The authors thank Maria Demertzis and Nicolas Véron for their comments. In the 2010s, the economic situation in the Middle East and North Africa (MENA) deteriorated as a result of lower oil and other ...commodity prices, a new round of domestic political instability, continuous intra-regional conflicts, stalled economic and governance reforms and, finally, the COVID-19 pandemic. The growth of real GDP, which slowed after the global financial crisis of 2008-2009,...
The authors are grateful for very helpful comments from Moritz Krämer, Patrice Cochelin and Paul Munday in the context of a related project, undertaken with Stavros Zenios. International debt ...investors increasingly demand assets that are aligned with environmental, social and governance objectives. Sovereign debt is being belatedly swept up in this change. This huge asset class represents a uniquely long-term claim and funds a wide range of public expenditure, both...
A classical approach to treating prostate cancer uses antagonist ligands - so-called anti-androgens, such as bicalutamide - which block gene transcription through binding to a lipophilic pocket at ...the ligand binding domain of the androgen receptor (AR). An alternative strategy has been developed using compounds which directly target the surface charge clamp by mimicking the coactivator's highly conserved α-helical motif. Thus, to gain additional knowledge about the AR-coactivator interaction, the use of natural miniproteins as a source of novel AR-coactivator inhibitors incorporating the FXXLF motif was explored. Their stable well-defined α-helical secondary structures make miniproteins ideal candidates for development into AR-coactivator inhibitors. Therefore, starting from two potent miniprotein scaffold structures, identified from previous work, systematic point mutations aimed at improving AR affinity were introduced using solid-phase peptide synthesis (SPPS). Structure-activity relationship studies were performed, from which a number of high affinity inhibitors, typically in the low micromolar-to-high nanomolar range, with a ten-fold gain in potency compared with the reference compounds, were identified, thus highlighting the high potential for these scaffolds.
Miniproteins featuring a stable α-helical motif allow exploring point mutations in and around FXXLF motifs to improve androgen receptor affinity.
A significant percentage of patients selected as candidates for heart transplantation can be stabilized by medical treatment, thereby enabling indefinite postponement of inclusion on the operation ...list. The aim of this study was to investigate the prognosis of these patients.
We studied retrospectively 118 patients with severe left ventricular systolic dysfunction (ejection fraction ≤35%) who were consecutively evaluated for cardiac transplantation but who did not undergo transplantation because they became clinically stable on medical treatment. The mean follow-up period was 2.14 (2.19) years. Kaplan-Meier survival analysis, and univariate and multivariate Cox proportional risk analyses of factors predicting survival were performed.
There were 18 deaths (15.2%): 12 were sudden (66.7%), 5 were due to heart failure (27.8%), and 1, to a non-cardiac cause (5.5%). The survival rate was 88% in the first year and 82% in the following 2 years. Univariate analysis showed that the parameters associated with mortality (
P≤.05) were pulmonary artery and capillary wedge pressures, diuretic treatment, and the absence of beta-blocker therapy. In the multivariate analysis, only the absence of beta-blocker therapy remained statistically significant (
P = .003; RR = 0.13; 95%CI, 0.03–0.50).
In a population of patients with severe left ventricular systolic dysfunction who were candidates for heart transplantation but who were stabilized by medical therapy, mortality during the first year of follow-up was 12%. Beta-blocker therapy was the only variable associated with better survival.
Un porcentaje importante de los pacientes evaluados como posibles candidatos a trasplante cardíaco logra, con tratamiento médico, una estabilización que permite posponer indefinidamente su en-trada en lista. El objetivo de este estudio es determinar el pronóstico de estos pacientes.
Estudio retrospectivo de 118 pacientes con disfunción sistólica severa de ventrículo izquierdo (fracción de eyección ≤ 35%), consecutivamente enviados para valoración de trasplante cardíaco, no trasplantados por estabilización clínica con tratamiento médico. El seguimiento medio fue de 2,14 ± 2,19 años. Se elaboraron las curvas de supervivencia de Kaplan-Meier, se realizó un análisis univariable y se ajustó un modelo de riesgos proporcionales de Cox para analizar los factores predictivos de supervivencia.
Murieron 18 pacientes (15,2%), 12 (66,7%) por muerte sübita, 5 (27,8%) por insuficiencia cardíaca y 1 (5,5%) por causa no cardíaca. La probabilidad de supervivencia el primer año fue de 0,88, y la de los 2 siguientes de 0,82. En el análisis univariable, las variables asociadas con la mortalidad (p ≤ 0,05) fueron el valor de las presiones arterial pulmonar y capilar pulmonar, el tratamiento diurético y la ausencia de tratamiento con bloqueadores beta; esta ültima fue la ünica variable que mantuvo la significación en el análisis multivariable (p = 0,003; riesgo relativo, 0,13; intervalo de confianza del 95%, 0,03–0,50).
En una población de pacientes con disfunción sistólica severa del ventrículo izquierdo, candidatos a trasplante cardíaco pero estabilizados con tratamiento médico, la mortalidad el primer año de seguimiento fue del 12%. El tratamiento con bloqueadores beta fue la ünica variable asociada con una mayor supervivencia.
This Policy Contribution is a version of a paper prepared for ‘Russian economy at the crossroads- how to boost long-term growth?’, a seminar co-organised by the Delegation of the European Union to ...Russia and Bruegel, with the support of the EU Russia Expert Network on Foreign Policy. The seminar was funded by the European Union. The content of this paper does not represent the official position of the European Union...
It was previously shown that opsin can be regenerated with the newly synthesized 11‐cis‐7‐methyl‐retinal forming an artificial visual pigment. We now extend this study to include mutants at positions ...close to the retinal to further dissect the interactions of native and artificial chromophores with opsin. Several mutants at M207, W265 and Y268 have been obtained and regenerated with 11‐cis‐retinal and the 7‐methyl analog. M207 is the site of the point mutation M207R associated with the retinal degenerative disease retinitis pigmentosa. All the studied mutants regenerated with 11‐cis‐retinal except for M207C which proved to be completely misfolded. The naturally occurring M207R mutant formed a pigment with an unprotonated Schiff base linkage, altered photobleaching and low MetarhodopsinII stability. Mutants regenerated with the 7‐methyl analog showed altered photobleaching reflecting a structural perturbation in the vicinity of M207. The newly obtained mutants at M207 also showed reduced levels of transducin activation with M207R showing essentially no transducin activation. Our results highlight the tight coupling of the vicinity of C7 of retinal and M207 and support the involvement of this amino acid residue in the conformational changes associated with rhodopsin photoactivation.
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