A human cancer-predisposing polymorphism in Cdc25A is embryonic lethal in the mouse and promotes ASK-1 mediated apoptosis

<p>Abstract</p> <p>Background</p> <p>Failure to regulate the levels of Cdc25A phosphatase during the cell cycle or during a checkpoint response causes bypass of DNA damage and replication checkpoints resulting in genomic instability and cancer. During G1 and S and in cellular response to DNA damage, Cdc25A is targeted for degradation through the Skp1-cullin-β-TrCP (SCF^β-TrCP) complex. This complex binds to the Cdc25A DSG motif which contains serine residues at positions 82 and 88. Phosphorylation of one or both residues is necessary for the binding and degradation to occur.</p> <p>Results</p> <p>We now show that mutation of serine 88 to phenylalanine, which is a cancer-predisposing polymorphic variant in humans, leads to early embryonic lethality in mice. The mutant protein retains its phosphatase activity both <it>in vitro </it>and in cultured cells. It fails to interact with the apoptosis signal-regulating kinase 1 (ASK1), however, and therefore does not suppress ASK1-mediated apoptosis.</p> <p>Conclusions</p> <p>These data suggest that the DSG motif, in addition to its function in Cdc25A-mediated degradation, plays a role in cell survival during early embyogenesis through suppression of ASK1-mediated apoptosis.</p

Sleep-Disordered Breathing and Mortality: A Prospective Cohort Study

In a cohort of 6,441 volunteers followed over an average of 8.2 years, Naresh Punjabi and colleagues find sleep-disordered breathing to be independently associated with mortality and identify predictive characteristics

Mild Idiopathic Infantile Hypercalcemia—Part 1: Biochemical and Genetic Findings

Context: Idiopathic infantile hypercalcemia (IIH), an uncommon disorder characterized by elevated serum concentrations of 1,25 dihydroxyvitamin D (1,25(OH)2D) and low parathyroid hormone (PTH) levels, may present with mild to severe hypercalcemia during the first months of life. Biallelic variants in the CYP24A1 or SLC34A1 genes are associated with severe IIH. Little is known about milder forms. Objective: This work aims to characterize the genetic associations and biochemical profile of mild IIH. Methods: This is a cross-sectional study including children between age 6 months and 17 years with IIH who were followed in the Calcium Clinic at the Hospital for Sick Children (SickKids), Toronto, Canada. Twenty children with mild IIH on calcium-restricted diets were evaluated. We performed a dietary assessment and analyzed biochemical measures including vitamin D metabolites and performed a stepwise molecular genetic analysis. Complementary biochemical assessments and renal ultrasounds were offered to first-degree family members of positive probands. Results: The median age was 16 months. Median serum levels of calcium (2.69 mmol/L), urinary calcium:creatinine ratio (0.72 mmol/mmol), and 1,25(OH)2D (209 pmol/L) were elevated, whereas intact PTH was low normal (22.5 ng/L). Mean 1,25(OH)2D/PTH and 1,25(OH)2D/25(OH)D ratios were increased by comparison to healthy controls. Eleven individuals (55%) had renal calcification. Genetic variants were common (65%), with the majority being heterozygous variants in SLC34A1 and SLC34A3, while a minority showed variants of CYP24A1 and other genes related to hypercalciuria. Conclusion: The milder form of IIH has a distinctive vitamin D metabolite profile and is primarily associated with heterozygous SLC34A1 and SLC34A3 variants. Keywords: CYP24A1; genetic; hypercalcemia; nephrocalcinosis; nephrolithiasis; vitamin

The psychological-type profile of clergywomen in ordained local ministry in the Church of England : pioneers or custodians?

This study employs psychological-type theory to compare the psychological profile of 144 clergywomen serving in ordained local ministry in the Church of England alongside the established profile of 237 professional mobile clergywomen serving in the Church of England published by Francis, Craig, Whinney, Tilley, and Slater. The data found no significant differences between these two groups of clergywomen in terms of orientations (introversion and extraversion) or in terms of the judging process (thinking and feeling). In terms of the perceiving process, there was a significantly higher proportion of sensing types among those serving in ordained local ministry (70% compared with 35%). In terms of the attitudes, there was a significantly higher proportion of judging types among those serving in ordained local ministry (83% compared with 65%). The combined sensing judging (SJ) temperament accounted for 65% of the clergywomen serving in ordained local ministry, compared with 29% of the clergywomen serving in professional mobile ministry in the earlier study. It is argued that the SJ temperament characterises a custodian style of ministry

Proteinuria, CrCl, and Immune Activation in Antiretroviral-Naïve HIV-Infected Subjects

Because both renal disease and immune activation predict progression to AIDS, we evaluated the relationships between dipstick proteinuria ≥1+ [7% of 1012 subjects], CrCl <90mL/min [18% of 1071 subjects], and percentages of peripheral activated CD8 cells (CD8+CD38+HLA-DR+) in antiretroviral-naïve, HIV-infected subjects enrolled into AIDS Clinical Trials Group studies 384 and A5095. Proteinuria, but not CrCl, was associated with higher percentages of CD8+CD38+HLA-DR+ cells [55% vs. 50%; P=0.01], with even more pronounced differences in men and among Blacks and Hispanics. Proteinuria may be a surrogate measure of greater immune activation in HIV-infected patients initiating antiretroviral therapy

A statistical review of light curves and the prevalence of contact binaries in the Kuiper Belt

We investigate what can be learned about a population of distant Kuiper Belt Objects (KBOs) by studying the statistical properties of their light curves. Whereas others have successfully inferred the properties of individual, highly variable KBOs, we show that the fraction of KBOs with low amplitudes also provides fundamental information about a population. Each light curve is primarily the result of two factors: shape and orientation. We consider contact binaries and ellipsoidal shapes, with and without flattening. After developing the mathematical framework, we apply it to the existing body of KBO light curve data. Principal conclusions are as follows. (1) When using absolute magnitude H as a proxy for the sizes of KBOs, it is more accurate to use the maximum of the light curve (minimum H) rather than the mean. (2) Previous investigators have noted that smaller KBOs tend to have higher-amplitude light curves, and have interpreted this as evidence that they are systematically more irregular in shape than larger KBOs; we show that a population of flattened bodies with uniform proportions, independent of size, could also explain this result. (3) Our method of analysis indicates that prior assessments of the fraction of contact binaries in the Kuiper Belt may be artificially low. (4) The pole orientations of some KBOs can be inferred from observed changes in their light curves over time scales of decades; however, we show that these KBOs constitute a biased sample, whose pole orientations are not representative of the population overall. (5) Although surface topography, albedo patterns, limb darkening, and other surface properties can affect individual light curves, they do not have a strong influence on the statistics overall. (6) Photometry from the Outer Solar System Origins Survey (OSSOS) survey is incompatible with previous results and its statistical properties defy easy interpretation. We also discuss the promise of this approach for the analysis of future, much larger data sets such as the one anticipated from the upcoming Vera C. Rubin Observatory

A statistical review of light curves and the prevalence of contact binaries in the Kuiper Belt

We investigate what can be learned about a population of distant Kuiper Belt Objects (KBOs) by studying the statistical properties of their light curves. Whereas others have successfully inferred the properties of individual, highly variable KBOs, we show that the fraction of KBOs with low amplitudes also provides fundamental information about a population. Each light curve is primarily the result of two factors: shape and orientation. We consider contact binaries and ellipsoidal shapes, with and without flattening. After developing the mathematical framework, we apply it to the existing body of KBO light curve data. Principal conclusions are as follows. (1) When using absolute magnitude H as a proxy for the sizes of KBOs, it is more accurate to use the maximum of the light curve (minimum H) rather than the mean. (2) Previous investigators have noted that smaller KBOs tend to have higher-amplitude light curves, and have interpreted this as evidence that they are systematically more irregular in shape than larger KBOs; we show that a population of flattened bodies with uniform proportions, independent of size, could also explain this result. (3) Our method of analysis indicates that prior assessments of the fraction of contact binaries in the Kuiper Belt may be artificially low. (4) The pole orientations of some KBOs can be inferred from observed changes in their light curves over time scales of decades; however, we show that these KBOs constitute a biased sample, whose pole orientations are not representative of the population overall. (5) Although surface topography, albedo patterns, limb darkening, and other surface properties can affect individual light curves, they do not have a strong influence on the statistics overall. (6) Photometry from the Outer Solar System Origins Survey (OSSOS) survey is incompatible with previous results and its statistical properties defy easy interpretation. We also discuss the promise of this approach for the analysis of future, much larger data sets such as the one anticipated from the upcoming Vera C. Rubin Observatory

The long lives of primates and the ‘invariant rate of ageing’ hypothesis

This work was supported by NIA P01AG031719 to J.W.V. and S.C.A., with additional support provided by the Max Planck Institute of Demographic Research and the Duke University Population Research Institute.Is it possible to slow the rate of ageing, or do biological constraints limit its plasticity? We test the ‘invariant rate of ageing’ hypothesis, which posits that the rate of ageing is relatively fixed within species, with a collection of 39 human and nonhuman primate datasets across seven genera. We first recapitulate, in nonhuman primates, the highly regular relationship between life expectancy and lifespan equality seen in humans. We next demonstrate that variation in the rate of ageing within genera is orders of magnitude smaller than variation in pre-adult and age-independent mortality. Finally, we demonstrate that changes in the rate of ageing, but not other mortality parameters, produce striking, species-atypical changes in mortality patterns. Our results support the invariant rate of ageing hypothesis, implying biological constraints on how much the human rate of ageing can be slowed.Publisher PDFPeer reviewe

Orally available Mn porphyrins with superoxide dismutase and catalase activities

Superoxide dismutase/catalase mimetics, such as salen Mn complexes and certain metalloporphyrins, catalytically neutralize reactive oxygen and nitrogen species, which have been implicated in the pathogenesis of many serious diseases. Both classes of mimetic are protective in animal models of oxidative stress. However, only AEOL11207 and EUK-418, two uncharged Mn porphyrins, have been shown to be orally bioavailable. In this study, EUK-418 and several new analogs (the EUK-400 series) were synthesized and shown to exhibit superoxide dismutase, catalase, and peroxidase activities in vitro. Some also protected PC12 cells against staurosporine-induced cell death. All EUK-400 compounds were stable in simulated gastric fluid, and most were substantially more lipophilic than the salen Mn complexes EUK-189 and EUK-207, which lack oral activity. Pharmacokinetics studies demonstrate the presence of all EUK-400 series compounds in the plasma of rats after oral administration. These EUK-400 series compounds are potential oral therapeutic agents for cellular damage caused by oxidative stress