Fat City: The Relationship Between Urban Sprawl and Obesity

We study the relationship between urban sprawl and obesity. Using data that tracks individuals over time, we find no evidence that urban sprawl causes obesity. We show that previous findings of a positive relationship most likely reflect a failure to properly control for the fact the individuals who are more likely to be obese choose to live in more sprawling neighborhoods. Our results indicate that current interest in changing the built environment to counter the rise in obesity is misguided.urban sprawl; obesity; selection effects

Causes of sprawl: A portrait from space

We study the extent to which US urban development is sprawling and consider what determines differences in sprawl across space. Using remote-sensing data to track the evolution of land use on a grid of 8.7 billion 30x30 metre cells, we measure sprawl as the amount of undeveloped land surrounding an average urban dwelling. On this measure, while the extent of sprawl remained roughly unchanged between 1976 and 1992, it varied dramatically across metropolitan areas. Ground water availability, temperate climate, rugged terrain, decentralized employment, early public transport infrastructure, uncertainty about metropolitan growth, and unincorporated land in the urban fringe all increase sprawl.urban sprawl; land development; remote sensing

Attenuation of hedgehog/GLI signaling by NT1721 extends survival in pancreatic cancer.

BackgroundPancreatic cancer is one of the most lethal malignancies due to frequent late diagnosis, aggressive tumor growth and metastasis formation. Continuously raising incidence rates of pancreatic cancer and a lack of significant improvement in survival rates over the past 30 years highlight the need for new therapeutic agents. Thus, new therapeutic agents and strategies are urgently needed to improve the outcome for patients with pancreatic cancer. Here, we evaluated the anti-tumor activity of a new natural product-based epidithiodiketopiperazine, NT1721, against pancreatic cancer.MethodsWe characterized the anticancer efficacy of NT1721 in multiple pancreatic cancer cell lines in vitro and in two orthotopic models. We also compared the effects of NT1721 to clinically used hedgehog inhibitors and the standard-of-care drug, gemcitabine. The effect of NT1721 on hedgehog/GLI signaling was assessed by determining the expression of GLI and GLI target genes both in vitro and in vivo.ResultsNT1721 displayed IC50 values in the submicromolar range in multiple pancreatic cancer cell lines, while largely sparing normal pancreatic epithelial cells. NT1721 attenuated hedgehog/GLI signaling through downregulation of GLI1/2 transcription factors and their downstream target genes, which reduced cell proliferation and invasion in vitro and significantly decreased tumor growth and liver metastasis in two preclinical orthotopic mouse models of pancreatic cancer. Importantly, treatment with NT1721 significantly improved survival times of mice with pancreatic cancer compared to the standard-of-care drug, gemcitabine.ConclusionsFavorable therapeutics properties, i.e. 10-fold lower IC50 values than clinically used hedgehog inhibitors (vismodegib, erismodegib), a 90% reduction in liver metastasis and significantly better survival times compared to the standard-of-care drug, gemcitabine, provide a rational for testing NT1721 in the clinic either as a single agent or possibly in combination with gemcitabine or other therapeutic agents in PDAC patients overexpressing GLI1/2. This could potentially result in promising new treatment options for patients suffering from this devastating disease

Majorana Electroformed Copper Mechanical Analysis

The MAJORANA DEMONSTRATOR is a large array of ultra-low background high-purity germanium detectors, enriched in 76Ge, designed to search for zero-neutrino double-beta decay. The DEMONSTRATOR will utilize ultra high purity electroformed copper for a variety of detector components and shielding. A preliminary mechanical evaluation was performed on the Majorana prototype electroformed copper material. Several samples were removed from a variety of positions on the mandrel. Tensile testing, optical metallography, scanning electron microscopy, and hardness testing were conducted to evaluate mechanical response. Analyses carried out on the Majorana prototype copper to this point show consistent mechanical response from a variety of test locations. Evaluation shows the copper meets or exceeds the design specifications

Impact of in vitro assembly defects on in vivo function of the phage P22 portal

AbstractThe podovirus P22, which infects O-antigen strains of Salmonella, incorporates a dsDNA translocating channel (portal dodecamer) at a unique vertex of the icosahedral capsid. The portal subunit (gp1, 82.7 kDa) exhibits multiple S–H⋯X hydrogen bonding states for cysteines 153, 173, 283 and 516 and these interactions are strongly perturbed by portal ring formation. Here, we analyze in vivo activities of wild type (wt) and Cys→Ser mutant portals, demonstrate that in vivo activity is correlated with in vitro assembly kinetics, and suggest mechanistic bases for the observed assembly defects. The C283S portal protein, which assembles into rings at about half the rate of wt, exhibits significantly diminished infectivity (∼50% of wt) and manifests its defect prior to DNA packaging, most likely at the stage of procapsid assembly. Conversely, the C516S mutant, which assembles at twice the rate of wt, is more severely deficient in vivo (∼20% of wt) and manifests its defect subsequent to capsid maturation and DNA packaging. Both C153S and C173S portals function at levels close to wt. The results suggest that C283S and C516S mutations may be exploited for improved characterization of the folding and assembly pathway of P22 portal protein

Stereocontrolled enantioselective total synthesis of the [2+2] quadrigemine alkaloids.

A unified strategy for enantioselective total synthesis of all stereoisomers of the 2+2 family of quadrigemine alkaloids is reported. In this approach, two enantioselective intramolecular Heck reactions are carried out at the same time on precursors fashioned in four steps from either meso- or (+)-chimonanthine to form the two critical quaternary carbons of the peripheral cyclotryptamine rings of these products. Useful levels of catalyst control are realized in either desymmetrizing a meso precursor or controlling diastereoselectivity in elaborating C2-symmetic intermediates. None of the synthetic quadrigemines are identical with alkaloids isolated previously and referred to as quadrigemines A and E. In addition, we report improvements in our previous total syntheses of (+)- or (-)-quadrigemine C that shortened the synthetic sequence to 10 steps and provided these products in 2.2% overall yield from tryptamine

An investigation of the cognitive basis for the selectivity of age-related memory impairment

Older adults have been found to have a selective impairment in certain types of episodic memory, although other types of memory are generally preserved. The goal of this research is to determine whether the selective age-related memory deficit is best explained by an impairment in perceptual processing, an impairment in the formation of associations between items and their contexts, or an impairment in controlled processing, which is presumed to be required for recollection. Three behavioral experiments were conducted which attempted to evaluate the relative merits of each of these three accounts of age-related memory impairment. To allow for a more meaningful comparison of the data from each experiment, the same participants completed all three behavioral experiments. In addition to the behavioral experiments, an event-related potential (ERP) experiment was conducted to provide further information regarding perceptual processing differences between older and younger adults. When relying solely on perceptual information, rather than semantic and perceptual information, older adults' memory performance was especially poor for perceptually impoverished stimuli (words), but less so for perceptually rich stimuli (pictures). Unlike young adults, older adults did not benefit from repeated presentations of pair information, suggesting that older adults do not form associative links between to-be-remembered stimuli. However, older adults did not show a recollection-specific impairment as the controlled processing hypothesis would have predicted. Older adults were equivalently impaired for both recollection and familiarity measures, suggesting that controlled processing is not specifically impaired in older adults. ERPs for older adults had much more individual variability than for young adults and the differences in ERP waveforms between age groups were observed more consistently in word conditions than in picture conditions, which is consistent with the behavioral results. Additionally, older adult ERPs to pictures were most similar to young adults, in accordance with the behavioral results. The behavioral data support the hypothesis that there is a deficit in perceptual processing which may help explain age-related memory impairments. The ERP data, though limited, lends some support to this explanation as it reveals perceptual and semantic processing differences between young and older adults. An associative deficit may be an additional source of memory impairment