Enhancing leptin response by preventing SH2-containing phosphatase 2 interaction with Ob receptor

Leptin is an adipocyte-derived cytokine that regulates food intake and body weight via interaction with its Ob receptor (ObR). Serum leptin levels are chronically elevated in obese humans, suggesting that obesity may be associated with leptin resistance and the inability to generate an adequate ObR response. Evidence suggests that transcriptional activation of target genes by STAT3 (signal transducer and activator of transcription) in the hypothalamus is a critical pathway that mediates leptin’s action. Herein we report that activation of ObR induces the tyrosine phosphorylation of the tyrosine phosphatase SH2-containing phosphatase 2 (SHP-2) and demonstrate that Tyr986 within the ObR cytoplasmic domain is essential to mediate phosphorylation of SHP-2 and binding of SHP-2 to ObR. Surprisingly, mutation of Tyr986 to Phe, which abrogates SHP-2 phosphorylation and binding to the receptor, dramatically increases gene induction mediated by STAT3. Our findings indicate that SHP-2 is a negative regulator of STAT3-mediated gene induction after activation of ObR and raise the possibility that blocking the interaction of SHP-2 with ObR could overcome leptin resistance by boosting leptin’s weight-reducing effects in obese individuals.

Multiple Perspectives on Academic Service-Learning Partnerships at the American University in Cairo: A Mixed Method Study

This mixed method study aimed to redress the gap in the literature on academic service-learning partnerships, especially in Eastern settings. It utilized Enos and Morton's (2003) theoretical framework to explore these partnerships at the American University in Cairo (AUC). Seventy-nine community partners, administrators, faculty members, and students from a diverse range of age, citizenship, racial, educational, and professional backgrounds participated in the study. Qualitative interviews were conducted with members of these four groups, and a survey with both close-ended and open-ended questions administered to students yielded 61 responses. Qualitative analyses revealed that the primary motivators for partners' engagement in service-learning partnerships included contributing to the community, enhancing students' learning and growth, and achieving the civic mission of the University. These partnerships were characterized by short-term relationships with partners' aspiring to progress toward long-term commitments. The challenges to these partnerships included issues pertaining to the institution, partnering organizations, culture, politics, pedagogy, students, and faculty members. Key strategies for improving these partnerships included institutionalizing service-learning in the University and cultivating an institutional culture supportive of community engagement. Quantitative analyses showed statistically significant relationships between students' scores on the Community Awareness and Interpersonal Effectiveness scales and their overall participation in community service activities inside and outside the classroom, as well as a statistically significant difference between their scores on the Community Awareness scale and department offering service-learning courses. The study's outcomes underscore the role of the local culture in shaping service-learning partnerships, as well as the role of both curricular and extracurricular activities in boosting students' awareness of their community and interpersonal effectiveness. Cultivating a culture of community engagement and building support mechanisms for engaged scholarship are among the critical steps required by public policy-makers in Egypt to promote service-learning in Egyptian higher education. Institutionalizing service-learning partnerships at AUC and enhancing the visibility of these partnerships on campus and in the community are essential to the future growth of these collaborations. Future studies should explore factors affecting community partners' satisfaction with these partnerships, top-down and bottom-up support to service-learning, the value of reflection to faculty members, and the influence of students' economic backgrounds on their involvement in service-learning partnerships.

Ultrathin high-index metasurfaces for shaping focused beams

The volume size of a converging wave, which plays a relevant role in image resolution, is governed by the wavelength of the radiation and the numerical aperture (NA) of the wavefront. We designed an ultrathin (λ/8 width) curved metasurface that is able to transform a focused field into a high-NA optical architecture, thus boosting the transverse and (mainly) on-axis resolution. The elements of the metasurface are metal-insulator subwavelength gratings exhibiting extreme anisotropy with ultrahigh index of refraction for TM polarization. Our results can be applied to nanolithography and optical microscopy.

A essência do Arbutus unedo: caraterização morfológica e genética do medronheiro de Castelo de Paiva

O medronheiro é um arbusto da região mediterrânica que pode ser encontrada por todo o país. Ao contrário do que verifica na região sul do país, no concelho de Castelo de Paiva é atribuída uma reduzida importância económica a esta espécie. Com o intuito de preservar e potenciar a produção desta espécie e contribuir para a dinamização da economia do concelho, procedeu-se à caracterização morfológica e genética de uma amostra da população de medronheiros de Castelo de Paiva. A caracterização morfológica e genética foi realizada para um total de 10 genótipos. Para tal recolheram-se 70 folhas aleatoriamente em cada árvore. Em 40 folhas mediu-se o comprimento, largura, comprimento do pedúnculo, peso fresco, peso seco e determinou-se a área foliar. Dos caracteres morfológicos analisados, aqueles que se revelaram mais úteis na distinção dos vários genótipos foram: comprimento do pedúnculo, peso fresco e peso seco. As restantes 30 folhas foram utilizadas para a caracterização genética. Esta caracterização foi realizada recorrendo a um marcador de DNA, ISSR. Os 5 primeiros exemplaresutilizados na técnica de ISSR demonstraram-se polimórficos. Os resultados da caracterização genética sugerem que a variabilidade genética na população é média a alta.

The Drivers of Current Account Surplus in Germany and the Politics of Rebalancing in the Eurozone. EU Centre, Singapore Working Paper No. 24, April 2015

Current account deficits have caught the public’s attention as they have contributed to the European debt crisis. However, surpluses also constitute an issue as a deficit in any country must be financed through a surplus in another country. In 2013, Germany, now the world’s largest surplus economy, registered a record high US$273 billion surplus. This paper looks at what accounts for Germany’s surplus, revealing that the major driving factors include strong global demand for quality German exports, domestic wage restraint, an undervalued single currency, high domestic savings rate and interest rate convergence in the euro area. This paper echoes the US Treasury’s view that a persistent German surplus makes it harder for the eurozone as a whole and the southern peripheral economies in particular to recover from the current financial crisis by imposing a Europe-wide “deflationary bias” through pushing up the exchange rate of the euro, exporting feeble German inflation and projecting its ultra-tight macroeconomic policies onto crisis economies. This paper contends that Germany’s trade surplus is likely to endure as Germany and other eurozone countries uphold diverging views on the nature of the surplus engage in a blame-game amidst a sluggish rebalancing process. Prizing the surplus as a reflection of hard work and economic competitiveness, German authorities urge their southern eurozone colleagues to undertake bold structural reforms to correct the imbalance, while the hand-tied governments in crisis-stricken economies call on Germany to do its “homework” by boosting German demands for European goods and services.

Can the new refugee relocation system work? Perils in the Dublin logic and flawed reception conditions in the EU. CEPS Policy Brief No. 332, October 2015 Thursday, 1 October 2015

This Policy Brief argues that the newly adopted EU temporary relocation (quota) system constitutes a welcome yet timid step forward in addressing a number of central controversies of the current refugee debate in Europe. Two main challenges affect the effective operability of the new EU relocation model. First, EU member states’ asylum systems show profound (on-the-ground) weaknesses in reception conditions and judicial/administrative capacities. These prevent a fair and humane processing of asylum applications. EU states are not implementing the common standards enshrined in the EU reception conditions Directive 2013/33. Second, the new relocation system constitutes a move away from the much-criticised Dublin system, but it is still anchored to its premises. The Dublin system is driven by an unfair and unsustainable rule according to which the first EU state of entry is responsible for assessing asylum applications. It does not properly consider the personal, private and family circumstances or the preferences of asylum-seekers. Policy Recommendations In order to respond to these challenges, the Policy Brief offers the following policy recommendations: The EU should strengthen and better enforce member states’ reception capacities, abolish the current Dublin system rule of allocation of responsibility and expand the new relocation distribution criteria to include in the assessment (as far as possible) asylum-seekers’ preferences and personal/family links to EU member states. EU member countries should give priority to boosting their current and forward-looking administrative and judicial capacities to deal and welcome asylum applications. The EU should establish a permanent common European border and asylum service focused on ensuring the highest standards through stable operational support, institutional solidarity across all EU external borders and the practical implementation of new distribution relocation criteria.

The EU and its Counter-Terrorism Policies after the Paris Attacks. Liberty and Security in Europe No. 84, 27 November 2015

This paper examines the EU’s counter-terrorism policies responding to the Paris attacks of 13 November 2015. It argues that these events call for a re-think of the current information-sharing and preventive-justice model guiding the EU’s counter-terrorism tools, along with security agencies such as Europol and Eurojust. Priority should be given to independently evaluating ‘what has worked’ and ‘what has not’ when it comes to police and criminal justice cooperation in the Union. Current EU counter-terrorism policies face two challenges: one is related to their efficiency and other concerns their legality. ‘More data’ without the necessary human resources, more effective cross-border operational cooperation and more trust between the law enforcement authorities of EU member states is not an efficient policy response. Large-scale surveillance and preventive justice techniques are also incompatible with the legal and judicial standards developed by the Court of Justice of the EU. The EU can bring further added value first, by boosting traditional policing and criminal justice cooperation to fight terrorism; second, by re-directing EU agencies’ competences towards more coordination and support in cross-border operational cooperation and joint investigations, subject to greater accountability checks (Europol and Eurojust +); and third, by improving the use of policy measures following a criminal justice-led cooperation model focused on improving cross-border joint investigations and the use of information that meets the quality standards of ‘evidence’ in criminal judicial proceedings. Any EU and national counter-terrorism policies must not undermine democratic rule of law, fundamental rights or the EU’s founding constitutional principles, such as the free movement of persons and the Schengen system. Otherwise, these policies will defeat their purpose by generating more insecurity, instability, mistrust and legal uncertainty for all.

‘The oil friendship’: the state of and prospects for Russian-Chinese energy cooperation. OSW Commentary NUMBER 197|17.02.2016

The oil sector has been the major element of Russian-Chinese energy cooperation. The years 2013–2015 saw a significant increase in the volume of crude oil exported by Russia. In 2015, China became the main importer of Russian oil; Russia became the second largest supplier of oil to the Chinese market, after Saudi Arabia. From Beijing’s perspective, supplies of Russian oil are of strategic importance because the main supply routes are overland routes. Russia, for its part, is interested in boosting its export because of its deteriorating position on the European market, which hitherto has been considered a strategic market.

Handling the Problem of Unbalanced Data Sets in the Classification of Technical Equipment States

Questions of handling unbalanced data considered in this article. As models for classification, PNN and MLP are used. Problem of estimation of model performance in case of unbalanced training set is solved. Several methods (clustering approach and boosting approach) considered as useful to deal with the problem of input data.

Essays on the Analysis of Dynamic Games

Thesis (Ph.D.)--University of Washington, 2016-06

Downregulation of IgE antibody and allergic responses in the lung by epidermal biolistic microparticle delivery

Background: Biolistic injections provide a needle-free delivery of antigen-laden microparticles to the epithelium. The precision of the injection preferentially targets the Langerhans cell network, which, although ideal for vaccination, might not be suitable for the downregulation of immune responses in immunotherapy. Objective: We sought to determine the ability of biolistic injection of antigen into the epithelium of sensitized mice to inhibit IgE antibody and lung inflammatory responses produced by further exposure to antigen. Methods: Mice were sensitized by means of a needle injection of ovalbumin (OVA) in alum and given a series of biolistic injections of OVA or vehicle control, followed by a boost of OVA in alum. Serum IgE and IgG antibodies were measured before and after the boost. The mice were then challenged intranasally, and the infiltration of inflammatory cells was measured by means of bronchoalveolar lavage. Airway reactivity of the challenged mice was measured by examining responses to methacholine with forced oscillatory techniques. Results: Biolistic injection of OVA into the dorsal skin of sensitized mice markedly inhibited IgE and IgG1 antibody responses induced by boosting. IgG2a antibody responses were reduced rather than stimulated. The eosinophilic inflammation in the bronchoalveolar lavage fluid induced by intranasal challenge was also markedly inhibited. Lung hyperreactivity showed an initial increase and then a decrease of responsiveness to methacholine, with elastance returning to the level of unsensitized mice. Biolistic injection into the buccal epithelium was also inhibitory. Conclusions: Biolistic injection of allergen inhibited the boosting of IgE antibody and eosinophilic lung inflammatory responses without inducing TO immunity.

Administration routes affect the quality of immune responses:a cross-sectional evaluation of particulate antigen-delivery systems

Particulate delivery systems such as liposomes and polymeric nano- and microparticles are attracting great interest for developing new vaccines. Materials and formulation properties essential for this purpose have been extensively studied, but relatively little is known about the influence of the administration route of such delivery systems on the type and strength of immune response elicited. Thus, the present study aimed at elucidating the influence on the immune response when of immunising mice by different routes, such as the subcutaneous, intradermal, intramuscular, and intralymphatic routes with ovalbumin-loaded liposomes, N-trimethyl chitosan (TMC) nanoparticles, and poly(lactide-co-glycolide) (PLGA) microparticles, all with and without specifically selected immune-response modifiers. The results showed that the route of administration caused only minor differences in inducing an antibody response of the IgG1 subclass, and any such differences were abolished upon booster immunisation with the various adjuvanted and non-adjuvanted delivery systems. In contrast, the administration route strongly affected both the kinetics and magnitude of the IgG2a response. A single intralymphatic administration of all evaluated delivery systems induced a robust IgG2a response, whereas subcutaneous administration failed to elicit a substantial IgG2a response even after boosting, except with the adjuvanted nanoparticles. The intradermal and intramuscular routes generated intermediate IgG2a titers. The benefit of the intralymphatic administration route for eliciting a Th1-type response was confirmed in terms of IFN-gamma production of isolated and re-stimulated splenocytes from animals previously immunised with adjuvanted and non-adjuvanted liposomes as well as with adjuvanted microparticles. Altogether the results show that the IgG2a associated with Th1-type immune responses are sensitive to the route of administration, whereas IgG1 response associated with Th2-type immune responses were relatively insensitive to the administration route of the particulate delivery systems. The route of administration should therefore be considered when planning and interpreting pre-clinical research or development on vaccine delivery systems.

Novel bioadhesive formulations for mucosal and parenteral delivery of vaccines

In this work we have established the efficient mucosal delivery of vaccines using absorption enhancers and chitosan. In addition, the use of chitosan was shown to enhance the action of other known adjuvants, such as CTB or Quil-A. Collectively, the results presented herein indicate that chitosan has excellent potential as a mucosal adjuvant. We have evaluated a number of absorption enhancers for their adjuvant activity in vivo. Polyornithine was shown to engender high scrum immune reasons to nasally delivered antigens, with higher molecular weight polyornithine facilitating the best results. We have demonstrated for the first time that vitamin E TPGS can act as mucosal adjuvant. Deoxycholic acid, cyclodextrins and acylcarnitines were also identified as effective mucosal adjuvants and showed enhanced immune responses to nasally delivered TT, DT and Yersinia pestis V and F1 antigens. Previously, none of these agents, common in their action as absorption enhancing agents, have been shown to have immunopotentiating activity for mucosal immunisation. We have successfully developed novel surface modified microspheres using chitosan as an emulsion stabiliser during the preparation of PLA microspheres. It was found that immune responses could be substantially increased, effectively exploiting the immunopenetrating characteristics of both chitosan and PLA microspheres in the same delivery vehicle. In the same study, comparison of intranasal and intramuscular routes of administration showed that with these formulations, the nasal route could be as effective as intramuscular delivery, highlighting the potential of mucosal administration for these particulate delivery systems. Chitosan was co-administered with polymer microspheres. It was demonstrated that this strategy facilitates markedly enhanced immune responses in both magnitude and duration following intramuscular administration. We conclude that this combination shows potential for single dose administration of vaccines. In another study, we have shown that the addition of chitosan to alum adsorbed TT was able to enhance immune responses. PLA micro/nanospheres were prepared and characterised with discreet particle size ranges. A smaller particle size was shown to facilitate higher scrum IgG responses following nasal administration. A lower antigen loading was additionally identified as being preferential for the induction of immune responses in combination with the smaller particle size. This may be due to the fact that the number of particles will be increased when antigen loading is low, which may in turn facilitate a more widespread uptake of particles. PLA lamellar particles were prepared and characterised. Adsorbed TT was evaluated for the potential to engender immune responses in vivo. These formulations were shown to generate effective immune responses following intramuscular administration. Positively charged polyethylcyanoacrylate and PLA nanoparticies were designed and characterised and their potential as delivery vehicles for DNA vaccines was investigated. Successful preparation of particles with narrow size distribution and positive surface charge (imparted by the inclusion of chitosan) was achieved. In the evaluation of antibody responses to DNA encoded antigen in the presence of alum administered intranasally, discrimination between the groups was only seen following intramuscular boosting with the corresponding protein. Our study showed that DNA vaccines in the presence of either alum or Quil-A may advantageously influence priming of the immune system by a mucosal route. The potential for the combination of adjuvants, Quil-A and chitosan, to enhance antibody responses to plasmid encoded antigen co-administered with the corresponding protein antigen was shown and this is worthy of further investigation. The findings here have identified novel adjuvants and approaches to vaccine delivery. In particular, chitosan or vitamin E TPGS are shown here to have considerable promise as non-toxic, safe mucosal adjuvants. In addition, biodegradable mucoadhesive delivery systems, surface modified with chitosan in a single step process, may have application for other uses such as drug and gene delivery.

Nanotechnology for the delivery of vaccines

Liposomes offer an ideal platform for the delivery of subunit vaccines, due to their versatility and flexibility, which allows for antigen as well as immunostimulatory lipids and TLR agonists to become associated with these bilayered vesicles. Liposomes have the ability to protect vaccine antigen, as well as enhance delivery to antigen presenting cells, whilst the importance of cationic surface charge for delivery of TB subunit vaccines and formation of an ‘antigen depot’ may play a key role in boosting cell-mediated immunity and Th1 immune responses. The rational design of vaccine adjuvants requires the thorough investigation into the physicochemical characteristics that dictate the function of a liposomal adjuvant. Within this thesis, physicochemical characteristics were investigated in order to show any effects on the biodistribution profiles and the ensuing immune responses of these formulations. Initially the role of liposome charge within the formulation was investigated and subsequently their efficacy as vaccine adjuvants in combination with their biodistribution was measured to allow the role of formulation in vaccine function to be considered. These results showed that cationic surface charge, in combination with high loading of H56 vaccine antigen through electrostatic binding, was crucial in the promotion of the ‘depot-effect’ at the injection site which increases the initiation of Th1 cell-mediated immune responses that are required to offer protection against tuberculosis. To further investigate this, different methods of liposome production were also investigated where antigen incorporation within the vesicles as well as surface adsorption were adopted. Using the dehydration-rehydration (DRV) method (where liposomes are freeze-dried in the presence of antigen to promote antigen encapsulation) and the double emulsion (DE) method, a range of liposomes entrapping antigen were formulated. Variation in the liposome preparation method can lead to antigen entrapment within the delivery system which has been shown to be greater for DRV-formulated liposomes compared to their DE-counterparts. This resulted in no significant effect on the vaccine biodistribution profile, as well as not significantly altering the efficacy of cationic liposomal adjuvants. To further enhance the efficacy of these systems, the addition of TLR agonists either at the vesicle surface as well as within the delivery system has been displayed through variation in the preparation method. Anionic liposomal adjuvants have been formulated, which displayed rapid drainage from the injection site to the draining lymph nodes and displayed a reduction in measured Th1 immune responses. However, variation in the preparation method can alter the immune response profile for anionic liposomal adjuvants with a bias in immune response to Th2 responses being noted. Through the use of high shear mixing and stepwise incorporation, the efficient loading of TLR agonist within liposomes has been shown. However, interestingly the conjugation between lipid and non-electrostatically bound TLR agonist, followed by insertion into the bilayer of DDA/TDB resulted in localised agonist retention at the injection site and further stimulation of the Th1 immune response at the SOI, spleen and draining lymphatics as well as enhanced antibody titres.

Digital Creativity: Advantages, Problems, Responsibilities

The paper focuses on the rapid development of the digital culture and the challenges it imposes to human creativity. It analyses e-learning, digital entertainment, digital art and the issues of creativity and improvisation. It also presents a classification of the levels in the creative structure including hardware and software tools; product developers; creators and end users. Special attention is paid to the advantages of the new digital culture and the responsibilities of all people who create it or use it. We conclude that more attention should be paid to the threats and to ways of boosting positive creativity in the various fields of application of information and communication technologies.