Macroeconomics for a Modern Economy

Nobel Prize Lecture, December 8, 2006Macroeconomics;

Insights Into Global Engineering Education After the Birth of Industry 5.0

Insights Into Global Engineering Education After the Birth of Industry 5.0 presents a comprehensive overview of recent developments in the fields of engineering and technology. The book comprises single chapters authored by various researchers and edited by an expert active in the engineering education research area. It provides a thorough overview of the latest research efforts by international authors on engineering education and opens potential new research paths for further novel developments

Reduced Basal Autophagy and Impaired Mitochondrial Dynamics Due to Loss of Parkinson's Disease-Associated Protein DJ-1

BACKGROUND: Mitochondrial dysfunction and degradation takes a central role in current paradigms of neurodegeneration in Parkinson's disease (PD). Loss of DJ-1 function is a rare cause of familial PD. Although a critical role of DJ-1 in oxidative stress response and mitochondrial function has been recognized, the effects on mitochondrial dynamics and downstream consequences remain to be determined. METHODOLOGY/PRINCIPAL FINDINGS: Using DJ-1 loss of function cellular models from knockout (KO) mice and human carriers of the E64D mutation in the DJ-1 gene we define a novel role of DJ-1 in the integrity of both cellular organelles, mitochondria and lysosomes. We show that loss of DJ-1 caused impaired mitochondrial respiration, increased intramitochondrial reactive oxygen species, reduced mitochondrial membrane potential and characteristic alterations of mitochondrial shape as shown by quantitative morphology. Importantly, ultrastructural imaging and subsequent detailed lysosomal activity analyses revealed reduced basal autophagic degradation and the accumulation of defective mitochondria in DJ-1 KO cells, that was linked with decreased levels of phospho-activated ERK2. CONCLUSIONS/SIGNIFICANCE: We show that loss of DJ-1 leads to impaired autophagy and accumulation of dysfunctional mitochondria that under physiological conditions would be compensated via lysosomal clearance. Our study provides evidence for a critical role of DJ-1 in mitochondrial homeostasis by connecting basal autophagy and mitochondrial integrity in Parkinson's disease

Development and Evaluation Of HIV gp120 Responsive Microbicide Formulation for the Prevention of HIV Sexual Transmission

Sexual transmission of HIV remains the primary route (75 to 85%) of HIV infection among all new infection cases. Furthermore, women represent the most vulnerable population and are more susceptible to HIV infections than their male counterpart. Thus, there is an urgent need to develop topical (vaginal/rectal) microbicide formulations capable of preventing HIV sexual transmission. The objective of this dissertation is to develop a mannose specific, lectin-based topical microbicide formulation capable of targeting HIV gp120 for the prevention of HIV sexual transmission. In Chapters 1 and 2, the general hypothesis, aims and scope of this work are introduced. Chapter 3 covers the literature review of anti-HIV lectins and current delivery approaches. In Chapter 4, the binding interactions between the mannose specific lectin Concanavalin A (ConA) and glycogen from Oster, as well as mannan from Saccharomyces cerevisiae, were studied using a quartz crystal microbalance (QCM). The equilibrium dissociation constant describing the interaction between Con A and glycogen (KD = 0.25 μM) was 12 fold lower than the equilibrium dissociation constant describing the binding between Con A and mannan (KD = 2.89 μM). That is, Con A was found to have a higher affinity for the glucose-base polysaccharide, than for the mannose-based. This observation was mainly attributed to steric effects, the difference in molecular weight and branching pattern of both polysaccharides. The knowledge gained in Chapter 4 was applied in Chapter 5 for the development of HIV 1 gp120 and mannose responsive particle (MRP) formulations. Thus, core dissolved MRP (−) and core containing MRP (+) were prepared through the layer-by-layer coating of calcium carbonate (CaCO3) with the mannose specific lectin (Con A) and a polysaccharide cross-linker (Glycogen). Particles were characterized and tested in vitro on Lactobacillus crispatus, Human vaginal keratinocytes (VK2/E6E7) and murine macrophage [RAW 264.7 (TIB 71)] cell lines. + average size and ζ-potential were 1130±15.72 nm [PDI = 0.153] and 15.1±0.55 mV, (n=3). Similarly, − average size and ζ-potential were 1089±23.33 nm (n=3) and -14.2±0.25 mV (n=3). Tenofovir (TFV) encapsulation efficiency in CaCO3 was 74.4% with drug loading of 16.3% w/w and 6.0% w/w in + and −, respectively. Both − and + were nontoxic to L. crispatus and did not induce any significant pro-inflammatory nitric oxide release in VK2 and RAW 264.7 cell culture. However, − was found to significantly affect VK2 and RAW 264.7 cells viability at concentrations ≥ 100 µg/ml. Similarly, − significantly increased pro-inflammatory cytokines (IL1α, IL1β, IL6, IL7, MKC and TNFα) release at concentrations ≥ 100 µg/ml. Conversely, + did not induce any significant changes in VK2 and RAW 264.7 cells viability nor in pro-inflammatory cytokines’ levels, in the concentration range tested (≤ 1000 µg/ml), for 24 h. + was then selected for further in vitro drug release studies as well as ex vivo vaginal mucoadhesion studies. HIV gp120 triggered TFV release from + in a concentration dependent manner, and following Hixson–Crowell and Hopfenberg kinetic models, consistent with drug release from diminishing surface or matrix eroding drug particles. + was further optimized by varying the number of Con A layer in the formulation, and in order to achieve lower HIV gp120 sensitivity (≤ 100 µg/ml). Furthermore, bioadhesion studies, performed ex vivo on porcine vaginal tissue, demonstrated that FITC−+ adheres to vaginal tissue at levels varying between 10% ± 1 and 20% ± 2, depending on the number of Con A layers in the formulation. In chapter 6, + preclinical safety was evaluated in 8-12 weeks old female C57BL/6 mice model. First, mice were treated with Depo-Provera® to maintain them in a diestrus-like state. Then the microbicide formulation was delivered vaginally at a dose of 100 mg/kg in PBS. Vaginal histology, immunohistochemistry evaluations, as well as pro-inflammatory cytokines release (vaginal lavage and tissue extract) were investigated after 24 h. The vaginal retention of FITC−+ was also evaluated, up to 24 h. Vaginal and major reproductive organs’ histology did not show major damage of the epithelial layer. This result was also consistent with immunohistochemistry evaluation of CD45+ cells infiltration in the vaginal epithelial layer, unlike the positive control treated groups (BZK and N-9). Furthermore + did not induce any significant changes in pro-inflammatory cytokines IL1α, Ilβ, IL7, IP10 and TNFα. In addition, it was also observed that FITC labeled + does not have a long-term retention in mice vaginal tract. This result suggested that a precoital or multiple vaginal application (i.e., BID) approaches of + should be investigated. Overall, this study demonstrates the feasibility of lectin-based microbicide formulations to target HIV gp120 for the prevention of HIV sexual transmission

Patient blood management bundles to facilitate implementation

More than 30% of the world's population are anemic with serious economic consequences including reduced work capacity and other obstacles to national welfare and development. Red blood cell transfusion is the mainstay to correct anemia, but it is also 1 of the top 5 overused procedures. Patient blood management (PBM) is a proactive, patient-centered, and multidisciplinary approach to manage anemia, optimize hemostasis, minimize iatrogenic blood loss, and harness tolerance to anemia. Although the World Health Organization has endorsed PBM in 2010, many hospitals still seek guidance with the implementation of PBM in clinical routine. Given the use of proven change management principles, we propose simple, cost-effective measures enabling any hospital to reduce both anemia and red blood cell transfusions in surgical and medical patients. This article provides comprehensive bundles of PBM components encompassing 107 different PBM measures, divided into 6 bundle blocks acting as a working template to develop institutions' individual PBM practices for hospitals beginning a program or trying to improve an already existing program. A stepwise selection of the most feasible measures will facilitate the implementation of PBM. In this manner, PBM represents a new quality and safety standard