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"Madison, B"
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A slave in the White House : Paul Jennings and the Madisons
Chronicles the life of a former slave to James and Dolley Madison, tracing his early years on their plantation, his service in the White House household staff and post-emancipation achievements as a memoirist.
Book
MicroRNAs in the etiology of colorectal cancer: pathways and clinical implications
MicroRNAs (miRNAs) are small single-stranded RNAs that repress mRNA translation and trigger mRNA degradation. Of the ∼1900 miRNA-encoding genes present in the human genome, ∼250 miRNAs are reported to have changes in abundance or altered functions in colorectal cancer. Thousands of studies have documented aberrant miRNA levels in colorectal cancer, with some miRNAs reported to actively regulate tumorigenesis. A recurrent phenomenon with miRNAs is their frequent participation in feedback loops, which probably serve to reinforce or magnify biological outcomes to manifest a particular cellular phenotype. Here, we review the roles of oncogenic miRNAs (oncomiRs), tumor suppressive miRNAs (anti-oncomiRs) and miRNA regulators in colorectal cancer. Given their stability in patient-derived samples and ease of detection with standard and novel techniques, we also discuss the potential use of miRNAs as biomarkers in the diagnosis of colorectal cancer and as prognostic indicators of this disease. MiRNAs also represent attractive candidates for targeted therapies because their function can be manipulated through the use of synthetic antagonists and miRNA mimics.
Journal Article
LIN28B fosters colon cancer migration, invasion and transformation through let-7-dependent and -independent mechanisms
Lin28b is an RNA-binding protein that inhibits biogenesis of
let-7
microRNAs.
LIN28B
is overexpressed in diverse cancers, yet a specific role in the molecular pathogenesis of colon cancer has to be elucidated. We have determined that human colon tumors exhibit decreased levels of mature
let-7
isoforms and increased expression of
LIN28B
. To determine
LIN28B
's mechanistic role in colon cancer, we expressed
LIN28B
in immortalized colonic epithelial cells and human colon cancer cell lines. We found that
LIN28B
promotes cell migration, invasion and transforms immortalized colonic epithelial cells. In addition, constitutive
LIN28B
expression increases expression of intestinal stem cell markers
LGR5
and
PROM1
in the presence of
let-7
restoration. This may occur as a result of Lin28b protein binding
LGR5
and
PROM1
mRNA, suggesting that a subset of
LIN28B
functions is independent of its ability to repress
let-7
. Our findings establish a new role for
LIN28B
in human colon cancer pathogenesis, and suggest
LIN28B
post-transcriptionally regulates
LGR5
and
PROM1
through a
let-7
-independent mechanism.
Journal Article
A Single Nucleotide Polymorphism in Human APOBEC3C Enhances Restriction of Lentiviruses
Humans express seven human APOBEC3 proteins, which can inhibit viruses and endogenous retroelements through cytidine deaminase activity. The seven paralogs differ in the potency of their antiviral effects, as well as in their antiviral targets. One APOBEC3, APOBEC3C, is exceptional as it has been found to only weakly block viruses and endogenous retroelements compared to other APOBEC3s. However, our positive selection analyses suggest that APOBEC3C has played a role in pathogen defense during primate evolution. Here, we describe a single nucleotide polymorphism in human APOBEC3C, a change from serine to isoleucine at position 188 (I188) that confers potent antiviral activity against HIV-1. The gain-of-function APOBEC3C SNP results in increased enzymatic activity and hypermutation of target sequences when tested in vitro, and correlates with increased dimerization of the protein. The I188 is widely distributed in human African populations, and is the ancestral primate allele, but is not found in chimpanzees or gorillas. Thus, while other hominids have lost activity of this antiviral gene, it has been maintained, or re-acquired, as a more active antiviral gene in a subset of humans. Taken together, our results suggest that APOBEC3C is in fact involved in protecting hosts from lentiviruses.
Journal Article
The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis
Cytosine mutations within TCA/T motifs are common in cancer. A likely cause is the DNA cytosine deaminase APOBEC3B (A3B). However,
A3B
-null breast tumours still have this mutational bias. Here we show that APOBEC3H haplotype I (A3H-I) provides a likely solution to this paradox.
A3B
-null tumours with this mutational bias have at least one copy of
A3H-I
despite little genetic linkage between these genes. Although deemed inactive previously, A3H-I has robust activity in biochemical and cellular assays, similar to A3H-II after compensation for lower protein expression levels. Gly105 in A3H-I (versus Arg105 in A3H-II) results in lower protein expression levels and increased nuclear localization, providing a mechanism for accessing genomic DNA. A3H-I also associates with clonal TCA/T-biased mutations in lung adenocarcinoma suggesting this enzyme makes broader contributions to cancer mutagenesis. These studies combine to suggest that A3B and A3H-I, together, explain the bulk of ‘APOBEC signature’ mutations in cancer.
The APOBEC family of enzymes are cytidine deaminases with APOBEC3A and APOBEC3B thought to contribute to DNA damage signatures detected in cancer genomes. Here, the authors demonstrate an unappreciated role for APOBEC3H haplotype I in the generation of DNA damage in breast cancer.
Journal Article
Retroviral Restriction Factor APOBEC3G Delays the Initiation of DNA Synthesis by HIV-1 Reverse Transcriptase
It is well established that the cytosine deaminase APOBEC3G can restrict HIV-1 virions in the absence of the virion infectivity factor (Vif) by inducing genome mutagenesis through deamination of cytosine to uracil in single-stranded HIV-1 (-)DNA. However, whether APOBEC3G is able to restrict HIV-1 using a deamination-independent mode remains an open question. In this report we use in vitro primer extension assays on primer/templates that model (-)DNA synthesis by reverse transcriptase from the primer binding site (PBS) and within the protease gene of HIV-1. We find that APOBEC3G is able to decrease the initiation of DNA synthesis by reverse transcriptase approximately 2-fold under conditions where reverse transcriptase is in excess to APOBEC3G, as found in HIV-1 virions. However, the delay in the initiation of DNA synthesis on RNA templates up to 120 nt did not decrease the total amount of primer extended after extended incubation unless the concentration of reverse transcriptase was equal to or less than that of APOBEC3G. By determining apparent Kd values of reverse transcriptase and APOBEC3G for the primer/templates and of reverse transcriptase binding to APOBEC3G we conclude that APOBEC3G is able to decrease the efficiency of reverse transcriptase-mediated DNA synthesis by binding to the RNA template, rather than by physically interacting with reverse transcriptase. All together the data support a model in which this deamination-independent mode of APOBEC3G would play a minor role in restricting HIV-1. We propose that the deamination-independent inhibition of reverse transcriptase we observed can be a mechanism used by APOBEC3G to slow down proviral DNA formation and increase the time in which single-stranded (-)DNA is available for deamination by APOBEC3G, rather than a direct mechanism used by APOBEC3G for HIV-1 restriction.
Journal Article
Effects of umbilical cord blood cells, and subtypes, to reduce neuroinflammation following perinatal hypoxic-ischemic brain injury
Background
It is well understood that hypoxic-ischemic (HI) brain injury during the highly vulnerable perinatal period can lead to cerebral palsy, the most prevalent cause of chronic disability in children. Recently, human clinical trials have reported safety and some efficacy following treatment of cerebral palsy using umbilical cord blood (UCB) cells. UCB is made up of many different cell types, including endothelial progenitor cells (EPCs), T regulatory cells (Tregs), and monocyte-derived suppressor cells (MDSCs). How each cell type contributes individually towards reducing neuroinflammation and/or repairing brain injury is not known. In this study, we examined whether human (h) UCB, or specific UCB cell types, could reduce peripheral and cerebral inflammation, and promote brain repair, when given early after perinatal HI brain injury.
Methods
HI brain injury was induced in postnatal day (PND) 7 rat pups and cells were administered intraperitoneally on PND 8. Behavioral testing was performed 7 days post injury, and then, brains and spleens were collected for analysis.
Results
We found in vitro that all UCB cell types, except for EPCs, were immunomodulatory. Perinatal HI brain injury induced significant infiltration of CD4+ T cells into the injured cerebral hemisphere, and this was significantly reduced by all hUCB cell types tested. Compared to HI, UCB, Tregs, and EPCs were able to reduce motor deficits, reduce CD4+ T cell infiltration into the brain, and reduce microglial activation. In addition to the beneficial effects of UCB, EPCs also significantly reduced cortical cell death, returned CD4+ T cell infiltration to sham levels, and reduced the peripheral Th1-mediated pro-inflammatory shift.
Conclusion
This study highlights that cells found in UCB is able to mediate neuroinflammation and is an effective neuroprotective therapy. Our study also shows that particular cells found in UCB, namely EPCs, may have an added advantage over using UCB alone. This work has the potential to progress towards tailored UCB therapies for the treatment of perinatal brain injury.
Journal Article
Genetically influenced tobacco and alcohol use behaviors impact erythroid trait variation
Genome wide association studies (GWAS) have associated thousands of loci with quantitative human blood trait variation. Loci and related genes that impact blood trait variation may regulate blood cell-intrinsic biological processes, or alternatively impact blood cell development and function via systemic factors. Clinical observations have linked tobacco or alcohol use with altered blood traits, but these trait relationships have not been systematically explored at the genetic level. Applying a Mendelian randomization (MR) framework to GWAS summary statistics, we explore relationships between smoking and drinking behaviors with 15 quantitative blood traits. We find that the effects of smoking and drinking are confined to red blood cell traits. An instrumental variable (IV) comprised of 113 single nucleotide polymorphisms (SNPs) associated with smoking initiation is associated with decreased hemoglobin (HGB: Effect = -0.07 standard deviation units [95% confidence interval = -0.03 to -0.10 SD units], P = 1x10 -4 ), hematocrit (HCT: Effect = -0.06 [-0.03 - -0.09] SD units, P = 4x10 -4 ), and red blood cell count (RBC: Effect = -0.05 [-0.02 - -0.09] SD units, P = 5x10 -3 ) without impacting platelet count (P = 0.9) or white blood cell count (P = 0.6). Similarly, an IV associated with an increased number of alcoholic drinks consumed per week is associated with decreased HGB (Effect = -0.22 [-0.42 - -0.02] SD units, P = 3x10 -2 ) and RBC (Effect = -0.27 [-0.51 - -0.03] SD units, P = 3x10 -2 ). Using multivariable MR and causal mediation analyses, we find that an increased genetic predisposition to smoking initiation is associated with increased alcohol intake, and that alcohol use mediates the genetic effect of smoking initiation on red blood cell traits. These findings demonstrate a novel role for genetically influenced behaviors on human blood traits, revealing opportunities to dissect related pathways and mechanisms that influence hematopoiesis and blood cell biology.
Journal Article
Umbilical Cord Blood-Derived Cell Therapy for Perinatal Brain Injury: A Systematic Review & Meta-Analysis of Preclinical Studies
Perinatal brain injury is a major contributor to long-term adverse neurodevelopment. There is mounting preclinical evidence for use of umbilical cord blood (UCB)-derived cell therapy as potential treatment. To systematically review and analyse effects of UCB-derived cell therapy on brain outcomes in preclinical models of perinatal brain injury. MEDLINE and Embase databases were searched for relevant studies. Brain injury outcomes were extracted for meta-analysis to calculate standard mean difference (SMD) with 95% confidence interval (CI), using an inverse variance, random effects model. Outcomes were separated based on grey matter (GM) and white matter (WM) regions where applicable. Risk of bias was assessed using SYRCLE, and GRADE was used to summarise certainty of evidence. Fifty-five eligible studies were included (7 large, 48 small animal models). UCB-derived cell therapy significantly improved outcomes across multiple domains, including decreased infarct size (SMD 0.53; 95% CI (0.32, 0.74), p < 0.00001), apoptosis (WM, SMD 1.59; 95%CI (0.86, 2.32), p < 0.0001), astrogliosis (GM, SMD 0.56; 95% CI (0.12, 1.01), p = 0.01), microglial activation (WM, SMD 1.03; 95% CI (0.40, 1.66), p = 0.001), neuroinflammation (TNF-α, SMD 0.84; 95%CI (0.44, 1.25), p < 0.0001); as well as improved neuron number (SMD 0.86; 95% CI (0.39, 1.33), p = 0.0003), oligodendrocyte number (GM, SMD 3.35; 95 %CI (1.00, 5.69), p = 0.005) and motor function (cylinder test, SMD 0.49; 95 %CI (0.23, 0.76), p = 0.0003). Risk of bias was determined as serious, and overall certainty of evidence was low. UCB-derived cell therapy is an efficacious treatment in pre-clinical models of perinatal brain injury, however findings are limited by low certainty of evidence.
Journal Article