Acquired Myelodysplasia or Myelodysplastic Syndrome: Clearing the Fog

Myelodysplastic syndromes (MDS) are clonal myeloid disorders characterized by progressive peripheral blood cytopenias associated with ineffective myelopoiesis. They are typically considered neoplasms because of frequent genetic aberrations and patient-limited survival with progression to acute myeloid leukemia (AML) or death related to the consequences of bone marrow failure including infection, hemorrhage, and iron overload. A progression to AML has always been recognized among the myeloproliferative disorders (MPD) but occurs only rarely among those with essential thrombocythemia (ET). Yet, the World Health Organization (WHO) has chosen to apply the designation myeloproliferative neoplasms (MPN), for all MPD but has not similarly recommended that all MDS become the myelodysplastic neoplasms (MDN). This apparent dichotomy may reflect the extremely diverse nature of MDS. Moreover, the term MDS is occasionally inappropriately applied to hematologic disorders associated with acquired morphologic myelodysplastic features which may rather represent potentially reversible hematological responses to immune-mediated factors, nutritional deficiency states, and disordered myelopoietic responses to various pharmaceutical, herbal, or other potentially myelotoxic compounds. We emphasize the clinical settings, and the histopathologic features, of such AMD that should trigger a search for a reversible underlying condition that may be nonneoplastic and not MDS

Protein Expression, Characterization and Activity Comparisons of Wild Type and Mutant DUSP5 Proteins

Background The mitogen-activated protein kinases (MAPKs) pathway is critical for cellular signaling, and proteins such as phosphatases that regulate this pathway are important for normal tissue development. Based on our previous work on dual specificity phosphatase-5 (DUSP5), and its role in embryonic vascular development and disease, we hypothesized that mutations in DUSP5 will affect its function. Results In this study, we tested this hypothesis by generating full-length glutathione-S-transferase-tagged DUSP5 and serine 147 proline mutant (S147P) proteins from bacteria. Light scattering analysis, circular dichroism, enzymatic assays and molecular modeling approaches have been performed to extensively characterize the protein form and function. We demonstrate that both proteins are active and, interestingly, the S147P protein is hypoactive as compared to the DUSP5 WT protein in two distinct biochemical substrate assays. Furthermore, due to the novel positioning of the S147P mutation, we utilize computational modeling to reconstruct full-length DUSP5 and S147P to predict a possible mechanism for the reduced activity of S147P. Conclusion Taken together, this is the first evidence of the generation and characterization of an active, full-length, mutant DUSP5 protein which will facilitate future structure-function and drug development-based studies

A novel metagenome-derived viral RNA polymerase and its application in a cell-free expression system for metagenome screening

The mining of genomes from non-cultivated microorganisms using metagenomics is a powerful tool to discover novel proteins and other valuable biomolecules. However, function-based metagenome searches are often limited by the time-consuming expression of the active proteins in various heterologous host systems. We here report the initial characterization of novel single-subunit bacteriophage RNA polymerase, EM1 RNAP, identified from a metagenome data set obtained from an elephant dung microbiome. EM1 RNAP and its promoter sequence are distantly related to T7 RNA polymerase. Using EM1 RNAP and a translation-competent Escherichia coli extract, we have developed an efficient medium-throughput pipeline and protocol allowing the expression of metagenome-derived genes and the production of proteins in cell-free system is sufficient for the initial testing of the predicted activities. Here, we have successfully identified and verified 12 enzymes acting on bis(2-hydroxyethyl) terephthalate (BHET) in a completely clone-free approach and proposed an in vitro high-throughput metagenomic screening method

Adaptation of the human nervous system for self-aware secure mobile and IoT systems

IT systems have been deployed across several domains, such as hospitals and industries, for the management of information and operations. These systems will soon be ubiquitous in every field due to the transition towards the Internet of Things (IoT). The IoT brings devices with sensory functions into IT systems through the process of internetworking. The sensory functions of IoT enable them to generate and process information automatically, either without human contribution or having the least human interaction possible aside from the information and operations management tasks. Security is crucial as it prevents system exploitation. Security has been employed after system implementation, and has rarely been considered as a part of the system. In this dissertation, a novel solution based on a biological approach is presented to embed security as an inalienable part of the system. The proposed solution, in the form of a prototype of the system, is based on the functions of the human nervous system (HNS) in protecting its host from the impacts caused by external or internal changes. The contributions of this work are the derivation of a new system architecture from HNS functionalities and experiments that prove the implementation feasibility and efficiency of the proposed HNS-based architecture through prototype development and evaluation. The first contribution of this work is the adaptation of human nervous system functions to propose a new architecture for IT systems security. The major organs and functions of the HNS are investigated and critical areas are identified for the adaptation process. Several individual system components with similar functions to the HNS are created and grouped to form individual subsystems. The relationship between these components is established in a similar way as in the HNS, resulting in a new system architecture that includes security as a core component. The adapted HNS-based system architecture is employed in two the experiments prove its implementation capability, enhancement of security, and overall system operations. The second contribution is the implementation of the proposed HNS-based security solution in the IoT test-bed. A temperature-monitoring application with an intrusion detection system (IDS) based on the proposed HNS architecture is implemented as part of the test-bed experiment. Contiki OS is used for implementation, and the 6LoWPAN stack is modified during the development process. The application, together with the IDS, has a brain subsystem (BrSS), a spinal cord subsystem (SCSS), and other functions similar to the HNS whose names are changed. The HNS functions are shared between an edge router and resource-constrained devices (RCDs) during implementation. The experiment is evaluated in both test-bed and simulation environments. Zolertia Z1 nodes are used to form a 6LoWPAN network, and an edge router is created by combining Pandaboard and Z1 node for a test-bed setup. Two networks with different numbers of sensor nodes are used as simulation environments in the Cooja simulator. The third contribution of this dissertation is the implementation of the proposed HNS-based architecture in the mobile platform. In this phase, the Android operating system (OS) is selected for experimentation, and the proposed HNS-based architecture is specifically tailored for Android. A context-based dynamically reconfigurable access control system (CoDRA) is developed based on the principles of the refined HNS architecture. CoDRA is implemented through customization of Android OS and evaluated under real-time usage conditions in test-bed environments. During the evaluation, the implemented prototype mimicked the nature of the HNS in securing the application under threat with negligible resource requirements and solved the problems in existing approaches by embedding security within the system. Furthermore, the results of the experiments highlighted the retention of HNS functions after refinement for different IT application areas, especially the IoT, due to its resource-constrained nature, and the implementable capability of our proposed HNS architecture.--- IT-järjestelmiä hyödynnetään tiedon ja toimintojen hallinnassa useilla aloilla, kuten sairaaloissa ja teollisuudessa. Siirtyminen kohti esineiden Internetiä (Internet of Things, IoT) tuo tällaiset laitteet yhä kiinteämmäksi osaksi jokapäiväistä elämää. IT-järjestelmiin liitettyjen IoT-laitteiden sensoritoiminnot mahdollistavat tiedon automaattisen havainnoinnin ja käsittelyn osana suurempaa järjestelmää jopa täysin ilman ihmisen myötävaikutusta, poislukien mahdolliset ylläpito- ja hallintatoimenpiteet. Turvallisuus on ratkaisevan tärkeää IT-järjestelmien luvattoman käytön estämiseksi. Valitettavan usein järjestelmäsuunnittelussa turvallisuus ei ole osana ydinsuunnitteluprosessia, vaan otetaan huomioon vasta käyttöönoton jälkeen. Tässä väitöskirjassa esitellään uudenlainen biologiseen lähestymistapaan perustuva ratkaisu, jolla turvallisuus voidaan sisällyttää erottamattomaksi osaksi järjestelmää. Ehdotettu prototyyppiratkaisu perustuu ihmisen hermoston toimintaan tilanteessa, jossa se suojelee isäntäänsä ulkoisten tai sisäisten muutosten vaikutuksilta. Tämän työn keskeiset tulokset ovat uuden järjestelmäarkkitehtuurin johtaminen ihmisen hermoston toimintaperiaatteesta sekä tällaisen järjestelmän toteutettavuuden ja tehokkuuden arviointi kokeellisen prototyypin kehittämisen ja toiminnan arvioinnin avulla. Tämän väitöskirjan ensimmäinen kontribuutio on ihmisen hermoston toimintoihin perustuva IT-järjestelmäarkkitehtuuri. Tutkimuksessa arvioidaan ihmisen hermoston toimintaa ja tunnistetaan keskeiset toiminnot ja toiminnallisuudet, jotka mall-innetaan osaksi kehitettävää järjestelmää luomalla näitä vastaavat järjestelmäkomponentit. Nä-istä kootaan toiminnallisuudeltaan hermostoa vastaavat osajärjestelmät, joiden keskinäinen toiminta mallintaa ihmisen hermoston toimintaa. Näin luodaan arkkitehtuuri, jonka keskeisenä komponenttina on turvallisuus. Tämän pohjalta toteutetaan kaksi prototyyppijärjestelmää, joiden avulla arvioidaan arkkitehtuurin toteutuskelpoisuutta, turvallisuutta sekä toimintakykyä. Toinen kontribuutio on esitetyn hermostopohjaisen turvallisuusratkaisun toteuttaminen IoT-testialustalla. Kehitettyyn arkkitehtuuriin perustuva ja tunkeutumisen estojärjestelmän (intrusion detection system, IDS) sisältävä lämpötilan seurantasovellus toteutetaan käyttäen Contiki OS -käytöjärjestelmää. 6LoWPAN protokollapinoa muokataan tarpeen mukaan kehitysprosessin aikana. IDS:n lisäksi sovellukseen kuuluu aivo-osajärjestelmä (Brain subsystem, BrSS), selkäydinosajärjestelmä (Spinal cord subsystem, SCSS), sekä muita hermoston kaltaisia toimintoja. Nämä toiminnot jaetaan reunareitittimen ja resurssirajoitteisten laitteiden kesken. Tuloksia arvioidaan sekä simulaatioiden että testialustan tulosten perusteella. Testialustaa varten 6LoWPAN verkon toteutukseen valittiin Zolertia Z1 ja reunareititin on toteutettu Pandaboardin ja Z1:n yhdistelmällä. Cooja-simulaattorissa käytettiin mallinnukseen ymp-äristönä kahta erillistä ja erikokoisuta sensoriverkkoa. Kolmas tämän väitöskirjan kontribuutio on kehitetyn hermostopohjaisen arkkitehtuurin toteuttaminen mobiilialustassa. Toteutuksen alustaksi valitaan Android-käyttöjärjestelmä, ja kehitetty arkkitehtuuri räätälöidään Androidille. Tuloksena on kontekstipohjainen dynaamisesti uudelleen konfiguroitava pääsynvalvontajärjestelmä (context-based dynamically reconfigurable access control system, CoDRA). CoDRA toteutetaan mukauttamalla Androidin käyttöjärjestelmää ja toteutuksen toimivuutta arvioidaan reaaliaikaisissa käyttöolosuhteissa testialustaympäristöissä. Toteutusta arvioitaessa havaittiin, että kehitetty prototyyppi jäljitteli ihmishermoston toimintaa kohdesovelluksen suojaamisessa, suoriutui tehtävästään vähäisillä resurssivaatimuksilla ja onnistui sisällyttämään turvallisuuden järjestelmän ydintoimintoihin. Tulokset osoittivat, että tämän tyyppinen järjestelmä on toteutettavissa sekä sen, että järjestelmän hermostonkaltainen toiminnallisuus säilyy siirryttäessä sovellusalueelta toiselle, erityisesti resursseiltaan rajoittuneissa IoT-järjestelmissä

BMP9 Mutations Cause a Vascular-Anomaly Syndrome with Phenotypic Overlap with Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, is caused by mutations in genes involved in the transforming growth factor beta (TGF-β) signaling pathway (ENG, ACVRL1, and SMAD4). Yet, approximately 15% of individuals with clinical features of HHT do not have mutations in these genes, suggesting that there are undiscovered mutations in other genes for HHT and possibly vascular disorders with overlapping phenotypes. The genetic etiology for 191 unrelated individuals clinically suspected to have HHT was investigated with the use of exome and Sanger sequencing; these individuals had no mutations in ENG, ACVRL1, and SMAD4. Mutations in BMP9 (also known as GDF2) were identified in three unrelated probands. These three individuals had epistaxis and dermal lesions that were described as telangiectases but whose location and appearance resembled lesions described in some individuals with RASA1-related disorders (capillary malformation-arteriovenous malformation syndrome). Analyses of the variant proteins suggested that mutations negatively affect protein processing and/or function, and a bmp9-deficient zebrafish model demonstrated that BMP9 is involved in angiogenesis. These data confirm a genetic cause of a vascular-anomaly syndrome that has phenotypic overlap with HHT

Modeling the Artificial Immune System to the Human Immune System with the Use of Agents

The purpose of this study is to provide a model and a work frame to approximate the artificial immune system to the human immune system with the use of agents to counter malicious software (malware). The artificial immune system components are commercial off-the-shelf products that are managed by the agent that coordinate and synchronize their activity. The behavior of the agent is a simulation of the B-cells in the Human Immune System in the encapsulation, analysis and digestion of the antigen. The proposed architecture can be implemented in almost certainty based on the use of the commercial off-the-shelf products (COTS). The agent can be constructed to perform the required functionality with the help of the sandbox tools that provide the encapsulation. Anomaly detectors provide the knowledge of any process' action that is considered abnormal, hence, a possible malware. The Antivirus applications provide the digestion of the antigen, where known malware is handled directly, while unknown malware is analyzed by signature extraction, then handled by the antivirus. Other components such as intrusion detection (ID) applications perform the defenses at the entrances to the system (communication channels) and the firewall applications provide the prevention of the spread of the antigen and quarantining it in the infected node. The implementation of the model will provide a parallel self-healing system against antigens along side the applications and hardware self-healing systems.Computer Science Departmen