Regulation of NKG2D-Dependent NK Cell Functions: The Yin and the Yang of Receptor Endocytosis.

Natural-killer receptor group 2, member D (NKG2D) is a well characterized natural killer (NK) cell activating receptor that recognizes several ligands poorly expressed on healthy cells but up-regulated upon stressing stimuli in the context of cancer or viral infection. Although NKG2D ligands represent danger signals that render target cells more susceptible to NK cell lysis, accumulating evidence demonstrates that persistent exposure to ligand-expressing cells causes the decrease of NKG2D surface expression leading to a functional impairment of NKG2D-dependent NK cell functions. Upon ligand binding, NKG2D is internalized from the plasma membrane and sorted to lysosomes for degradation. However, receptor endocytosis is not only a mechanism of receptor clearance from the cell surface, but is also required for the proper activation of signalling events leading to the functional program of NK cells. This review is aimed at providing a summary of current literature relevant to the molecular mechanisms leading to NKG2D down-modulation with particular emphasis given to the role of NKG2D endocytosis in both receptor degradation and signal propagation. Examples of chronic ligand-induced down-regulation of NK cell activating receptors other than NKG2D, including natural cytotoxicity receptors (NCRs), DNAX accessory molecule-1 (DNAM1) and CD16, will be also discussed

PRM102 Budget Impact Analysis of Delayed-Release Dimethylfumarate In The Treatment of Relapsing-Remitting Multiple Sclerosis In Italy

INTRODUCTION: Multiple Sclerosis (MS) is a condition with a significant economic and social burden that affects young adults, in their active working phase. The most recent evaluations show an annual average social cost of € 38-39 thousand per patient. Today the approval of the new oral therapies allows physicians to select further options that can meet patients’ clinical unmet needs. OBJECTIVES: To evaluate the economic impact of a recently approved therapy, delayed-release dimethyl-fumarate (DMF; also known as gastro-resistant DMF), on the overall management costs of relapsing-remitting multiple sclerosis (RRMS) in Italy. METHODS: A budget impact model, adopting the perspective of the Italian National Healthcare Service (NHS), was used to compare healthcare costs of two different treatment scenarios: a) base-case, where DMF is not available for RRMS patients (Scenario A), vs. b) alternative-case, where DMF is available for RRMS patients (Scenario B). Healthcare costs sustained by the Italian NHS to manage the RRMS population (drug treatment, administration, therapy and disease monitoring, relapse management, treatment-related adverse events) have been calculated over 3 years and compared for the two scenarios. Impact of relapses for the disease modifying therapies (DMTs) included in the analysis was estimated using an elaboration of the results from published mixed treatment comparison. RRMS population treated with DMTs was estimated using Italian prevalence and incidence data. According to these estimates, the number of treated patients amounted to 36,078 at Year 1, 38,832 at Year 2, and 40,673 at Year 3. RESULTS: According to the current price and to the assumptions reported in the methodology section, it was estimated that the introduction of DMF (Scenario B) determines a decrease of the budget impact, if compared with the base case (Scenario A) in the perspective of Italian NHS. Over three years, the budget impact would be € 1,376 mln in the Scenario A and € 1,354 mln in the Scenario B (-22.18 mln €; -1.61% relative budget variation). The main drivers for cost-saving were pharmacological treatment costs and reduced burden of relapses (corresponding to more than 1,800 avoided relapses). CONCLUSIONS: At the current cost conditions applied in Italy and according to the described assumptions, the use of DMF is economically sustainable for the Italian NHS. Plausibly, the introduction and usage of this new therapy in RRMS patients will ensure clinical benefits for patients without resulting in additional costs for the Italian NHS. [In Italian

Effective Field Theory for the perturbations of a slowly rotating black hole

We develop the effective theory for perturbations around black holes with scalar hair, in two directions. First, we show that the scalar-Gauss-Bonnet theory, often used as an example exhibiting scalar black hole hair, can be deformed by galileon operators leading to order unity changes to its predictions. The effective theory for perturbations thus provides an efficient framework for describing and constraining broad classes of scalar-tensor theories, of which the addition of galileon operators is an example. Second, we extend the effective theory to perturbations around an axisymmetric, slowly rotating black hole, at linear order in the black hole spin. We also discuss the inclusion of parity-breaking operators in the effective theory.We develop the effective theory for perturbations around black holes with scalar hair, in two directions. First, we show that the scalar-Gauss-Bonnet theory, often used as an example exhibiting scalar black hole hair, can be deformed by galileon operators leading to order unity changes to its predictions. The effective theory for perturbations thus provides an efficient framework for describing and constraining broad classes of scalar-tensor theories, of which the addition of galileon operators is an example. Second, we extend the effective theory to perturbations around an axisymmetric, slowly rotating black hole, at linear order in the black hole spin. We also discuss the inclusion of parity-breaking operators in the effective theory

Immigrant entrepreneurs, diasporas, and exports

This paper demonstrates the positive effect of immigrant entrepreneurs on manufacturing exports over and above that of diasporas. Using small\u2010scale regional administrative data, our instrumental variable estimates of export gravity models imply that ceteris paribus, that is, holding constant the total number of immigrants, the expected protrade effect of a migrant becoming an entrepreneur amounts to an average increase of US$5,946 in the export flows toward her country of origin. Besides these dyadic effects, immigrant entrepreneurs unlike nonentrepreneurial immigrants raise a region's overall competitiveness and export flows toward other destinations as well

Network Analysis of World Trade using the BACI-CEPII dataset

In this paper we explore the BACI-CEPII database using Network Analysis. Starting from the visualization of the World Trade Network, we then define and describe the topology of the network, both in its binary version and in its weighted version, calculating and discussing some of the commonly used network's statistics. We finally discuss some specic topics that can be studied using Network Analysis and International Trade data, both at the aggregated and sectoral level. The analysis is done using multiple software (Stata, R, and Pajek). The scripts to replicate part of the analysis are included in the appendix, and can be used as an handson tutorial. Moreover,the World Trade Network local and global centrality measures, for the unweighted and the weighted version of the Network, calculated using the bilateral aggregate trade data for each country (178 in total) and each year (from 1995 to 2010,) can be downloaded from the CEPII webpage

Cu-catalyzed Si-NWS grown on “carbon paper” as anodes for Li-ion cells

The very high theoretical capacity of the silicon (4200mAh/g more than 10 times larger than graphite), environmental-friendly, abundant and low-cost, makes it a potential candidate to replace graphite in high energy density Li-ion batteries. As a drawback, silicon suffers from huge volume changes (300%) on alloying and dealloying with Li, leading a structural deformation that induces disruption. The use of nanostructured silicon materials has been shown to be an effective way to avoid this mechanical degradation of the active material. In this paper the synthesis of silicon nanowires, grown on a highly porous 3D-like carbon paper substrate by CVD using Cu as the catalyst, is presented. The use of carbon paper allows to achieve remarkable loadings of active material (2-5 mg/cm2) and, consequently, high capacity densities. The silicon electrode was investigated both morphologically and electrochemically. To improve the electrochemical performance various strategies have been carried out. It was observed that a very slow first cycle (C/40), which helps the formation of a stable solid electrolyte interphase on the silicon surface, improves the performance of the cells; nevertheless, their cycle life has been found not fully satisfactory. Morphological analysis of the Si-NWs electrodes before and after cycling showed the presence of a dense silicon layer below the nanowires which could reduce the electrical contact between the active material and the substrate

Tinjauan Geografis Perumahan Gading Jaya Kotabaru Kecamatan Tanjung Karang Timur Bandar Lampung Tahun 2016

The research aimed to find out geographical review of Gading Jaya Residence Kotabaru, East Tanjung Karang Sub-district, Bandar Lampung in 2016.The data collecting technique was done through field observation technique and documentation.The research method used in the research was explorative description. Results of the research showed that: (1) the topography of Gading Jaya Residence is appropriate since its height difference is 18 mand its slope is 2% - 15%, (2) the soil type of Gading Jaya Residence is Mediterranean (lime) and Latosol which are appropriate for residence construction, (3) the average rainfall at Gading Jaya residence is average since yearly average rainfall is below 4.000 mm, (4) the land use for housing at Gading Jaya is based on the criteria issued by PU (Pekerjaan Umum) department, and (5) the depth of ground water at Gading Jaya Residence is 100% or entirely considered deep.Penelitian ini dilakukan bertujuan untuk mengetahui tinjauan geografis Perumahan Gading Jaya Kotabaru Kecamatan Tanjung Karang Timur Bandar LampungTahun 2016. Pengumpulan data dilakukan dengan menggunakan teknik observasi lapangan dan dokumentasi.Teknik analisis deskriptif eksploratif. Hasil penelitian menunjukan bahwa: (1) Topografi Perumahan Gading Jaya sesuai karena memiliki beda tinggi 18 meter serta memiliki kemiringan lereng 2% - 15%. (2) Jenis tanah Perumahan Gading Jaya adalah mediteranian (kapur) dan latosol sesuai untuk dibangun Perumahan. (3) Rata-rata curah hujan di Perumahan Gading Jaya sesuai karena rata-rata curah hujan per tahunnya < 4.000 mm. (4) Penggunaan lahan di Perumahan Gading Jaya sudah sesuai dengan kriteria penggunaan lahan untuk Perumahan yang dikeluarkan kementerian Pekerjaan Umum (PU) serta,(5) Kedalaman air tanah di Perumahan Gading Jaya 100% atau seluruhnya termasuk dalam kriteria dalam

LEO object’s light-curve acquisition system and their inversion for attitude reconstruction

In recent years, the increase in space activities has brought the space debris issue to the top of the list of all space agencies. The fact of there being uncontrolled objects is a problem both for the operational satellites in orbit (avoiding collisions) and for the safety of people on the ground (re-entry objects). Optical systems provide valuable assistance in identifying and monitoring such objects. The Sapienza Space System and Space Surveillance (S5Lab) has been working in this field for years, being able to take advantage of a network of telescopes spread over different continents. This article is focused on the re-entry phase of the object; indeed, the knowledge of the state of the object, in terms of position, velocity, and attitude during the descent, is crucial in order to predict as accurately as possible the impact point on the ground. A procedure to retrieve the light curves of orbiting objects by means of optical data will be shown and a method to obtain the attitude determination from their inversion based on a stochastic optimization (genetic algorithm) will be proposed

Unveiling the Molecular Mechanisms Driving the Capsaicin-Induced Immunomodulatory Effects on PD-L1 Expression in Bladder and Renal Cancer Cell Lines

The blockade of the PD-L1/PD-1 immune checkpoint has promising efficacy in cancer treatment. However, few patients with bladder cancer (BC) or renal cell carcinoma (RCC) respond to this approach. Thus, it is important to implement a strategy to stimulate the immune anti-tumor response. In this scenario, our study evaluated the effects of a low capsaicin (CPS) dose in BC and RCC cell lines. Western blot, qRT-PCR and confocal microscopy were used to assess PD-L1 mRNA and protein expression. Alterations to the cellular oxidative status and changes to the antioxidant NME4 levels, mRNA modulation of cytokines, growth factors, transcriptional factors and oncogene, and the activation of Stat1/Stat3 pathways were examined using Western blot, cytofluorimetry and qRT-PCR profiling assays. In BC, CPS triggers an altered stress oxidative-mediated DNA double-strand break response and increases the PD-L1 expression. On the contrary, in RCC, CPS, by stimulating an efficient DNA damage repair response, thus triggering protein carbonylation, reduces the PD-L1 expression. Overall, our results show that CPS mediates a multi-faceted approach. In modulating PD-L1 expression, there is a rationale for CPS exploitation as a stimulus that increases BC cells' response to immunotherapy or as an immune adjuvant to improve the efficacy of the conventional therapy in RCC patients