Trade Structure, Economic Development and International Transactions in Services

The goal of this paper is to investigate the empirical significance of trade in services for countries with different levels of economic development. Data are presented that characterize the relative importance of trade in services for countries with widely differing per capita income levels, population, and growh experiences.Research Seminar in International Economics, Department of Economics, University of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/100760/1/ECON224.pd

Deficiency of the bone mineralization inhibitor NPP1 protects against obesity and diabetes

The emergence of bone as an endocrine regulator has prompted a re-evaluation of the role of bone mineralization factors in the development of metabolic disease. Ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) controls bone mineralization through the generation of pyrophosphate, and levels of NPP1 are elevated both in dermal fibroblast cultures and muscle of individuals with insulin resistance. We investigated the metabolic phenotype associated with impaired bone metabolism in mice lacking the gene that encodes NPP1 (Enpp1−/− mice). Enpp1−/− mice exhibited mildly improved glucose homeostasis on a normal diet but showed a pronounced resistance to obesity and insulin resistance in response to chronic high-fat feeding. Enpp1−/− mice had increased levels of the insulin-sensitizing bone-derived hormone osteocalcin but unchanged insulin signalling within osteoblasts. A fuller understanding of the pathways of NPP1 could inform the development of novel therapeutic strategies for treating insulin resistance

A nuclear factor 1 binding site mediates the transcriptional activation of a type I collagen promoter by transforming growth factor-beta

Transforming growth factor-beta (TGF-beta) increases the steady-state RNA levels of several fibroblast extracellular matrix proteins. Using DNA transfection, we show that TGF-beta stimulates the activity of the mouse alpha 2(l) collagen promoter 5- to 10-fold in mouse NIH 3T3 and rat osteosarcoma cells. Deletion analysis indicates that a segment of this promoter between -350 and -300, overlapping a nuclear factor 1 (NF1) binding site, is needed for TGF-beta stimulation. A 3 bp substitution mutation abolishing NF1 binding to this site inhibits TGF-beta activation. Insertion of this NF1 binding site 5' to the SV40 early promoter makes the promoter TGF-beta inducible, but the 3 bp substitution does not. Similarly, when the NF1 binding site at the replication origin of adenovirus 2 and 5 is inserted 5' to the SV40 promoter, the promoter responds to TGF-beta. Therefore an NF1 binding site mediates the transcriptional activation of the mouse alpha 2(l) collagen promoter by TGF-beta

Multi-Armed Bandits for Correlated Markovian Environments with Smoothed Reward Feedback

We study a multi-armed bandit problem in a dynamic environment where arm rewards evolve in a correlated fashion according to a Markov chain. Different than much of the work on related problems, in our formulation a learning algorithm does not have access to either a priori information or observations of the state of the Markov chain and only observes smoothed reward feedback following time intervals we refer to as epochs. We demonstrate that existing methods such as UCB and $\varepsilon$-greedy can suffer linear regret in such an environment. Employing mixing-time bounds on Markov chains, we develop algorithms called EpochUCB and EpochGreedy that draw inspiration from the aforementioned methods, yet which admit sublinear regret guarantees for the problem formulation. Our proposed algorithms proceed in epochs in which an arm is played repeatedly for a number of iterations that grows linearly as a function of the number of times an arm has been played in the past. We analyze these algorithms under two types of smoothed reward feedback at the end of each epoch: a reward that is the discount-average of the discounted rewards within an epoch, and a reward that is the time-average of the rewards within an epoch.Comment: Significant revision of prior version including deeper discussion of related work, gap-independent regret bounds, and regret bounds for discounted reward

Identification of novel genes expressed during metanephric induction through single-cell library screening

Identification of novel genes expressed during metanephric induction through single-cell library screening.BackgroundDevelopment of the mature kidney is dependent on a series of inductive events between a portion of the epithelial bud at the distal end of the nephric duct and a neighboring domain of committed metanephric mesenchyme. Several genes have been identified to date that are critical in the inductive process. For example, the deletion of Bmp7 from the mouse genome results in dysgenesis or agenesis of the kidney. These findings suggest that Bmp7 controls the expression of genes important for nephrogenesis, but the identity of these genes has remained largely undetermined.MethodsSingle cells were isolated from mouse metanephric mesenchyme during the time of induction (between E11.0 and E11.5) and cDNA libraries constructed from induced and uninduced tissue. Subtractive hybridization was performed to isolate genes that were expressed during E11.5 but not E11.0.ResultsUsing this approach, we identified eight previously known genes, three of which were known to be involved in metanephric induction, thus validating our approach, and nine novel genes. Eight of these genes were completely novel, whereas one was similar to a member of the yeast Anaphase Promoting Complex.ConclusionsThrough subtractive hybridization of mouse E11.0 and E11.5 metanephric mesenchyme single-cell cDNA libraries, we have identified novel genes that are candidates for involvement in nephrogenesis through their up-regulation during the inductive process

Multiple verification in computational modeling of bone pathologies

We introduce a model checking approach to diagnose the emerging of bone pathologies. The implementation of a new model of bone remodeling in PRISM has led to an interesting characterization of osteoporosis as a defective bone remodeling dynamics with respect to other bone pathologies. Our approach allows to derive three types of model checking-based diagnostic estimators. The first diagnostic measure focuses on the level of bone mineral density, which is currently used in medical practice. In addition, we have introduced a novel diagnostic estimator which uses the full patient clinical record, here simulated using the modeling framework. This estimator detects rapid (months) negative changes in bone mineral density. Independently of the actual bone mineral density, when the decrease occurs rapidly it is important to alarm the patient and monitor him/her more closely to detect insurgence of other bone co-morbidities. A third estimator takes into account the variance of the bone density, which could address the investigation of metabolic syndromes, diabetes and cancer. Our implementation could make use of different logical combinations of these statistical estimators and could incorporate other biomarkers for other systemic co-morbidities (for example diabetes and thalassemia). We are delighted to report that the combination of stochastic modeling with formal methods motivate new diagnostic framework for complex pathologies. In particular our approach takes into consideration important properties of biosystems such as multiscale and self-adaptiveness. The multi-diagnosis could be further expanded, inching towards the complexity of human diseases. Finally, we briefly introduce self-adaptiveness in formal methods which is a key property in the regulative mechanisms of biological systems and well known in other mathematical and engineering areas.Comment: In Proceedings CompMod 2011, arXiv:1109.104

Inactivation of the Osteopontin Gene Enhances Vascular Calcification of Matrix Gla Protein–deficient Mice: Evidence for Osteopontin as an Inducible Inhibitor of Vascular Calcification In Vivo

Osteopontin (OPN) is abundantly expressed in human calcified arteries. To examine the role of OPN in vascular calcification, OPN mutant mice were crossed with matrix Gla protein (MGP) mutant mice. Mice deficient in MGP alone (MGP−/− OPN+/+) showed calcification of their arteries as early as 2 weeks (wk) after birth (0.33 ± 0.01 mmol/g dry weight), and the expression of OPN in the calcified arteries was greatly up-regulated compared with MGP wild-types. OPN accumulated adjacent to the mineral and colocalized to surrounding cells in the calcified media. Cells synthesizing OPN lacked smooth muscle (SM) lineage markers, SM α-actin and SM22α. However, most of them were not macrophages. Importantly, mice deficient in both MGP and OPN had twice as much arterial calcification as MGP−/− OPN+/+ at 2 wk, and over 3 times as much at 4 wk, suggesting an inhibitory effect of OPN in vascular calcification. Moreover, these mice died significantly earlier (4.4 ± 0.2 wk) than MGP−/− OPN+/+ counterparts (6.6 ± 1.0 wk). The cause of death in these animals was found to be vascular rupture followed by hemorrhage, most likely due to enhanced calcification. These studies are the first to demonstrate a role for OPN as an inducible inhibitor of ectopic calcification in vivo

A Twist Code Determines the Onset of Osteoblast Differentiation

AbstractRunx2 is necessary and sufficient for osteoblast differentiation, yet its expression precedes the appearance of osteoblasts by 4 days. Here we show that Twist proteins transiently inhibit Runx2 function during skeletogenesis. Twist-1 and -2 are expressed in Runx2-expressing cells throughout the skeleton early during development, and osteoblast-specific gene expression occurs only after their expression decreases. Double heterozygotes for Twist-1 and Runx2 deletion have none of the skull abnormalities observed in Runx2+/− mice, a Twist-2 null background rescues the clavicle phenotype of Runx2+/− mice, and Twist-1 or -2 deficiency leads to premature osteoblast differentiation. Furthermore, Twist-1 overexpression inhibits osteoblast differentiation without affecting Runx2 expression. Twist proteins' antiosteogenic function is mediated by a novel domain, the Twist box, which interacts with the Runx2 DNA binding domain to inhibit its function. In vivo mutagenesis confirms the antiosteogenic function of the Twist box. Thus, relief of inhibition by Twist proteins is a mandatory event precluding osteoblast differentiation

ProtoNet 6.0: organizing 10 million protein sequences in a compact hierarchical family tree

ProtoNet 6.0 (http://www.protonet.cs.huji.ac.il) is a data structure of protein families that cover the protein sequence space. These families are generated through an unsupervised bottom–up clustering algorithm. This algorithm organizes large sets of proteins in a hierarchical tree that yields high-quality protein families. The 2012 ProtoNet (Version 6.0) tree includes over 9 million proteins of which 5.5% come from UniProtKB/SwissProt and the rest from UniProtKB/TrEMBL. The hierarchical tree structure is based on an all-against-all comparison of 2.5 million representatives of UniRef50. Rigorous annotation-based quality tests prune the tree to most informative 162 088 clusters. Every high-quality cluster is assigned a ProtoName that reflects the most significant annotations of its proteins. These annotations are dominated by GO terms, UniProt/Swiss-Prot keywords and InterPro. ProtoNet 6.0 operates in a default mode. When used in the advanced mode, this data structure offers the user a view of the family tree at any desired level of resolution. Systematic comparisons with previous versions of ProtoNet are carried out. They show how our view of protein families evolves, as larger parts of the sequence space become known. ProtoNet 6.0 provides numerous tools to navigate the hierarchy of clusters