Trade costs, 1870–2000

What has driven trade booms and trade busts in the past century and a half? Was it changes in global output or in the costs of international trade? To address this question, we derive a micro-founded measure of aggregate bilateral trade costs based on a standard model of trade in differentiated goods. These trade costs gauge the difference between observed bilateral trade and frictionless trade in terms of an implied markup on retail prices of foreign goods. Thus, we are able to estimate the combined magnitude of tariffs, transportation costs, and all other macroeconomic frictions that impede international trade but that are inherently difficult to observe. We use this measure to examine the growth of global trade between 1870 and 1913, its retreat from 1921 to 1939, and its subsequent rise from 1950 to 2000. We find that trade cost declines explain roughly 55 percent of the pre–World War I trade boom and 33 percent of the post–World War II trade boom, while a precipitous rise in trade costs explains the entire interwar trade bust

Real inequality in Europe since 1500

Introducing a concept of real, as opposed to nominal, inequality of income or wealth suggests some historical reinterpretations, buttressed by a closer look at consumption by the rich. The purchasing powers of different income classes depend on how relative prices move. Relative prices affected real inequality more strongly in earlier centuries than in the twentieth. Between 1500 and about 1800, staple food and fuels became dearer, while luxury goods, especially servants, became cheaper, greatly widening the inequality of lifestyles. Peace, industrialization, and globalization reversed this inegalitarian price effect in the nineteenth century, at least for England

Prices and Real Inequality in Europe since 1500

Introducing a concept of real, as opposed to nominal, inequality of income or wealth suggests some historical reinterpretations, buttressed by a closer look at consumption by the rich. The purchasing powers of different income classes depend on how relative prices move. The influence of relative prices on real inequality was greater in the sixteenth through nineteenth centuries than in the twentieth. Between 1500 and about 1800, staple food and fuels became dearer, while luxury goods, especially servants, became cheaper, greatly widening the inequality of lifestyles. Peace, industrialization, and globalization reversed this inegalitarian price effect in the nineteenth century

Metal contamination at a wood preservation site : characterisation and experimental studies on remediation

http://www.elsevier.com/locate/issn/00489697The aim of this investigation was to determine the occurrence of As, Cu, Cr and Zn in the soil at an abandoned wood preservation unit and to examine some possible extractants for the contaminants in the soil.The mean As content of the contaminated surface soils (0–10 cm) was 186 mg kgy1, where as the mean concentrations of Cu, Cr and Zn in soils from the contaminated area were 26, 29 and 91 mg kgy1, respectively.The elevated As content in the mineral soils is related to adsorption of inorganic As phases in the fine grained fractions, which are characterised by large surface area and high positive surface charge under the current acidic conditions.Cu and Cr were found to be rather mobile, which is reflected in their lower abundance in soils and significant accumulation in sediments in the drainage leaving the area.The fine fraction of the soil (-0.125 mm) has an average metal content increased by nearly 34% as compared to the -2-mm fraction conventionally used for the analysis and assessment of soil contamination.The -2-mm fraction constitutes approximately 65% of the total weight while the fine fraction (- 0.125 mm) constitutes approximately 10%.These facts, taken together, are essential for the choice of remediation measures.Oxalate solutions have been tested as extractants for soil remediation. Dark acid oxalate extraction dissolves the amorphous Al- and Fe-oxides and hydroxides and mobilises the adsorbed inorganic As species.Oxalate also acts as a ligand for the cationic heavy metals, releasing them from exchangeable sites.With a three-step sequential leaching, up to 98–99% of the metals could be removed.At lower concentrations and higher pH, the leaching decreased to approximately 70%

Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype

We demonstrate CRISPR-Cas9–mediated correction of a Fah mutation in hepatocytes in a mouse model of the human disease hereditary tyrosinemia. Delivery of components of the CRISPR-Cas9 system by hydrodynamic injection resulted in initial expression of the wild-type Fah protein in ~1/250 liver cells. Expansion of Fah-positive hepatocytes rescued the body weight loss phenotype. Our study indicates that CRISPR-Cas9–mediated genome editing is possible in adult animals and has potential for correction of human genetic diseases.National Cancer Institute (U.S.) (Grant 2-PO1-CA42063)National Cancer Institute (U.S.) (Core Grant P30-CA14051)National Institutes of Health (U.S.) (Grant R01-CA133404)David H. Koch Institute for Integrative Cancer Research at MIT (Marie D. and Pierre Casimir-Lambert Fund)National Institutes of Health (U.S.) (Centers for Cancer Nanotechnology Excellence 5-U54-CA151884-04)MIT-Harvard Center of Cancer Nanotechnology ExcellenceNational Institutes of Health (U.S.) (1K99CA169512

Dicer loss and recovery induce an oncogenic switch driven by transcriptional activation of the oncofetal Imp1–3 family

MicroRNAs(miRNAs) are post-transcriptional regulators of gene expressioncritical for organismal viability. Changes inmiRNAactivity arecommonin cancer, buthowthese changes relate to subsequent alterations in transcription and the process of tumorigenesis is not well understood. Here, we report a deep transcriptional, oncogenic network regulated bymiRNAs. Wepresent analysis of the gene expression and phenotypic changes associated with globalmiRNA restoration in miRNA-deficient fibroblasts. This analysis uncovers a miRNA-repressed network containing oncofetal genesImp1, Imp2, and Imp3(Imp1–3) that is up-regulated primarily transcriptionally > 100-fold uponDicer loss and is resistant to resilencing by complete restoration of miRNA activity. This Dicer-resistant epigenetic switch confers tumorigenicity to these cells. Let-7 targets Imp1–3 are required for this tumorigenicity and feed back to reinforce and sustain expression of the oncogenic network. Together, these Dicer-resistant genes constitute an mRNA expression signature that is present in numerous human cancers and is associated with poor survival.United States. Public Health Service (Grant R01CA133404)National Cancer Institute (U.S.) (Grant P01CA42063)Marie D. and Pierre Casimir-Lamber

LincRNA-p21 Activates p21 In cis to Promote Polycomb Target Gene Expression and to Enforce the G1/S Checkpoint

The p53-regulated long noncoding RNA lincRNA-p21 has been proposed to act in trans via several mechanisms ranging from repressing genes in the p53 transcriptional network to regulating mRNA translation and protein stability. To further examine lincRNA-p21 function, we generated a conditional knockout mouse model. We find that lincRNA-p21 predominantly functions in cis to activate expression of its neighboring gene, p21. Mechanistically, we show that lincRNA-p21 acts in concert with hnRNP-K as a coactivator for p53-dependent p21 transcription. Additional phenotypes of lincRNA-p21 deficiency could be attributed to diminished p21 levels, including deregulated expression and altered chromatin state of some Polycomb target genes, a defective G1/S checkpoint, increased proliferation rates, and enhanced reprogramming efficiency. These findings indicate that lincRNA-p21 affects global gene expression and influences the p53 tumor suppressor pathway by acting in cis as a locus-restricted coactivator for p53-mediated p21 expression.National Institutes of Health (U.S.)Howard Hughes Medical InstituteLudwig Center for Molecular OncologyDamon Runyon Cancer Research Foundatio

Ozone Induces Nerve Growth Factor Release from Rat Tracheal Epithelial Cells during an Early Postnatal Critical Period

Ozone, one of the major air pollutants in urban areas, produces epithelial cell injury and inflammation in the airways upon exposure. Previous studies have shown that ozone exposure leads to increased substance P (SP) expression in nerves innervating the smooth muscle in the extrapulmonary airway. Nerve growth factor (NGF), a neurotrophin, is known to increase SP expression. To determine the effect of ozone exposure on the release of NGF, a cell culture technique was developed for studying a homogenous rat tracheal epithelial cell population for analysis of NGF mRNA and protein expression. Furthermore, to determine if this effect is age-dependent, a critical period exposure paradigm was used. Rat pups exposed to ozone at postnatal day (PD) 6 showed an increase in the level of NGF mRNA while pups exposed after PD 6 showed no change in NGF expression. When rat pups exposed to ozone on PD 6 were reexposed at a later date, an increase in NGF mRNA was observed. These data suggest that exposure to ozone has an effect on NGF expression in early postnatal life and that this exposure might play a role in ozone sensitivity later in life

Stage-specific sensitivity to p53 restoration during lung cancer progression

2011 May 25Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumour suppressor pathways. Personalized cancer therapy that is based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumour suppressors and activation of oncogenes is essential in advanced cancers. Mutations in the p53 tumour-suppressor pathway are common in human cancer and significant efforts towards pharmaceutical reactivation of defective p53 pathways are underway1, 2, 3. Here we show that restoration of p53 in established murine lung tumours leads to significant but incomplete tumour cell loss specifically in malignant adenocarcinomas, but not in adenomas. We define amplification of MAPK signalling as a critical determinant of malignant progression and also a stimulator of Arf tumour-suppressor expression. The response to p53 restoration in this context is critically dependent on the expression of Arf. We propose that p53 not only limits malignant progression by suppressing the acquisition of alterations that lead to tumour progression, but also, in the context of p53 restoration, responds to increased oncogenic signalling to mediate tumour regression. Our observations also underscore that the p53 pathway is not engaged by low levels of oncogene activity that are sufficient for early stages of lung tumour development. These data suggest that restoration of pathways important in tumour progression, as opposed to initiation, may lead to incomplete tumour regression due to the stage-heterogeneity of tumour cell populations.National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051)American Cancer Society (New England Area Fellow)Leukemia & Lymphoma Society of America (Fellow)Massachusetts Institute of Technology. Undergraduate Research Program (John Reed Fund)Damon Runyon Cancer Research Foundation (Merck Fellow)Genentech, Inc. (Postdoctoral Fellow)Howard Hughes Medical Institut

Recombinase-based conditional and reversible gene regulation via XTR alleles

Synthetic biological tools that enable precise regulation of gene function within in vivo systems have enormous potential to discern gene function in diverse physiological settings. Here we report the development and characterization of a synthetic gene switch that, when targeted in the mouse germline, enables conditional inactivation, reports gene expression and allows inducible restoration of the targeted gene. Gene inactivation and reporter expression is achieved through Cre-mediated stable inversion of an integrated gene-trap reporter, whereas inducible gene restoration is afforded by Flp-dependent deletion of the inverted gene trap. We validate our approach by targeting the p53 and Rb genes and establishing cell line and in vivo cancer model systems, to study the impact of p53 or Rb inactivation and restoration. We term this allele system XTR, to denote each of the allelic states and the associated expression patterns of the targeted gene: eXpressed (XTR), Trapped (TR) and Restored (R)