Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy

Background - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder characterized by loss of cardiomyocytes and their replacement by adipose and fibrous tissue. It is considered a disease of cell adhesion because mutations in desmosomal genes, desmoplakin and plakoglobin, have been implicated in the pathogenesis of ARVC. In a recent report, mutations in plakophilin-2, a gene highly expressed in cardiac desmosomes, have been shown to cause ARVC.Methods and Results - We investigated 100 white patients with ARVC for mutations in plakophilin-2. Nine different mutations were identified by direct sequencing in 11 cases. Five of these mutations are novel (A733fsX740, L586fsX658, V570fsX576, R413X, and P533fsX561) and predicted to cause a premature truncation of the plakophilin-2 protein. Family studies showed incomplete disease expression in mutation carriers and identified a number of individuals who would be misdiagnosed with the existing International Task Force and modified diagnostic criteria for ARVC.Conclusions - In this study, we provide new evidence that mutations in the desmosomal plakophilin-2 gene can cause ARVC. A systematic clinical evaluation of mutation carriers within families demonstrated variable phenotypic expression, even among individuals with the same mutation, and highlighted the need for a more accurate set of diagnostic criteria for ARVC

Functional Brain Imaging with Multi-Objective Multi-Modal Evolutionary Optimization

Functional brain imaging is a source of spatio-temporal data mining problems. A new framework hybridizing multi-objective and multi-modal optimization is proposed to formalize these data mining problems, and addressed through Evolutionary Computation (EC). The merits of EC for spatio-temporal data mining are demonstrated as the approach facilitates the modelling of the experts' requirements, and flexibly accommodates their changing goals

Hybrid integration of microfabricated chemοcapacitor arrays with miniaturized read-out electronics towards low-power gas sensing module

AbstractA hybrid gas sensing module consisting of an array of 8 polymer coated capacitive sensors and low power read-out electronics is introduced. The chemocapacitor array is fabricated with standard microelectronics/micromachining processes allowing for the realization of planar InterDigitated Electrodes (IDEs). The read-out electronics sub- module consists of an analog multiplexer for the sequential measurement of the sensor array elements, a capacitance to 24-bit converter and a USB to I2C interface. The compact hybrid module has been successfully applied in the detection of sub-100ppm concentrations of p-xylene and toluene. The responses to various humidity levels have been also evaluated

PhOTO Zebrafish: A Transgenic Resource for In Vivo Lineage Tracing during Development and Regeneration

Background: Elucidating the complex cell dynamics (divisions, movement, morphological changes, etc.) underlying embryonic development and adult tissue regeneration requires an efficient means to track cells with high fidelity in space and time. To satisfy this criterion, we developed a transgenic zebrafish line, called PhOTO, that allows photoconvertible optical tracking of nuclear and membrane dynamics in vivo. Methodology: PhOTO zebrafish ubiquitously express targeted blue fluorescent protein (FP) Cerulean and photoconvertible FP Dendra2 fusions, allowing for instantaneous, precise targeting and tracking of any number of cells using Dendra2 photoconversion while simultaneously monitoring global cell behavior and morphology. Expression persists through adulthood, making the PhOTO zebrafish an excellent tool for studying tissue regeneration: after tail fin amputation and photoconversion of a ~100µm stripe along the cut area, marked differences seen in how cells contribute to the new tissue give detailed insight into the dynamic process of regeneration. Photoconverted cells that contributed to the regenerate were separated into three distinct populations corresponding to the extent of cell division 7 days after amputation, and a subset of cells that divided the least were organized into an evenly spaced, linear orientation along the length of the newly regenerating fin. Conclusions/Significance: PhOTO zebrafish have wide applicability for lineage tracing at the systems-level in the early embryo as well as in the adult, making them ideal candidate tools for future research in development, traumatic injury and regeneration, cancer progression, and stem cell behavior

smart sustainable islands vs smart sustainable cities

This paper has several aims: a) the presentation of a critical analysis of the terms "smart sustainable cities" and "smart sustainable islands" b) the presentation of a number of principles towards to the development methodological framework of concepts and actions, in a form of a manual and actions guide, for the smartification and sustainability of islands. This kind of master plan is divided in thematic sectors (key factors) which concern the insular municipalities c) the creation of an island's smartification and sustainability index d) the first steps towards the creation of a portal for the presentation of our smartification actions manual, together with relative resources, smart applications examples, and, in the near future the first results of our index application in a number of Greek islands and e) the presentation of some proposals of possible actions towards their sustainable development and smartification for the municipalities - islands of Paros and Antiparos in Greece, as case studies

Pathwise Sensitivity Analysis in Transient Regimes

The instantaneous relative entropy (IRE) and the corresponding instanta- neous Fisher information matrix (IFIM) for transient stochastic processes are pre- sented in this paper. These novel tools for sensitivity analysis of stochastic models serve as an extension of the well known relative entropy rate (RER) and the corre- sponding Fisher information matrix (FIM) that apply to stationary processes. Three cases are studied here, discrete-time Markov chains, continuous-time Markov chains and stochastic differential equations. A biological reaction network is presented as a demonstration numerical example

GEOGRAPHIC OBJECTS: THEORY OR TECHNOLOGY DRIVEN?

This article aims to compare the geo-graphic (spatial) objects in 2D (planar objects) proposed by CON.G.O.O. and ISO standards, and the ability of a number of GIS software to handle them. The results achieved so far showed that the actual technical possibilities are not always sufficient to support the complex spatial objects proposed by CON.G.O.O

Todellista asiakasarvoa luomassa – myynnistä arvomyyntiin : case Mediamaisteri Oy

Tämän opinnäytetyön tavoite oli case-yritys Mediamaisteri Oy:n B2B-myyntiprosessin kehittäminen. Tarkoitus oli hyödyntää palvelumuotoilua lisäämään asiakasymmärrystä ja tukemaan asiakkaiden kokeman arvon muodostumista sekä positiivisten asiakaskokemusten syntymistä myyntiprosessin alkuvaiheen asiakaskohtaamisissa. Lisäksi tarkoitus oli kiteyttää empiirisen aineiston pohjalta saatu tieto asiakasprofiileiksi, joita voidaan hyödyntää asiakaslähtöisten ratkaisujen suunnittelussa heti asiakkuuden alusta ja ensimmäisestä myyntitapaamisesta lähtien. Opinnäytetyön tutkimuksellisen osuuden toteuttamisen pohjana on kvalitatiivinen tutkimusote ja palvelumuotoilun prosessi. Tutkimuskohde tarkennettiin kuvaamalla Mediamaisteri Oy:n asiakkuuden alkuvaiheen palvelupolku, josta rajattiin tutkimuksen kohteeksi ensimmäinen asiakastapaaminen ja sitä edeltävä aika, jolloin asiakas kiinnostuu yrityksen palveluista ja ensikontakti yritykseen tapahtuu. Tutkimusaineisto muodostuu kuudesta Mediamaisteri Oy:n yritysasiakkaan haastattelusta, jotka toteutettiin virtuaalisesti teemahaastattelun muodossa. Aineiston analysoinnissa hyödynnettiin induktiivista sisällönanalyysiä. Opinnäytetyön teoreettinen viitekehys rakentuu B2B-myynnin, asiakasarvon muodostumisen ja positiivisen asiakaskokemuksen teorioista. Opinnäytetyön empiirisessä osassa kuvataan yksityiskohtaisesti työn toteuttaminen ja toteutuksen vaiheittainen eteneminen. Opinnäytetyön tuloksien mukaan Mediamaisteri Oy:n yritysasiakkaan positiivinen asiakaskokemus palvelujen hankintavaiheessa ja ensimmäisen asiakastapaamisen aikana koostuu myyjäyrityksen koetusta osaamisesta ja ammattitaidosta, palveluasenteesta, asiakaslähtöisyydestä, vuorovaikutustaidoista, yhteistyötaidoista, avoimuuden ja luottamuksen tunteen herättämisestä ja projektinhallinnasta. Opinnäytetyön tutkimusaineiston pohjalta kerätty asiakastieto kiteytettiin Mediamaisteri Oy:n yritysasiakkaan asiakasprofiileiksi, joita voidaan tulevaisuudessa hyödyntää yrityksen asiakaslähtöisen myyntiprosessin kehittämisessä suuntaamaan toimintaa kohti todellista asiakasarvoa asiakkuuden alkuvaiheesta alkaen. Voidaan todeta, että opinnäytetyön tuloksilla on yhteyttä opinnäytetyön viitekehyksessä esitettyyn aikaisempaan teoreettiseen tietoon B2B-myynnistä, asiakasarvon muodostumisesta ja positiivisesta asiakaskokemuksesta. Opinnäytetyön tuloksissa ilmeni, että asiakasymmärryksen tavoittelu jää palvelujen hankintavaiheessa ja ensimmäisessä asiakastapaamisessa usein pinnalliselle tasolle. Jatkotutkimus etenkin vuorovaikutustaitojen merkityksestä B2B-myyntiprosessin alussa ja ensimmäisessä B2B-myyntitapaamisessa arvonluonnin ja arvomyynnin edellyttämän asiakasymmärryksen saavuttamiseksi on suositeltavaa.The aim of this thesis was to develop the B2B sales process of the case company Mediamaisteri Oy. The purpose was to utilize service design to promote the customer insight and to support the formation of the customer value and positive customer experiences in customer touchpoints during the early stages of the sales process. In addition, the purpose was to crystallize the information obtained from the empirical data into customer profiles that can be used to design customer-oriented solutions right from the beginning of a customer relationship and the initial B2B sales meeting. The basis for carrying out the empirical part of the thesis was the qualitative research and the process of service design. The research subject was defined by describing the business client’s customer journey in the beginning of the customer relationship with Mediamaisteri Oy, and by focusing to the initial B2B sales meeting and the time when the client became interested in the company's services and made the first contact. The research material consisted of six interviews of Mediamaisteri Oy's business clients, made as online theme interviews. The material was analyzed by utilizing inductive content analysis. The theoretical framework of the thesis was based on the theories of B2B sales, customer value creation and positive customer experience. In the empirical part of the thesis, the implementation of the work and the steps of the process are described in detail. The findings of the thesis indicate that the positive customer experience of a Mediamaisteri business client during the procurement phase and the initial B2B sales meeting consists of proven expertise and professionalism, service attitude, customer orientation, interaction skills, co-operation skills, openness and trust, and the project management. The research data collected was crystallized into the business client profiles of Mediamaisteri Oy, which can be used in the future to develop the customer-oriented sales process of the company in order to direct the business towards the real customer value starting right from the beginning of the customer relationship. It can be concluded that the results of the thesis are related to the previous theoretical knowledge of B2B sales, customer value creation and a positive customer experience presented in the theoretical framework of the thesis. The results of the thesis showed that the pursuit of customer understanding during the procurement phase and the initial B2B sales meeting often remains superficial. Further research on the significance of interaction skills in the beginning of the sales process and at the initial B2B sales meeting is desirable to achieve value creation and value-based customer insight

Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection

The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n = 122) recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression. Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL) and CD4 T cell count) and the trial endpoint (time to CD4 count <350 cells/μl or initiation of antiretroviral therapy). To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed. Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants. Expression of 'exhaustion' or 'immune checkpoint' markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches