GMZ27 is a new organic arsenic derivative with anti-leukemic activity, via the induction of reactive oxygen species through NADPH oxidase and mitochondrial pathway that lead to leukemia cell apoptosis

Arsenic trioxide (ATO) is an inorganic arsenic derivative that is very effective against relapsed acute promyelocytic leukemia. It is being investigated as therapy for other cancers, but the risk/benefit ratio is questionable due to significant side effects. In contrast, organic arsenic derivatives (OAD) are known to be much less toxic than ATO. Based on high activity, we selected GMZ27 (dipropil-s-glycerol arsenic) for further study and have confirmed its potent activity against human acute leukemia cell lines. This anti-leukemic activity is significantly higher than that of ATO. Both in vivo and in vitro tests have shown that GMZ27 is significantly less toxic to normal bone marrow mononuclear cells and normal mice. Therefore, further study of the biological activity of GMZ27 was undertaken. ^ GMZ27, in contrast to ATO, can only marginally induce maturation of leukemic cells. GMZ27 has no effect on cell cycle. The anti-leukemic activity of GMZ27 against acute myeolocytic leukemia cells is not dependent upon degradation of PML-RARα fusion protein. GMZ27 causes dissipation of mitochondrial transmembrane potential, cleavage of caspase 9, caspase 3 activation. Further studies indicated that GMZ27 induces intracellular reactive oxygen species (ROS) production, and modification of intracellular ROS levels had profound effect on its potential to inhibit proliferation of leukemic cells. Therefore ROS production plays a major role in the anti-leukemic activity of GMZ27. ^ To identify how GMZ27 induces ROS, our studies focused on mitochondria and NADPH oxidase. The results indicated that the source of ROS generation induced by GMZ27 is dose dependent. At the low dose (0.3 uM) GMZ27 induces NADPH oxidase activity that leads to late ROS production, while at the high dose (2.0 uM) mitochondria function is disrupted and early ROS production is induced leading to dramatic cell apoptosis. Therefore, late, ROS production can be detected in mitochondria are depleted Rho-0 cells. Our work not only delineates a major biologic pathway for the anti-leukemic activity of GMZ27, but also discusses possible ways of enhancing the effect by the co-application of NADPH oxidase activator. Further study of this interaction may lead to achieving better therapeutic index.^

InGen of creative production in the health sciences: A workbook companion to innovation generation

InGen of Creative Production in the Health Sciences is a compendium of innovative thinking exercises for individuals and groups, derived from an eclectic array of practical guides for professionals in a variety of fields. Segmented into five subcategories across twenty two chapters, the effort seeks to make techniques for increasing innovative problem solving more accessible to a diverse audience of problem solvers. The chapters of Roberta Ness. Innovation Generation (2012, Oxford University Press) provide the themes for each of the chapters in the workbook. It is intended that those who read Ness. Innovation Generation will benefit from practicing the constructs of innovative thinking exemplified in each exercise.^ The methods used to gather data, in this case mostly innovative thinking exercises, included literature reviews of existing innovative thinking tools, classroom materials, and theory-driven exploration of exercises to fill in gaps in extant materials. Specifically, Google.com and Amazon.com searches were conducted using the terms “innovation,” “innovative,” “innovator,” “creative,” “novelty,” “thinking,” together with some variance of “book,” “workbook,” and “exercise.” The results were sorted thematically to show correspondence with the themes in Ness (2012) and compared to suggested best practices of 50 years of scientific research on innovative thinking. Where themes were suggested by Ness (2012) and peer-reviewed research on innovation but unavailable in published innovation thinking workbooks, new exercises were developed. The five type subcategories into which these results were organized are: individual direct, individual indirect, group direct, group indirect and probing question. It is anticipated that the five type subcategories and spectrum of themes will equip problem solvers in a variety of capacities.^

THE NEW ROLE OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9: A CONNECTION OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9, APOLIPOPROTEIN B, and AUTOPHAGY

Plasma low-density lipoprotein (LDL) levels are positively correlated with the incidence of coronary artery disease. In the circulation, the plasma LDL clearance is mainly achieved by the uptake via LDL receptor (LDLR). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a newly discovered gene, playing an important role in LDL metabolism. Gain-of-function mutations of PCSK9 lead to hypercholesterolemia and loss-of-function mutations of PCSK9 are associated with decrease of LDL cholesterol. The effects of PCSK9 on cholesterol levels are the consequence of a strong interaction between the catalytic domain of PCSK9 and epidermal growth factor-like repeat A (EGF-A) domain of LDLR on the cell surface of hepatocytes. This PCSK9/LDLR complex enters the cell via endocytosis, where both PCSK9 and LDLR are removed via the lysosome pathway, resulting in decreased levels of LDLR and accumulation of LDL in the plasma. However, whether this is the exclusive function of PCSK9 on LDL metabolism was challenged by us; we observed PCSK9 interacted with apolipoprotein B (apoB) and increased apoB production, irrespective of the LDLR. ApoB is the primary structure protein of LDL particle and it also serves as the ligand for the LDL receptor. There is ample evidence showing that the levels of apoB are a better indicator for heart disease than either total cholesterol or LDL cholesterol levels. We used a second-generation adenoviral vector to overexpress PCSK9 (Ad-PCSK9) in wild-type C57BL/6 and LDLR deficient mice (Ldlr-/- and Ldlr-/-Apobec1-/-). Our study revealed that overexpression of PCSK9 promoted the production and secretion of apoB in the form of very-low density lipoprotein (VLDL), which is the precursor of LDL, in the 3 mouse models studied (C57BL/6J, Ldlr-/-, and Ldlr-/-Apobec1-/-). The increased apoB production in mice was regulated at post-transcriptional levels, since there was no difference in apoB mRNA levels between mice treated with Ad-PCSK9 and control vector Ad-Null. By using pulse-chase experiment on primary hepatocytes, we showed that overexpression of PCSK9 increased the secretion of apoB, independent of LDLR. In the circulation, we showed that PCSK9 was associated with LDL particles. By using 3 different protein–protein interaction assays of co-immunoprecipitation, mammalian two-hybrid system, and in situ proximity ligation assay, we demonstrated a direct protein–protein interaction between PCSK9 and apoB. The impact of this interaction inhibited the physiological removal process of apoB via autophagosome/lysosome pathway in an LDLR-independent fashion, resulting in increased production and secretion of apoB-containing lipoproteins. The significance of this process was shown in the Pcsk9 knockout mice in the background of Ldlr-/-Apobec1-/- mice (triple knockout mice); in the absence of Pcsk9 (triple knockout mice) the levels of cholesterol, triacylglycerol, and apoB decreased significantly in comparison to that of Ldlr-/-Apobec1-/- mice. Taken together, our study demonstrated a direct intracellular interaction of PCSK9 with apoB, resulting in the inhibition of apoB degradation via the autophagosome/lysosome pathway independent of LDLR. This discovery provides a new concept of the importance of PCSK9 and suggests new approaches for the therapeutic intervention of hyperlipidemia.

Seagrass biofilm communities at a naturally CO2-rich vent at Papua New Guinea

Seagrass meadows are a crucial component of tropical marine reef ecosystems. The seagrass plants are colonized by a multitude of epiphytic organisms that contribute to determining the ecological role of seagrasses. To better understand how environmental changes like ocean acidification might affect epiphytic assemblages, the microbial community composition of the epiphytic biofilm of Enhalus acroides was investigated at a natural CO2 vent in Papua New Guinea using molecular fingerprinting and next generation sequencing of 16S and 18S rRNA genes. Both bacterial and eukaryotic epiphytes formed distinct communities at the CO2-impacted site compared to the control site. This site-related CO2 effect was also visible in the succession pattern of microbial epiphytes. We further found an increased abundance of bacterial types associated with coral diseases at the CO2-impacted site (Fusobacteria, Thalassomonas) whereas eukaryotes such as certain crustose coralline algae commonly related to healthy reefs were less diverse. These trends in the epiphytic community of E. acroides suggest a potential role of seagrasses as vectors of coral pathogens and may support previous predictions of a decrease in reef health and prevalence of diseases under future ocean acidification scenarios.

Blogs: On the Cutting Edge of the Next-generation Web

This article analyses a number of social and cultural aspects of the blog phenomenon with the methodological aid of a complexity model, the New Techno-social Environment (hereinafter also referred to by its Spanish acronym, NET, or Nuevo Entorno Tecnosocial) together with the socio-technical approach of the two blogologist authors. Both authors are researchers interested in the new reality of the Digital Universal Network (DUN). After a review of some basic definitions, the article moves on to highlight some key characteristics of an emerging blog culture and relates them to the properties of the NET. Then, after a brief practical parenthesis for people entering the blogosphere for the first time, we present some reflections on blogs as an evolution of virtual communities and on the changes experienced by the inhabitants of the infocity emerging from within the NET. The article concludes with a somewhat disturbing question; whether among these changes there might not be a gradual transformation of the structure and form of human intelligence.

A user-centric approach to service creation and delivery over next generation networks

Next Generation Networks (NGN) provide Telecommunications operators with the possibility to share their resources and infrastructure, facilitate the interoperability with other networks, and simplify and unify the management, operation and maintenance of service offerings, thus enabling the fast and cost-effective creation of new personal, broadband ubiquitous services. Unfortunately, service creation over NGN is far from the success of service creation in the Web, especially when it comes to Web 2.0. This paper presents a novel approach to service creation and delivery, with a platform that opens to non-technically skilled users the possibility to create, manage and share their own convergent (NGN-based and Web-based) services. To this end, the business approach to user-generated services is analyzed and the technological bases supporting the proposal are explained.

Distributed power generation in the United States

With electricity consumption increasing within the UnitedStates, new paradigms of delivering electricity are required in order to meet demand. One promising option is the increased use of distributedpowergeneration. Already a growing percentage of electricity generation, distributedgeneration locates the power plant physically close to the consumer, avoiding transmission and distribution losses as well as providing the possibility of combined heat and power. Despite the efficiency gains possible, regulators and utilities have been reluctant to implement distributedgeneration, creating numerous technical, regulatory, and business barriers. Certain governments, most notable California, are making concerted efforts to overcome these barriers in order to ensure distributedgeneration plays a part as the country meets demand while shifting to cleaner sources of energy.

Public support for the deployment of next generation access networks-Common themes, methodological caveats and further research

Next generation telecommunications infrastructures are considered as a principal example of a new technology for sustainable economic growth. From their deployment it is expected that a wealth of innovations – hopefully converted into economic growth – new sources of employment and improved quality of life will result. In line with these prospects, public administrations at supranational, national, regional and local levels have encouraged the development of these new infrastructures. Moreover, in times of economic crisis, public assistance to deploy such networks encompasses the promise of placing a weak economy on the road to prosperity. However, such arguments and political claims clearly require rigorous assessment. In particular, any such assessment must adequately address the appropriate form of modelling that best captures key elements for identifiable progress from next generation access networks (NGAN).

A simplified energy consumption model for fiber-based Next Generation Access Networks

ICTs account nowadays for 2% of total carbon emissions. However, in a time when strict measures to reduce energyconsumption in all the industrial and services sectors are required, the ICT sector faces an increase in services and bandwidth demand. The deployment of NextGenerationNetworks (NGN) will be the answer to this new demand and specifically, the NextGenerationAccessNetworks (NGANs) will provide higher bandwidth access to users. Several policy and cost analysis are being carried out to understand the risks and opportunities of new deployments, though the question of which is the role of energyconsumption in NGANs seems off the table. Thus, this paper proposes amodel to analyze the energyconsumption of the main fiber-based NGAN architectures, i.e. Fiber To The House (FTTH) in both Passive Optical Network (PON) and Point-to-Point (PtP) variations, and FTTx/VDSL. The aim of this analysis is to provide deeper insight on the impact of new deployments on the energyconsumption of the ICT sector and the effects of energyconsumption on the life-cycle cost of NGANs. The paper presents also an energyconsumption comparison of the presented architectures, particularized in the specific geographic and demographic distribution of users of Spain, but easily extendable to other countries.

Next Generation of Energy Residential Gateways for Demand Response and Dynamic Pricing

Predictions about electric energy needs, based on current electric energy models, forecast that the global energy consumption on Earth for 2050 will double present rates. Using distributed procedures for control and integration, the expected needs can be halved. Therefore implementation of Smart Grids is necessary. Interaction between final consumers and utilities is a key factor of future Smart Grids. This interaction is aimed to reach efficient and responsible energy consumption. Energy Residential Gateways (ERG) are new in-building devices that will govern the communication between user and utility and will control electric loads. Utilities will offer new services empowering residential customers to lower their electric bill. Some of these services are Smart Metering, Demand Response and Dynamic Pricing. This paper presents a practical development of an ERG for residential buildings.

A new approach for publishing workflows: abstractions, standards, and linked data

In recent years, a variety of systems have been developed that export the workflows used to analyze data and make them part of published articles. We argue that the workflows that are published in current approaches are dependent on the specific codes used for execution, the specific workflow system used, and the specific workflow catalogs where they are published. In this paper, we describe a new approach that addresses these shortcomings and makes workflows more reusable through: 1) the use of abstract workflows to complement executable workflows to make them reusable when the execution environment is different, 2) the publication of both abstract and executable workflows using standards such as the Open Provenance Model that can be imported by other workflow systems, 3) the publication of workflows as Linked Data that results in open web accessible workflow repositories. We illustrate this approach using a complex workflow that we re-created from an influential publication that describes the generation of 'drugomes'.

An educational initiative between the Universidad Politécnica de Madrid and Spanish Young Generation in Nuclear (Jóvenes Nucleares): The Seminar of Nuclear Safety in Advanced Reactors

Jóvenes Nucleares (Spanish Young Generation in Nuclear, JJNN) is a non-profit organization and a commission of the Spanish Nuclear Society (SNE). The Universidad Politécnica de Madrid (Technical University of Madrid, UPM) is one of the most prestigious technical universities of Spain, and has a very strong curriculum in nuclear engineering training and research. Finishing 2009, JJNN and the UPM started to plan a new and first-of-a-kind Seminar in Nuclear Safety focused on the Advanced Reactors (Generation III, III+ and IV). The scope was to make a general description of the safety in the new reactors, comparing them with the built Generation II reactors from a technical point of view but simple and without the need of strong background in nuclear engineering to try to be interesting for the most number of people possible.

Helping to Close the Generational Gap in Nuclear: The Seminars and Conferences of Spanish Young Generation in Nuclear (Jóvenes Nucleares)

As in each country of Europe with nuclear power, there is a clear gap between those generation that have built the power plants in the eighties and the new generations with less than ten years of experience in the nuclear field. From its creation, Spanish Young Generation in Nuclear (Jóvenes Nucleares) has as an important scope to help transferring the knowledge between those generations in the way that it can be possible. Some years ago, JJNN have started organizing seminars periodically trying to cover as many areas as possible in the nuclear engineering field, and some of them outside the industry but related with it.

A New Method to Retrieve, Cluster And Annotate Clinical Literature Related To Electronic Health Records

The access to medical literature collections such as PubMed, MedScape or Cochrane has been increased notably in the last years by the web-based tools that provide instant access to the information. However, more sophisticated methodologies are needed to exploit efficiently all that information. The lack of advanced search methods in clinical domain produce that even using well-defined questions for a particular disease, clinicians receive too many results. Since no information analysis is applied afterwards, some relevant results which are not presented in the top of the resultant collection could be ignored by the expert causing an important loose of information. In this work we present a new method to improve scientific article search using patient information for query generation. Using federated search strategy, it is able to simultaneously search in different resources and present a unique relevant literature collection. And applying NLP techniques it presents semantically similar publications together, facilitating the identification of relevant information to clinicians. This method aims to be the foundation of a collaborative environment for sharing clinical knowledge related to patients and scientific publications.

Which could be the role of Hybrid Fibre Coax in Next Generation Access networks?

Next generation access networks (NGAN) will support a renewed communication structure where opportunities lie in the provision of ubiquitous broadband connectivity, a wide variety of new applications, appealing contents and a general support to the sustainable growth of diverse sectors. From their deployment it is expected a wealth of innovations, jobs creation and a new wave of economic growth. In this paper we discuss which could be the role of Hybrid Fibre Coax (HFC) in the Next Generation Access Network (NGAN) roadmap. Thus, we propose a simplified model for making approximate cost calculations for HFC deployment based on the geographic and sociodemographic characteristics of Spain. Considering the latest evolution of HFC based on DOCSIS 3.0 from integrated (I-CMTS) towards modular (M-CMTS), the results from the model are compared with the most competitive NGAN for ultrabroadband speeds: Fibre to the Home (FTTH) based on Gigabitcapable Passive Optical Networks (GPON)