Case-control study of multiple myeloma and farming.

A previous case-control study which utilised the occupational information available on the New Zealand Cancer Registry found an increased risk of multiple myeloma in agricultural workers consistent with previous findings in the United States. The findings are now presented for the second phase of the study which involved interviewing 76 cases of multiple myeloma (who had been included in the previous study) together with 315 controls with other types of cancer. The previous finding on an excess of farmers in the case group was confirmed by the interview data (odds ratio = 1.7, 95% confidence limits 1.0-2.9, P = 0.04). There were no significant differences between cases and controls regarding potential exposure to phenoxy herbicides or chlorophenols. There were also no significant differences regarding activities involving potential exposure to other agricultural chemicals, although the odds ratio for fencing work, which may involve exposure to arsenic and sodium pentachlorophenate, was 1.6 (95% confidence limits 0.9-2.7, P = 0.11). The odds ratios were significantly elevated for sheep farming (odds ratio = 1.9, 95% confidence limits 1.0-3.6, P = 0.04) and exposure to beef cattle (odds ratio = 1.7, 95% confidence limits 1.0-2.9, P = 0.05). The odds ratio was also elevated for persons reporting a history of hay fever (odds ratio = 1.9, 95% confidence limits 1.0-3.5, P = 0.05). Overall, these findings suggest that the search for the causes of elevated mortality in farmers from multiple myeloma should be directed to potential causes other than pesticide exposure

Emission-Line Galaxy Surveys as Probes of the Spatial Distribution of Dwarf Galaxies. I. The University of Michigan Survey

Objective-prism surveys which select galaxies on the basis of line-emission are extremely effective at detecting low-luminosity galaxies and constitute some of the deepest available samples of dwarfs. In this study, we confirm that emission-line galaxies (ELGs) in the University of Michigan (UM) objective-prism survey (MacAlpine et al. 1977-1981) are reliable tracers of large-scale structure, and utilize the depth of the samples to examine the spatial distribution of low-luminosity (M$_{B} >$ -18.0) dwarfs relative to higher luminosity giant galaxies (M$_{B} \leq$ -18.0) in the Updated Zwicky Catalogue (Falco et al. 1999). New spectroscopic data are presented for 26 UM survey objects. We analyze the relative clustering properties of the overall starbursting ELG and normal galaxy populations, using nearest neighbor and correlation function statistics. This allows us to determine whether the activity in ELGs is primarily caused by gravitational interactions. We conclude that galaxy-galaxy encounters are not the sole cause of activity in ELGs since ELGs tend to be more isolated and are more often found in the voids when compared to their normal galaxy counterparts. Furthermore, statistical analyses performed on low-luminosity dwarf ELGs show that the dwarfs are less clustered when compared to their non-active giant neighbors. The UM dwarf samples have greater percentages of nearest neighbor separations at large values and lower correlation function amplitudes relative to the UZC giant galaxy samples. These results are consistent with the expectations of galaxy biasing.Comment: 17 pages, 4 tables, 10 figures. Accepted for publication in the Ap

Exploiting transient protein states for the design of small-molecule stabilizers of mutant p53

The destabilizing p53 cancer mutation Y220C creates an extended crevice on the surface of the protein that can be targeted by small-molecule stabilizers. Here, we identify different classes of small molecules that bind to this crevice and determine their binding modes by X-ray crystallography. These structures reveal two major conformational states of the pocket and a cryptic, transiently open hydrophobic subpocket that is modulated by Cys220. In one instance, specifically targeting this transient protein state by a pyrrole moiety resulted in a 40-fold increase in binding affinity. Molecular dynamics simulations showed that both open and closed states of this subsite were populated at comparable frequencies along the trajectories. Our data extend the framework for the design of high-affinity Y220C mutant binders for use in personalized anticancer therapy and, more generally, highlight the importance of implementing protein dynamics and hydration patterns in the drug-discovery process

Serum kynurenic acid is reduced in affective psychosis

A subgroup of individuals with mood and psychotic disorders shows evidence of inflammation that leads to activation of the kynurenine pathway and the increased production of neuroactive kynurenine metabolites. Depression is hypothesized to be causally associated with an imbalance in the kynurenine pathway, with an increased metabolism down the 3-hydroxykynurenine (3HK) branch of the pathway leading to increased levels of the neurotoxic metabolite, quinolinic acid (QA), which is a putative Nmethyl- D-aspartate (NMDA) receptor agonist. In contrast, schizophrenia and psychosis are hypothesized to arise from increased metabolism of the NMDA receptor antagonist, kynurenic acid (KynA), leading to hypofunction of GABAergic interneurons, the disinhibition of pyramidal neurons and striatal hyperdopaminergia. Here we present results that challenge the model of excess KynA production in affective psychosis. After rigorous control of potential confounders and multiple testing we find significant reductions in serum KynA and/or KynA/QA in acutely ill inpatients with major depressive disorder (N = 35), bipolar disorder (N = 53) and schizoaffective disorder (N = 40) versus healthy controls (N = 92). No significant difference was found between acutely ill inpatients with schizophrenia (n = 21) and healthy controls. Further, a post hoc comparison of patients divided into the categories of non-psychotic affective disorder, affective psychosis and psychotic disorder (non-affective) showed that the greatest decrease in KynA was in the affective psychosis group relative to the other diagnostic groups. Our results are consistent with reports of elevations in proinflammatory cytokines in psychosis, and preclinical work showing that inflammation upregulates the enzyme, kynurenine mono-oxygenase (KMO), which converts kynurenine into 3-hydroxykynurenine and quinolinic acid

ALMA chemical survey of disk-outflow sources in Taurus (ALMA-DOT) III: The interplay between gas and dust in the protoplanetary disk of DG Tau

Planets form in protoplanetary disks and inherit their chemical composition. It is therefore crucial to understand the disks molecular content. We aim to characterize the distribution and abundance of molecules in the disk of DG Tau. In the context of the ALMA chemical survey of Disk-Outflow sources in Taurus (ALMA-DOT) we analyse ALMA observations of the disk of DG Tau in H2CO 3(1,2)-2(1,1), CS 5-4, and CN 2-1 at ~0.15", i.e. ~18 au at 121 pc. H2CO and CS originate from a disk ring at the edge of the 1.3mm dust continuum, with CS probing an outer disk region with respect to H2CO (peaking at ~70 and ~60 au, respectively). CN originates from an outermost disk/envelope region peaking at ~80 au. H2CO is dominated by disk emission, while CS probes also two streams of material possibly accreting onto the disk with a peak of emission where the stream connects to the disk. The ring- and disk-height- averaged column densities are ~2.4-8.6e13 cm-2 (H2CO), ~1.7-2.5e13 cm-2 (CS), and ~1.9-4.7e13 cm-2 (CN). Unsharp masking reveals a ring of enhanced dust emission at ~40 au, i.e. just outside the CO snowline (~30 au). CS and H2CO emissions are co-spatial suggesting that they are chemically linked. The observed rings of molecular emission at the edge of the 1.3mm continuum may be due to dust opacity effects and/or continnum over-subtraction in the inner disk; as well as to increased UV penetration and/or temperature inversion at the edge of the mm-dust which would cause an enhanced gas-phase formation and desorption of these molecules. Moreover, H2CO and CS originate from outside the ring of enhanced dust emission, which also coincides with a change of the linear polarization at 0.87mm. This suggests that outside the CO snowline there could be a change of the dust properties which would reflect in the increase of the intensity (and change of polarization) of continuum, and of molecular emission.Comment: 13 pages, accepted for publication on A&

Statistical Model of Shape Moments with Active Contour Evolution for Shape Detection and Segmentation

This paper describes a novel method for shape representation and robust image segmentation. The proposed method combines two well known methodologies, namely, statistical shape models and active contours implemented in level set framework. The shape detection is achieved by maximizing a posterior function that consists of a prior shape probability model and image likelihood function conditioned on shapes. The statistical shape model is built as a result of a learning process based on nonparametric probability estimation in a PCA reduced feature space formed by the Legendre moments of training silhouette images. A greedy strategy is applied to optimize the proposed cost function by iteratively evolving an implicit active contour in the image space and subsequent constrained optimization of the evolved shape in the reduced shape feature space. Experimental results presented in the paper demonstrate that the proposed method, contrary to many other active contour segmentation methods, is highly resilient to severe random and structural noise that could be present in the data