44 Matching Annotations
  1. Dec 2017
    1. A recent outbreak of Zika virus in Brazil

      Zika is known to be a flavivirus that is transmitted by mosquitoes such as yellow fever, West Nile, and dengue virus. In May 2015, Brazil was the first to associate Zika virus infection with microcephaly in newborns.

      Watch more about the history of Zika virus at: https://www.youtube.com/watch?v=FOcSe0LtoTg

    2. ZIKV is highly neurotropic and interferes specifically with fetal brain development, causing microcephaly, cortical malformations, and intracranial calcifications (7–10). We hypothesized that the single-stranded RNA flavivirus ZIKV may hijack RNA-binding factors present in the developing central nervous system (11). Host RNA-binding proteins are known to interact with untranslated regions (UTRs) to regulate replication, translation, and stabilization of viral genomes

      Zika is known to have the ability to reinfect other humans because it is known to be found in the blood and continuously be transmitted by mosquitos. Zika virus utilizes host cellular machinery to replicate, and symptoms may emerge a few days to a week after infection.

      Watch more about the symptoms, pathology, and outbreak at: https://www.youtube.com/watch?v=oGNxGlltnOs

    3. This work suggests that high MSI1 expression levels in neural precursors could be a key contributor to the fetal neurotropism exhibited by ZIKV (2, 10, 37) (fig. S13). Intriguingly, MSI1 is also highly expressed in the retina and testis, other tissues deemed vulnerable to ZIKV infection

      A contributor to the infection of nerve cells in fetuses caused by ZIKV is the expression of MSI1. The ZIKV infection can affect other areas of the body also, such as the retina and the testis, because MSI1 is highly expressed in these regions.

    4. These findings also imply that MSI1 expression increases susceptibility of HEK293T cells to ZIKV infection (35). Furthermore, we noted an apparent dose-dependent effect of MSI1 on viral replication; those U-251 and HEK293T clones that express higher levels of MSI1 displayed greater viral RNA levels and increased cell death (Fig. 4, B and D to G, and figs. S11 and S12).

      Cells that contain A148V mutations in MSI1 cannot support Zika virus replication. Musashi 1 wild types cells had an increase in Zika virus RNA levels and cell death while the cells containing the mutant Musashi 1 gene did not replicate the Zika virus. Thus, HEK293 cells, cells that normally lack Musashi 1 expression, are better able to replicate Zika virus infection when the Musashi 1 gene is expressed.

    5. In summary, we identify MSI1 as an important factor for ZIKV replication, both in primary and transformed neural cell lines.

      MSI1 and the genome of the ZIKV RNA directly interact to cause ZIKV to replicate. The replication can be seen in the replication assays conducted after MSI1 was introduced into cells.

    6. revealed three consensus binding sites in the 3′UTR for the highly conserved Musashi family of RNA-binding proteins, Musashi-1 (MSI1) and Musashi-2 (MSI2), both important translational regulators in stem cells

      Imai and colleagues (2001) used in vivo RNA that possesses Msi1 binding sites to determine the specific RNA-binding sequences for Msi1. Results demonstrated that Msi1 can regulate expression of its target gene at the translational level.

    7. Notably, defective chromosome condensation has been recently found to cause MCPH

      C. A. Martin and colleagues (2016) researched mutations in genes encoding condensin subunits (which usually enable chromosomes to condense) and sister chromatids to de-tangle and stabilize chromosome structure. The team of researchers found that mutations caused microcephaly in mice as well as reduced brain size and DNA bridges in neural progenitors and condensin-deficient cells during neurogenesis.

    8. CLIP and RNA electrophoretic mobility shift assays suggest a direct interaction between MSI1 and MCPH1_L 

      To test the possibility of MSI1 controlling the expression of MPCH1, an RNA immunoprecipitation, which maps interactions between RNA and other proteins, was conducted along with a CLIP and RNA mobility shift assays, which are also used to detect protein and RNA interactions. The scientists found that MSI1 can act as an activator or inhibitor of the MPHC1 locus.

    9. The PCC phenotype seen in MSI1A184V-patient cells has been previously described in cells deficient of the MCPH-associated protein microcephalin (MCPH1)

      Jackson and peers (2002) relate the microcephalin gene to molecular defects that can cause microcephaly. Microcephalin was found in developing ventricles of the forebrain, indicating that the microcephalin protein can regulate sizes of the cerebral cortex. Mutations in the microcephalin gene can result in disruption of the regulation of the cell cycle and development of neurons in the brain.

    10. We find MSI1 to be abundant in neural precursors of the ventricular and subventricular zones of the human embryonic brain, but absent from mature neurons

      An immunohistochemistry assay was conducted on a human embryonic brain 10 and 12 weeks after conception. The tissue was stained with antibodies against MSI1 and neuron-specific beta-III tubulin along with DNA. The scientists found that MSI1 is high in ventricular and subventricular precursors, but not found in mature neurons, which is evidence for the ZIKV attack of brain cells in the womb.

    11. These data confirm an interaction between MSI1 and ZIKV RNA, which is, at least in part, mediated by the 3′UTR of the virus.

      Authors found that MSI1 binds to the 3’ untranslated region (UTR) of PE243 by analyzing RNA pulldowns. Results were confirmed by mutating the MSI1 sites in the 3’UTR. The weakened interactions demonstrate an interaction between MSI1 and PE243 ZIKV RNA mediated by 3’UTR, revealing where the protein binds to the RNA.

    12. immunoprecipitation

      a molecular technique that purifies proteins and finds binding partners by using antibodies that can bind specifically to the protein. Can help find protein complexes.

    13. RNA pull-down

      a test used to confirm the presence of a protein species or to identify natural binding partners for the RNA

    14. In silico

      computer run simulations

    15. We hypothesized that the single-stranded RNA flavivirus ZIKV may hijack RNA-binding factors present in the developing central nervous system (11). Host RNA-binding proteins are known to interact with untranslated regions (UTRs) to regulate replication, translation, and stabilization of viral genomes

      Li and Nagy (2011) studied plus-stranded RNA viruses.

      RNA-binding proteins are found to determine virus-cell interactions with host untranslated regions to regulate cellular processes. Understanding the functions of host RNA-binding proteins in viral replications can lead to antiviral therapies, such as for Zika virus.

    16. Zika virus (ZIKV) recently emerged as a major public health risk because of its devastating effect on fetal neurodevelopment

      Mlakar and peers (2016) associated Zika virus with microcephaly.

      An increase in microcephaly cases was found to be observed in children who were born to mothers that were infected with Zika virus.One expectant mother, who contracted Zika virus, was studied. After 29 weeks of gestation, the fetus was recognized to express microcephaly with brain calcifications. The mother decided to terminate the pregnancy, an a fetal autopsy revealed the complete genome of Zika virus in the fetal brain. 
    17. This work suggests that high MSI1 expression levels in neural precursors could be a key contributor to the fetal neurotropism exhibited by ZIKV

      Brault and colleagues (2016) recognized that microcephaly is associated with Zika within South American and French Polynesia. After infecting mouse embryonic brain slices with Zika virus, an assay revealed that Zika virus impairs neural stem cell growth and can inhibit apoptosis at early infection stages. Thus, Zika virus prefers neural stem cells to infect.

    18. Intriguingly, MSI1 is also highly expressed in the retina and testis, other tissues deemed vulnerable to ZIKV infection

      Lazear, Govero, Smith, Platt, Fernandez, Miner, Diamond (2016) studied the disease development of zika virus in different types of knockout mice. The knockout mice that had no functioning interferon pathways were the mice that picked up the disease. It was also observed that zik virus was found in the highest viral load in the testes of affected male mice.

    19. Brazilian ZIKV belongs to the Asian lineage which affected New Caledonia and French Polynesia, where cases of microcephaly were reported retrospectively

      Cauchemez and colleagues (2016) found that infection of Zika virus during the first trimester of pregnancy is associated with newborns with microcephaly. The study provides a quantitative estimate of microcephaly risk in newborns of mothers who are infected by Zika. 95 cases per 10,000 infected woman within the first trimester was associated with microcephaly risk.

  2. Nov 2017
    1. Turkish family in which two siblings displayed clinical features suggestive of autosomal primary microcephaly (MCPH),

      Chavali, Putz, and Gergely (2014) researched the genetics behind microcephaly.

          Microcephaly can be caused by abnormal development of neurons, recessive mutations, and centrosome abnormality. Microcephaly may be classified as a centrosome disorder. Although centrosomes are recognized to have importance in cellular processes, more evidence needs to be conducted to further understand the significance of microcephaly and disease, specifically diseases that affect brain development. 
    2. Intrauterine infections can impair neurodevelopment

      Adams Waldorf and McAdams researched the side effects of infections on the fetus during pregnancy.

      Depending on the type of pathogen, the fetus may die, acquire organ injury, or obtain abnormal bone growth. Pathogens that disturb fetal development are the pathogens that seem to be the most detrimental to the fetus in utero. Understanding the mechanisms the pathogens use to disrupt development may lead to the development of therapies that can be used to help fetal development and survival

    3. fetal neurodevelopment

      Cugola et al., (2016) found that ZIKV infects fetuses, causes intrauterine growth restriction (IUGR), and causes signs of microcephaly in mice.

      Data demonstrated that the infection of ZIKV into human brain organoids (a miniature organ in vitro) reduced proliferation and disrupted cortical layers. This indicates that ZIKV is able to cross the placenta and cause microcephaly by inducing apoptosis in cortical progenitor cells.

    4. consanguineous

      marriage between close relatives

    5. luciferase

      enzyme that produces fluorescent colors when activated and is often used to study gene expression

    6. (CRISPR)–Cas9

      bacterial DNA sequences that contain snippets of viral DNA, allowing scientists to modify genes within an organism (by removing or adding DNA)

    7. cytopathicity

      the change that occurs in a cell due to disease or infection

    8. neonatal

      newborn children, specifically up to 4 weeks old

    9. flavivirus

      single stranded RNA viruses that are transmitted by insects, such as mosquitos

    10. knockouts (KOs)

      a genetic technique that genetically modifies genome sequences to have a specific missing or inactivate gene that is “knocked-out” of the organism

    11. premature chromosome condensation (PCC)

      when mitotic cells fuse with interphase cells, causing premature mitosis

    12. wild-type (WT)

      a gene or characteristic that prevails among individuals in natural conditions

    13. cytomegalovirus

      a virus belonging to the herpesvirus family causing a variety of symptoms in those with a weakened immune system or pregnant

    14. recapitulated

      summarize or state the main point again

    15. cyclin-dependent kinase

      family of kinases that regulate the cell cycle through the transfer of phosphate groups

    16. neuroblastoma

      tumors that arise from early forms of nerve cells in an embryo/fetus

    17. glioblastoma

      tumors that arise from cells that make up supportive tissue in the brain

    18. neural progenitors

      a stem cell that has limited cellular divisions and can differentiate into a neuron or glial cell

    19. pleiotropic

      two or more phenotypic traits are influenced by one gene

    20. in vivo

      in a living organism

    21. in vitro

      happens outside of the normal environment, such as in a test tube or petri dish

    22. transfected

      inserting RNA or DNA into a cell through a plasmid

    23. intracranial calcifications

      abnormal calcium deposits in certain parts of the brain

    24. cortical malformations

      abnormal development of the outer layer of the cerebrum of the brain

    25. microcephaly

      underdevelopment of the brain causing a child’s head to be smaller than normal