Over the last few decades we have witnessed an emerging interest in security topics and mechanisms to analyse these. In the context of globalization, new threats have appeared (not only interstate, ...but mainly, intra- and trans-state), as well as theoretical approaches (such as Critical Security Studies, CSS) to deal with them. Regarding the South American region it is useful to consider the constitution of the Unasur as a forum to coordinate policies with a very relevant geostrategic and security influence. In this paper, I deal with the logics that motivated the birth of the UNASUR project, in order to examine the way this regional project acts against different types of security threats and regional crises until 2016-17, when Venezuelan crises escalated. Furthermore, empirical evidences are tested with the common characteristics proposed by Peoples and Vaughan-Williams for the CSS. Some conclusions are drawn as new aspects have been incorporated to the way UNASUR addressed regional conflicts (security as a derivate concept and a broader security agenda), while an important element remained the same: a state-centric perspective.
Massive Open Online Courses (MOOCs) have democratized access to higher education, but low entry and exit barriers make dropout rates in these courses much higher than in traditional in-person ...courses. Previous research has explored the main factors driving student dropout and proposed predictive models to identify students at risk. However, it is still unclear what type of interventions should be implemented to effectively reduce the dropout rate in MOOCs. We use findings from the literature to propose a theoretical framework to guide the design of interventions to reduce dropout in MOOCs. We design four interventions and implement them using A/B testing and natural experiment approaches in courses of the MITx MicroMasters® Program in Supply Chain Management (a MOOC-based program). Our findings reveal that ad hoc interventions communicated via email are not effective in reducing dropout, but interventions that modify course contents to make them more approachable for students show a positive impact on dropout reduction. By proposing a theoretical framework and uncovering the design features that can help to create effective interventions for dropout reduction, we provide a foundation for further research in the area of dropout interventions. This paper offers guidance to MOOC designers and instructors on how to improve student engagement and increase completion rates.
•Dropout rate in Massive Open Online Courses is much higher than in traditional in-person courses.•Dropout interventions can be designed using institutional factors as levers to influence personal factors.•Implementing interventions using A/B testing and natural experiment approaches reveal their effectiveness.•Ad hoc interventions communicated via email are not effective in reducing dropout.•Interventions that modify course contents to make them more attainable for students are effective in reducing dropout.
En este trabajo se abordan las relaciones político-diplomáticas entre España y Brasil desde un enfoque histórico de política exterior, entendiendo la política exterior como una política pública ...diseñada en base a las negociaciones entre actores diversos y tendente a satisfacer el bienestar de los ciudadanos. A través de un recorrido histórico por las relaciones entre estos dos países y en aras a analizar el estado de los lazos entre Brasilia y Madrid, en este artículo se desglosa en primer lugar la naturaleza de esas relaciones en las últimas décadas. Después, se incorporan las respectivas perspectivas de política exterior desde ambas cancillerías (el Palacio de Santa Cruz e Itamaraty), enmarcándolas en sus propios procesos regionales y a la luz de los constreñimientos contextuales y estructurales que modulan o delimitan las posibilidades de actuación en el ámbito internacional. Seguidamente se diseccionan las relaciones bilaterales en el escenario actual y finalmente se extraen una suerte de conclusiones o claves que sirvan de brújula para interpretar adecuadamente estas relaciones, sustentadas en una fuerte divergencia entre los agentes que diseñan las respectivas políticas exteriores.
Abstract Informed by an understanding that the quest for autonomy can serve as a compass of Brazil’s foreign policy, this paper undertakes an extensive interpretative analysis of the concept in ...relation to the agency/structure debate. Our aim is to use these theoretical tools to analyse Brazil’s international action during the 21st century, paying special attention to Bolsonaro’s administration. This article argues that we are witnessing a dual break in autonomy: an essentially structural break related to the underlying trends currently redesigning the international world as we know it, and another more agential break, resulting from president Bolsonaro’s particular worldview.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Midkine (MK) is a neurotrophic factor that participates in the embryonic central nervous system (CNS) development and neural stem cell regulation, interacting with sulfated glycosaminoglycans (GAGs). ...Chondroitin sulfate (CS) is the natural ligand in the CNS. In this work, we describe the interactions between a library of synthetic models of CS‐types and mimics. We did a structural study of this library by NMR and MD (Molecular Dynamics), concluding that the basic shape is controlled by similar geometry of the glycosidic linkages. Their 3D structures are a helix with four residues per turn, almost linear. We have studied the tetrasaccharide‐midkine complexes by ligand observed NMR techniques and concluded that the shape of the ligands does not change upon binding. The ligand orientation into the complex is very variable. It is placed inside the central cavity of MK formed by the two structured beta‐sheets domains linked by an intrinsically disordered region (IDR). Docking analysis confirmed the participation of aromatics residues from MK completed with electrostatic interactions. Finally, we test the biological activity by increasing the MK expression using CS tetrasaccharides and their capacity in enhancing the growth stimulation effect of MK in NIH3T3 cells.
The spatial structures of the active complex of midkine and synthetic chondroitin sulfate tetrasaccharides have been solved by NMR spectroscopy and molecular dynamics simulations. The rigid ligand is enclosed by a flexible receptor, with an intrinsically disordered region. The 3D structure of the ligands remains as a helical, almost lineal structure, independently of the aromatic substituents introduced.
Chondroitin sulfate (CS) is a member of the glycosaminoglycan (GAG) family, a class of polysaccharides implicated in relevant biological functions. The structural complexity of these carbohydrates ...demands the development of simple glycomimetics as useful tools to study the biological processes in which GAGs are involved. In this work we described the synthesis of the disaccharide unit of the CS‐E (GlcA‐GalNAc(4,6‐di‐OSO3)), in a multivalent presentation. Using a fluorescence polarization competition assay we have demonstrated that a hexavalent dendrimer of this disaccharide interact with midkine, in the low micromolar range. This result highlights the potency of these disaccharide‐displaying multivalent systems as interesting mimetics of longer and synthetically more complex GAG oligosaccharides.
Click for chondroitin sulfates: Dendrimers displaying CS disaccharides were efficiently synthesized. These multivalent systems showed high protein binding affinities, mimicking the activity of this biologically relevant polysaccharide.
Ischemic Vascular Damage Can Be Repaired by Healthy, but Not Diabetic, Endothelial Progenitor Cells
Sergio Caballero 1 ,
Nilanjana Sengupta 1 ,
Aqeela Afzal 1 ,
Kyung-Hee Chang 1 ,
Sergio Li Calzi 1 ...,
Dennis L. Guberski 2 ,
Timothy S. Kern 3 and
Maria B. Grant 1
1 Program in Stem Cell Biology, Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida
2 Biomedical Research Models, Worcester, Massachusetts
3 Department of Medicine, Case Western Reserve University, Cleveland, Ohio
Address correspondence and reprint requests to Maria B. Grant, MD, Pharmacology and Therapeutics, University of Florida, P.O.
Box 100267, Gainesville, FL 32610-0267. E-mail: grantma{at}pharmacology.ufl.edu
Abstract
Endothelial precursor cells (EPCs) play a key role in vascular repair and maintenance, and their function is impeded in diabetes.
We previously demonstrated that EPCs isolated from diabetic patients have a profound inability to migrate in vitro. We asked
whether EPCs from normal individuals are better able to repopulate degenerate (acellular) retinal capillaries in chronic (diabetes)
and acute (ischemia/reperfusion I/R injury and neonatal oxygen-induced retinopathy OIR) animal models of ocular vascular
damage. Streptozotocin-induced diabetic mice, spontaneously diabetic BBZDR/Wor rats, adult mice with I/R injury, or neonatal
mice with OIR were injected within the vitreous or the systemic circulation with fluorescently labeled CD34 + cells from either diabetic patients or age- and sex-matched healthy control subjects. At specific times after administering
the cells, the degree of vascular repair of the acellular capillaries was evaluated immunohistologically and quantitated.
In all four models, healthy human (hu)CD34 + cells attached and assimilated into vasculature, whereas cells from diabetic donors uniformly were unable to integrate into
damaged vasculature. These studies demonstrate that healthy huCD34 + cells can effectively repair injured retina and that there is defective repair of vasculature in patients with diabetes.
Defective EPCs may be amenable to pharmacological manipulation and restoration of the cells’ natural robust reparative function.
EPC, endothelial precursor cell
I/R, ischemia/reperfusion
LSCM, laser scanning confocal microscope
OIR, oxygen-induced retinopathy
SDF, stromal-derived factor
STZ, streptozotocin
VEGF, vascular endothelial growth factor
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted December 25, 2006.
Received September 6, 2006.
DIABETES
Angiotensin-converting enzyme (ACE)-2 is the primary enzyme of the vasoprotective axis of the renin angiotensin system that regulates the classic renin angiotensin system axis. We aimed to determine ...whether local retinal overexpression of adenoassociated virus (AAV)–ACE2 prevents or reverses diabetic retinopathy. Green fluorescent protein ( GFP )–chimeric mice were generated to distinguish resident (retinal) from infiltrating bone marrow–derived inflammatory cells and were made diabetic using streptozotocin injections. Retinal digestion using trypsin was performed and acellular capillaries enumerated. Capillary occlusion by GFP+ cells was used to measure leukostasis. Overexpression of ACE2 prevented (prevention cohort: untreated diabetic, 11.3 ± 1.4; ACE2 diabetic, 6.4 ± 0.9 per mm2 ) and partially reversed (reversal cohort: untreated diabetic, 15.7 ± 1.9; ACE2 diabetic, 6.5 ± 1.2 per mm2 ) the diabetes-associated increase of acellular capillaries and the increase of infiltrating inflammatory cells into the retina (F4/80+ ) (prevention cohort: untreated diabetic, 24.2 ± 6.7; ACE2 diabetic, 2.5 ± 1.6 per mm2 ; reversal cohort: untreated diabetic, 56.8 ± 5.2; ACE2 diabetic, 5.6 ± 2.3 per mm2 ). In both study cohorts, intracapillary bone marrow–derived cells, indicative of leukostasis, were only observed in diabetic animals receiving control AAV injections. These results indicate that diabetic retinopathy, and possibly other diabetic microvascular complications, can be prevented and reversed by locally restoring the balance between the classic and vasoprotective renin angiotensin system.
E-commerce's rapid growth, combined with customer demand for fast shipping, has significantly escalated last-mile transportation, particularly home deliveries. This surge calls for novel strategies ...to optimize vehicle utilization while maintaining timely delivery. In response, many online retailers are incentivizing customers to embrace delayed home deliveries by offering economic incentives. Nonetheless, current transportation systems fall short in accommodating orders with extended delivery windows, primarily adhering to the First-In-First-Out rule and distance minimization via the Vehicle Routing Problem (VRP). In this paper, we introduce a new consolidation-based delivery methodology that addresses these challenges. Our approach accounts for orders with daily-based time windows and also anticipates future demand realizations (i.e., expected incoming orders). We characterize this consolidation problem using a Mixed Integer Linear Programming model and propose a custom metaheuristic approach that can tackle the problem on a large-scale setting, introducing a significant novelty approach in last-mile delivery research. We applied our methodology to one of Mexico's largest retailers and compared its performance against the company's existing transportation systems. Our approach substantially improves vehicle utilization and yields considerable reductions in distance traveled, time, and overall transportation costs, achieving cost savings of up to 52%. These savings represent tangible benefits, enabling potential revenue enhancements for businesses and cost-effective, timely deliveries for consumers. Additionally, the increased vehicle utilization implies fewer vehicles are needed for the same volume of deliveries, thereby enhancing operational efficiency. This innovative approach, therefore, presents a practical and highly effective solution for managing large-scale last-mile delivery scenarios.
Lemon balm is herbal tea used for soothing stomach cramps, indigestion, and nausea. Rosmarinic acid (RA) is one of its chemical constituents known for its therapeutic potentials against cancer, ...inflammatory and neuronal diseases such as the treatment of neurofibromatosis or prevention from Alzheimer's diseases (AD). Despite efforts, recovery and purification of RA in high yields has not been entirely successful. Here, we report its aqueous extraction with optimal conditions and decipher the structure by nuclear magnetic resonance (NMR) spectroscopy. Using various physical-chemical and biological assays, we highlight its anti-aggregation inhibition potentials against the formation of Tau filaments, one of the hallmarks of AD. We then examine its anti-cancer potentials through reduction of the mitochondrial reductase activity in tumor cells and investigate its electrochemical properties by cyclic voltammetry. Our data demonstrates that RA is a prominent biologically active natural product with therapeutic potentials for drug discovery in AD, cancer therapy and inflammatory diseases.
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