-names>D. T.</given-names>
</name>
</person-group>
(<year>1986</year>
). <article-title>Morphogenesis of isotretinoin-induced microcephaly and micrognathia studied by scanning electron microscopy</article-title>
. <source>Teratology</source>
<volume>34</volume>
, <fpage>141</fpage>
–<lpage>153</lpage>
. <pub-id pub-id-type="doi">10.1002/tera.1420340203</pub-id>
<pub-id pub-id-type="pmid">3465061</pub-id>
</mixed-citation>
</ref>
<ref id="B29"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jain</surname>
<given-names>S.</given-names>
</name>
<name><surname>Kim</surname>
<given-names>H.-G.</given-names>
</name>
<name><surname>Lacbawan</surname>
<given-names>F.</given-names>
</name>
<name><surname>Meliciani</surname>
<given-names>I.</given-names>
</name>
<name><surname>Wenzel</surname>
<given-names>W.</given-names>
</name>
<name><surname>Kurth</surname>
<given-names>I.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2011</year>
). <article-title>Unique phenotype in a patient with CHARGE syndrome</article-title>
. <source>Int. J. Pediatr. Endocrinol.</source>
<volume>2011</volume>
:<fpage>11</fpage>
. <pub-id pub-id-type="doi">10.1186/1687-9856-2011-11</pub-id>
<pub-id pub-id-type="pmid">21995344</pub-id>
</mixed-citation>
</ref>
<ref id="B30"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kam</surname>
<given-names>R. K. T.</given-names>
</name>
<name><surname>Deng</surname>
<given-names>Y.</given-names>
</name>
<name><surname>Chen</surname>
<given-names>Y.</given-names>
</name>
<name><surname>Zhao</surname>
<given-names>H.</given-names>
</name>
</person-group>
(<year>2012</year>
). <article-title>Retinoic acid synthesis and functions in early embryonic development</article-title>
. <source>Cell Biosci.</source>
<volume>2</volume>
, <fpage>1</fpage>
. <pub-id pub-id-type="doi">10.1186/2045-3701-2-11</pub-id>
<pub-id pub-id-type="pmid">22214309</pub-id>
</mixed-citation>
</ref>
<ref id="B31"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kimura-Kuroda</surname>
<given-names>J.</given-names>
</name>
<name><surname>Ichikawa</surname>
<given-names>M.</given-names>
</name>
<name><surname>Ogata</surname>
<given-names>A.</given-names>
</name>
<name><surname>Nagashima</surname>
<given-names>K.</given-names>
</name>
<name><surname>Yasui</surname>
<given-names>K.</given-names>
</name>
</person-group>
(<year>1993</year>
). <article-title>Specific tropism of Japanese encephalitis virus for developing neurons in primary rat brain culture</article-title>
. <source>Arch. Virol.</source>
<volume>130</volume>
, <fpage>477</fpage>
–<lpage>484</lpage>
. <pub-id pub-id-type="doi">10.1007/BF01309676</pub-id>
<pub-id pub-id-type="pmid">8517798</pub-id>
</mixed-citation>
</ref>
<ref id="B32"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>König</surname>
<given-names>R.</given-names>
</name>
<name><surname>Stillfried</surname>
<given-names>M.</given-names>
</name>
<name><surname>Aperdannier</surname>
<given-names>P.</given-names>
</name>
<name><surname>Clarner</surname>
<given-names>T.</given-names>
</name>
<name><surname>Beyer</surname>
<given-names>C.</given-names>
</name>
<name><surname>Kipp</surname>
<given-names>M.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2012</year>
). <article-title>Expression of retinoid X receptor beta is induced in astrocytes during corpus callosum demyelination</article-title>
. <source>J. Chem. Neuroanat.</source>
<volume>43</volume>
, <fpage>120</fpage>
–<lpage>132</lpage>
. <pub-id pub-id-type="doi">10.1016/j.jchemneu.2012.01.002</pub-id>
<pub-id pub-id-type="pmid">22306550</pub-id>
</mixed-citation>
</ref>
<ref id="B33"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kot-Leibovich</surname>
<given-names>H.</given-names>
</name>
<name><surname>Fainsod</surname>
<given-names>A.</given-names>
</name>
</person-group>
(<year>2009</year>
). <article-title>Ethanol induces embryonic malformations by competing for retinaldehyde dehydrogenase activity during vertebrate gastrulation</article-title>
. <source>Dis. Models Mech.</source>
<volume>2</volume>
, <fpage>295</fpage>
–<lpage>305</lpage>
. <pub-id pub-id-type="doi">10.1242/dmm.001420</pub-id>
<pub-id pub-id-type="pmid">19380308</pub-id>
</mixed-citation>
</ref>
<ref id="B34"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Koyuncu</surname>
<given-names>O. O.</given-names>
</name>
<name><surname>Hogue</surname>
<given-names>I. B.</given-names>
</name>
<name><surname>Enquist</surname>
<given-names>L. W.</given-names>
</name>
</person-group>
(<year>2013</year>
). <article-title>Virus infections in the nervous system</article-title>
. <source>Cell Host Microbe</source>
<volume>13</volume>
, <fpage>379</fpage>
–<lpage>393</lpage>
. <pub-id pub-id-type="doi">10.1016/j.chom.2013.03.010</pub-id>
<pub-id pub-id-type="pmid">23601101</pub-id>
</mixed-citation>
</ref>
<ref id="B35"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lammer</surname>
<given-names>E. J.</given-names>
</name>
<name><surname>Chen</surname>
<given-names>D. T.</given-names>
</name>
<name><surname>Hoar</surname>
<given-names>R. M.</given-names>
</name>
<name><surname>Agnish</surname>
<given-names>N. D.</given-names>
</name>
<name><surname>Benke</surname>
<given-names>P. J.</given-names>
</name>
<name><surname>Braun</surname>
<given-names>J. T.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>1985</year>
). <article-title>Retinoic acid embryopathy</article-title>
. <source>New Engl. J. Med.</source>
<volume>313</volume>
, <fpage>837</fpage>
–<lpage>841</lpage>
. <pub-id pub-id-type="doi">10.1056/NEJM198510033131401</pub-id>
<pub-id pub-id-type="pmid">3162101</pub-id>
</mixed-citation>
</ref>
<ref id="B36"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lau</surname>
<given-names>S. K.</given-names>
</name>
<name><surname>Woo</surname>
<given-names>P. C.</given-names>
</name>
<name><surname>Yip</surname>
<given-names>C. C.</given-names>
</name>
<name><surname>Tse</surname>
<given-names>H.</given-names>
</name>
<name><surname>Tsoi</surname>
<given-names>H. W.</given-names>
</name>
<name><surname>Cheng</surname>
<given-names>V. C.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2006</year>
). <article-title>Coronavirus HKU1 and other coronavirus infections in Hong Kong</article-title>
. <source>J. Clin. Microbiol.</source>
<volume>44</volume>
, <fpage>2063</fpage>
–<lpage>2071</lpage>
. <pub-id pub-id-type="doi">10.1128/JCM.02614-05</pub-id>
<pub-id pub-id-type="pmid">16757599</pub-id>
</mixed-citation>
</ref>
<ref id="B37"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname>
<given-names>P.</given-names>
</name>
<name><surname>Jamaluddin</surname>
<given-names>M.</given-names>
</name>
<name><surname>Li</surname>
<given-names>K.</given-names>
</name>
<name><surname>Garofalo</surname>
<given-names>R. P.</given-names>
</name>
<name><surname>Casola</surname>
<given-names>A.</given-names>
</name>
<name><surname>Brasier</surname>
<given-names>A. R.</given-names>
</name>
</person-group>
(<year>2007</year>
). <article-title>Retinoic acid-inducible gene I mediates early antiviral response and Toll-like receptor 3 expression in respiratory syncytial virus-infected airway epithelial cells</article-title>
. <source>J. Virol.</source>
<volume>81</volume>
, <fpage>1401</fpage>
–<lpage>1411</lpage>
. <pub-id pub-id-type="doi">10.1128/JVI.01740-06</pub-id>
<pub-id pub-id-type="pmid">17108032</pub-id>
</mixed-citation>
</ref>
<ref id="B38"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ludlow</surname>
<given-names>M.</given-names>
</name>
<name><surname>Kortekaas</surname>
<given-names>J.</given-names>
</name>
<name><surname>Herden</surname>
<given-names>C.</given-names>
</name>
<name><surname>Hoffmann</surname>
<given-names>B.</given-names>
</name>
<name><surname>Tappe</surname>
<given-names>D.</given-names>
</name>
<name><surname>Trebst</surname>
<given-names>C.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2016</year>
). <article-title>Neurotropic virus infections as the cause of immediate and delayed neuropathology</article-title>
. <source>Acta Neuropathol.</source>
<volume>131</volume>
, <fpage>159</fpage>
–<lpage>184</lpage>
. <pub-id pub-id-type="doi">10.1007/s00401-015-1511-3</pub-id>
<pub-id pub-id-type="pmid">26659576</pub-id>
</mixed-citation>
</ref>
<ref id="B39"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Martínez-Morales</surname>
<given-names>P. L.</given-names>
</name>
<name><surname>del Corral</surname>
<given-names>R. D.</given-names>
</name>
<name><surname>Olivera-Martínez</surname>
<given-names>I.</given-names>
</name>
<name><surname>Quiroga</surname>
<given-names>A. C.</given-names>
</name>
<name><surname>Das</surname>
<given-names>R. M.</given-names>
</name>
<name><surname>Barbas</surname>
<given-names>J. A.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2011</year>
). <article-title>FGF and retinoic acid activity gradients control the timing of neural crest cell emigration in the trunk</article-title>
. <source>J. Cell Biol.</source>
<volume>194</volume>
, <fpage>489</fpage>
–<lpage>503</lpage>
. <pub-id pub-id-type="doi">10.1083/jcb.201011077</pub-id>
<pub-id pub-id-type="pmid">21807879</pub-id>
</mixed-citation>
</ref>
<ref id="B40"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mic</surname>
<given-names>F. A.</given-names>
</name>
<name><surname>Molotkov</surname>
<given-names>A.</given-names>
</name>
<name><surname>Molotkova</surname>
<given-names>N.</given-names>
</name>
<name><surname>Duester</surname>
<given-names>G.</given-names>
</name>
</person-group>
(<year>2004</year>
). <article-title>Raldh2 expression in optic vesicle generates a retinoic acid signal needed for invagination of retina during optic cup formation</article-title>
. <source>Dev. Dyn.</source>
<volume>231</volume>
, <fpage>270</fpage>
–<lpage>277</lpage>
. <pub-id pub-id-type="doi">10.1002/dvdy.20128</pub-id>
<pub-id pub-id-type="pmid">15366004</pub-id>
</mixed-citation>
</ref>
<ref id="B41"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Micucci</surname>
<given-names>J. A.</given-names>
</name>
<name><surname>Layman</surname>
<given-names>W. S.</given-names>
</name>
<name><surname>Hurd</surname>
<given-names>E. A.</given-names>
</name>
<name><surname>Sperry</surname>
<given-names>E. D.</given-names>
</name>
<name><surname>Frank</surname>
<given-names>S. F.</given-names>
</name>
<name><surname>Durham</surname>
<given-names>M. A.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2014</year>
). <article-title>CHD7 and retinoic acid signaling cooperate to regulate neural stem cell and inner ear development in mouse models of CHARGE syndrome</article-title>
. <source>Hum. Mol. Genet.</source>
<volume>23</volume>
, <fpage>434</fpage>
–<lpage>448</lpage>
. <pub-id pub-id-type="doi">10.1093/hmg/ddt435</pub-id>
<pub-id pub-id-type="pmid">24026680</pub-id>
</mixed-citation>
</ref>
<ref id="B42"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mlakar</surname>
<given-names>J.</given-names>
</name>
<name><surname>Korva</surname>
<given-names>M.</given-names>
</name>
<name><surname>Tul</surname>
<given-names>N.</given-names>
</name>
<name><surname>Popović</surname>
<given-names>M.</given-names>
</name>
<name><surname>Poljšak-Prijatelj</surname>
<given-names>M.</given-names>
</name>
<name><surname>Mraz</surname>
<given-names>J.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2016</year>
). <article-title>Zika virus associated with microcephaly</article-title>
. <source>New Engl. J. Med.</source>
<volume>374</volume>
, <fpage>951</fpage>
–<lpage>958</lpage>
. <pub-id pub-id-type="doi">10.1056/NEJMoa1600651</pub-id>
<pub-id pub-id-type="pmid">26862926</pub-id>
</mixed-citation>
</ref>
<ref id="B43"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mochida</surname>
<given-names>G. H.</given-names>
</name>
<name><surname>Walsh</surname>
<given-names>C. A.</given-names>
</name>
</person-group>
(<year>2001</year>
). <article-title>Molecular genetics of human microcephaly</article-title>
. <source>Curr. Opin. Neurol.</source>
<volume>14</volume>
, <fpage>151</fpage>
–<lpage>156</lpage>
. <pub-id pub-id-type="doi">10.1097/00019052-200104000-00003</pub-id>
<pub-id pub-id-type="pmid">11262728</pub-id>
</mixed-citation>
</ref>
<ref id="B44"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mupapa</surname>
<given-names>K.</given-names>
</name>
<name><surname>Mukundu</surname>
<given-names>W.</given-names>
</name>
<name><surname>Bwaka</surname>
<given-names>M. A.</given-names>
</name>
<name><surname>Kipasa</surname>
<given-names>M.</given-names>
</name>
<name><surname>Roo</surname>
<given-names>A. D.</given-names>
</name>
<name><surname>Kuvula</surname>
<given-names>K.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>1999</year>
). <article-title>Ebola Hemorrhagic Fever and Pregnancy.</article-title>
<source>J. Infect. Dis.</source>
<volume>179</volume>
(<issue>Suppl. 1</issue>
), <fpage>S11</fpage>
–<lpage>S12</lpage>
. <pub-id pub-id-type="doi">10.1086/514289</pub-id>
<pub-id pub-id-type="pmid">9988157</pub-id>
</mixed-citation>
</ref>
<ref id="B45"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Okuda</surname>
<given-names>D. T.</given-names>
</name>
<name><surname>Prados</surname>
<given-names>M. D.</given-names>
</name>
</person-group>
(<year>2009</year>
). <article-title>Recurrent asymptomatic demyelinating disease following 13-cis-retinoic acid exposure</article-title>
. <source>BMJ Case Rep.</source>
2009:pii: <fpage>bcr05.2009.1908</fpage>
. <pub-id pub-id-type="doi">10.1136/bcr.05.2009.1908</pub-id>
<pub-id pub-id-type="pmid">21901115</pub-id>
</mixed-citation>
</ref>
<ref id="B46"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Paganelli</surname>
<given-names>A.</given-names>
</name>
<name><surname>Gnazzo</surname>
<given-names>V.</given-names>
</name>
<name><surname>Acosta</surname>
<given-names>H.</given-names>
</name>
<name><surname>López</surname>
<given-names>S. L.</given-names>
</name>
<name><surname>Carrasco</surname>
<given-names>A. E.</given-names>
</name>
</person-group>
(<year>2010</year>
). <article-title>Glyphosate-based herbicides produce teratogenic effects on vertebrates by impairing retinoic acid signaling</article-title>
. <source>Chem. Res. Toxicol.</source>
<volume>23</volume>
, <fpage>1586</fpage>
–<lpage>1595</lpage>
. <pub-id pub-id-type="doi">10.1021/tx1001749</pub-id>
<pub-id pub-id-type="pmid">20695457</pub-id>
</mixed-citation>
</ref>
<ref id="B47"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rajaii</surname>
<given-names>F.</given-names>
</name>
<name><surname>Bitzer</surname>
<given-names>Z. T.</given-names>
</name>
<name><surname>Xu</surname>
<given-names>Q.</given-names>
</name>
<name><surname>Sockanathan</surname>
<given-names>S.</given-names>
</name>
</person-group>
(<year>2008</year>
). <article-title>Expression of the dominant negative retinoid receptor, RAR403, alters telencephalic progenitor proliferation, survival, and cell fate specification</article-title>
. <source>Dev. Biol.</source>
<volume>316</volume>
, <fpage>371</fpage>
–<lpage>382</lpage>
. <pub-id pub-id-type="doi">10.1016/j.ydbio.2008.01.041</pub-id>
<pub-id pub-id-type="pmid">18329011</pub-id>
</mixed-citation>
</ref>
<ref id="B48"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rasmussen</surname>
<given-names>S. A.</given-names>
</name>
<name><surname>Jamieson</surname>
<given-names>D. J.</given-names>
</name>
<name><surname>Honein</surname>
<given-names>M. A.</given-names>
</name>
<name><surname>Petersen</surname>
<given-names>L. R.</given-names>
</name>
</person-group>
(<year>2016</year>
). <article-title>Zika virus and birth defects—reviewing the evidence for causality</article-title>
. <source>New Engl. J. Med.</source>
<volume>374</volume>
, <fpage>1981</fpage>
–<lpage>1987</lpage>
. <pub-id pub-id-type="doi">10.1056/NEJMsr1604338</pub-id>
<pub-id pub-id-type="pmid">27074377</pub-id>
</mixed-citation>
</ref>
<ref id="B49"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rhinn</surname>
<given-names>M.</given-names>
</name>
<name><surname>Dollé</surname>
<given-names>P.</given-names>
</name>
</person-group>
(<year>2012</year>
). <article-title>Retinoic acid signalling during development</article-title>
. <source>Development</source>
<volume>139</volume>
, <fpage>843</fpage>
–<lpage>858</lpage>
. <pub-id pub-id-type="doi">10.1242/dev.065938</pub-id>
<pub-id pub-id-type="pmid">22318625</pub-id>
</mixed-citation>
</ref>
<ref id="B50"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rubin</surname>
<given-names>S. A.</given-names>
</name>
<name><surname>Amexis</surname>
<given-names>G.</given-names>
</name>
<name><surname>Pletnikov</surname>
<given-names>M.</given-names>
</name>
<name><surname>Vanderzanden</surname>
<given-names>J.</given-names>
</name>
<name><surname>Mauldin</surname>
<given-names>J.</given-names>
</name>
<name><surname>Sauder</surname>
<given-names>C.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2003</year>
). <article-title>Changes in mumps virus gene sequence associated with variability in neurovirulent phenotype</article-title>
. <source>J. Virol.</source>
<volume>77</volume>
, <fpage>11616</fpage>
–<lpage>11624</lpage>
. <pub-id pub-id-type="doi">10.1128/JVI.77.21.11616-11624.2003</pub-id>
<pub-id pub-id-type="pmid">14557647</pub-id>
</mixed-citation>
</ref>
<ref id="B51"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Salazar</surname>
<given-names>M. I.</given-names>
</name>
<name><surname>Pérez-García</surname>
<given-names>M.</given-names>
</name>
<name><surname>Terreros-Tinoco</surname>
<given-names>M.</given-names>
</name>
<name><surname>Castro-Mussot</surname>
<given-names>M. E.</given-names>
</name>
<name><surname>Diegopérez-Ramírez</surname>
<given-names>J.</given-names>
</name>
<name><surname>Ramírez-Reyes</surname>
<given-names>A. G.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2013</year>
). <article-title>Dengue virus type 2: protein binding and active replication in human central nervous system cells</article-title>
. <source>Sci. World J.</source>
<volume>2013</volume>
:<fpage>904067</fpage>
. <pub-id pub-id-type="doi">10.1155/2013/904067</pub-id>
<pub-id pub-id-type="pmid">24302878</pub-id>
</mixed-citation>
</ref>
<ref id="B52"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Samarasekera</surname>
<given-names>U.</given-names>
</name>
<name><surname>Triunfol</surname>
<given-names>M.</given-names>
</name>
</person-group>
(<year>2016</year>
). <article-title>Concern over Zika virus grips the world</article-title>
. <source>Lancet</source>
<volume>387</volume>
, <fpage>521</fpage>
–<lpage>524</lpage>
. <pub-id pub-id-type="doi">10.1016/S0140-6736(16)00257-9</pub-id>
<pub-id pub-id-type="pmid">26852261</pub-id>
</mixed-citation>
</ref>
<ref id="B53"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Samuel</surname>
<given-names>M. A.</given-names>
</name>
<name><surname>Wang</surname>
<given-names>H.</given-names>
</name>
<name><surname>Siddharthan</surname>
<given-names>V.</given-names>
</name>
<name><surname>Morrey</surname>
<given-names>J. D.</given-names>
</name>
<name><surname>Diamond</surname>
<given-names>M. S.</given-names>
</name>
</person-group>
(<year>2007</year>
). <article-title>Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis</article-title>
. <source>Proc. Natl. Acad. Sci. U.S.A.</source>
<volume>104</volume>
, <fpage>17140</fpage>
–<lpage>17145</lpage>
. <pub-id pub-id-type="doi">10.1073/pnas.0705837104</pub-id>
<pub-id pub-id-type="pmid">17939996</pub-id>
</mixed-citation>
</ref>
<ref id="B54"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sauerbrei</surname>
<given-names>A.</given-names>
</name>
<name><surname>Wutzler</surname>
<given-names>P.</given-names>
</name>
</person-group>
(<year>2000</year>
). <article-title>The congenital varicella syndrome</article-title>
. <source>J. Perinatol.</source>
<volume>20</volume>
, <fpage>548</fpage>
–<lpage>554</lpage>
. <pub-id pub-id-type="doi">10.1038/sj.jp.7200457</pub-id>
<pub-id pub-id-type="pmid">11190597</pub-id>
</mixed-citation>
</ref>
<ref id="B55"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Scheffer</surname>
<given-names>I. E.</given-names>
</name>
<name><surname>Baraitser</surname>
<given-names>M.</given-names>
</name>
<name><surname>Brett</surname>
<given-names>E. M.</given-names>
</name>
</person-group>
(<year>1991</year>
). <article-title>Severe microcephaly associated with congenital varicella infection</article-title>
. <source>Dev. Med. Child Neurol.</source>
<volume>33</volume>
, <fpage>916</fpage>
–<lpage>920</lpage>
. <pub-id pub-id-type="doi">10.1111/j.1469-8749.1991.tb14803.x</pub-id>
<pub-id pub-id-type="pmid">1743417</pub-id>
</mixed-citation>
</ref>
<ref id="B56"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schuler-Faccini</surname>
<given-names>L.</given-names>
</name>
<name><surname>Ribeiro</surname>
<given-names>E. M.</given-names>
</name>
<name><surname>Feitosa</surname>
<given-names>I. M. L.</given-names>
</name>
<name><surname>Horovitz</surname>
<given-names>D. D. G.</given-names>
</name>
<name><surname>Cavalcanti</surname>
<given-names>D. P.</given-names>
</name>
<name><surname>Pessoa</surname>
<given-names>A.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2016</year>
). <article-title>Possible association between Zika virus infection and microcephaly—Brazil, (2015)</article-title>
. <source>MMWR</source>
<volume>65</volume>
, <fpage>59</fpage>
–<lpage>62</lpage>
. <pub-id pub-id-type="doi">10.15585/mmwr.mm6503e2</pub-id>
<pub-id pub-id-type="pmid">26820244</pub-id>
</mixed-citation>
</ref>
<ref id="B57"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shimozono</surname>
<given-names>S.</given-names>
</name>
<name><surname>Iimura</surname>
<given-names>T.</given-names>
</name>
<name><surname>Kitaguchi</surname>
<given-names>T.</given-names>
</name>
<name><surname>Higashijima</surname>
<given-names>S.</given-names>
</name>
<name><surname>Miyawaki</surname>
<given-names>A.</given-names>
</name>
</person-group>
(<year>2013</year>
). <article-title>Visualization of an endogenous retinoic acid gradient across embryonic development</article-title>
. <source>Nature</source>
<volume>496</volume>
, <fpage>363</fpage>
–<lpage>366</lpage>
. <pub-id pub-id-type="doi">10.1038/nature12037</pub-id>
<pub-id pub-id-type="pmid">23563268</pub-id>
</mixed-citation>
</ref>
<ref id="B58"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Siegenthaler</surname>
<given-names>J. A.</given-names>
</name>
<name><surname>Ashique</surname>
<given-names>A. M.</given-names>
</name>
<name><surname>Zarbalis</surname>
<given-names>K.</given-names>
</name>
<name><surname>Patterson</surname>
<given-names>K. P.</given-names>
</name>
<name><surname>Hecht</surname>
<given-names>J. H.</given-names>
</name>
<name><surname>Kane</surname>
<given-names>M. A.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2009</year>
). <article-title>Retinoic acid from the meninges regulates cortical neuron generation</article-title>
. <source>Cell</source>
<volume>139</volume>
, <fpage>597</fpage>
–<lpage>609</lpage>
. <pub-id pub-id-type="doi">10.1016/j.cell.2009.10.004</pub-id>
<pub-id pub-id-type="pmid">19879845</pub-id>
</mixed-citation>
</ref>
<ref id="B59"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Slater</surname>
<given-names>L.</given-names>
</name>
<name><surname>Bartlett</surname>
<given-names>N. W.</given-names>
</name>
<name><surname>Haas</surname>
<given-names>J. J.</given-names>
</name>
<name><surname>Zhu</surname>
<given-names>J.</given-names>
</name>
<name><surname>Message</surname>
<given-names>S. D</given-names>
</name>
<name><surname>Walton</surname>
<given-names>R. P.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2010</year>
). <article-title>Co-ordinated role of TLR3, RIG-I and MDA5 in the innate response to rhinovirus in bronchial epithelium</article-title>
. <source>PLoS Pathog</source>
<volume>6</volume>
:<fpage>e1001178</fpage>
. <pub-id pub-id-type="doi">10.1371/journal.ppat.1001178</pub-id>
<pub-id pub-id-type="pmid">21079690</pub-id>
</mixed-citation>
</ref>
<ref id="B60"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Straface</surname>
<given-names>G.</given-names>
</name>
<name><surname>Selmin</surname>
<given-names>A.</given-names>
</name>
<name><surname>Zanardo</surname>
<given-names>V.</given-names>
</name>
<name><surname>De Santis</surname>
<given-names>M.</given-names>
</name>
<name><surname>Ercoli</surname>
<given-names>A.</given-names>
</name>
<name><surname>Scambia</surname>
<given-names>G.</given-names>
</name>
</person-group>
(<year>2012</year>
). <article-title>Herpes simplex virus infection in pregnancy</article-title>
. <source>Infect. Dis. Obstet. Gynecol.</source>
<volume>2012</volume>
:<fpage>385697</fpage>
. <pub-id pub-id-type="doi">10.1155/2012/385697</pub-id>
<pub-id pub-id-type="pmid">22566740</pub-id>
</mixed-citation>
</ref>
<ref id="B61"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Takano</surname>
<given-names>T.</given-names>
</name>
<name><surname>Takikita</surname>
<given-names>S.</given-names>
</name>
<name><surname>Shimada</surname>
<given-names>M.</given-names>
</name>
</person-group>
(<year>1999</year>
). <article-title>Experimental mumps virus-induced hydrocephalus: viral neurotropism and neuronal maturity</article-title>
. <source>Neuroreport</source>
<volume>10</volume>
, <fpage>2215</fpage>
–<lpage>2221</lpage>
. <pub-id pub-id-type="doi">10.1097/00001756-199908020-00001</pub-id>
<pub-id pub-id-type="pmid">10439437</pub-id>
</mixed-citation>
</ref>
<ref id="B62"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Teissier</surname>
<given-names>N.</given-names>
</name>
<name><surname>Fallet-Bianco</surname>
<given-names>C.</given-names>
</name>
<name><surname>Delezoide</surname>
<given-names>A.-L.</given-names>
</name>
<name><surname>Laquerrière</surname>
<given-names>A.</given-names>
</name>
<name><surname>Marcorelles</surname>
<given-names>P.</given-names>
</name>
<name><surname>Khung-Savatovsky</surname>
<given-names>S.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2014</year>
). <article-title>Cytomegalovirus-lnduced Brain Malformations in Fetuses</article-title>
. <source>J. Neuropathol. Exp. Neurol.</source>
<volume>73</volume>
, <fpage>143</fpage>
–<lpage>158</lpage>
. <pub-id pub-id-type="doi">10.1097/NEN.0000000000000038</pub-id>
<pub-id pub-id-type="pmid">24423639</pub-id>
</mixed-citation>
</ref>
<ref id="B63"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tsiang</surname>
<given-names>H.</given-names>
</name>
<name><surname>Koulakoff</surname>
<given-names>A.</given-names>
</name>
<name><surname>Bizzini</surname>
<given-names>B.</given-names>
</name>
<name><surname>Berwald-Netter</surname>
<given-names>Y.</given-names>
</name>
</person-group>
(<year>1983</year>
). <article-title>Neurotropism of Rabies virus: an <italic>in vitro</italic>
study</article-title>
. <source>J. Neuropathol. Exp. Neurol.</source>
<volume>42</volume>
, <fpage>439</fpage>
–<lpage>452</lpage>
. <pub-id pub-id-type="doi">10.1097/00005072-198307000-00006</pub-id>
<pub-id pub-id-type="pmid">6864237</pub-id>
</mixed-citation>
</ref>
<ref id="B64"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tuiskunen</surname>
<given-names>A.</given-names>
</name>
<name><surname>Wahlström</surname>
<given-names>M.</given-names>
</name>
<name><surname>Bergström</surname>
<given-names>J.</given-names>
</name>
<name><surname>Buchy</surname>
<given-names>P.</given-names>
</name>
<name><surname>Leparc-Goffart</surname>
<given-names>I.</given-names>
</name>
<name><surname>Lundkvist</surname>
<given-names>Å.</given-names>
</name>
</person-group>
(<year>2011</year>
). <article-title>Phenotypic characterization of patient dengue virus isolates in BALB/c mice differentiates dengue fever and dengue hemorrhagic fever from dengue shock syndrome</article-title>
. <source>Virol. J.</source>
<volume>8</volume>
, <fpage>1</fpage>
. <pub-id pub-id-type="doi">10.1186/1743-422X-8-398</pub-id>
<pub-id pub-id-type="pmid">21205327</pub-id>
</mixed-citation>
</ref>
<ref id="B65"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vansant</surname>
<given-names>G.</given-names>
</name>
<name><surname>Reynolds</surname>
<given-names>W. F.</given-names>
</name>
</person-group>
(<year>1995</year>
). <article-title>The consensus sequence of a major Alu subfamily contains a functional retinoic acid response element</article-title>
. <source>Proc. Natl. Acad. Sci. U.S.A.</source>
<volume>92</volume>
, <fpage>8229</fpage>
–<lpage>8233</lpage>
. <pub-id pub-id-type="doi">10.1073/pnas.92.18.8229</pub-id>
<pub-id pub-id-type="pmid">7667273</pub-id>
</mixed-citation>
</ref>
<ref id="B66"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ventura</surname>
<given-names>C. V.</given-names>
</name>
<name><surname>Maia</surname>
<given-names>M.</given-names>
</name>
<name><surname>Bravo-Filho</surname>
<given-names>V.</given-names>
</name>
<name><surname>Góis</surname>
<given-names>A. L.</given-names>
</name>
<name><surname>Belfort</surname>
<given-names>R.</given-names>
</name>
</person-group>
(<year>2016</year>
). <article-title>Zika virus in Brazil and macular atrophy in a child with microcephaly</article-title>
. <source>Lancet</source>
<volume>387</volume>
, <fpage>228</fpage>
. <pub-id pub-id-type="doi">10.1016/S0140-6736(16)00006-4</pub-id>
<pub-id pub-id-type="pmid">26775125</pub-id>
</mixed-citation>
</ref>
<ref id="B67"><mixed-citation publication-type="webpage"><person-group person-group-type="author"><collab>WHO | Zika situation report</collab>
</person-group>
(<year>2016</year>
). Retrieved May 16, 2016, from Available online at: <ext-link ext-link-type="uri" xlink:href="http://www.who.int/emergencies/zika-virus/situation-report/19-february-2016/en/">http://www.who.int/emergencies/zika-virus/situation-report/19-february-2016/en/</ext-link>
</mixed-citation>
</ref>
<ref id="B68"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wilson</surname>
<given-names>L. J.</given-names>
</name>
<name><surname>Myat</surname>
<given-names>A.</given-names>
</name>
<name><surname>Sharma</surname>
<given-names>A.</given-names>
</name>
<name><surname>Maden</surname>
<given-names>M.</given-names>
</name>
<name><surname>Wingate</surname>
<given-names>R. J.</given-names>
</name>
</person-group>
(<year>2007</year>
). <article-title>Retinoic acid is a potential dorsalising signal in the late embryonic chick hindbrain</article-title>
. <source>BMC Dev. Biol.</source>
<volume>7</volume>
:<fpage>138</fpage>
. <pub-id pub-id-type="doi">10.1186/1471-213X-7-138</pub-id>
<pub-id pub-id-type="pmid">18093305</pub-id>
</mixed-citation>
</ref>
<ref id="B69"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wood</surname>
<given-names>B. R.</given-names>
</name>
<name><surname>Klein</surname>
<given-names>J. P.</given-names>
</name>
<name><surname>Lyons</surname>
<given-names>J. L.</given-names>
</name>
<name><surname>Milner</surname>
<given-names>D. A.</given-names>
</name>
<name><surname>Phillips</surname>
<given-names>R. E.</given-names>
</name>
<name><surname>Schutten</surname>
<given-names>M.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2012</year>
). <article-title>HIV-2 encephalitis: case report and literature review</article-title>
. <source>AIDS Patient Care STDS</source>
<volume>26</volume>
, <fpage>383</fpage>
–<lpage>387</lpage>
. <pub-id pub-id-type="doi">10.1089/apc.2012.0048</pub-id>
<pub-id pub-id-type="pmid">22694171</pub-id>
</mixed-citation>
</ref>
<ref id="B70"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Xu</surname>
<given-names>J.</given-names>
</name>
<name><surname>Zhong</surname>
<given-names>S.</given-names>
</name>
<name><surname>Liu</surname>
<given-names>J.</given-names>
</name>
<name><surname>Li</surname>
<given-names>L.</given-names>
</name>
<name><surname>Li</surname>
<given-names>Y.</given-names>
</name>
<name><surname>Wu</surname>
<given-names>X.</given-names>
</name>
<etal></etal>
</person-group>
. (<year>2005</year>
). <article-title>Detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine mig in pathogenesis</article-title>
. <source>Clin. Infect. Dis.</source>
<volume>41</volume>
, <fpage>1089</fpage>
–<lpage>1096</lpage>
. <pub-id pub-id-type="doi">10.1086/444461</pub-id>
<pub-id pub-id-type="pmid">16163626</pub-id>
</mixed-citation>
</ref>
<ref id="B71"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yamamoto</surname>
<given-names>M.</given-names>
</name>
<name><surname>Zhang</surname>
<given-names>J.</given-names>
</name>
<name><surname>Smith</surname>
<given-names>D.</given-names>
</name>
<name><surname>Hayakawa</surname>
<given-names>Y.</given-names>
</name>
<name><surname>McCaffery</surname>
<given-names>P.</given-names>
</name>
</person-group>
(<year>2003</year>
). <article-title>A critical period for retinoic acid teratogenesis and loss of neurophilic migration of pontine nuclei neurons</article-title>
. <source>Mech. Dev.</source>
<volume>120</volume>
, <fpage>701</fpage>
–<lpage>709</lpage>
. <pub-id pub-id-type="doi">10.1016/S0925-4773(03)00047-9</pub-id>
<pub-id pub-id-type="pmid">12834869</pub-id>
</mixed-citation>
</ref>
<ref id="B72"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yazigi</surname>
<given-names>A.</given-names>
</name>
<name><surname>De Pecoulas</surname>
<given-names>A. E.</given-names>
</name>
<name><surname>Vauloup-Fellous</surname>
<given-names>C.</given-names>
</name>
<name><surname>Grangeot-Keros</surname>
<given-names>L.</given-names>
</name>
<name><surname>Ayoubi</surname>
<given-names>J.-M.</given-names>
</name>
<name><surname>Picone</surname>
<given-names>O.</given-names>
</name>
</person-group>
(<year>2016</year>
). <article-title>Fetal and neonatal abnormalities due to congenital rubella syndrome: a review of literature</article-title>
. <source>J. Matern Fetal Neonatal Med.</source>
<pub-id pub-id-type="doi">10.3109/14767058.2016.1169526</pub-id>
. [Epub ahead of print].<pub-id pub-id-type="pmid">27002428</pub-id>
</mixed-citation>
</ref>
</ref-list>
</back>
</pmc>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/CovidV2/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000858 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000858 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Wicri/Sante |area= CovidV2 |flux= Pmc |étape= Corpus |type= RBID |clé= PMC:4977292 |texte= A Possible Mechanism of Zika Virus Associated Microcephaly: Imperative Role of Retinoic Acid Response Element (RARE) Consensus Sequence Repeats in the Viral Genome }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:27555815" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \ | NlmPubMed2Wicri -a CovidV2
![]() | This area was generated with Dilib version V0.6.33. | ![]() |