Supernova 2007bi as a pair-instability explosion

Stars with initial masses 10 M_{solar} < M_{initial} < 100 M_{solar} fuse progressively heavier elements in their centres, up to inert iron. The core then gravitationally collapses to a neutron star or a black hole, leading to an explosion -- an iron-core-collapse supernova (SN). In contrast, extremely massive stars (M_{initial} > 140 M_{solar}), if such exist, have oxygen cores which exceed M_{core} = 50 M_{solar}. There, high temperatures are reached at relatively low densities. Conversion of energetic, pressure-supporting photons into electron-positron pairs occurs prior to oxygen ignition, and leads to a violent contraction that triggers a catastrophic nuclear explosion. Tremendous energies (>~ 10^{52} erg) are released, completely unbinding the star in a pair-instability SN (PISN), with no compact remnant. Transitional objects with 100 M_{solar} < M_{initial} < 140 M_{solar}, which end up as iron-core-collapse supernovae following violent mass ejections, perhaps due to short instances of the pair instability, may have been identified. However, genuine PISNe, perhaps common in the early Universe, have not been observed to date. Here, we present our discovery of SN 2007bi, a luminous, slowly evolving supernova located within a dwarf galaxy (~1% the size of the Milky Way). We measure the exploding core mass to be likely ~100 M_{solar}, in which case theory unambiguously predicts a PISN outcome. We show that >3 M_{solar} of radioactive 56Ni were synthesized, and that our observations are well fit by PISN models. A PISN explosion in the local Universe indicates that nearby dwarf galaxies probably host extremely massive stars, above the apparent Galactic limit, perhaps resulting from star formation processes similar to those that created the first stars in the Universe.Comment: Accepted version of the paper appearing in Nature, 462, 624 (2009), including all supplementary informatio

Synthetic Lethality of Chk1 Inhibition Combined with p53 and/or p21 Loss During a DNA Damage Response in Normal and Tumor Cells

Cell cycle checkpoints ensure genome integrity and are frequently compromised in human cancers. A therapeutic strategy being explored takes advantage of checkpoint defects in p53-deficient tumors in order to sensitize them to DNA-damaging agents by eliminating Chk1-mediated checkpoint responses. Using mouse models, we demonstrated that p21 is a key determinant of how cells respond to the combination of DNA damage and Chk1 inhibition (combination therapy) in normal cells as well as in tumors. Loss of p21 sensitized normal cells to the combination therapy much more than did p53 loss and the enhanced lethality was partially blocked by CDK inhibition. In addition, basal pools of p21 (p53 independent) provided p53 null cells with protection from the combination therapy. Our results uncover a novel p53-independent function for p21 in protecting cells from the lethal effects of DNA damage followed by Chk1 inhibition. As p21 levels are low in a significant fraction of colorectal tumors, they are predicted to be particularly sensitive to the combination therapy. Results reported in this study support this prediction

Calcium-dependent release of adenosine and uridine nucleotides from A549 cells

Extracellular nucleotides play an important role in lung defense, but the release mechanism and relative abundance of different nucleotide species secreted by lung epithelia are not well defined. In this study, to minimize cell surface hydrolysis, we used a low-volume, flow-through chamber and examined adenosine and uridine nucleotide concentrations in perfusate aliquots of human lung A549 cells challenged by 50% hypotonic shock. Adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine (Ado) were quantified in high-performance liquid chromatography (HPLC) analysis of fluorescent etheno derivatives, and uridine triphosphate (UTP) and uridine diphosphate (UDP) were measured using HPLC-coupled radioenzymatic assays. After the onset of hypotonic shock, ATP, ADP, UTP, and UDP in the perfusates increased markedly and peaked at approximately 2.5 min, followed by a gradual decay in the next 15–20 min; peak changes in Ado and AMP were relatively minor. The peak concentrations and fold increment (in parentheses) were: 34 ± 13 nM ATP (5.6), 11 ± 5 nM ADP (3.7), 3.3 ± 1.2 nM AMP (1.4), 23 ± 7 nM Ado (2.1), 21 nM UTP (>7), and 11 nM UDP (27). Nucleotide release was almost completely abolished from cells loaded with the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Under isotonic conditions, elevation of intracellular calcium with the calcium ionophore ionomycin (5 μM, 3 min) also released nucleotides with kinetics and relative abundance as above, albeit less robust. ADP:ATP (1:3) and UDP:UTP (1:2) ratios in perfusates from stimulated cells were markedly higher than the cytosolic ratios of these species, suggesting that a nucleotide diphosphate (NDP)-rich compartment, e.g., the secretory pathway, contributed to nucleotide release. Laser confocal microscopy experiments illustrated increased FM1-43 uptake into the plasma membrane upon hypotonic shock or ionomycin treatment, consistent with enhanced vesicular exocytosis under these conditions. In summary, our results strongly suggest that calcium-dependent exocytosis is responsible, at least in most part, for adenosine and uridine nucleotide release from A549 cells

Platinum-(IV)-derivative satraplatin induced G2/M cell cycle perturbation via p53-p21(waf1/cip1)-independent pathway in human colorectal cancer cells

Platinum-(IV)-derivative satraplatin represents a new generation of orally available anti-cancer drugs that are under development for the treatment of several cancers. Understanding the mechanisms of cell cycle modulation and apoptosis is necessary to define the mode of action of satraplatin. In this study, we investigate the ability of satraplatin to induce cell cycle perturbation, clonogenicity loss and apoptosis in colorectal cancer (CRC) cells.Platinum-(IV)-derivative satraplatin represents a new generation of orally available anti-cancer drugs that are under development for the treatment of several cancers. Understanding the mechanisms of cell cycle modulation and apoptosis is necessary to define the mode of action of satraplatin. In this study, we investigate the ability of satraplatin to induce cell cycle perturbation, clonogenicity loss and apoptosis in colorectal cancer (CRC) cells

Use of the ODD-Luciferase Transgene for the Non-Invasive Imaging of Spontaneous Tumors in Mice

In humans, imaging of tumors provides rapid, accurate assessment of tumor growth and location. In laboratory animals, however, the imaging of spontaneously occurring tumors continues to pose many technical and logistical problems. Recently a mouse model was generated in which a chimeric protein consisting of HIF-1α oxygen-dependent degradation domain (ODD) fused to luciferase was ubiquitously expressed in all tissues. Hypoxic stress leads to the accumulation of ODD-luciferase in the tissues of this mouse model which can be identified by non-invasive bioluminescence measurement. Since solid tumors often contain hypoxic regions, we performed proof-of-principle experiments testing whether this transgenic mouse model may be used as a universal platform for non-invasive imaging analysis of spontaneous solid tumors.ODD-luciferase transgenic mice were bred with MMTV-neu/beclin1+/- mice. Upon injection of luciferin, bioluminescent background of normal tissues in the transgenic mice and bioluminescent signals from spontaneously mammary carcinomas were measured non-invasively with an IVIS Spectrum imaging station. Tumor volumes were measured manually and the histology of tumor tissues was analyzed.Our results show that spontaneous mammary tumors in ODD-luciferase transgenic mice generate substantial bioluminescent signals, which are clearly discernable from background tissue luminescence. Moreover, we demonstrate a strong quantitative correlation between the bioluminescent tumor contour and the volume of palpable tumors. We further demonstrate that shrinkage of the volume of spontaneous tumors in response to chemotherapeutic treatment can be determined quantitatively using this system. Finally, we show that the growth and development of spontaneous tumors can be monitored longitudinally over several weeks. Thus, our results suggest that this model could potentially provide a practical, reliable, and cost-effective non-invasive quantitative method for imaging spontaneous solid tumors in mice

Limited genetic variation and structure in softshell clams (Mya arenaria) across their native and introduced range

Author Posting. © Springer, 2009. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Conservation Genetics 10 (2009): 803-814, doi:10.1007/s10592-008-9641-y.To offset declines in commercial landings of the softshell clam, Mya arenaria, resource managers are engaged in extensive stocking of seed clams throughout its range in the northwest Atlantic. Because a mixture of native and introduced stocks can disrupt locally adapted genotypes, we investigated genetic structure in M. arenaria populations across its current distribution to test for patterns of regional differentiation. We sequenced mitochondrial cytochrome oxidase I (COI) for a total of 212 individuals from 12 sites in the northwest Atlantic (NW Atlantic), as well as two introduced sites, the northeast Pacific (NE Pacific) and the North Sea and Europe (NS Europe). Populations exhibited extremely low genetic variation, with one haplotype dominating (65-100%) at all sites sampled. Despite being introduced in the last 150-400 years, both NE Pacific and NS Europe populations had higher diversity measures than those in the NW Atlantic and both contained private haplotypes at frequencies of 10% to 27% consistent with their geographic isolation. While significant genetic structure (FST = 0.159, p<0.001) was observed between NW Atlantic and NS Europe, there was no evidence for genetic structure across the pronounced environmental clines of the NW Atlantic. Reduced genetic diversity in mtDNA combined with previous studies reporting reduced genetic diversity in nuclear markers strongly suggests a recent population expansion in the NW Atlantic, a pattern that may result from the retreat of ice sheets during Pleistocene glacial periods. Lack of genetic diversity and regional genetic differentiation suggests that present management strategies for the commercially important softshell clam are unlikely to have a significant impact on the regional distribution of genetic variation, although the possibility of disrupting locally adapted stocks cannot be excluded.This work was supported by NSF grants OCE-0326734 and OCE-0215905 to L. Mullineaux and OCE- 0349177 (Biological Oceanography) to PHB

Armed conflicts have an impact on the spread of tuberculosis: the case of the Somali Regional State of Ethiopia

<p>Abstract</p> <p/> <p>A pessimistic view of the impact of armed conflicts on the control of infectious diseases has generated great interest in the role of conflicts on the global TB epidemic. Nowhere in the world is such interest more palpable than in the Horn of Africa Region, comprising Ethiopia, Somalia, Eritrea, Djibouti, Kenya and Sudan. An expanding literature has demonstrated that armed conflicts stall disease control programs through distraction of health system, interruption of patients' ability to seek health care, and the diversion of economic resources to military ends rather than health needs. Nonetheless, until very recently, no research has been done to address the impact of armed conflict on TB epidemics in the Somali Regional State (SRS) of Ethiopia.</p> <p>Methods</p> <p>This study is based on the cross-sectional data collected in 2007, utilizing structured questionnaires filled-out by a sample of 226 TB patients in the SRS of Ethiopia. Data was obtained on the delay patients experienced in receiving a diagnosis of TB, on the biomedical knowledge of TB that patients had, and the level of self-treatment by patients. The outcome variables in this study are the delay in the diagnosis of TB experienced by patients, and extent of self-treatment utilized by patients. Our main explanatory variable was place of residence, which was dichotomized as being in 'conflict zones' and in 'non-conflict zones'. Demographic data was collected for statistical control. Chi-square and Mann-Whitney tests were used on calculations of group differences. Logistic regression analysis was used to determine the association between outcome and predictor variables.</p> <p>Results</p> <p>Two hundred and twenty six TB patients were interviewed. The median delay in the diagnosis of TB was 120 days and 60 days for patients from conflict zones and from non-conflict zones, respectively. Moreover, 74% of the patients residing in conflict zones undertook self-treatment prior to their diagnosis. The corresponding proportion from non-conflict zones was 45%. Fully adjusted logistic regression analysis shows that patients from conflict zones had significantly greater odds of delay (OR = 3.06; 95% CI: 1.47-6.36) and higher self treatment utilization (OR = 3.34; 95% CI: 1.56-7.12) compared to those from non-conflict zones.</p> <p>Conclusion</p> <p>Patients from conflict zones have a longer delay in receiving a diagnosis of TB and have higher levels of self treatment utilization. This suggests that access to TB care should be improved by the expansion of user friendly directly observed therapy short-course (DOTS) in the conflict zones of the region.</p