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Matsuba C.,University of Florida | Lewis S.,University of Florida | Ostrow D.G.,University of Florida | Salomon M.P.,University of Florida | And 6 more authors.
G3: Genes, Genomes, Genetics | Year: 2012

Evidence is accumulating that individuals in poor physiologic condition may accumulate mutational damage faster than individuals in good condition. If poor condition results from pre-existing deleterious mutations, the result is "fitness-dependent mutation rate," which has interesting theoretical implications. Here we report a study in which 10 mutation accumulation (MA) lines of the nematode Caenorhabditis elegans that had previously accumulated mutations for 250 generations under relaxed selection were expanded into sets of "second-order" MA lines and allowed to accumulate mutations for an additional 150 generations. The 10 lines were chosen on the basis of the relative change in fitness over the first 250 generations of MA, five high-fitness lines and five low-fitness lines. On average, the mutational properties (per-generation change in mean relative fitness, mutational variance, and Bateman-Mukai estimates of genomic mutation rate and average mutational effect) of the high-fitness and low-fitness did not differ significantly, and averaged over all lines, the point estimates were extremely close to those of the firstorder MA experiment after 200 generations of MA. However, several nonsignificant trends indicate that low-fitness lines may in fact be more likely to suffer mutational damage than high-fitness lines. © 2012 Matsuba et al. Source


Norrie J.L.,University of Texas at Austin | Lewandowski J.P.,University of Texas at Austin | Bouldin C.M.,UF Genetics Institute | Bouldin C.M.,University of Washington | And 6 more authors.
Developmental Biology | Year: 2014

Mutations in the Bone Morphogenetic Protein (BMP) pathway are associated with a range of defects in skeletal formation. Genetic analysis of BMP signaling requirements is complicated by the presence of three partially redundant BMPs that are required for multiple stages of limb development. We generated an inducible allele of a BMP inhibitor, Gremlin, which reduces BMP signaling. We show that BMPs act in a dose and time dependent manner in which early reduction of BMPs result in digit loss, while inhibiting overall BMP signaling between E10.5 and E11.5 allows polydactylous digit formation. During this period, inhibiting BMPs extends the duration of FGF signaling. Sox9 is initially expressed in normal digit ray domains but at reduced levels that correlate with the reduction in BMP signaling. The persistence of elevated FGF signaling likely promotes cell proliferation and survival, inhibiting the activation of Sox9 and secondarily, inhibiting the differentiation of Sox9-expressing chondrocytes. Our results provide new insights into the timing and clarify the mechanisms underlying BMP signaling during digit morphogenesis. © 2014 Elsevier Inc. Source


Gorbatyuk M.S.,UF Genetics Institute | Gorbatyuk M.S.,University of North Texas Health Science Center | Shabashvili A.,UF Genetics Institute | Chen W.,UF Genetics Institute | And 13 more authors.
Molecular Therapy | Year: 2012

Accumulation of human wild-type (wt) α-synuclein (α-syn) induces neurodegeneration in humans and in experimental rodent models of Parkinson disease (PD). It also leads to endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). We overexpressed glucose regulated protein 78, also known as BiP (GRP78/BiP), to test the hypothesis that this ER chaperone modulates the UPR, blocks apoptosis, and promotes the survival of nigral dopamine (DA) neurons in a rat model of PD induced by elevated level of human α-syn. We determined that α-syn activates ER stress mediators associated with pancreatic ER kinase-like ER kinase (PERK) and activating transcription factor-6 (ATF6) signaling pathways as well as proaoptotic CCAAT/-enhancer-binding protein homologous protein (CHOP) in nigral DA neurons. At the same time, overexpression of GRP78/BiP diminished α-syn neurotoxicity by down regulating ER stress mediators and the level of apoptosis, promoted survival of nigral tyrosine hydroxylase (TH) positive cells and resulted in higher levels of striatal DA, while eliminating amphetamine induced behavioral asymmetry. We also detected a complex between GRP78/BiP and α-syn that may contribute to prevention of the neurotoxicity caused by α-syn. Our data suggest that the molecular chaperone GRP78/BiP plays a neuroprotective role in α-syn-induced Parkinson-like neurodegeneration. © The American Society of Gene & Cell Therapy. Source


Sefah K.,University of Florida | Sefah K.,UF Genetics Institute | Bae K.-M.,University of Florida | Phillips J.A.,University of Florida | And 9 more authors.
International Journal of Cancer | Year: 2013

Cancer stem cells (CSC) represent a malignant subpopulation of cells in hierarchically organized tumors. They constitute a subpopulation of malignant cells within a tumor mass and possess the ability to self-renew giving rise to heterogeneous tumor cell populations with a complex set of differentiated tumor cells. CSC may be the cause of metastasis and therapeutic refractory disease. Because few markers exist to identify and isolate pure CSC, we used cell-based Systematic Evolution of Ligands by EXponential enrichment (cell-SELEX) to create DNA aptamers that can identify novel molecular targets on the surfaces of live CSC. Out of 22 putative DNA sequences, 3 bound to ∼90% and 5 bound to ∼15% of DU145 prostate cancer cells. The 15% of cells that were positive for the second panel of aptamers expressed high levels of E-cadherin and CD44, had high aldehyde dehydrogenase 1 activity, grew as spheroids under nonadherent culture conditions, and initiated tumors in immune-compromised mice. The discovery of the molecular targets of these aptamers could reveal novel CSC biomarkers. Copyright © 2012 UICC. Source


Zhu B.,Beijing Institute of Technology | Jia H.,CAS Institute of Chemistry | Zhang X.,Beijing Institute of Technology | Chen Y.,UF Genetics Institute | And 5 more authors.
Analytical and Bioanalytical Chemistry | Year: 2010

A new, visible-light-excited and red-emitting fluorescent Ca2+ probe, STDBT, was synthesized, which consists of 1,2-bis(2-aminophenoxy)ethane- N,N,N′,N′-tetraacetic acid as a Ca2+-chelating moiety and two benzothiazolium hemicyanine dyes as fluorophores. The spectral profiles of its free and Ca2+-bound forms were studied. Upon addition of Ca 2+, the fluorescence spectra of STDBT displayed a significant enhancement (about 48-fold) in fluorescence intensity and a 20-nm blueshift (from 600 to 580 nm) in the emission spectrum. Both the absorption and the excitation spectra of STDBT showed a very large (more than 100 nm) hypsochromic shift in the long-wavelength maxima upon binding with Ca2+. Interestingly, in contrast with the commonly used Ca2+ indicator Fluo-3, when the acetoxymethyl ester of STDBT enters into cells, it distributes both in the cytosol and the nucleus, but displays a very clear boundary between the two compartments. This allows STDBT to be used as a double targetable Ca2+ probe that can be used to report cytoplasmic Ca2+ and nuclear Ca2+ simultaneously. © Springer-Verlag 2010. Source

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