The Macroeconomic Implications of a Key Currency

What are the macroeconomic consequences of the dominant role of the dollar in the international monetary system? Here, we present a calibrated two country model in which exports are invoiced in the key currency, and government bonds denominated in the key currency are held internationally to facilitate trade. Domestic government bonds and money are held in each country to facilitate domestic transactions. Our model generates deviations from uncovered interest parity that are as volatile as some empirical estimates, but much too small by others. Our model also speaks to some other empirical anomalies, such as the Backus - Smith puzzle. Shocks affecting asset supplies -- such as bond financed tax cuts, and open market operations -- have large effects in our model because they generate non-Ricardian changes in household wealth. Generally, shocks emanating from the key currency country do more to destabilize the world economy than equal sized shocks coming from the other country. Similarly, monetary and fiscal policy innovations in the key currency country are more potent than those in the other country. On the other hand, the key currency country is more vulnerable to financial market turbulence, such as a sell off of key currency bonds, which can lower consumption dramatically.

Site-to-site interdomain communication may mediate different loss-of-function mechanisms in a cancer-associated NQO1 polymorphism

Disease associated genetic variations often cause intracellular enzyme inactivation, dysregulation and instability. However, allosteric communication of mutational effects to distant functional sites leading to loss-of-function remains poorly understood. We characterize here interdomain site-to-site communication by which a common cancer-associated single nucleotide polymorphism (c.C609T/p.P187S) reduces the activity and stability in vivo of NAD(P)H:quinone oxidoreductase 1 (NQO1). NQO1 is a FAD-dependent, two-domain multifunctional stress protein acting as a Phase II enzyme, activating cancer pro-drugs and stabilizing p53 and p73a oncosuppressors. We show that p.P187S causes structural and dynamic changes communicated to functional sites far from the mutated site, affecting the FAD binding site located at the N-terminal domain (NTD) and accelerating proteasomal degradation through dynamic effects on the C-terminal domain (CTD). Structural protein:protein interaction studies reveal that the cancer-associated polymorphism does not abolish the interaction with p73a, indicating that oncosuppressor destabilization largely mirrors the low intracellular stability of p.P187S. In conclusion, we show how a single disease associated amino acid change may allosterically perturb several functional sites in an oligomeric and multidomain protein. These results have important implications for the understanding of loss-of-function genetic diseases and the identification of novel structural hot spots as targets for pharmacological intervention

The genetic basis for adaptation of model-designed syntrophic co-cultures.

Understanding the fundamental characteristics of microbial communities could have far reaching implications for human health and applied biotechnology. Despite this, much is still unknown regarding the genetic basis and evolutionary strategies underlying the formation of viable synthetic communities. By pairing auxotrophic mutants in co-culture, it has been demonstrated that viable nascent E. coli communities can be established where the mutant strains are metabolically coupled. A novel algorithm, OptAux, was constructed to design 61 unique multi-knockout E. coli auxotrophic strains that require significant metabolite uptake to grow. These predicted knockouts included a diverse set of novel non-specific auxotrophs that result from inhibition of major biosynthetic subsystems. Three OptAux predicted non-specific auxotrophic strains-with diverse metabolic deficiencies-were co-cultured with an L-histidine auxotroph and optimized via adaptive laboratory evolution (ALE). Time-course sequencing revealed the genetic changes employed by each strain to achieve higher community growth rates and provided insight into mechanisms for adapting to the syntrophic niche. A community model of metabolism and gene expression was utilized to predict the relative community composition and fundamental characteristics of the evolved communities. This work presents new insight into the genetic strategies underlying viable nascent community formation and a cutting-edge computational method to elucidate metabolic changes that empower the creation of cooperative communities

Structural basis of the pleiotropic and specific phenotypic consequences of missense mutations in the multifunctional NAD(P)H:quinone oxidoreductase 1 and their pharmacological rescue

The multifunctional nature of human flavoproteins is critically linked to their ability to populate multiple conformational states. Ligand binding, post-translational modifications and disease-associated mutations can reshape this functional landscape, although the structure-function relationships of these effects are not well understood. Herein, we characterized the structural and functional consequences of two mutations (the cancer-associated P187S and the phosphomimetic S82D) on different ligation states which are relevant to flavin binding, intracellular stability and catalysis of the disease-associated NQO1 flavoprotein. We found that these mutations affected the stability locally and their effects propagated differently through the protein structure depending both on the nature of the mutation and the ligand bound, showing directional preference from the mutated site and leading to specific phenotypic manifestations in different functional traits (FAD binding, catalysis and inhibition, intracellular stability and pharmacological response to ligands). Our study thus supports that pleitropic effects of disease-causing mutations and phosphorylation events on human flavoproteins may be caused by long-range structural propagation of stability effects to different functional sites that depend on the ligation-state and site-specific perturbations. Our approach can be of general application to investigate these pleiotropic effects at the flavoproteome scale in the absence of high-resolution structural models. © 202

Drug-eluting wound dressings having sustained release of antimicrobial compounds

Wound healing is a complex and costly public health problem that should be timely addressed to achieve a rapid and adequate tissue repair avoiding or even eliminating potential pathogenic infection. Chronic infected non-healing wounds represent a serious concern for health care systems. Efficient wound dressings with tailored therapy having the best response and highest safety margin for the management of chronic non-healing wounds are still needed. The use of novel wound dressing materials has emerged as a promising tool to fulfil these requirements. In this work, asymmetric electrospun polycaprolactone (PCL)-based nanofibers (NFs) were decorated with electrosprayed poly(lactic-co-glycolic acid) microparticles (PLGA MPs) containing the natural antibacterial compound thymol (THY) in order to obtain drug eluting antimicrobial dressings having sustained release. The synthesized dressings successfully inhibited the in vitro growth of Staphylococcus aureus ATCC 25923, showing also at the same doses cytocompatibility on human dermal fibroblasts and keratinocyte cultures after treatment for 24 h, which was not observed when using free thymol. An in vivo murine excisional wound splinting model, followed by the experimental infection of the wounds with S. aureus and their treatment with the synthesized dressings, pointed to the reduction of the bacterial load in wounds after 7 days, though the total elimination of the infection was not reached. The findings indicated the relevance of the direct contact between the dressings and the bacteria, highlighting the need to tune their design considering the wound surface and the nature of the antimicrobial cargo contained

Specific gene correction of the AGXT gene and direct cell reprogramming for the treatment of Primary Hyperoxaluria Type 1

P428 Primary Hyperoxaluria Type 1 (PH1) is an inherited rare metabolic liver disease caused by the deficiency in the alanine: glyoxylate aminotransferase enzyme (AGXT), involved in the glyoxylate metabolism. The only potentially curative treatment is organ transplantation. Thus, the development of new therapeutic approaches for the treatment of these patients appears as a priority.We propose the combination of site-specific gene correction and direct cell reprogramming for the generation of autologous phenotypically healthy induced hepatocytes (iHeps) from skin-derived fibroblast of PH1 patients. For the correction of AGXT mutations, we have designed specific gene editing tools to address gene correction by two different strategies, assisted by CRISPR/Cas9 system. Accurate specific point mutation correction (c.853T-C) has been achieved by homologydirected repair (HDR) with ssODN harbouring wild-type sequence. In the second strategy, an enhanced version ofAGXTcDNAhas been inserted near the transcription start codon of the endogenous gene, constituting an almost universal correction strategy for PH1 mutations. Direct reprogramming of fibroblasts has been conducted by overexpression of hepatic transcription factors and in vitro culture in defined media. In vitro characterization of healthy induced hepatocytes (iHeps) has demonstrated hepatic function of the reprogrammed cells. PH1 patient fibroblasts and , ,

Finding robust solutions for constraint satisfaction problems with discrete and ordered domains by coverings

Constraint programming is a paradigm wherein relations between variables are stated in the form of constraints. Many real life problems come from uncertain and dynamic environments, where the initial constraints and domains may change during its execution. Thus, the solution found for the problem may become invalid. The search forrobustsolutions for constraint satisfaction problems (CSPs) has become an important issue in the ¿eld of constraint programming. In some cases, there exists knowledge about the uncertain and dynamic environment. In other cases, this information is unknown or hard to obtain. In this paper, we consider CSPs with discrete and ordered domains where changes only involve restrictions or expansions of domains or constraints. To this end, we model CSPs as weighted CSPs (WCSPs) by assigning weights to each valid tuple of the problem constraints and domains. The weight of each valid tuple is based on its distance from the borders of the space of valid tuples in the corresponding constraint/domain. This distance is estimated by a new concept introduced in this paper: coverings. Thus, the best solution for the modeled WCSP can be considered as a most robust solution for the original CSP according to these assumptionsThis work has been partially supported by the research projects TIN2010-20976-C02-01 (Min. de Ciencia e Innovacion, Spain) and P19/08 (Min. de Fomento, Spain-FEDER), and the fellowship program FPU.Climent Aunés, LI.; Wallace, RJ.; Salido Gregorio, MA.; Barber Sanchís, F. (2013). Finding robust solutions for constraint satisfaction problems with discrete and ordered domains by coverings. Artificial Intelligence Review. 1-26. https://doi.org/10.1007/s10462-013-9420-0S126Climent L, Salido M, Barber F (2011) Reformulating dynamic linear constraint satisfaction problems as weighted csps for searching robust solutions. In: Ninth symposium of abstraction, reformulation, and approximation (SARA-11), pp 34–41Dechter R, Dechter A (1988) Belief maintenance in dynamic constraint networks. In: Proceedings of the 7th national conference on, artificial intelligence (AAAI-88), pp 37–42Dechter R, Meiri I, Pearl J (1991) Temporal constraint networks. Artif Intell 49(1):61–95Fargier H, Lang J (1993) Uncertainty in constraint satisfaction problems: a probabilistic approach. In: Proceedings of the symbolic and quantitative approaches to reasoning and uncertainty (EC-SQARU-93), pp 97–104Fargier H, Lang J, Schiex T (1996) Mixed constraint satisfaction: a framework for decision problems under incomplete knowledge. In: Proceedings of the 13th national conference on, artificial intelligence, pp 175–180Fowler D, Brown K (2000) Branching constraint satisfaction problems for solutions robust under likely changes. In: Proceedings of the international conference on principles and practice of constraint programming (CP-2000), pp 500–504Goles E, Martínez S (1990) Neural and automata networks: dynamical behavior and applications. Kluwer Academic Publishers, DordrechtHays W (1973) Statistics for the social sciences, vol 410, 2nd edn. Holt, Rinehart and Winston, New YorkHebrard E (2006) Robust solutions for constraint satisfaction and optimisation under uncertainty. PhD thesis, University of New South WalesHerrmann H, Schneider C, Moreira A, Andrade Jr J, Havlin S (2011) Onion-like network topology enhances robustness against malicious attacks. J Stat Mech Theory Exp 2011(1):P01,027Larrosa J, Schiex T (2004) Solving weighted CSP by maintaining arc consistency. Artif Intell 159:1–26Larrosa J, Meseguer P, Schiex T (1999) Maintaining reversible DAC for Max-CSP. J Artif Intell 107(1):149–163Mackworth A (1977) On reading sketch maps. In: Proceedings of IJCAI’77, pp 598–606Sam J (1995) Constraint consistency techniques for continuous domains. These de doctorat, École polytechnique fédérale de LausanneSchiex T, Fargier H, Verfaillie G (1995) Valued constraint satisfaction problems: hard and easy problems. In: Proceedings of the 14th international joint conference on, artificial intelligence (IJCAI-95), pp 631–637Taillard E (1993) Benchmarks for basic scheduling problems. Eur J Oper Res 64(2):278–285Verfaillie G, Jussien N (2005) Constraint solving in uncertain and dynamic environments: a survey. Constraints 10(3):253–281Wallace R, Freuder E (1998) Stable solutions for dynamic constraint satisfaction problems. In: Proceedings of the 4th international conference on principles and practice of constraint programming (CP-98), pp 447–461Wallace RJ, Grimes D (2010) Problem-structure versus solution-based methods for solving dynamic constraint satisfaction problems. In: Proceedings of the 22nd international conference on tools with artificial intelligence (ICTAI-10), IEEEWalsh T (2002) Stochastic constraint programming. In: Proceedings of the 15th European conference on, artificial intelligence (ECAI-02), pp 111–115William F (2006) Topology and its applications. Wiley, New YorkWiner B (1971) Statistical principles in experimental design, 2nd edn. McGraw-Hill, New YorkYorke-Smith N, Gervet C (2009) Certainty closure: reliable constraint reasoning with incomplete or erroneous data. J ACM Trans Comput Log (TOCL) 10(1):

Propuesta para el showroom de la agencia de viajes La Vida en Viajes como ventaja competitiva

En el presente trabajo de investigación, se describe la propuesta de desarrollo de un modelo para showroom de la agencia de viajes “La vida en viajes” , en el que se muestran propuestas de productos, proveedores, mercado meta, acomodo de showroom, etc. Así mismo se describen los procedimiento que fueron utilizados, al igual que las herramientas que se desarrollaron para conseguir resultados positivos para el crecimiento y funcionamiento de la estrategia planteada.ITESO, A.C

Liver cirrhosis in HIV/HCV ‐coinfected individuals is related to NK cell dysfunction and exhaustion, but not to an impaired NK cell modulation by CD 4 + T‐cells

Introduction HIV worsens HCV‐related liver disease by accelerating fibrosis progression; however, progression rates are extremely variable among HIV/HCV‐coinfected individuals. NK cells are associated with modulation of liver fibrosis and are profoundly altered during HCV and HIV infections. CD4+ T‐cells modulate NK cell function, and are also affected by HIV infection. Here, we aim to characterize the association of hepatic fibrosis with both the phenotype and function of peripheral NK cells and their regulation by CD4+ T‐cells, in HIV/HCV‐coinfected individuals. Methods Thirty‐four HIV/HCV‐coinfected individuals with minimal (n = 16) and advanced (n = 18) fibrosis (METAVIR F0/F1 and F4 scores respectively) and 20 healthy volunteers were enrolled. PBMC were obtained from peripheral blood samples and NK and CD4+ T‐cells were isolated and analysed. NK cell phenotype (CD25, CD69, Nkp46, NKG2D, PD‐1), degranulation (CD107a) and IFN‐γ and TNF‐α production, as well as CD4+ T‐cell activation (CD69, CD25 and CD38) were measured by flow cytometry. CD4+ T‐cell conditioned medium (CM) derived from F0/F1 or F4 individuals was assessed for IL‐2 levels by ELISA. Modulation of NK cell functionality by these CMs was also analysed. Results When comparing to NK cells from individuals with minimal fibrosis, degranulation and cytokine secretion by NK cells from subjects with F4 scores was significantly impaired, while PD‐1 expression was augmented. On the one hand, neither the expression of activation markers nor IL‐2 secretion was distinctly induced in CD4+ T‐cells from subjects with F0/F1 or F4 METAVIR scores. Finally, NK cell degranulation and cytokine secretion were not differentially modulated by CD4+ T‐cell CM, whether CD4+ T‐cells derived from subjects with minimal or advanced fibrosis. Conclusions Low levels of NK and CD4+ T‐cells in HIV/HCV‐coinfected individuals with advanced liver fibrosis have been previously described. Here, we show that advanced liver fibrosis in coinfected individuals is associated to a defective function of NK cells and an increased expression of the exhaustion/senescence marker PD‐1. This NK signature could not be attributed to changes in the ability of CD4+ T‐cells to modulate NK cell function.Fil: Polo, María L.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina. Universidad de Buenos Aires; ArgentinaFil: Ghiglione, Yanina Alexandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Salido, Jimena Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Urioste, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Poblete, Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Sisto, Alicia E. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Martinez, Ana. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; ArgentinaFil: Rolón, María Eugenia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Ojeda, Diego Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Cahn, Pedro. Fundación Huésped; ArgentinaFil: Turk, Gabriela Julia Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina. Universidad de Buenos Aires; ArgentinaFil: Laufer, Natalia Lorna. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina. Universidad de Buenos Aires; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentin