1,884 research outputs found
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
Relativistic Hartree-Bogoliubov description of sizes and shapes of A=20 isobars
Ground-state properties of A = 20 nuclei (N, O, F,
Ne, Na, Mg) are described in the framework of Relativistic
Hartree-Bogoliubov (RHB) theory. The model uses the NL3 effective interaction
in the mean-field Lagrangian, and describes pairing correlations by the pairing
part of the finite range Gogny interaction D1S. Binding energies, quadrupole
deformations, nuclear matter radii, and differences in radii of proton and
neutron distributions are compared with recent experimental data.Comment: LaTeX 11 pages, 6 eps figs, submitted to Nucl. Phys.
Consequences of HIV for children: avoidable or inevitable?
The HIV/AIDS epidemic has many serious consequences for children. These consequences are, however, rarely inevitable. Families can provide a protective barrier that deflects blows, or minimises their impact and a supportive nurturing environment that can help children recover from harm. If strong enough, and with sufficient access to quality services and support from communities, families can reduce the impacts of HIV/AIDS on children to negligible levels in most areas of impact. It is apparent that the impacts felt by children are not simply unfortunate, inevitable consequences of this epidemic. A strong and supported family with good access to quality services can deflect almost all of the impact. It is as a result of an interaction of the context of poverty, which weakens families, and a failure to adequately respond, that impacts are felt by children
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<sup>ARF </sup>protein, 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<sup>ARF </sup></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<sup>ARF</sup>. To study p14<sup>ARF </sup>biogenesis, 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<sup>ARF </sup></it>mRNA was disproportionally high relative to the level of p14<sup>ARF </sup>protein expression, suggesting a perturbation of p14<sup>ARF </sup>regulation. When p14<sup>ARF </sup>was over-expressed by an adenovirus vector, expression of p53 and downstream targets increased and cell growth was inhibited indicating an intact p14<sup>ARF</sup>-p53 axis. To investigate the discrepancy between <it>p14<sup>ARF </sup></it>mRNA and protein in retinoblastoma, we examined p14<sup>ARF </sup>biogenesis. The proteasome inhibitor, MG132, did not cause p14<sup>ARF </sup>accumulation, although p14<sup>ARF </sup>normally is degraded by proteasomes. miR-24, a microRNA that represses p14<sup>ARF </sup>expression, is expressed in retinoblastoma cell lines and correlates with lower protein expression when compared to other cell lines with high <it>p14<sup>ARF </sup></it>mRNA. Transient over-expression of siRNA against miR-24 led to elevated p14<sup>ARF </sup>protein in retinoblastoma cells.</p> <p>Conclusions</p> <p>In retinoblastoma cells where high levels of <it>p14<sup>ARF </sup></it>mRNA are not accompanied by high p14<sup>ARF </sup>protein, we found a correlation between miR-24 expression and low p14<sup>ARF </sup>protein. p14<sup>ARF </sup>protein 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
An assessment of the accuracy and availability of data in electronic patient tracking systems for patients receiving HIV treatment in central Mozambique
Vertical funding, non-governmental organizations, and health system strengthening: perspectives of public sector health workers in Mozambique
'Education, education, education' : legal, moral and clinical
This article brings together Professor Donald Nicolson's intellectual interest in professional legal ethics and his long-standing involvement with law clinics both as an advisor at the University of Cape Town and Director of the University of Bristol Law Clinic and the University of Strathclyde Law Clinic. In this article he looks at how legal education may help start this process of character development, arguing that the best means is through student involvement in voluntary law clinics. And here he builds upon his recent article which argues for voluntary, community service oriented law clinics over those which emphasise the education of students
Structure of the mirror nuclei Be and B in a microscopic cluster model
The structure of the mirror nuclei Be and B is studied in a
microscopic and 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 Be is obtained accurately with the
stochastic variational method, while several particle-unbound states of both
Be and B are investigated with the complex scaling method.The
calculation for Be supports the recent identification for the existence of
two broad states around 6.5 MeV, and predicts the and
states at about 4.5 MeV and 8 MeV, respectively. The
similarity of the calculated spectra of Be and B enables one to
identify unknown spins and parities of the B states. Available data on
electromagnetic moments and elastic electron scatterings are reproduced very
well. The enhancement of the 1 transition of the first excited state in
Be is well accounted for. The calculated density of Be is found to
reproduce the reaction cross section on a Carbon target. The analysis of the
beta decay of Li to Be clearly shows that the wave function of Be
must contain a small component that cannot be described by the simple model. This small component can be well accounted for by extending a
configuration space to include the distortion of the -particle to
and partitions.Comment: 24 page
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
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