Structural shifts of aldehyde dehydrogenase enzymes were instrumental for the early evolution of retinoid-dependent axial patterning in metazoans

Aldehyde dehydrogenases (ALDHs) catabolize toxic aldehydes and process the vitamin A-derived retinaldehyde into retinoic acid (RA), a small diffusible molecule and a pivotal chordate morphogen. In this study, we combine phylogenetic, structural, genomic, and developmental gene expression analyses to examine the evolutionary origins of ALDH substrate preference. Structural modeling reveals that processing of small aldehydes, such as acetaldehyde, by ALDH2, versus large aldehydes, including retinaldehyde, by ALDH1A is associated with small versus large substrate entry channels (SECs), respectively. Moreover, we show that metazoan ALDH1s and ALDH2s are members of a single ALDH1/2 clade and that during evolution, eukaryote ALDH1/2s often switched between large and small SECs after gene duplication, transforming constricted channels into wide opened ones and vice versa. Ancestral sequence reconstructions suggest that during the evolutionary emergence of RA signaling, the ancestral, narrow-channeled metazoan ALDH1/2 gave rise to large ALDH1 channels capable of accommodating bulky aldehydes, such as retinaldehyde, supporting the view that retinoid-dependent signaling arose from ancestral cellular detoxification mechanisms. Our analyses also indicate that, on a more restricted evolutionary scale, ALDH1 duplicates from invertebrate chordates (amphioxus and ascidian tunicates) underwent switches to smaller and narrower SECs. When combined with alterations in gene expression, these switches led to neofunctionalization from ALDH1-like roles in embryonic patterning to systemic, ALDH2-like roles, suggesting functional shifts from signaling to detoxification.

Structural Breaks in the Real Exchange Rate and Real Interest Rate Relationship

In this paper we empirically examine the relationship between the real exchange rate and real interest rate differentials using recent econometric methods robust to potential structural breaks. Generally, our study provides evidence of this relationship in the long-run context. More specifically, we first focus on the UK-US relationship, and interestingly find limited evidence of this long-run relationship using traditional methods. But when an approach robust to endogenously determined structural breaks is employed, we find evidence that the real interest rate differential is an important determinant of the real exchange rate. Secondly, in order to investigate the relevance of structural shifts in a more global context, we carry out multiple country analysis. While providing evidence of this long-run relationship, European data suggest that the presence of structural breaks is not very common across countries and is indeed country-specific.

Dynamic ecosystems under anthropogenic stress : how does macrotidal sandy fauna respond to green tides?

Highly dynamic systems, often considered as resilient systems, are characterised by abiotic and biotic processes under continuous and strong changes in space and time. Because of this variability, the detection of overlapping anthropogenic stress is challenging. Coastal areas harbour dynamic ecosystems in the form of open sandy beaches, which cover the vast majority of the world’s ice-free coastline. These ecosystems are currently threatened by increasing human-induced pressure, among which mass-development of opportunistic macroalgae (mainly composed of Chlorophyta, so called green tides), resulting from the eutrophication of coastal waters. The ecological impact of opportunistic macroalgal blooms (green tides, and blooms formed by other opportunistic taxa), has long been evaluated within sheltered and non-tidal ecosystems. Little is known, however, on how more dynamic ecosystems, such as open macrotidal sandy beaches, respond to such stress. This thesis assesses the effects of anthropogenic stress on the structure and the functioning of highly dynamic ecosystems using sandy beaches impacted by green tides as a study case. The thesis is based on four field studies, which analyse natural sandy sediment benthic community dynamics over several temporal (from month to multi-year) and spatial (from local to regional) scales. In this thesis, I report long-lasting responses of sandy beach benthic invertebrate communities to green tides, across thousands of kilometres and over seven years; and highlight more pronounced responses of zoobenthos living in exposed sandy beaches compared to semi-exposed sands. Within exposed sandy sediments, and across a vertical scale (from inshore to nearshore sandy habitats), I also demonstrate that the effects of the presence of algal mats on intertidal benthic invertebrate communities is more pronounced than that on subtidal benthic invertebrate assemblages, but also than on flatfish communities. Focussing on small-scale variations in the most affected faunal group (i.e. benthic invertebrates living at low shore), this thesis reveals a decrease in overall beta-diversity along a eutrophication-gradient manifested in the form of green tides, as well as the increasing importance of biological variables in explaining ecological variability of sandy beach macrobenthic assemblages along the same gradient. To illustrate the processes associated with the structural shifts observed where green tides occurred, I investigated the effects of high biomasses of opportunistic macroalgae (Ulva spp.) on the trophic structure and functioning of sandy beaches. This work reveals a progressive simplification of sandy beach food web structure and a modification of energy pathways over time, through direct and indirect effects of Ulva mats on several trophic levels. Through this thesis I demonstrate that highly dynamic systems respond differently (e.g. shift in δ13C, not in δ15N) and more subtly (e.g. no mass-mortality in benthos was found) to anthropogenic stress compared to what has been previously shown within more sheltered and non-tidal systems. Obtaining these results would not have been possible without the approach used through this work; I thus present a framework coupling field investigations with analytical approaches to describe shifts in highly variable ecosystems under human-induced stress.

Debt financing rollercoaster: Latin American and Caribbean access to international bond markets since the debt crisis, 1982-2012

Includes bibliography

ロウハーニー大統領の登場から核協議の進展へ -- 米国オバマ政権の対イラン外交の転換と日本

The recent rapprochement between Iran and the United States after Hassan Rouhani was elected president in June 2013 may represent an important geopolitical shift that would alter the politics of the Middle East. The main purpose of this paper is to evaluate this political shift, examine whether the interim nuclear agreement between Iran and the United States would lead to some structural shifts in the Middle East, and analyze to what extent this change can be sustainable for both sides. The main Part of this paper is divided into three sections. The first section examines in detail the process of Iran's Presidential election in June 2013, especially the sudden change of atmosphere which took place just three days before election day. The second section is devoted to analyzing the Obama administration’s shift to diplomacy with Iran. And the third section treats the on-going nuclear negotiations between Iran and P5+1, which is expected to reach a comprehensive solution. The paper argues that the dramatic shift in the US policy toward Iran is not limited to the bilateral relationships between the US and Iran, but it is related to several key issues in the Middle East, in particular to those in Syria, Iraq and Afghanistan. This changing process in Iranian politics and the path to diplomacy is profitable for Japanese national interest, and that Japan should also contribute to Iran's return to the international community.

A versenyszféra teljesítményéről nemzetközi összehasonlításban

Napjaink gazdasági nehézségei miatt a közvélemény hajlandó a rendszerváltás óta eltelt időszakot teljes egészében sikertelennek minősíteni. Ez felettébb veszélyes, mert nem veszi kellőképpen figyelembe azt a jelentős fejlődést, amelyet az ország ezen időszak alatt befutott és így egy féleredmény eredménnyé fejlesztése helyett könnyen tönkre teheti mindazt, amit elértünk. A tanulmány ezt a fejlődést kívánja bemutatni nemzetközi összehasonlításban és azt a továbblépés lehetőségeinek feszegetésével értékelni. A tanulmány központi mondanivalója, hogy egy fájdalmas, de elkerülhetetlen struktúraváltáson vagyunk túl, mely egy korábbi torz fejlődést az ország jelenlegi gazdasági fejlettségének megfelelően korrigált. A múltbeli teljesítményt rontja, hogy egyoldalúan a mikrovállalkozásokra orientálódott és nem tudta a szerkezetváltás során a kis és közepes vállalatok részarányát növelni. Jelenlegi gazdasági nehézségek megoldását is részben az jelentené, ha a szerkezetváltást ebbe az irányba tudnánk vezérelni. _____ For our everyday economic difficulties the public opinion is inclined to evaluate the period that passed since the transition as totally unsuccessful. This is very dangerous because it does not take into account properly that significant development that has been achieved by the country in this period and instead to complete the achieved half results everything could be destroyed what we have positively done. The study intends to present this development in international comparison and tries to evaluate it by trying to show the possibilities of further development. The central message of the study is, that we are behind a painful, but unavoidable structural change that has corrected a former distorted development and the achieved one corresponds to the present economic development level of the country. This performance is deteriorated by the exaggerated orientation onto micro enterprises and the inability to increase the share of small and micro enterprises properly. Our present economic difficulties could be eased significantly if we could stimulate structural shifts into this direction.

Essays in Environmental Economic Valuation and Decision Making in the Presence of an Environmental Disaster

The first essay developed a respondent model of Bayesian updating for a double-bound dichotomous choice (DB-DC) contingent valuation methodology. I demonstrated by way of data simulations that current DB-DC identifications of true willingness-to-pay (WTP) may often fail given this respondent Bayesian updating context. Further simulations demonstrated that a simple extension of current DB-DC identifications derived explicitly from the Bayesian updating behavioral model can correct for much of the WTP bias. Additional results provided caution to viewing respondents as acting strategically toward the second bid. Finally, an empirical application confirmed the simulation outcomes. The second essay applied a hedonic property value model to a unique water quality (WQ) dataset for a year-round, urban, and coastal housing market in South Florida, and found evidence that various WQ measures affect waterfront housing prices in this setting. However, the results indicated that this relationship is not consistent across any of the six particular WQ variables used, and is furthermore dependent upon the specific descriptive statistic employed to represent the WQ measure in the empirical analysis. These results continue to underscore the need to better understand both the WQ measure and its statistical form homebuyers use in making their purchase decision. The third essay addressed a limitation to existing hurricane evacuation modeling aspects by developing a dynamic model of hurricane evacuation behavior. A household’s evacuation decision was framed as an optimal stopping problem where every potential evacuation time period prior to the actual hurricane landfall, the household’s optimal choice is to either evacuate, or to wait one more time period for a revised hurricane forecast. A hypothetical two-period model of evacuation and a realistic multi-period model of evacuation that incorporates actual forecast and evacuation cost data for my designated Gulf of Mexico region were developed for the dynamic analysis. Results from the multi-period model were calibrated with existing evacuation timing data from a number of hurricanes. Given the calibrated dynamic framework, a number of policy questions that plausibly affect the timing of household evacuations were analyzed, and a deeper understanding of existing empirical outcomes in regard to the timing of the evacuation decision was achieved.

Global Value Chain Analysis: A Primer, 2nd Edition

The first edition of Global Value Chain Analysis: A Primer was released five years ago (May 2011) in order to provide an overview of the key concepts and methodological tools used by Duke University’s Center on Globalization, Governance & Competitiveness (Duke CGGC) a university-based research center that focuses on innovative applications of the GVC framework, which was developed by Duke CGGC’s founding director, Gary Gereffi. The Second Edition of Global Value Chain Analysis: A Primer (July 2016) retains a simple, expository style and use of recent research examples in order to offer an entry point for those wishing to better understand and use the GVC framework as a tool to analyze how local actors (firms, communities, workers) are linked to and affected by major transformations in the global economy. The GVC framework focuses on structural shifts in global industries, anchored by the core concepts of governance and upgrading. This Second Edition highlights some of the refinements in these concepts, and introduces a number of new illustrations drawing from recent Duke CGGC research. The bibliography offers a sampling of the broad array of studies available on the Duke CGGC website and in related academic publications. We hope this work stimulates continued interest in and use of the GVC framework as a tool to promote more dynamic, inclusive and sustainable development outcomes for all economies and the local actors within them.

Structural Organization of the Corpus Callosum Predicts Attentional Shifts after Continuous Theta Burst Stimulation

Repetitive transcranial magnetic stimulation (rTMS) applied over the right posterior parietal cortex (PPC) in healthy participants has been shown to trigger a significant rightward shift in the spatial allocation of visual attention, temporarily mimicking spatial deficits observed in neglect. In contrast, rTMS applied over the left PPC triggers a weaker or null attentional shift. However, large interindividual differences in responses to rTMS have been reported. Studies measuring changes in brain activation suggest that the effects of rTMS may depend on both interhemispheric and intrahemispheric interactions between cortical loci controlling visual attention. Here, we investigated whether variability in the structural organization of human white matter pathways subserving visual attention, as assessed by diffusion magnetic resonance imaging and tractography, could explain interindividual differences in the effects of rTMS. Most participants showed a rightward shift in the allocation of spatial attention after rTMS over the right intraparietal sulcus (IPS), but the size of this effect varied largely across participants. Conversely, rTMS over the left IPS resulted in strikingly opposed individual responses, with some participants responding with rightward and some with leftward attentional shifts. We demonstrate that microstructural and macrostructural variability within the corpus callosum, consistent with differential effects on cross-hemispheric interactions, predicts both the extent and the direction of the response to rTMS. Together, our findings suggest that the corpus callosum may have a dual inhibitory and excitatory function in maintaining the interhemispheric dynamics that underlie the allocation of spatial attention. SIGNIFICANCE STATEMENT: The posterior parietal cortex (PPC) controls allocation of attention across left versus right visual fields. Damage to this area results in neglect, characterized by a lack of spatial awareness of the side of space contralateral to the brain injury. Transcranial magnetic stimulation over the PPC is used to study cognitive mechanisms of spatial attention and to examine the potential of this technique to treat neglect. However, large individual differences in behavioral responses to stimulation have been reported. We demonstrate that the variability in the structural organization of the corpus callosum accounts for these differences. Our findings suggest novel dual mechanism of the corpus callosum function in spatial attention and have broader implications for the use of stimulation in neglect rehabilitation.

NMR of conotoxins: structural features and an analysis of chemical shifts of post-translationally modified amino acids

Conotoxins are small conformationally constrained peptides found in the venom of marine snails of the genus Conus. They are usually cysteine rich and frequently contain a high degree of post-translational modifications such as C-terminal amidation, hydroxylation, carboxylation, bromination, epimerisation and glycosylation. Here we review the role of NMR in determining the three-dimensional structures of conotoxins and also provide a compilation and analysis of H-1 and C-13 chemical shifts of post-translationally modified amino acids and compare them with data from common amino acids. This analysis provides a reference source for chemical shifts of post-translationally modified amino acids. Copyright (C) 2006 John Wiley & Sons, Ltd.

Kinase Inhibitor Profile For Human Nek1, Nek6, And Nek7 And Analysis Of The Structural Basis For Inhibitor Specificity.

Human Neks are a conserved protein kinase family related to cell cycle progression and cell division and are considered potential drug targets for the treatment of cancer and other pathologies. We screened the activation loop mutant kinases hNek1 and hNek2, wild-type hNek7, and five hNek6 variants in different activation/phosphorylation statesand compared them against 85 compounds using thermal shift denaturation. We identified three compounds with significant Tm shifts: JNK Inhibitor II for hNek1(Δ262-1258)-(T162A), Isogranulatimide for hNek6(S206A), andGSK-3 Inhibitor XIII for hNek7wt. Each one of these compounds was also validated by reducing the kinases activity by at least 25%. The binding sites for these compounds were identified by in silico docking at the ATP-binding site of the respective hNeks. Potential inhibitors were first screened by thermal shift assays, had their efficiency tested by a kinase assay, and were finally analyzed by molecular docking. Our findings corroborate the idea of ATP-competitive inhibition for hNek1 and hNek6 and suggest a novel non-competitive inhibition for hNek7 in regard to GSK-3 Inhibitor XIII. Our results demonstrate that our approach is useful for finding promising general and specific hNekscandidate inhibitors, which may also function as scaffolds to design more potent and selective inhibitors.

X-ray phase measurements as a probe of small structural changes in doped nonlinear optical crystals

X-ray multiple diffraction experiments with synchrotron radiation were carried out on pure and doped nonlinear optical crystals: NH(4)H(2)PO(4) and KH(2)PO(4) doped with Ni and Mn, respectively. Variations in the intensity profiles were observed from pure to doped samples, and these variations correlated with shifts in the structure factor phases, also known as triplet phases. This result demonstrates the potential of X-ray phase measurements to study doping in this type of single crystal. Different methodologies for probing structural changes were developed. Dynamical diffraction simulations and curve fitting procedures were also necessary for accurate phase determination. Structural changes causing the observed phase shifts are discussed.

Folding, calcium binding, and structural characterization of a concatemer of the first and second ligand-binding modules of the low-density lipoprotein receptor

The ligand-binding domain of the low-density lipoprotein (LDL) receptor is comprised of seven tandemly repeated ligand-binding modules, each being approximately 40 amino acids long and containing six conserved cysteine residues. We have expressed and characterized a concatemer of the first two modules (LB1 and LB2) of the human LDL receptor. Oxidative folding of the recombinant concatemer (rLB(1-2)), in the presence of calcium ions, gave a single dominant isomer with six disulfide bonds. Peptic cleavage of the short Linker region that connects the last cysteine residue of LB1 and the first cysteine residue of LB2 yielded two discrete fragments, thus excluding the presence of intermodule disulfide bonds. The N-terminal module, LB1, reacted with a conformation-specific monoclonal antibody (IgG-C7) made to LB1 in the native LDL receptor. From this, we concluded that the first module was correctly folded, with the same set of disulfide bonds as LB1 of the LDL receptor. The disulfide bond connections of LB2 were identified from mass spectral analysis of fragments formed by digestion of the C-terminal peptic fragment with elastase. These data showed that the disulfide bonds of LB2 connected Cys(I) and Cys(III), Cys(II) and Cys(V), and Cys(IV) and Cys(VI). This pattern is identical to that found for recombinant LB1 and LB2. The concatemer has two high-affinity calcium-binding sites, one per module. An analysis of the secondary chemical shifts of C alpha protons shows that the conformations of LB1 and LB2 in the concatemer are very similar to those of the individual modules, with no evidence for strong interactions between the two modules.

H-1-NMR structural studies of a cystine-linked peptide containing residues 71-93 of transthyretin and effects of a Ser84 substitution implicated in familial amyloidotic polyneuropathy

The Ile-->Ser84 substitution in the thyroid hormone transport protein transthyretin is one of over 50 variations found to be associated with familial amyloid polyneuropathy, a hereditary type of lethal amyloidosis. Using a peptide analogue of the loop containing residue 84 in transthyretin, we have examined the putative local structural effects of this substitution using H-1-NMR spectroscopy. The peptide, containing residues 71-93 of transthyretin with its termini linked via a disulfide bond, was found to possess the same helix-turn motif as in the corresponding region of the crystallographically derived structure of transthyretin in 20% trifluoroethanol (TFE) solution. It therefore, represents a useful model with which to examine the effects of amyloidogenic substitutions. In a peptide analogue containing the Ile84-->Ser substitution it was found that the substitution does not greatly disrupt the overall three-dimensional structure, but leads to minor local differences at the turn in which residue 84 is involved. Coupling constant and NOE measurements indicate that the helix-turn motif is still present, but differences in chemical shifts and amide-exchange rates reflect a small distortion. This is in keeping with observations that several other mutant forms of transthyretin display similar subunit interactions and those that have been structurally analysed possess a near native structure. We propose that the Ser84 mutation induces only subtle perturbations to the transthyretin structure which predisposes the protein to amyloid formation.