The Importance of DNA Repair in Tumor Suppression

The transition from a normal to cancerous cell requires a number of highly specific mutations that affect cell cycle regulation, apoptosis, differentiation, and many other cell functions. One hallmark of cancerous genomes is genomic instability, with mutation rates far greater than those of normal cells. In microsatellite instability (MIN tumors), these are often caused by damage to mismatch repair genes, allowing further mutation of the genome and tumor progression. These mutation rates may lie near the error catastrophe found in the quasispecies model of adaptive RNA genomes, suggesting that further increasing mutation rates will destroy cancerous genomes. However, recent results have demonstrated that DNA genomes exhibit an error threshold at mutation rates far lower than their conservative counterparts. Furthermore, while the maximum viable mutation rate in conservative systems increases indefinitely with increasing master sequence fitness, the semiconservative threshold plateaus at a relatively low value. This implies a paradox, wherein inaccessible mutation rates are found in viable tumor cells. In this paper, we address this paradox, demonstrating an isomorphism between the conservatively replicating (RNA) quasispecies model and the semiconservative (DNA) model with post-methylation DNA repair mechanisms impaired. Thus, as DNA repair becomes inactivated, the maximum viable mutation rate increases smoothly to that of a conservatively replicating system on a transformed landscape, with an upper bound that is dependent on replication rates. We postulate that inactivation of post-methylation repair mechanisms are fundamental to the progression of a tumor cell and hence these mechanisms act as a method for prevention and destruction of cancerous genomes.Comment: 7 pages, 5 figures; Approximation replaced with exact calculation; Minor error corrected; Minor changes to model syste

Hidden in plain sight: The importance of cryptic interactions in marine plankton

Here, we present a range of interactions, which we term “cryptic interactions.” These are interactions that occur throughout the marine planktonic foodweb but are currently largely overlooked by established methods, which mean large‐scale data collection for these interactions is limited. Despite this, current evidence suggests some of these interactions may have perceptible impacts on foodweb dynamics and model results. Incorporation of cryptic interactions into models is especially important for those interactions involving the transport of nutrients or energy. Our aim is to highlight a range of cryptic interactions across the plankton foodweb, where they exist, and models that have taken steps to incorporate these interactions. Additionally, it is discussed where additional research and effort is required to continue advancing our understanding of these cryptic interactions. We call for more collaboration between ecologists and modelers in order to incorporate cryptic interactions into biogeochemical and foodweb models

Climate variability, oceanography, bowhead whale distribution, and Iñupiat subsistence whaling near Barrow, Alaska

Author Posting. © Arctic Institute of North America, 2010. This article is posted here by permission of Arctic Institute of North America for personal use, not for redistribution. The definitive version was published in Arctic 63 (2010): 179-194.The annual migration of bowhead whales (Balaena mysticetus) past Barrow, Alaska, has provided subsistence hunting to Iñupiat for centuries. Bowheads recurrently feed on aggregations of zooplankton prey near Barrow in autumn. The mechanisms that form these aggregations, and the associations between whales and oceanography, were investigated using field sampling, retrospective analysis, and traditional knowledge interviews. Oceanographic and aerial surveys were conducted near Barrow during August and September in 2005 and 2006. Multiple water masses were observed, and close coupling between water mass type and biological characteristics was noted. Short-term variability in hydrography was associated with changes in wind speed and direction that profoundly affected plankton taxonomic composition. Aggregations of ca. 50–100 bowhead whales were observed in early September of both years at locations consistent with traditional knowledge. Retrospective analyses of records for 1984–2004 also showed that annual aggregations of whales near Barrow were associated with wind speed and direction. Euphausiids and copepods appear to be upwelled onto the Beaufort Sea shelf during Eor SEwinds. A favorable feeding environment is produced when these plankton are retained and concentrated on the shelf by the prevailing westward Beaufort Sea shelf currents that converge with the Alaska Coastal Current flowing to the northeast along the eastern edge of Barrow Canyon.This work was supported by NSF Grants OPPPP-0436131 to C. Ashjian (S. Braund Subcontract), OPPPP-0436110 to R. Campbell, OPPPP-0436127 to W. Maslowski, OPPPP-0436009 to C. Nicolson and J. Kruse, OPPPP-043166 to S. Okkonen, and OPPPP-0435956 to Y. Spitz, E. Sherr, and B. Sherr

Nature of the Na 20 2646-keV level and the stellar reaction rate for Ne 19 ( p ,γ ) 20 Na

Careful comparison of F20 and Na20, and available data on reactions leading to both, suggests that Jπ(2646)=3+. Other mirror identifications are indicated and quantities of astrophysical interest are calculated

Regulation of p14ARF expression by miR-24: a potential mechanism compromising the p53 response during retinoblastoma development

<p>Abstract</p> <p>Background</p> <p>Most human cancers show inactivation of both pRB- and p53-pathways. While retinoblastomas are initiated by loss of the <it>RB1 </it>tumor suppressor gene, <it>TP53 </it>mutations have not been found. High expression of the p53-antagonist MDM2 in human retinoblastomas may compromise p53 tumor surveillance so that <it>TP53 </it>mutations are not selected for in retinoblastoma tumorigenesis. We previously showed that p14^ARFprotein, which activates p53 by inhibiting MDM2, is low in retinoblastomas despite high mRNA expression.</p> <p>Methods</p> <p>In human fetal retinas, adult retinas, and retinoblastoma cells, we determined endogenous <it>p14^ARF</it>mRNA, ARF protein, and miR-24 expression, while integrity of p53 signalling in WERI-Rb1 cells was tested using an adenovirus vector expressing p14^ARF. To study p14^ARFbiogenesis, retinoblastoma cells were treated with the proteasome inhibitor, MG132, and siRNA against miR-24.</p> <p>Results</p> <p>In human retinoblastoma cell lines, <it>p14^ARF</it>mRNA was disproportionally high relative to the level of p14^ARFprotein expression, suggesting a perturbation of p14^ARFregulation. When p14^ARFwas over-expressed by an adenovirus vector, expression of p53 and downstream targets increased and cell growth was inhibited indicating an intact p14^ARF-p53 axis. To investigate the discrepancy between <it>p14^ARF</it>mRNA and protein in retinoblastoma, we examined p14^ARFbiogenesis. The proteasome inhibitor, MG132, did not cause p14^ARFaccumulation, although p14^ARFnormally is degraded by proteasomes. miR-24, a microRNA that represses p14^ARFexpression, is expressed in retinoblastoma cell lines and correlates with lower protein expression when compared to other cell lines with high <it>p14^ARF</it>mRNA. Transient over-expression of siRNA against miR-24 led to elevated p14^ARFprotein in retinoblastoma cells.</p> <p>Conclusions</p> <p>In retinoblastoma cells where high levels of <it>p14^ARF</it>mRNA are not accompanied by high p14^ARFprotein, we found a correlation between miR-24 expression and low p14^ARFprotein. p14^ARFprotein levels were restored without change in mRNA abundance upon miR-24 inhibition suggesting that miR-24 could functionally repress expression, effectively blocking p53 tumor surveillance. During retinal tumorigenesis, miR-24 may intrinsically compromise the p53 response to <it>RB1 </it>loss.</p

Opposing brain differences in 16p11.2 deletion and duplication carriers

Deletions and duplications of the recurrent ∼600 kb chromosomal BP4–BP5 region of 16p11.2 are associated with a broad variety of neurodevelopmental outcomes including autism spectrum disorder. A clue to the pathogenesis of the copy number variant (CNV)'s effect on the brain is that the deletion is associated with a head size increase, whereas the duplication is associated with a decrease. Here we analyzed brain structure in a clinically ascertained group of human deletion (N = 25) and duplication (N = 17) carriers from the Simons Variation in Individuals Project compared with age-matched controls (N = 29 and 33, respectively). Multiple brain measures showed increased size in deletion carriers and reduced size in duplication carriers. The effects spanned global measures of intracranial volume, brain size, compartmental measures of gray matter and white matter, subcortical structures, and the cerebellum. Quantitatively, the largest effect was on the thalamus, but the collective results suggest a pervasive rather than a selective effect on the brain. Detailed analysis of cortical gray matter revealed that cortical surface area displays a strong dose-dependent effect of CNV (deletion > control > duplication), whereas average cortical thickness is less affected. These results suggest that the CNV may exert its opposing influences through mechanisms that influence early stages of embryonic brain development

FoxM1, a Forkhead Transcription Factor Is a Master Cell Cycle Regulator for Mouse Mature T Cells but Not Double Positive Thymocytes

FoxM1 is a forkhead box transcription factor and a known master regulator required for different phases of the cell cycle. In cell lines, FoxM1 deficient cells exhibit delayed S phase entry, aneuploidy, polyploidy and can't complete mitosis. In vivo, FoxM1 is expressed mostly in proliferating cells but is surprisingly also found in non-proliferating CD4+CD8+ double positive thymocytes. Here, we addressed the role of FoxM1 in T cell development by generating and analyzing two different lines of T-cell specific FoxM1 deficient mice. As expected, FoxM1 is required for proliferation of early thymocytes and activated mature T cells. Defective expression of many cell cycle proteins was detected, including cyclin A, cyclin B1, cdc2, cdk2, p27 and the Rb family members p107 and p130 but surprisingly not survivin. Unexpectedly, loss of FoxM1 only affects a few cell cycle proteins in CD4+CD8+ thymocytes and has little effect on their sensitivity to apoptosis and the subsequent steps of T cell differentiation. Thus, regulation of cell cycle genes by FoxM1 is stage- and context-dependent

A bovine lymphosarcoma cell line infected with theileria annulata exhibits an irreversible reconfiguration of host cell gene expression

Theileria annulata, an intracellular parasite of bovine lymphoid cells, induces substantial phenotypic alterations to its host cell including continuous proliferation, cytoskeletal changes and resistance to apoptosis. While parasite induced modulation of host cell signal transduction pathways and NFκB activation are established, there remains considerable speculation on the complexities of the parasite directed control mechanisms that govern these radical changes to the host cell. Our objectives in this study were to provide a comprehensive analysis of the global changes to host cell gene expression with emphasis on those that result from direct intervention by the parasite. By using comparative microarray analysis of an uninfected bovine cell line and its Theileria infected counterpart, in conjunction with use of the specific parasitacidal agent, buparvaquone, we have identified a large number of host cell gene expression changes that result from parasite infection. Our results indicate that the viable parasite can irreversibly modify the transformed phenotype of a bovine cell line. Fifty percent of genes with altered expression failed to show a reversible response to parasite death, a possible contributing factor to initiation of host cell apoptosis. The genes that did show an early predicted response to loss of parasite viability highlighted a sub-group of genes that are likely to be under direct control by parasite infection. Network and pathway analysis demonstrated that this sub-group is significantly enriched for genes involved in regulation of chromatin modification and gene expression. The results provide evidence that the Theileria parasite has the regulatory capacity to generate widespread change to host cell gene expression in a complex and largely irreversible manner

Structure of the mirror nuclei 9^9Be and 9^9B in a microscopic cluster model

The structure of the mirror nuclei $^9$Be and $^9$B is studied in a microscopic $\alpha+ \alpha+ n$ and $\alpha+ \alpha+ p$ three-cluster model using a fully antisymmetrized 9-nucleon wave function. The two-nucleon interaction includes central and spin-orbit components and the Coulomb potential. The ground state of $^9$Be is obtained accurately with the stochastic variational method, while several particle-unbound states of both $^9$Be and $^9$B are investigated with the complex scaling method.The calculation for $^9$Be supports the recent identification for the existence of two broad states around 6.5 MeV, and predicts the $\frac{3}{2}^{-}_2$ and $\frac{5}{2}^{-}_2$ states at about 4.5 MeV and 8 MeV, respectively. The similarity of the calculated spectra of $^9$Be and $^9$B enables one to identify unknown spins and parities of the $^9$B states. Available data on electromagnetic moments and elastic electron scatterings are reproduced very well. The enhancement of the $E$1 transition of the first excited state in $^9$Be is well accounted for. The calculated density of $^9$Be is found to reproduce the reaction cross section on a Carbon target. The analysis of the beta decay of $^9$Li to $^9$Be clearly shows that the wave function of $^9$Be must contain a small component that cannot be described by the simple $\alpha+ \alpha+ n$ model. This small component can be well accounted for by extending a configuration space to include the distortion of the $\alpha$-particle to $t+p$ and $h+n$ partitions.Comment: 24 page