171 research outputs found
Factors that affect short-term commercial bank lending to developing countries
No full textDeveloping countries rely on short-term trade credits for imports of several essential consumer goods, including medicines and basic food supplies. The credits also facilitate export-related transactions. The mechanisms commercial banks use to provide trade credits to developing countries are complex and costly. Even a temporary break in the flow of short-term credit can seriously hurt a country's business. But since short-term trade credits can be structured so that they involve a few risks to a bank and at the same time are very costly to the debtor, they are generally the last forms of credit to be cut and the first to be reestablished in debt-distressed developing countries. To gauge the likelihood of continued short-term trade related financial flows to developing countries, the authors examined the factors that affect short-term commercial bank loans. They studied relevant data over time for seven countries for which data were available: Argentina, Brazil, Egypt,India, Kenya, Mexico, and Turkey. They found that : a) countries with greater growth prospects get more short-term credit; b) short-term credits are usually meant to finance countries with significant trade deficits; c) higher levels of external indebtedness are generally coupled with higher levels of short-term indebtedness to commercial banks; and d) country-specific factors affect the volume of short-term lending to a country.Financial Intermediation,Banks&Banking Reform,Economic Theory&Research,Strategic Debt Management,Financial Crisis Management&Restructuring
Lessons from International Experience
No full textIn the aftermath of the global financial
crisis, policymakers around the world are focusing once
again on government debt sustainability. In China,
subnational government debt is an important part of total
government debt, and therefore deserves the attention that
policymakers have paid to the topic. Subnational debt has
played an important role in financing China’s impressive
infrastructure that is the envy of the world. And
subnational debt was instrumental in the economic stimulus
that China so effectively staged after the global financial
crisis, through which China maintained high levels of
economic activity. This e-book starts with a summary and
presentation of the Chinese perspective on this subject of
subnational debt in session one. Session two introduced some
international cases which are highly relevant to the current
situation in China. Session three brought these
international case studies and experts’ perspectives
together to arrive at syntheses that narrowed down key
issues which China needs to consider going forward in
subnational debt management and restructuring. The
roundtable discussion among international and Chinese
experts on the way forward for China in session four
provided an illuminating discussion of this issue. The
author hope that this will inform specific policies that
will be formulated to help local governments in China manage
their subnational debts
Aberrant disulphide bonding contributes to the ER retention of alpha1-antitrypsin deficiency variants.
No full textMutations in alpha1-antitrypsin (AAT) can cause the protein to polymerise and be retained in the endoplasmic reticulum (ER) of hepatocytes. The ensuing systemic AAT deficiency leads to pulmonary emphysema, while intracellular polymers are toxic and cause chronic liver disease. The severity of this process varies considerably between individuals, suggesting the involvement of mechanistic co-factors and potential for therapeutically beneficial interventions. We show in Hepa1.6 cells that the mildly polymerogenic I (Arg39Cys) AAT mutant forms aberrant inter- and intra-molecular disulphide bonds involving the acquired Cys39 and the only cysteine residue in the wild-type (M) sequence (Cys232). Substitution of Cys39 to serine partially restores secretion, showing that disulphide bonding contributes to the intracellular retention of I AAT. Covalent homodimers mediated by inter-Cys232 bonding alone are also observed in cells expressing the common Z and other polymerising AAT variants where conformational behaviour is abnormal, but not in those expressing M AAT. Prevention of such disulphide linkage through the introduction of the Cys232Ser mutation or by treatment of cells with reducing agents increases Z AAT secretion. Our results reveal that disulphide interactions enhance intracellular accumulation of AAT mutants and implicate the oxidative ER state as a pathogenic co-factor. Redox modulation, e.g. by anti-oxidant strategies, may therefore be beneficial in AAT deficiency-associated liver disease
Three new Alpha1-Antitrypsin deficiency variants help to define a C-Terminal region regulating conformational change and polymerization
No full textAlpha1-antitrypsin (AAT) deficiency is a hereditary disorder associated with reduced AAT plasma levels, predisposing adults to pulmonary emphysema. The most common genetic AAT variants found in patients are the mildly deficient S and the severely deficient Z alleles, but several other pathogenic rare alleles have been reported. While the plasma AAT deficiency is a common trait of the disease, only a few AAT variants, including the prototypic Z AAT and some rare variants, form cytotoxic polymers in the endoplasmic reticulum of hepatocytes and predispose to liver disease. Here we report the identification of three new rare AAT variants associated to reduced plasma levels and characterize their molecular behaviour in cellular models. The variants, called Mpisa (Lys259Ile), Etaurisano (Lys368Glu) and Yorzinuovi (Pro391His), showed reduced secretion compared to control M AAT, and accumulated to different extents in the cells as ordered polymeric structures resembling those formed by the Z variant. Structural analysis of the mutations showed that they may facilitate polymerization both by loosening ‘latch’ interactions constraining the AAT reactive loop and through effects on core packing. In conclusion, the new AAT deficiency variants, besides increasing the risk of lung disease, may predispose to liver disease, particularly if associated with the common Z variant. The new mutations cluster structurally, thus defining a region of the AAT molecule critical for regulating its conformational state
Polymers and inflammation: disease mechanisms of the serpinopathies
No full textMembers of the serpin (serine proteinase inhibitor) superfamily play a central role in the control of inflammatory, coagulation, and fibrinolytic cascades. Point mutations that cause abnormal conformational transitions in these proteins can trigger disease. Recent work has defined three pathways by which these conformers cause tissue damage. Here, we describe how these three mechanisms can be integrated into a new model of the pathogenesis of emphysema caused by mutations in the serpin α1-antitrypsin
Real-world clinical applicability of pathogenicity predictors assessed on SERPINA1 mutations in alpha-1-antitrypsin deficiency
No full textThe growth of publicly available data informing upon genetic variations, mechanisms of disease, and disease subphenotypes offers great potential for personalized medicine. Computational approaches are likely required to assess a large number of novel genetic variants. However, the integration of genetic, structural, and pathophysiological data still represents a challenge for computational predictions and their clinical use. We addressed these issues for alpha-1-antitrypsin deficiency, a disease mediated by mutations in the SERPINA1 gene encoding alpha-1-antitrypsin. We compiled a comprehensive database of SERPINA1 coding mutations and assigned them apparent pathological relevance based upon available data. "Benign" and "pathogenic" variations were used to assess performance of 31 pathogenicity predictors. Well-performing algorithms clustered the subset of variants known to be severely pathogenic with high scores. Eight new mutations identified in the ExAC database and achieving high scores were selected for characterization in cell models and showed secretory deficiency and polymer formation, supporting the predictive power of our computational approach. The behavior of the pathogenic new variants and consistent outliers were rationalized by considering the protein structural context and residue conservation. These findings highlight the potential of computational methods to provide meaningful predictions of the pathogenic significance of novel mutations and identify areas for further investigation
Rent - seeking trade policy : a time series approach
No full textUsing a time-series approach, the author analyzes the relationship between the extent of rent-seeking trade policy and both political and economic variables. For rent-seeking trade policy, the indicator he uses is the number of foreign-trade regulations passed each year for the benefit of a single firm or industry. The author uses data from Uruguay for 1925-83. Uruguay, which experienced an impressive economic decline, is an outstanding example of a rent-seeking society. After being a wealthy economy in midcentury, it suffered almost complete stagnation, which led to social and policital disintegration by the end of the 1960s. Three decades of restrictive regulations on foreign trade had created a nearly closed economy by the end of the 1960s. It was worth analyzing whether policymakers'great receptiveness to demands for protection could account for Uruguay's decline. Over the period 1925-83, the author finds almost 4,000 laws, decrees, and administrative resolutions that create, maintain, or modify a foreign-trade regulation for the benefit of a single firm or industry. About half of them explicitly identify the petitioner - usually a firm or guild. Since the size of the Uruguayan economy changed over the period studied, the author scales the annual number of regulations by output or exports to measure the extent of rent-seeking trade policy. The author shows that the extent of rent-seeking trade policy increased with discretionary policies and under dictatorship. (In the period studied, there were two stages of democracy - until 1932 and from 1943-72 - and two stages of dictatorship.) He also shows that rent-seeking trade restrictions increased under import-substitution strategies and, more unexpectedly, under active export promotion. This suggests that discretionary power leads to wasteful distribution, whether it is used to support inward- or outward-oriented policies. Finally, the author analyzes the correlation between innovations in the trade policy indicator and innovations in the growth rates of output and exports, with a lag of up to 20 years. Surprisingly, he finds a positive correlation with output growth rates after two or three years. But the correlation becomes negative some years later, particularly in the case of exports. The short-run positive impact on growth rates, together with the surprisingly long time lag before the negative impact, may account for policymakers'receptiveness to demands for protection.Trade Policy,Achieving Shared Growth,TF054105-DONOR FUNDED OPERATION ADMINISTRATION FEE INCOME AND EXPENSE ACCOUNT,Economic Theory&Research,Environmental Economics&Policies
In silico assessment of potential druggable pockets on the surface of α1-Antitrypsin conformers
No full textThe search for druggable pockets on the surface of a protein is often performed on a single conformer, treated as a rigid body. Transient druggable pockets may be missed in this approach. Here, we describe a methodology for systematic in silico analysis of surface clefts across multiple conformers of the metastable protein α1-antitrypsin (A1AT). Pathological mutations disturb the conformational landscape of A1AT, triggering polymerisation that leads to emphysema and hepatic cirrhosis. Computational screens for small molecule inhibitors of polymerisation have generally focused on one major druggable site visible in all crystal structures of native A1AT. In an alternative approach, we scan all surface clefts observed in crystal structures of A1AT and in 100 computationally produced conformers, mimicking the native solution ensemble. We assess the persistence, variability and druggability of these pockets. Finally, we employ molecular docking using publicly available libraries of small molecules to explore scaffold preferences for each site. Our approach identifies a number of novel target sites for drug design. In particular one transient site shows favourable characteristics for druggability due to high enclosure and hydrophobicity. Hits against this and other druggable sites achieve docking scores corresponding to a Kd in the µM–nM range, comparing favourably with a recently identified promising lead. Preliminary ThermoFluor studies support the docking predictions. In conclusion, our strategy shows considerable promise compared with the conventional single pocket/single conformer approach to in silico screening. Our best-scoring ligands warrant further experimental investigation
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