Immunosuppressant cyclosporine A induces endoplasmic reticulum stress and apoptosis in kidney epithelial cells due to suppression of cyclophilin activity

Calcineurin inhibitors (CNI) such as cyclosporine A (CsA) and tacrolimus (Tac), are widely-used as immunosuppressants after solid organ transplantations to prevent allo-graft rejection. However, their therapeutic benefits are limited by nephrotoxicity. In particular, CsA is associated with greater nephrotoxicity than Tac. CNI inhibit calcineurin indirectly by building complexes with different immunophilins: CsA binds to cyclophilins and Tac interacts with the FK506-binding protein (FKBP). These complexes then bind to and inhibit calcineurin. We hypothesized that the stronger nephrotoxicity of CsA may be as-sociated with suppression of cyclophilins, whose chaperone function is crucial in proteo-stasis. Imbalanced proteostasis may lead to endoplasmic reticulum (ER) stress and mal-adaptive unfolded protein response (UPR) in kidney epithelia. To this end, the effects of CsA and Tac treatment (10 μM, for 6 hours each) on UPR and apoptosis markers were evaluated in human embryonic kidney 293 (HEK 293) cells, primary human renal proximal tubular epithelial cells (HRPTEpC) and freshly isolated rat proximal tubules (PT). CsA treatment in cultured cells and isolated PTs induced significant increases to the levels of UPR and proapoptotic markers, whereas Tac treatment resulted in either mild or no effect. Knockdown of cyclophilin A (CYPA) or cyclophilin B (CYPB) via small interfering RNA (siRNA) stimulated proapoptotic UPR and apoptosis, similar to CsA treatment. Concom-itant application of the chemical chaperones tauroursodeoxycholic acid (TUDCA) or 4-phenylbutyric acid (4-PBA) alleviated CsA-induced ER stress and UPR. Similarly, inacti-vation of critical UPR pathways by CRISPR/Cas9 mediated deletion of protein kinase RNA-like ER kinase (PERK) or activating transcription factor 6 (ATF6) in HEK 293 cells also blunted CsA-induced UPR. In summary, CsA induces stronger expression of UPR and proapoptic markers than Tac, which suggests that higher nephrotoxicity associated with CsA treatment may be, at least in part, derived from the suppression of cyclophilins rather than calcineurin inhibition. In-deed, concomitant treatment with chemical chaperones alleviated the CsA-induced UPR, and genetic suppression of the UPR also blunted the detrimental effects of CsA. Thus, modulation of the UPR may be an effective adjuvant approach to mitigate the nephrotox-icity associated with CsA.Der Einsatz der Calcineurin-Inhibitoren (CNI), Cyclosporin A (CsA) oder Tacrolimus (Tac), gehört zu den Standards bei immunsuppressiver Therapie nach Organtransplan-tation. Die nephrotoxischen Nebenwirkungen von CNI stellen jedoch ein Problem für deren klinische Verwendung dar. Im Vergleich mit Tac hat CsA eine stärker toxische Wirkung. Calcineurin wird durch CNI indirekt über dessen Komplexbildung mit verschiedenen Immunophilinen gehemmt. Dabei bindet CsA an Cyclophiline und Tac an FK506-bindendes Protein (FKBP). Die dadurch entstehenden Komplexe binden dann an Calcineurin und hemmen es. Wir stellten die Hypothese auf, dass eine angenommene höhere Nephrotoxizität von CsA mit der Unterdrückung von Cyclophilinen in Verbindung steht, weil deren Chaperonfunktion für die Erhaltung der zellulären Proteostase entscheidend ist. Eine unausgeglichene Proteostase kann zu Stress des endoplasmatischen Retiku-lums (ER) und zu maladaptiver Unfolded protein response (UPR) in Nierenepithelien führen. Zur Überprüfung der Hypothese wurden Effekte von CsA und Tac (10 μM, 6 Stunden, jeweils) auf UPR- und Apoptosemarker in humanen embryonalen Nierenzellen 293 (HEK 293), primären humanen proximalen tubulären Nierenepithelzellen (HRPTEpC) und frisch isolierten proximalen Tubuli (PT) von Ratten vergleichend untersucht. Die Behand-lung mit CsA induzierte eine signifikant stärkere Expression von UPR- und Apoptosemar-kern in kultivierten Zellen und isolierten PTs als mit Tac. Die Synthesehemmung (Knock-down) von Cyclophilin A (CYPA) oder Cyclophilin B (CYPB) mittels kleiner interferierender RNA (siRNA) stimulierte proapoptotische UPR und Apoptose in ähnlicher Weise wie die CsA-Behandlung. CsA-induzierte UPR und Apoptose wurden durch die gleichzeitige Anwendung der chemischen Chaperone, Tauroursodeoxycholsäure (TUDCA) oder 4-Phenylbuttersäure (4-PBA), gelindert. In ähnlicher Weise wurden die zelltoxischen Ef-fekte von CsA durch Hemmung der kritischen UPR-Komponenten, Proteinkinase-RNA-ähnliche ER-Kinase (PERK) und Transkriptionsfaktor 6 (ATF6), in HEK 293 Zellen über CRISPR/Cas9-vermittelte Gen-Edition jeweils deutlich gemildert. Zusammenfassend verursacht CsA ein höheres Ausmass an epithelialer UPR und Apoptose als Tac. Die mit CsA-Behandlung einhergehende höhere Nephrotoxizität kommt offenbar anteilig durch Unterdrückung der zugehörigen Cyclophiline zustande. Die Dämpfung der UPR durch chemische Chaperone oder Hemmung ihrer genetischen Kom-ponenten sollte dazu beitragen können, die zelltoxischen Effekte von CsA zu vermindern

DOES HIGHER SHARE IN TOTAL TRADE STIMULATE REGIONAL LABOR MARKET OUTCOMES? THE CASE OF TURKEY

Standard trade theory relies on the assumption of long-run full-employment, thus implying that although trade can affect wage rates and change the sectoral distribution of employment, it has no effect on the overall level of employment. In the empirical literature, it is a controversial debate that trade openness is good for employment in the long-run. If so, the further question is about the poorer regions in the developing countries which are fully open to trade. Turkey is one of these countries experienced trade liberalization three decades ago. Although its regions’ connection to markets is effective due to limited lack of access to key inputs and low transport costs, their shares in total trade and labor market outcomes strikingly vary depending on the density of local economic activities. While trade volumes and employment creation capacities of some regions are quite high, relevant indicators for some others are disappointing. The aim of this paper is to explore the relation between regional trade volumes and major labor market indicators. To this end, empirical analyses are designed to test the hypothesis that more regional trade volume leads to more employment opportunities and stimulates the job creation capacities of local labor markets. The data sets used in the analyses are from Turkish Statistical Institute, one being trade statistics by province which consists of export and import volume data for 81 provinces. The other set contains individual-based micro data from Household Labor Force Survey and both of these sets are at NUTS level 2, analyzing Turkey with 26 statistical regions. Time-interval for the analyses is from the year 2004 to 2008. Since the nature of labor market data set is cross-sectional and the dependent variable created is a dummy, the methodology used in the study is based on the probit regression. The preliminary results of the paper shows that higher the trade volumes of regions generally improve the indicators of local labor markets in Turkey.

Natural processes behind the CO2 sink variability in the Southern Ocean during the last three decades

Anthropogenic activities during the past two centuries have caused an increase in atmospheric CO2 which has driven a linear increase in oceanic CO2 uptake. The Southern Ocean (SO, < 35¿S) is one of the major uptake areas for anthropogenic CO2, responsible for ~40% of ocean CO2 sink. Apart from the linear increase in the CO2 sinking trend, in the SO pronounced variations have been observed in recent decades, driven by natural processes, but the exact mechanisms behind them are still debated. Aiming to fill this knowledge gap, we investigated the natural drivers of CO2 flux variations in the SO using existing observation-based datasets between the years 1982-2019. We removed the long-term linear trend in the time series of CO2 flux and other indexes to focus on decadal variations. We found that two mechanisms explain the interannual to decadal variations in the SO: Ekman upwelling and eddy kinetic energy, by their controls on different components of surface pCO2 variations. The pattern of variability in Ekman upwelling during the time period studied was markedly circumpolar, and the time series of its 1st principal component was strongly correlated with the detrended SAM Index (r=0.81, p<0.05). Similarly, leading EOF maps of CO2 flux anomalies and the components of surface pCO2 changes (i.e., nonthermal and thermal) show that their variations were dominantly symmetric. As previously shown, weakening of SO CO2 sink in the 1990s coincides with intense positive SAM episodes. Following the late 1990s, the intensity of SAM decreased, which strengthened the CO2 sink in the early 2000s. At the same time, the relative contribution of the thermal component grew south of the Polar Front, indicating positive temperature anomalies during this period. Such warming events, following intense and recursive SAM episodes were reported before and were attributed to the increased mesoscale eddy activity in the region. In agreement with these studies, our results show that eddy kinetic energy increased after intense SAM periods with a lagged response of ~2 years, and a positive temperature anomaly in low frequency was observed following these peaks. This warming prevented the CO2 uptake rate from reaching immediately to its potential strength in the absence of strong westerlies, and explains the growing effect of the thermal pCO2 component.Postprint (published version

Stability, Cyclicality and Sustainability of Migration: A Literature Review

The aim of this essay is to present in a complete way the kernel of such a production. People migrate and this decision is sometimes permanent, but there are links with the country of origin that stand up to time and distances. With respect to this, the so called economic diaspora well depicts the broad transnationalism that has established as a consequence of the increasing amount of money migrants have been sending back home. The data collected and the estimates fully agree on this positive trend but the outlines of these peculiar private capital flows are still controversial. This is due to three aspects each section of this work tries to address. The first part analyses those remittances’ features on which the results of the econometric studies are still causing discussion: stability, cyclicality and sustainability. The second one deals with the reasons why people do remit, concluding that the world is more balanced than a clear-cut division between behavioural and economic motives. Finally, the third one tries to go through the relationship between remittances and development, topic on which lots of studies have been conducted but that is still far from a comprehensive and convincing conclusion

Understanding Social Network in International Migration: Evidences from EU

Kinship, religious and other social networks play a key role in the decision to migrate, and in determining migration journeys and return. This includes the role of family members in host countries, who may encourage prospective migrants through remittances and information. Migrants proactively seek information from broader networks and are exposed to information through mass media, word of mouth and social media. Technology has changed the ways in which social networks operate in relation to migration. TV and mobile technology remain a main source of information for migrants, but recent evidence points to the increasing role of online and social media. Internet-based technology and social media are putting different groups of migrants and non-migrant populations in direct contact. However, the documentation on the use of mobile social media is almost exclusively confined to Syrians. Local social networks often involve ties with other migrants, and with smugglers. Migrants often provide each other with reciprocal support for day-to-day subsistence, sharing food and accommodation, as well as information on travel routes and destinations. These local networks are often informal and kept ‘under the radar’

Migration Decision Making: Review and Evidences

The reasons why people migrate are often multiple and changing, and the categories of ‘economic migrant’ and ‘asylum-seeker’ are too rigid to reflect reality. There are many shared motivations for regular and irregular migration. Having the capability and economic means to migrate is particularly important; in conflict situations people may be very keen to migrate, but may not have sufficient resources to do so. Lack of economic opportunities in the country of origin and the hope of greater opportunities in another country are important drivers of irregular migration, though expectations vary according to the nature and reliability of the sources of information individual migrants have. Irregular migration is usually a collective effort in which families and social and religious networks play a crucial role. Irregular migrants are commonly supported financially by friends or family; as migration from a society becomes common, a ‘culture of migration’ may emerge in communities of origin which drives further migration. Many people who migrate irregularly use the services of smugglers or agents, who influence which destination is offered, promoted, or available, and the route taken. Smugglers’ networks have become increasingly professionalised, in particular as a result of the ability of Syrian migrants to pay for more sophisticated services. While tightening border security may change migration patterns and routes, migration policies are unlikely to influence the volume of people migrating. A person’s need to leave their home is likely to be far more important to them than different countries’ welfare and asylum support systems. Trade and investment in a source country is likely to increase, not reduce, migration. It is not individuals from the poorest households who migrate to Europe, but rather those who have access to sufficient resources to pay for their journey

An Econometric Analysis of Remittances-Growth: A Macroeconomic Study in Developing Country

The importance of the flow of workers’ remittances in the economies of developing countries during the last few decades or so cannot be ignored at the face changing global order where most of the economies in the world are transforming themselves to the call of globalization and transmuting towards more open markets with freer flows of goods and factors across borders. The macroeconomic impacts of remittances flows on developing economies are not well understood. The paper is an attempt to understand the impact of inward remittances flows on per capita GDP growth in Bangladesh during 1974-2006. This study find that the growth effect of remittances is negative at first but becomes positive at a later stage- a strong evidence of a non-linear relationship. This could be due to unproductive use of remittances in the beginning followed by more productive utilisation. Remittances positively affect per capita GDP growth in Bangladesh when the complementarity between remittances and financial development is incorporated into the analysis