Eliciting the mitochondrial unfolded protein response via NAD(+) repletion reverses fatty liver disease

With no approved pharmacological treatment, non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease in western countries and its worldwide prevalence continues to increase along with the growing obesity epidemic. Here we show that a high-fat high-sucrose (HFHS) diet, eliciting chronic hepatosteatosis resembling human fatty liver, lowers hepatic NAD(+) levels driving reductions in hepatic mitochondrial content, function and ATP levels, in conjunction with robust increases in hepatic weight, lipid content and peroxidation in C57BL/6J mice. In an effort to assess the effect of NAD(+) repletion on the development of steatosis in mice, nicotinamide riboside (NR), a precursor for NAD(+) biosynthesis, was given to mice concomitant, as preventive strategy (NR-Prev), and as a therapeutic intervention (NR-Ther), to a HFHS diet. We demonstrate that NR prevents and reverts NAFLD by inducing a SIRT1- and SIRT3-dependent mitochondrial unfolded protein response (UPR(mt) ), triggering an adaptive mitohormetic pathway to increase hepatic β-oxidation and mitochondrial complex content and activity. The cell-autonomous beneficial component of NR treatment was revealed in liver-specific Sirt1 KO mice (Sirt1(hep-/-) ), while Apolipoprotein E-deficient (Apoe(-/-) ) mice challenged with a high-fat high-cholesterol diet (HFC), affirmed the use of NR in other independent models of NAFLD. CONCLUSION Our data warrant the future evaluation of NAD(+) boosting strategies to manage the development or progression of NAFLD. This article is protected by copyright. All rights reserved.

European mobility and local political incorporation: The case of British and Romanian residents in Spain

This paper analyses the impact of European mobility in the field of the political nomination of intra-EU migrants in local elections. The study contributes to the debates in the literature related to immigrant nomination and representation by showing how group resources and political opportunities in the country of residence interact with the political opportunities of the European citizenship regime. It argues that the symbolic and legal status of European identity, representation in the European Parliament and strong links between political institutions in the countries of destination and origin play a positive role in boosting immigrant political entrepreneurs’ visibility vis-à-vis host country political actors. In order to illustrate these findings, the paper provides a qualitative comparison of British and Romanian residents in Spain.

Retinal slit lamp video mosaicking

Purpose To this day, the slit lamp remains the first tool used by an ophthalmologist to examine patient eyes. Imaging of the retina poses, however, a variety of problems, namely a shallow depth of focus, reflections from the optical system, a small field of view and non-uniform illumination. For ophthalmologists, the use of slit lamp images for documentation and analysis purposes, however, remains extremely challenging due to large image artifacts. For this reason, we propose an automatic retinal slit lamp video mosaicking, which enlarges the field of view and reduces amount of noise and reflections, thus enhancing image quality. Methods Our method is composed of three parts: (i) viable content segmentation, (ii) global registration and (iii) image blending. Frame content is segmented using gradient boosting with custom pixel-wise features. Speeded-up robust features are used for finding pair-wise translations between frames with robust random sample consensus estimation and graph-based simultaneous localization and mapping for global bundle adjustment. Foreground-aware blending based on feathering merges video frames into comprehensive mosaics. Results Foreground is segmented successfully with an area under the curve of the receiver operating characteristic curve of 0.9557. Mosaicking results and state-of-the-art methods were compared and rated by ophthalmologists showing a strong preference for a large field of view provided by our method. Conclusions The proposed method for global registration of retinal slit lamp images of the retina into comprehensive mosaics improves over state-of-the-art methods and is preferred qualitatively.

Prime and boost vaccination against HER2/neu in breast cancer

Breast cancer is the most common cancer among women with approximately 180,000 new cases being diagnosed yearly in the United States (1). HER2/neu gene amplification and subsequent protein overexpression is found in 20–30% of breast cancer patients and can lead to the promotion of various metastasis-related properties (2–4) and/or resistance to cancer therapies such as chemotherapy and radiation (5). ^ The protein product of the HER2/neu gene, p185, is a proven target for immunological therapy. Recently, passive immunotherapy with the monoclonal antibody Trastuzumab® has validated an immunological approach to HER2/neu+ breast cancer. Immunity to HER2/ neu, when found in breast cancer patients, is of low magnitude. Vaccination-induced HER2/neu-specific antibodies and HER2/neu-specific cytotoxic T cells could result in long-lived immunity with therapeutic benefit. Many features of DNA vaccines and attenuated viral vectors may contribute to the efficacy of prime-boost vaccination. In particular, vaccines capable of eliciting strong cell-mediated immunity are thought to hold the greatest promise for control of cancer (6–9). ^ To optimize cellular immunization to HER2/neu in my study, the HER2/neu gene was presented to the immune system using a priming vector followed by a second vector used as the boost. In both animals and humans, priming with DNA and boosting with a poxviruses, vaccinia or canarypox appears to be particularly promising for induction of a broad immune responses (10). ^ I tested three gene vaccines encoding the HER2/neu gene: (1) a plasmid, SINCP, that contains part of the genome of Sindbis virus; (2) Viral Replicon Particles (VRP) of Venezuela Equine Encephalitis virus (VEE) and (3) E1/E2a-deleted human Type 5 Adenovirus. In SINCP and the VRP, the caspid and envelope genes of the virus were deleted and replaced with the gene for HER2/neu. SINCP-neu, VRP- neu and Adeno-neu when used alone were effective vaccines protecting healthy mice from challenge with a breast cancer cell line injected in the mammary fat pad or injected i.v. to induce experimental lung metastasis. However, SINCP-neu, VRP-neu or Adeno-neu when used alone were not able to prolong survival of mice in therapeutic models in which vaccination occurred after injection of a breast cancer cell line. ^ When the vaccines were combined in a mixed regimen of a SINCP- neu prime VRP-neu or Adeno-neu boost, there was a significant difference in tumor growth and survival in the therapeutic vaccine models. In vitro assays demonstrated that vaccination with each of the three vaccines induced IgG specific for p185, the gene product of HER2/neu, induced p185-specific T lymphocytes, as measured by tetramer analysis. Vaccination also induced intracellular INF-γ and a positive ELISPOT assay. These findings indicate that SINCP-neu, VRP-neu and Adeno-neu, used alone or in combination, may have clinical potential as adjuvant immunotherapy for the treatment of HER2/neu-expressing tumors. ^

Use of intranet and other interventions to increase influenza vaccination among health care workers

Influenza (the flu) is a serious respiratory illness that can cause severe complications, often leading to hospitalization and even death. Influenza epidemics occur in most countries every year, usually during the winter months. Despite recommendations from the Centers for Disease Control and Prevention (CDC) and efforts by health care institutions across the United States, influenza vaccination rates among health care workers in the United States remain low. How to increase the number of vaccinated health care workers is an important public health question and is examined in two journal articles included here. ^ The first journal article evaluates the effectiveness of an Intranet intervention in increasing the proportion of health care workers (HCWs) who received influenza vaccination. Hospital employees were required go to the hospital's Intranet and select "vaccine received," "contraindicated," or "declined" from the online questionnaire. Declining employees automatically received an online pop-up window with education about vaccination; managers were provided feedback on employees' participation rates via e-mail messages. Employees were reminded of the Intranet requirement in articles in the employee newsletter and on the hospital's Intranet. Reminders about the Intranet questionnaire were provided through managers and newsletters to the HCWs. Fewer than half the employees (43.7%) completed the online questionnaire. Yet the hospital witnessed a statistically significant increase in the percentage of employees who received the flu vaccine at the hospital – 48.5% in the 2008-09 season as compared to 36.5%, 38.5% and 29.8% in the previous three years (P < 0.05). ^ The second article assesses current interventions employed by hospitals, health systems and nursing homes to determine which policies have been the most effective in boosting vaccination rates among American health care workers. A systematic review of research published between January 1994 and March 2010 suggests that education is necessary but not usually sufficient to increase vaccine uptake. Education about the flu and flu vaccines is most effective when complemented with easy access and making the vaccine free, although this combination may not be sufficient to achieve the desired vaccination levels among HCWs. The findings point toward adding incentives for HCWs to get vaccinated and requiring them to record their vaccination status on a declination/consent form – either written or electronic. ^ Based on these findings, American health care organizations, such as hospitals, nursing homes, and long-term care facilities, should consider using online declination forms as a method for increasing influenza vaccination rates among their employees. These online forms should be used in conjunction with other policies, including free vaccine, mobile distribution and incentives. ^ To further spur health care organizations to adopt policies and practices that will raise influenza vaccination rates among employees, The Joint Commission – an independent, not-for- profit organization that accredits and certifies more than 17,000 health care organizations and programs in the United States – should consider altering its standards. Currently, The Joint Commission does not require signed declination forms from employees who eschew vaccination; it only echoes the CDC's recommendations: "Health care facilities should require personnel who refuse vaccination to complete a declination form." Because participation in Joint Commission accreditation is required for Medicare reimbursement, action taken by the Joint Commission to require interventions such as mandatory declination/consent forms might result in immediate action by health care organizations to follow these new standards and lead to higher vaccination rates among HCWs.^ 1“Frequently Asked Questions for H1N1 and Seasonal Influenza.” The Joint Commission - Infection Control: http://www.jointcommission.org/PatientSafety/InfectionControl/h1n1_faq.htm. ^

Elemental contents, non-carbonate, fatty acids and alcohols analysis from different Holes of IODP Expedition 310

During IODP Expedition 310 (Tahiti Sea Level), drowned Pleistocene-Holocene barrier-reef terraces were drilled on the slope of the volcanic island. The deglacial reef succession typically consists of a coral framework encrusted by coralline algae and later by microbialites; the latter make up < 80% of the rock volume. Lipid biomarkers were analyzed in order to identify organisms involved in reef-microbialite formation at Tahiti, as the genesis of deglacial microbialites and the conditions favoring their formation are not fully understood. Sterols plus saturated and monounsaturated short-chain fatty acids predominantly derived from both marine primary producers (algae) and bacteria comprise 44 wt% of all lipids on average, whereas long-chain fatty acids and long-chain alcohols derived from higher land plants represent an average of only 24 wt%. Bacterially derived mono-O-alkyl glycerol ethers (MAGEs) and branched fatty acids (10-Me-C16:0; iso- and anteiso-C15:0 and -C17:0) are exceptionally abundant in the microbial carbonates (average, 19 wt%) and represent biomarkers of intermediate-to-high specificity for sulfate-reducing bacteria. Both are relatively enriched in 13C compared to eukaryotic lipids. No lipid biomarkers indicative of cyanobacteria were preserved in the microbialites. The abundances of Al, Si, Fe, Mn, Ba, pyroxene, plagioclase, and magnetite reflect strong terrigenous influx with Tahitian basalt as the major source. Chemical weathering of the basalt most likely elevated nutrient levels in the reefs and this fertilization led to an increase in primary production and organic matter formation, boosting heterotrophic sulfate reduction. Based on the observed biomarker patterns, sulfate-reducing bacteria were apparently involved in the formation of microbialites in the coral reefs off Tahiti during the last deglaciation.

Transcriptional response to cardiac injury in the zebrafish: systematic identification of genes with highly concordant activity across in vivo models

BACKGROUND Zebrafish is a clinically-relevant model of heart regeneration. Unlike mammals, it has a remarkable heart repair capacity after injury, and promises novel translational applications. Amputation and cryoinjury models are key research tools for understanding injury response and regeneration in vivo. An understanding of the transcriptional responses following injury is needed to identify key players of heart tissue repair, as well as potential targets for boosting this property in humans. RESULTS We investigated amputation and cryoinjury in vivo models of heart damage in the zebrafish through unbiased, integrative analyses of independent molecular datasets. To detect genes with potential biological roles, we derived computational prediction models with microarray data from heart amputation experiments. We focused on a top-ranked set of genes highly activated in the early post-injury stage, whose activity was further verified in independent microarray datasets. Next, we performed independent validations of expression responses with qPCR in a cryoinjury model. Across in vivo models, the top candidates showed highly concordant responses at 1 and 3 days post-injury, which highlights the predictive power of our analysis strategies and the possible biological relevance of these genes. Top candidates are significantly involved in cell fate specification and differentiation, and include heart failure markers such as periostin, as well as potential new targets for heart regeneration. For example, ptgis and ca2 were overexpressed, while usp2a, a regulator of the p53 pathway, was down-regulated in our in vivo models. Interestingly, a high activity of ptgis and ca2 has been previously observed in failing hearts from rats and humans. CONCLUSIONS We identified genes with potential critical roles in the response to cardiac damage in the zebrafish. Their transcriptional activities are reproducible in different in vivo models of cardiac injury.

Outward FDI from developing countries : a case of Chinese firms in South Africa

Outward foreign direct investment (FDI) from developing countries is increasing. In the research on FDI, it has been considered that only competitive and productive firms can invest in foreign countries. However, since the differences in competitiveness and productivity between multinational enterprises (MNEs) from developed and developing countries have not been explicitly investigated, we cannot say whether MNEs from developing countries can or cannot survive in competition with MNEs from developed countries as well as against competitive and productive indigenous firms in host countries. To examine the activities of MNEs from developing countries, this study investigates Chinese firms in South Africa. It reveals that in order to compensate for the weak brand recognition of Chinese products and to expand sales, Chinese firms have mainly been making products that are sold under the brand names of indigenous South African firms. Chinese firms have expanded their business in South Africa relying on the business resources of indigenous firms in the host country. This indicates that business with indigenous firms is significant for MNEs from developing countries in boosting competitiveness.

Agglomeration and firm-level productivity : a Bayesian spatial approach

This paper estimates the impact of industrial agglomeration on firm-level productivity in Chinese manufacturing sectors. To account for spatial autocorrelation across regions, we formulate a hierarchical spatial model at the firm level and develop a Bayesian estimation algorithm. A Bayesian instrumental-variables approach is used to address endogeneity bias of agglomeration. Robust to these potential biases, we find that agglomeration of the same industry (i.e. localization) has a productivity-boosting effect, but agglomeration of urban population (i.e. urbanization) has no such effects. Additionally, the localization effects increase with educational levels of employees and the share of intermediate inputs in gross output. These results may suggest that agglomeration externalities occur through knowledge spillovers and input sharing among firms producing similar manufactures.

Desarrollo de estructuras nanofotonicas de campo cercano para intensificacion localizada de luz en celulas solares de banda intermedia - Near-field nanophotonic structures for localized light enhancement in intermediate band solar cells

This doctoral thesis explores some of the possibilities that near-field optics can bring to photovoltaics, and in particular to quantum-dot intermediate band solar cells (QD-IBSCs). Our main focus is the analytical optimization of the electric field distribution produced in the vicinity of single scattering particles, in order to produce the highest possible absorption enhancement in the photovoltaic medium in their surroundings. Near-field scattering structures have also been fabricated in laboratory, allowing the application of the previously studied theoretical concepts to real devices. We start by looking into the electrostatic scattering regime, which is only applicable to sub-wavelength sized particles. In this regime it was found that metallic nano-spheroids can produce absorption enhancements of about two orders of magnitude on the material in their vicinity, due to their strong plasmonic resonance. The frequency of such resonance can be tuned with the shape of the particles, allowing us to match it with the optimal transition energies of the intermediate band material. Since these metallic nanoparticles (MNPs) are to be inserted inside the cell photovoltaic medium, they should be coated by a thin insulating layer to prevent electron-hole recombination at their surface. This analysis is then generalized, using an analytical separation-of-variables method implemented in Mathematica7.0, to compute scattering by spheroids of any size and material. This code allowed the study of the scattering properties of wavelengthsized particles (mesoscopic regime), and it was verified that in this regime dielectric spheroids perform better than metallic. The light intensity scattered from such dielectric spheroids can have more than two orders of magnitude than the incident intensity, and the focal region in front of the particle can be shaped in several ways by changing the particle geometry and/or material. Experimental work was also performed in this PhD to implement in practice the concepts studied in the analysis of sub-wavelength MNPs. A wet-coating method was developed to self-assemble regular arrays of colloidal MNPs on the surface of several materials, such as silicon wafers, amorphous silicon films, gallium arsenide and glass. A series of thermal and chemical tests have been performed showing what treatments the nanoparticles can withstand for their embedment in a photovoltaic medium. MNPs arrays are then inserted in an amorphous silicon medium to study the effect of their plasmonic near-field enhancement on the absorption spectrum of the material. The self-assembled arrays of MNPs constructed in these experiments inspired a new strategy for fabricating IBSCs using colloidal quantum dots (CQDs). Such CQDs can be deposited in self-assembled monolayers, using procedures similar to those developed for the patterning of colloidal MNPs. The use of CQDs to form the intermediate band presents several important practical and physical advantages relative to the conventional dots epitaxially grown by the Stranski-Krastanov method. Besides, this provides a fast and inexpensive method for patterning binary arrays of QDs and MNPs, envisioned in the theoretical part of this thesis, in which the MNPs act as antennas focusing the light in the QDs and therefore boosting their absorption

The introduction of teaching innovations into the traditional teaching of construction and building materials

The traditional teaching methods used for training civil engineers are currently being called into question as a result of the new knowledge and skills now required by the labor market. In addition, the European Higher Education Area is requesting that students be given a greater say in their learning. In the subject called Construction and Building Materials at the Civil Engineering School of the Universidad Politécnica de Madrid, a path was set three academic years ago to lead to an improvement in traditional teaching by introducing active methodologies. The innovations are based on cooperative learning, new technologies, and continuous assessment. The writers’ proposal is to offer their experience as a contribution to the debate on how students can be encouraged to acquire the skills currently demanded from a civil engineer, though not overlooking solid, top-quality training. From the outcomes obtained, it can be concluded that using new teaching techniques to supplement a traditional approach provides more opportunities for students to learn while boosting their motivation. In our case, the introduction of these changes has resulted in an increased pass rate of 29% on average, when such a figure is considered in the light of the mean value of passes during the last decade.

A new feature extraction method for signal classification applied to cat spinal cord signals

In the spinal cord of the anesthetized cat, spontaneous cord dorsum potentials (CDPs) appear synchronously along the lumbo-sacral segments. These CDPs have different shapes and magnitudes. Previous work has indicated that some CDPs appear to be specially associated with the activation of spinal pathways that lead to primary afferent depolarization and presynaptic inhibition. Visual detection and classification of these CDPs provides relevant information on the functional organization of the neural networks involved in the control of sensory information and allows the characterization of the changes produced by acute nerve and spinal lesions. We now present a novel feature extraction approach for signal classification, applied to CDP detection. The method is based on an intuitive procedure. We first remove by convolution the noise from the CDPs recorded in each given spinal segment. Then, we assign a coefficient for each main local maximum of the signal using its amplitude and distance to the most important maximum of the signal. These coefficients will be the input for the subsequent classification algorithm. In particular, we employ gradient boosting classification trees. This combination of approaches allows a faster and more accurate discrimination of CDPs than is obtained by other methods.

Short tethers for electrodynamic thrust

The operational advantages of electrodynamic tethers of moderate length are becoming evident from studies of collision avoidance. Although long tethers (of order of 10 kilometers) provide high efficiency and good adaptability to varying plasma conditions, boosting tethers of moderate length (- 1 kilometer) and suitable design might still operate at acceptable efficiencies and adequate adaptability to a changing environment. In this paper we carry out a parametric analysis of the performance of 1-km long boosting tethers, to maximize their efficiency. We also discuss the possible use of multiple, parallel such tethers for keeping thrust high when length is decreased. We then estimate the survivability of short tethers to micrometeoroids and orbital debris. Finally, a few considerations are made on the dynamic stability of electrodynamic tether systems versus length.

Electrodynamic tether applications and constraints

Propulsion and power generation by bare electrodynamic tethers are revisited in a unified way and issues and constraints are addressed. In comparing electrodynamic tethers, which do not use propellant, with other propellantconsuming systems, mission duration is a discriminator that defines crossover points for systems with equal initial masses. Bare tethers operating in low Earth orbit can be more competitive than optimum ion thrusters in missions exceeding two-three days for orbital deboost and three weeks for boosting operations. If the tether produces useful onboard power during deboost, the crossover point reaches to about 10 days. Power generation by means of a bare electrodynamic tether in combination with chemical propulsion to maintain orbital altitude of the system is more efficient than use of the same chemicals (liquid hydrogen and liquid oxygen) in a fuel cell to produce power for missions longer than one week. Issues associated with tether temperature, bowing, deployment, and arcing are also discussed. Heating/cooling rates reach about 4 K/s for a 0.05-mm-thick tape and a fraction of Kelvin/second for the ProSEDS (0.6-mm-radius) wire; under dominant ohmic effects, temperatures areover200K (night) and 380 K (day) for the tape and 320 and 415 K for that wire. Tether applications other than propulsion and power are briefly discussed.

Road fright transport decoupling: A comparative analysis between the United Kingdom and Spain

Economic growth has traditionally been linked to road freight transport demand, leading to a steady rise in social and environmental impacts. Concern about this problem has caused the EU to promote a decoupling strategy aimed at boosting sustainable development in European countries by improving the efficiency of transport systems without curbing economic growth. Over the last few years empirical evidence in some countries such as the United Kingdom has shown an increase in GDP while the volume of road freight traffic has remained stable or even decreased. This paper compares recent decoupling trends by analyzing the evolution of road tonne-kms/GDP relationship in the United Kingdom and Spain from 1999 to 2007. This comparison seeks to identify the main differences and key drivers of decoupling in both countries. We first provide an overview of the divergences between both economic structures and levels of road transport intensity. Then we conduct a decomposition analysis in order to identify the variables that explain the evolution of truck traffic per unit of GDP in each country. The results show that the increasing share of services in GDP has substantially contributed to decreasing road transport demand in both cases. Changes in road transport intensity due to improvements in logistic and supply chain management have been more successful in the UK than in Spain.