Computational mapping of regulatory domains of human genes

Das menschliche Genom enthält Millionen von regulatorischen Elementen - Enhancern -, die die Genexpression quantitativ regulieren. Trotz des enormen Fortschritts beim Verständnis, wie Enhancer die Genexpression steuern, fehlt es in diesem Bereich immer noch an einem systematischen, integrativen und zugänglichen Ansatz zur Entdeckung und Dokumentation von cis-regulatorischen Beziehungen im gesamten Genom. Wir haben eine neuartige Methode - reg2gene - entwickelt, die Genexpression~Enhancer-Aktivität modelliert und integriert. reg2gene besteht aus drei Hauptschritten: 1) Datenquantifizierung, 2) Datenmodellierung und Signifikanzbewertung und 3) Datenintegration, die in dem R-Paket reg2gene zusammengefasst sind. Als Ergebnis haben wir zwei Sätze von Enhancer-Gen-Assoziationen (EGAs) identifiziert: den flexiblen Satz von ~230K EGAs (flexibleC) und den stringenten Satz von ~60K EGAs (stringentC). Wir haben große Unterschiede zwischen den bisher veröffentlichten Berechnungsmodellen für Enhancer-Gene-Assoziationen festgestellt, vor allem in Bezug auf die Lage, die Anzahl und die Eigenschaften der definierten Enhancer-Regionen und EGAs. Wir führten ein detailliertes Benchmarking von sieben Sets von rechnerisch modellierten EGAs durch, zeigten jedoch, dass keiner der derzeit verfügbaren Benchmark-Datensätze als "goldener Standard" verwendet werden kann. Wir definierten einen zusätzlichen Benchmark-Datensatz mit positiven und negativen EGAs, mit dem wir zeigten, dass das stringentC-Modell den höchsten positiven Vorhersagewert (PPV) hatte. Wir haben das Potenzial von EGAs zur Identifizierung von Genzielen von nicht-kodierenden SNP-Gene-Assoziationen nachgewiesen. Schließlich führten wir eine funktionelle Analyse durch, um neue Genziele, Enhancer-Pleiotropie und Mechanismen der Enhancer-Aktivität zu ermitteln. Insgesamt bringt diese Arbeit unser Verständnis der durch Enhancer vermittelten Regulierung der Genexpression in Gesundheit und Krankheit voran.Human genome contains millions of regulatory elements - enhancers - that quantitatively regulate gene expression. Multiple experimental and computational approaches were developed to associate enhancers with their gene targets. Despite the tremendous progress in understanding how enhancers tune gene expression, the field still lacks an approach that is systematic, integrative and accessible for discovering and documenting cis-regulatory relationships across the genome. We developed a novel computational approach - reg2gene- that models and integrates gene expression ~ enhancer activity. reg2gene consists of three main steps: 1) data quantification, 2) data modelling and significance assessment, and 3) data integration gathered in the reg2gene R package. As a result we identified two sets of enhancer-gene associations (EGAs): the flexible set of ~230K EGAs (flexibleC), and the stringent set of ~60K EGAs (stringentC). We identified major differences across previously published computational models of enhancer-gene associations; mostly in the location, number and properties of defined enhancer regions and EGAs. We performed detailed benchmarking of seven sets of computationally modelled EGAs, but showed that none of the currently available benchmark datasets could be used as a “golden-standard” benchmark dataset. To account for that observation, we defined an additional benchmark set of positive and negative EGAs with which we showed that the stringentC model had the highest positive predictive value (PPV) across all analyzed computational models. We reviewed the influence of EGA sets on the functional analysis of risk SNPs and demonstrated the potential of EGAs to identify gene targets of non-coding SNP-gene associations. Lastly, we performed a functional analysis to detect novel gene targets, enhancer pleiotropy, and mechanisms of enhancer activity. Altogether, this work advances our understanding of enhancer-mediated gene expression regulation in health and disease.Ljudski genom sadrži milijune regulatornih elemenata - enhancera - koji kvantitativno reguliraju ekspresiju gena. Unatoč ogromnom napretku u razumijevanju načina na koji enhanceri reguliraju ekspresiju gena, području još uvijek nedostaje pristup koji je sustavan, integrativan i dostupan za otkrivanje i dokumentiranje cis-regulatornih odnosa u cijelom genomu. Razvili smo novu računalnu metodu - reg2gene - koja modelira i integrira aktivnost enhancera~ekspresije gena. reg2gene sastoji se od tri glavna koraka: 1) kvantifikacija podataka, 2) modeliranje podataka i procjena značaja, i 3) integracija podataka prikupljenih u reg2gene R paketu. Kao rezultat toga, identificirali smo dva skupa enhancer-gen interakcija (EGA): fleksibilni skup od ~ 230K EGA (flexibleC) i strogi skup od ~ 60K EGA (stringentC). Utvrdili smo velike razlike u prethodno objavljenim računalnim modelima enhancer-gen interakcija; uglavnom u lokaciji, broju i svojstvima definiranih enhancera i EGA. Izveli smo detaljno mjerenje performansi sedam skupova računalno modeliranih EGA-a, ali smo pokazali da se niti jedan od trenutno dostupnih skupova referentnih podataka ne može koristiti kao referentni skup podataka "zlatnI standard". Definirali smo dodatni referentni skup pozitivnih i negativnih EGA -a pomoću kojih smo pokazali da stringentC ima najveću pozitivnu prediktivnu vrijednost (PPV). Pokazali smo potencijal EGA-a za identifikaciju genskih meta nekodirajucih SNP-ova. Proveli smo funkcionalnu analizu kako bismo otkrili nove genske mete, pleiotropiju enhancera i mehanizme aktivnosti enhancera. Ovaj rad poboljšava naše razumijevanje regulacije ekspresije gena posredovane enhancerima

Adoption of Transparency and Openness Promotion (TOP) guidelines across journals

Journal policies continuously evolve to enable knowledge sharing and support reproducible science. However, that change happens within a certain framework. Eight modular standards with three levels of increasing stringency make Transparency and Openness Promotion (TOP) guidelines which can be used to evaluate to what extent and with which stringency journals promote open science. Guidelines define standards for data citation, transparency of data, material, code and design and analysis, replication, plan and study pre-registration, and two effective interventions: “Registered reports” and “Open science badges”, and levels of adoption summed up across standards define journal’s TOP Factor. In this paper, we analysed the status of adoption of TOP guidelines across two thousand journals reported in the TOP Factor metrics. We show that the majority of the journals’ policies align with at least one of the TOP’s standards, most likely “Data citation” (70%) followed by “Data transparency” (19%). Two-thirds of adoptions of TOP standard are of the stringency Level 1 (less stringent), whereas only 9% is of the stringency Level 3. Adoption of TOP standards differs across science disciplines and multidisciplinary journals (N = 1505) and journals from social sciences (N = 1077) show the greatest number of adoptions. Improvement of the measures that journals take to implement open science practices could be done: (1) discipline-specific, (2) journals that have not yet adopted TOP guidelines could do so, (3) the stringency of adoptions could be increased

Adoption of Transparency and Openness Promotion (TOP) Guidelines across Journals

Journal policies continuously evolve to enable knowledge sharing and support reproducible science. However, that change happens within a certain framework. Eight modular standards with three levels of increasing stringency make Transparency and Openness Promotion (TOP) guidelines which can be used to evaluate to what extent and with which stringency journals promote open science. Guidelines define standards for data citation, transparency of data, material, code and design and analysis, replication, plan and study pre-registration, and two effective interventions: “Registered reports” and “Open science badges”, and levels of adoption summed up across standards define journal’s TOP Factor. In this paper, we analysed the status of adoption of TOP guidelines across two thousand journals reported in the TOP Factor metrics. We show that the majority of the journals’ policies align with at least one of the TOP’s standards, most likely “Data citation” (70%) followed by “Data transparency” (19%). Two-thirds of adoptions of TOP standard are of the stringency Level 1 (less stringent), whereas only 9% is of the stringency Level 3. Adoption of TOP standards differs across science disciplines and multidisciplinary journals (N = 1505) and journals from social sciences (N = 1077) show the greatest number of adoptions. Improvement of the measures that journals take to implement open science practices could be done: (1) discipline-specific, (2) journals that have not yet adopted TOP guidelines could do so, (3) the stringency of adoptions could be increased

SEASONAL DYNAMICAL DOWNSCALING WITH ERA-4O DATA: A SENSITIVITY STUDY

The Regional Climate Model (RegCM) with 50 km horizontal resolution was used for seasonal dynamical downscaling of ECMWF ERA-40 data over central and southern Europe and the northern Mediterranean region for one winter and one summer season. Various configurations in initial conditions (ICs) and lateral boundary conditions (LBCs) as well as in the model vertical domain were tested. First, the horizontal resolution of ICs and LBCs was increased from T42 to T159 and then a gradual "degradation" was conducted: the frequency of the LBCs update was reduced from 6-hourly to 12-hourly intervals, the model top was lowered from 100 to 200 hPa and the number of vertical levels was reduced from 18 to 14. The latest, most "degraded", configuration is the closest to that available in the ECMWF seasonal forecast archive. The limited number of experiments (a single experiment per configuration and per season) did not allow a thorough statistical assessment of model responses; however, it can be concluded that, though the differences between various configurations and resolutions are generally small, they are far from being negligible. The increase in the ICs and LBCs horizontal resolution yields a reduction in geopotential, in both the upper-air and surface temperature (cooling) and a reduction in the summer convective precipitation. The reduced, 12-hourly, frequency of the LBCs update mostly renders the opposite result, i.e. an increase in geopotential and temperature. However, it was not possible to fully establish how actually detrimental this reduced frequency in LBCs is, because the input ERA-40 upper-air data "osciliate" between consecutive 6 hours due to the difference in the processing of temperatures from satellites and from radiosondes within the ECMWF 3D-Var assimilation system. The model upper troposphere winds are strengthened when the model top is lowered; however, this effect is partly offset when the number of model levels is reduced. Changes in the model vertical configuration cause on average much weaker effects on surface fields than changes in LBCs. The Arakawa-Schubert ciosure in the parameterisation of convection reduces the amount of summer convective precipitation over the northern European lowlands when compared with the Fritsch,Chappel closure. However, in a large portion of the integration domain precipitation is still too high in respect of the CRU observational data

The association between salt taste perception, mediterranean diet and metabolic syndrome: a cross-sectional study

Metabolic syndrome (MetS) is a widespread disorder and an important public health challenge. The purpose of this study was to identify the association between salt taste perception, Mediterranean diet and MetS. This cross-sectional study included 2798 subjects from the general population of Dalmatia, Croatia. MetS was determined using the Joint Interim Statement definition, and Mediterranean diet compliance was estimated using Mediterranean Diet Serving Score. Salt taste perception was assessed by threshold and suprathreshold testing (intensity and hedonic perception). Logistic regression was used in the analysis, adjusting for important confounding factors. As many as 44% of subjects had MetS, with elevated waist circumference as the most common component (77%). Higher salt taste sensitivity (lower threshold) was associated with several positive outcomes: lower odds of MetS (OR = 0.69; 95% CI 0.52-0.92), lower odds for elevated waist circumference (0.47; 0.27-0.82), elevated fasting glucose or diabetes (0.65; 0.45-0.94), and reduced HDL cholesterol (0.59; 0.42-0.84), compared to the higher threshold group. Subjects with lower salt taste threshold were more likely to consume more fruit, and less likely to adhere to olive oil and white meat guidelines, but without a difference in the overall Mediterranean diet compliance. Salt taste intensity perception was not associated with any of the investigated outcomes, while salty solution liking was associated with MetS (OR = 1.85, CI 95% 1.02-3.35). This study identified an association between salt taste perception and MetS and gave a new insight into taste perception, nutrition, and possible health outcomes

Host genetics and susceptibility to congenital and childhood cytomegalovirus infection: a systematic review

Aim To summarize available evidence on the role of host genetics in the susceptibility to congenital and childhood cytomegalovirus (CMV) infections by conducting a systematic review of published studies. Methods We searched online databases (PubMed, Web of Science, Scopus and HuGe Navigator) for relevant studies with well-defined inclusion and exclusion criteria and assessed the risk of bias using novel Confounding-Selection- Information bias score (CSI). Results 5105 studies were initially identified, but only 5 met all the inclusion criteria and were analyzed in detail. Polymorphisms of the toll-like receptors (TLRs) and mannose- binding lectin (MBL) genes were shown to have an impact on the CMV infection in infants. Polymorphisms of the TLR2 (rs3804100, rs1898830), TLR4 (rs4986791), and TLR9 (rs352140) were shown to have a role in congenital CMV infection. Low MBL levels were associated with CMV infection in Chinese individuals, a finding that was not replicated in Caucasians. The overall credibility of evidence was weak. Conclusions Based on currently available very limited amount of evidence, it is uncertain whether congenital and childhood CMV infections are under host genetic control. Additional primary studies are needed with more specific research hypotheses that will enable gradual understanding of specific mechanisms of the CMV pathogenesis. More genetic studies in the future will facilitate better understanding of host susceptibility and likely enable novel preventative and curative measure

Dynamical and statistical downscaling of seasonal temperature forecasts in Europe: Added value for user applications

This work describes the results of a comprehensive intercomparison experiment of dynamical and statistical downscaling methods performed in the framework of the SPECS (http://www.specs-fp7.eu) and EUPORIAS (http://www.euporias.eu) projects for seasonal forecasting over Europe, a region which exhibits low-to-moderate seasonal forecast skill. We considered a 15-member hindcast provided by the ECEARTH global model (similar to ECMWF System 4, but using bias corrected SST) for the period 1991-2012. In particular, we focus on summer mean temperature and evaluate the added value of downscaling for representation of the local climatology (mean values and extremes), improvement of model skill and performance in particular heatwave episodes. Whereas the suitability of dynamical downscaling for reducing the orographic biases of the global model depends on the region and model considered, statistical downscaling can systematically reduce errors in different order moments, from the mean to the extremes (as represented by the 95th percentile here). However, both dynamical and statistical methods lead to similar skill patterns with about the same overall performance as the global model, which shows higher values in south-eastern Europe. Therefore, no relevant added value is found in terms of model skill improvement. Finally, when focusing on the heatwaves of 2003, 2006, 2010 and 2012, the limitations of the global model to detect these hot episodes are inherited by all dynamical and statistical downscaling methods so no added value is neither found in this aspect. This work provides, to our knowledge, the largest and most comprehensive intercomparison of statistical and dynamical downscaling for seasonal forecasting over Europe.This study was supported by the SPECS and EUPORIAS projects, funded by the European Commission through the Seventh Framework Programme for Research under grant agreements 308378 and 308291, respectively. We are also grateful to the E-OBS dataset from the EU-FP6 project ENSEMBLES and the data providers in the ECA&D project. One of the authors (EvM) wants to thank Michael Kolax from SMHI (Norrköping, Sweden) for making available the full EC-EARTH hindcast ensemble for dynamical downscaling at KNMI. Finally, for the WRF simulations, the authors acknowledge the access provided to the Altamira Supercomputer at the Institute of Physics of Cantabria (IFCA-CSIC), member of the Spanish Supercomputing Network (http://grid.ifca.es/wiki/Supercomputing)

PRIJEDLOG STRATEGIJE DIGITALNOG MARKETINGA I MONETIZACIJE KRONOGRAF BLOGA

Tradicionalni blog odličan je primjer više mehanizama i koncepata digitalnog marketinga. Blog u marketinškom smislu primarno služi kao platforma za marketing kroz sadržaj te je danas popularan marketinški alat unutar strategije digitalnog marketinga brojnih tvrtki i internetskih trgovina. Iako je jedan internetski blog u usporedbi sa internetskom trgovinom često jednostavniji u konceptu i izvedbi, za kvalitetan internetski blog potrebno je pažljivo izrađena i implementirana digitalna strategija. Upravo je suodnos internetskog bloga i internetske trgovine te njihova međuovisnost tema ovog završnog rada. U završnom radu „Prijedlog strategije digitalnog marketinga i monetizacije Kronograf bloga-a“ predstaviti će se strategije i taktike digitalnog marketinga te monetizacije za Kronograf blog, originalno izrađen u sklopu kolegija Standardi u primjeni internetske tehnologije (SUPIT), i suplementarnu Kronograf internetsku trgovinu. Završni rad može se podijeliti u 3 glavna dijela, istraživanje tržišta, prijedlog marketinške strategije i prijedlog strategije monetizacije.A traditional blog is a great example of multiple digital marketing mechanisms and concepts. In terms of marketing, a blog primarily serves as a platform for content marketing and is today a popular marketing tool within the digital marketing strategy of numerous companies and online stores. Although an online blog is often simpler in concept and execution compared to an online store, for a quality online blog it is necessary to carefully create and implement a digital strategy. It is precisely the relationship between an online blog and an online store and their interdependence that is the subject of this final paper. The final paper "Proposal of digital marketing and monetization strategy of Kronograf blog" will present the digital marketing and monetization strategy and tactics for Kronograf blog, originally developed as part of the course Standards in the Application of Internet Technology (SUPIT), and Kronograf online store. The final paper can be divided into 3 main sections, market research, marketing strategy proposal, and monetization strategy proposal

Inaccurate perceptions of God

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