Everyday legitimacy and international administration: global governance and local legitimacy in Kosovo

International administrations are a very specific form of statebuilding. This paper examines the limits illustrated by the experience in Kosovo. Here, the international administration faced the same requirements of any legitimate, Liberal government, but without the checks and balances normally associated with Liberal governance. Thus, the international administration was granted full authority and the power thereby associated, but without the legitimacy upon which the Liberal social contract rests. The state-building agenda put forth came to be seen as more exogenous, reinforcing the delegitimization process. This paper will specifically address the influence of the Weberian approach to legitimacy on the statebuilding literature, as well as its limits. It will then propose other possible avenues for statebuilding, more in line with a wider understanding of legitimacy and intervention

Care of patients with inborn errors of immunity in thirty J Project countries between 2004 and 2021

IntroductionThe J Project (JP) physician education and clinical research collaboration program was started in 2004 and includes by now 32 countries mostly in Eastern and Central Europe (ECE). Until the end of 2021, 344 inborn errors of immunity (IEI)-focused meetings were organized by the JP to raise awareness and facilitate the diagnosis and treatment of patients with IEI.ResultsIn this study, meeting profiles and major diagnostic and treatment parameters were studied. JP center leaders reported patients’ data from 30 countries representing a total population of 506 567 565. Two countries reported patients from JP centers (Konya, Turkey and Cairo University, Egypt). Diagnostic criteria were based on the 2020 update of classification by the IUIS Expert Committee on IEI. The number of JP meetings increased from 6 per year in 2004 and 2005 to 44 and 63 in 2020 and 2021, respectively. The cumulative number of meetings per country varied from 1 to 59 in various countries reflecting partly but not entirely the population of the respective countries. Altogether, 24,879 patients were reported giving an average prevalence of 4.9. Most of the patients had predominantly antibody deficiency (46,32%) followed by patients with combined immunodeficiencies (14.3%). The percentages of patients with bone marrow failure and phenocopies of IEI were less than 1 each. The number of patients was remarkably higher that those reported to the ESID Registry in 13 countries. Immunoglobulin (IgG) substitution was provided to 7,572 patients (5,693 intravenously) and 1,480 patients received hematopoietic stem cell therapy (HSCT). Searching for basic diagnostic parameters revealed the availability of immunochemistry and flow cytometry in 27 and 28 countries, respectively, and targeted gene sequencing and new generation sequencing was available in 21 and 18 countries. The number of IEI centers and experts in the field were 260 and 690, respectively. We found high correlation between the number of IEI centers and patients treated with intravenous IgG (IVIG) (correlation coefficient, cc, 0,916) and with those who were treated with HSCT (cc, 0,905). Similar correlation was found when the number of experts was compared with those treated with HSCT. However, the number of patients treated with subcutaneous Ig (SCIG) only slightly correlated with the number of experts (cc, 0,489) and no correlation was found between the number of centers and patients on SCIG (cc, 0,174).Conclusions1) this is the first study describing major diagnostic and treatment parameters of IEI care in countries of the JP; 2) the data suggest that the JP had tremendous impact on the development of IEI care in ECE; 3) our data help to define major future targets of JP activity in various countries; 4) we suggest that the number of IEI centers and IEI experts closely correlate to the most important treatment parameters; 5) we propose that specialist education among medical professionals plays pivotal role in increasing levels of diagnostics and adequate care of this vulnerable and still highly neglected patient population; 6) this study also provides the basis for further analysis of more specific aspects of IEI care including genetic diagnostics, disease specific prevalence, newborn screening and professional collaboration in JP countries

Arg126 and Asp49 Are Essential for the Catalytic Function of Microsomal Prostaglandin E2 Synthase 1 and Ser127 Is Not.

Prostaglandins are signaling molecules that regulate different physiological processes, involving allergic and inflammatory responses and cardiovascular control. They are involved in several pathophysiological processes, including inflammation and cancer. The inducible terminal enzyme, microsomal prostaglandin E synthase 1 (MPGES1), catalyses prostaglandin E2 production during inflammation. MPGES1 has therefore been intensively studied as a pharmaceutical target and many competitive inhibitors targeting its active site have been developed. However, little is known about its catalytic mechanism.The objective of this study was to investigate which amino acids play a key role in the catalytic mechanism of MPGES1.Based on results and predictions from previous structural studies, the amino acid residues Asp49, Arg73, Arg126, and Ser127 were chosen and altered by site-directed mutagenesis. The mutated enzyme variants were cloned and expressed in both the E. coli and the Baculovirus expression systems. Their catalytic significance was evaluated by activity measurements with prostanoid profiling.Our study shows that Arg126 and Asp49 are absolutely required for the catalytic activity of MPGES1, as when exchanged, the enzyme variants loose activity. Ser127 and Arg73 on the other hand, don't seem to be central to the catalytic mechanism because when exchanged, their variants retain considerable activity. Our finding that the Ser127Ala variant retains activity was surprising since high-resolution structural data supported a role in glutathione activation. The close proximity of Ser127 to the active site is, however, supported since the Ser127Cys variant displays 80% lowered activity

Multi-Objects Robotic Grasping Optimization Employing a 2D camera

Artificial intelligence algorithms can be exploited to enhance identification, localization, and grasping performance in robotics applications, employing low-cost vision systems (such as 2D cameras). The aim of this paper is, indeed, to optimize the camera pose to improve object detection tasks considering a mul- tiple objects scenario. Therefore, transfer learning capabilities are required to minimize the experimental effort in subsequent grasps. Bayesian optimization (BO) with transfer learning (TL) capabilities has been proposed to address the mentioned scenario. A grasping task of multiple parts has been considered, being executed by an ABB Yumi single-arm manipulator IRB 14050 with a 2D Cognex AE3 In-Sight camera mounted at its end- effector. The proposed BO+ TL methodology has been compared with BO (without TL). The achieved results show that BO+TL is more efficient than BO exploiting the already available data

Prostanoid profiles for WT MPGES1 and variants Asp49Ala, Arg73Ala, Arg73Leu, Arg126Ala, Arg126Leu, Ser127Ala, expressed in <i>E</i>. <i>Coli</i>.

<p>Prostanoid production was measured by LC-MS/MS after 60 seconds incubations of membrane fractions with PGH₂ (10μM final concentration) and GSH (2.5mM final concentration) at room temperature. Denatured enzymes by boiling were incorporated in the activity assay as controls. All prostanoid measurements of membrane fractions are expressed as mean ± SD from two independent experiment performed in duplicates.</p

Suggested chemical mechanism of PGH₂ isomerization to PGE₂ by MPGES1 and its active site structure highlighting the amino acids altered.

<p>(A) The thiolate of glutathione (GSH) could be stabilized by Arg126 and attack the C9 oxygen of the PGH₂ endoperoxide forming a sulfenic acid ester. An unidentified proton donor protonates the developing C11 oxyanion. This is followed by proton abstraction at C9 via Asp49. A carbonyl forms and the oxygen sulfur bond is broken forming PGE₂. The leaving GSH thiolate could again be stabilized by Arg126. The unidentified proton donor could then take up the proton from Asp49. (B) The reaction starts by proton abstraction at C9 via Asp49. A carbonyl forms and the endoperoxide bridge is broken. The thiol of GSH functions as a proton donor to the developing C11 oxyanion. After that the proton taken up by Asp49 can reprotonate the GSH thiolate. (C) The interaction between MPGES1 and GSH highlighting the positions of Asp49, Arg126 as well as Ser127 that was proposed to stabilize the GSH thiolate.</p

Western Blot analysis of WT MPGES1 and variants Asp49Ala, Arg73Ala, Arg73Leu, Arg126Ala, Arg126Leu, Ser127Ala, expressed in <i>E</i>. <i>Coli</i>.

<p>40μg of membrane fraction was loaded into each well. The exposure time was 5 minutes. As a positive control purified MPGES1 was loaded at different concentrations, yielding: 75ng, 100ng, 150ng, 200ng and 450ng.</p