Ocular defects associated with a null mutation in the mouse arylamine <Emphasis Type="Italic">N</Emphasis>-acetyltransferase 2 gene

The xenobiotic metabolizing enzyme, mouse arylamine N-acetyltransferase type 2 (Nat2), is expressed during embryogenesis from the blastocyst stage and in the developing neural tube and eye. Mouse Nat2 is widely believed to have an endogenous role distinct from xenobiotic metabolism, and polymorphisms in the human ortholog have been implicated in susceptibility to spina bifida and orofacial clefting. The developmental role of Nat2 was investigated using transgenic Nat2 knockout/lacZ knockin (Nat2 ^tm1Esim) mice. The transgene was bred onto an A/J background and offspring were scored for developmental defects at weaning. After backcross generation eight, an ocular defect, ranging from cataract to microphthalmia and anophthalmia, was recorded among offspring of backcross and intercross pairs. Histologic analysis of cataract cases revealed a failure of the lens to separate from the cornea and plaques within the lens tissue. While Nat2 ^−/− mice have been described as overtly aphenotypic, the presence of a Nat2 null allele in one or both parents can result in ocular defects. These ocular phenotypes and their association with Nat2 genotype indicate that the Nat2 locus may be responsible for the previously described microphthalmic Cat4 phenotype and implicate the orthologous human NAT as a phenotypic modifier of microphthalmia and anophthalmia.     

Attitudes toward genetic testing for cancer risk after genetic counseling and decision support: a qualitative comparison between hereditary cancer types

This study aimed to qualitatively assess individuals' attitudes toward genetic testing for cancer risk after genetic counseling and decision support. As part of a larger study, 78 women considering genetic testing for hereditary breast/ovarian cancer (HBOC) risk and 22 individuals considering genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC) completed an open-ended table of their perceived pros and cons of genetic testing. The most frequently reported pros were "to help manage my risk of developing cancer," "to help my family," and "to know my cancer risk." With regards to risk management, the HBOC group perceived genetic testing as most helpful in informing their general risk management practices, while the HN-PCC group focused on the potential to clarify their need for bowel cancer screening, suggesting that patients' perceptions of the benefits of genetic testing may differ across cancer syndromes. Individuals in both groups expressed concern about the potential psychological impact of genetic testing. We also found that some affected individuals may not fully comprehend the meaning of their potential test results. Eliciting patients' perceived pros and cons during genetic counseling is likely to be a valuable tool for improving patient care. This data also provides an improved evidence base for the development of patient education tools.     

Brightfield Proximity Ligation Assay Reveals Both Canonical and Mixed Transforming Growth Factor-β/Bone Morphogenetic Protein Smad Signaling Complexes in Tissue Sections

Transforming growth factor-β (TGF-β) is an important regulator of cellular homeostasis and disease pathogenesis. Canonical TGF-β signaling occurs through Smad2/3–Smad4 complexes; however, recent in vitro studies suggest that elevated levels of TGF-β may activate a novel mixed Smad complex (Smad2/3-Smad1/5/9), which is required for some of the pro-oncogenic activities of TGF-β. To determine if mixed Smad complexes are evident in vivo, we developed antibodies that can be used with a proximity ligation assay to detect either canonical or mixed Smad complexes in formalin-fixed paraffin-embedded sections. We demonstrate high expression of mixed Smad complexes in the tissues from mice genetically engineered to express high levels of TGF-β1. Mixed Smad complexes were also prominent in 15–16 day gestation mouse embryos and in breast cancer xenografts, suggesting important roles in embryonic development and tumorigenesis. In contrast, mixed Smad complexes were expressed at extremely low levels in normal adult mouse tissue, where canonical complexes were correspondingly higher. We show that this methodology can be used in archival patient samples and tissue microarrays, and we have developed an algorithm to quantitate the brightfield read-out. These methods will allow quantitative analysis of cell type-specific Smad signaling pathways in physiological and pathological processes.     

Habitat-mediated population limitation in a colonial central-place forager: the sky is not the limit for the black-browed albatross

Animal populations are frequently limited by the availability of food or of habitat. In central-place foragers, the cost of accessing these resources is distance-dependent rather than uniform in space. However, in seabirds, a widely studied exemplar of this paradigm, empirical population models have hitherto ignored this cost. In part, this is because non-independence among colonies makes it difficult to define population units. Here, we model the effects of both resource availability and accessibility on populations of a wide-ranging, pelagic seabird, the black-browed albatross Thalassarche melanophris. Adopting a multi-scale approach, we define regional populations objectively as spatial clusters of colonies. We consider two readily quantifiable proxies of resource availability: the extent of neritic waters (the preferred foraging habitat) and net primary production (NPP). We show that the size of regional albatross populations has a strong dependence, after weighting for accessibility, on habitat availability and to a lesser extent, NPP. Our results provide indirect support for the hypothesis that seabird populations are regulated from the bottom-up by food availability during the breeding season, and also suggest that the spatio-temporal predictability of food may be limiting. Moreover, we demonstrate a straightforward, widely applicable method for estimating resource limitation in populations of central-place foragers.     

Synthesis and pharmacological characterization of a potent,orally active p38 kinase inhibitor

Inhibitors of the MAP kinase p38 provide a novel approach for the treatment of osteoporosis, inflammatory disorders, and cancer. We have identified N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea as a potent and selective p38 kinase inhibitor in biochemical and cellular assays. This compound is orally active in two acute models of cytokine release (TNF-induced IL-6 and LPS-induced TNF) and a chronic model of arthritis (20-day murine collagen-induced arthritis).     

Validity of the bereavement exclusion to major depression: does the empirical evidence support the proposal to eliminate the exclusion in DSM-5?

The DSM-IV major depression "bereavement exclusion" (BE), which recognizes that depressive symptoms are sometimes normal in recently bereaved individuals, is proposed for elimination in DSM-5. Evidence cited for the BE's invalidity comes from two 2007 reviews purporting to show that bereavement-related depression is similar to other depression across various validators, and a 2010 review of subsequent research. We examined whether the 2007 and 2010 reviews and subsequent relevant literature support the BE's invalidity. Findings were: a) studies included in the 2007 reviews sampled bereavement-related depression groups most of whom were not BE-excluded, making them irrelevant for evaluating BE validity; b) three subsequent studies cited by the 2010 review as supporting BE elimination did examine BE-excluded cases but were in fact inconclusive; and c) two more recent articles comparing recurrence of BE-excluded and other major depressive disorder cases both support the BE's validity. We conclude that the claimed evidence for the BE's invalidity does not exist. The evidence in fact supports the BE's validity and its retention in DSM-5 to prevent false positive diagnoses. We suggest some improvements to increase validity and mitigate risk of false negatives.     

Centrosomes have a role in regulating the destruction of cyclin B in early Drosophila embryos

We reported previously that the disappearance of cyclin B at the end of mitosis in early Drosophila embryos starts at centrosomes and spreads into the spindle [1]. Here, we used a novel mutation, centrosome fall off (cfo), to investigate whether centrosomes are required to initiate the disappearance of cyclin B from the spindle. In embryos laid by homozygous cfo mutant mothers, the centrosomes co-ordinately detached from the mitotic spindle during mitosis, and the centrosomeless spindles arrested at anaphase. Cyclin B levels decreased on the detached centrosomes, but not on the arrested centrosomeless spindles, presumably explaining why the spindles arrest in anaphase in these embryos. We found that the expression of a non-degradable cyclin B in embryos also caused an anaphase arrest, but most centrosomes remained attached to the arrested spindles, and non-degradable cyclin B levels remained high on both the centrosomes and spindles. These findings suggest that the disappearance of cyclin B from centrosomes and spindles is closely linked to its destruction, and that a connection between centrosomes and spindles is required for the proper destruction of the spindle-associated cyclin B in early Drosophila embryos. These results may have important implications for the mechanism of the spindle-assembly checkpoint, as they suggest that unattached kinetochores may arrest cells in mitosis, at least in part, by signalling to centrosomes to block the initiation of cyclin B destruction.