Ancestry deconvolution and partial polygenic score can improve susceptibility predictions in recently admixed individuals

Polygenic Scores (PSs) describe the genetic component of an individual’s quantitative phenotype or their susceptibility to diseases with a genetic basis. Currently, PSs rely on population-dependent contributions of many associated alleles, with limited applicability to understudied populations and recently admixed individuals. Here we introduce a combination of local ancestry deconvolution and partial PS computation to account for the population-specific nature of the association signals in individuals with admixed ancestry. We demonstrate partial PS to be a proxy for the total PS and that a portion of the genome is enough to improve susceptibility predictions for the traits we test. By combining partial PSs from different populations, we are able to improve trait predictability in admixed individuals with some European ancestry. These results may extend the applicability of PSs to subjects with a complex history of admixture, where current methods cannot be applied

Enhanced light emission from top-emitting organic light-emitting diodes by optimizing surface plasmon polariton losses

We demonstrate enhanced light extraction for monochrome top-emitting organic light-emitting diodes (OLEDs). The enhancement by a factor of 1.2 compared to a reference sample is caused by the use of a hole transport layer (HTL) material possessing a low refractive index (1.52). The low refractive index reduces the in-plane wave vector of the surface plasmon polariton (SPP) excited at the interface between the bottom opaque metallic electrode (anode) and the HTL. The shift of the SPP dispersion relation decreases the power dissipated into lost evanescent excitations and thus increases the outcoupling efficiency, although the SPP remains constant in intensity. The proposed method is suitable for emitter materials owning isotropic orientation of the transition dipole moments as well as anisotropic, preferentially horizontal orientation, resulting in comparable enhancement factors. Furthermore, for sufficiently low refractive indices of the HTL material, the SPP can be modeled as a propagating plane wave within other organic materials in the optical microcavity. Thus, by applying further extraction methods, such as micro lenses or Bragg gratings, it would become feasible to obtain even higher enhancements of the light extraction.Comment: 11 pages, 6 figures, will be submitted to PR

Local density of states, spectrum, and far-field interference of surface plasmon polaritons probed by cathodoluminescence

The surface plasmon polariton (SPP) field intensity in the vicinity of gratings patterned in an otherwise planar gold surface is spatially resolved using cathodoluminescence (CL). A detailed theoretical analysis is presented that successfully explains the measured CL signal based upon interference of transition radiation directly generated by electron impact and SPPs launched by the electron and outcoupled by the grating. The measured spectral dependence of the SPP yield per incoming electron is in excellent agreement with rigorous electromagnetic calculations. The CL emission is shown to be similar to that of a dipole oriented perpendicular to the surface and situated at the point of electron impact, which allows us to establish a solid connection between the CL signal and the photonic local density of states associated to the SPPs

Verbetering van de persoonlijke predictie van complexe eigenschappen en ziektes: een toepassing op Type 2 Diabetes

Väitekirja elektrooniline versioon ei sisalda publikatsiooneDoktoritöö kaitsmine toimub Groningeni Ülikoolis 7. septembril 2022Tänapäeva maailmas on komplekshaigused üheks juhtivaks haigestumuse ja suremuse põhjuseks. Komplekshaigused tekivad mitmete geneetiliste ja mitte-geneetiliste (nt elustiili ja keskkonna) riskitegurite ning nendevaheliste keerukate koosmõjude tulemusel. Kuna need haigused põhjustavad terviseprobleeme ja on liigselt koormavad tervishoiusüsteemidele, siis otsivad teadlased lahendusi, kuidas neid haigusi avastada veel enne nende väljakujunemist. On teada, et erinevused geneetiliste komponentide ja elustiili osas põhjustavad haigusriski varieerumist inimeste vahel, mistõttu üheks lahenduseks selliste keerukate haiguste ennetamisel peetakse personaalset lähenemist, mis inimese geneetilise ja mitte-geneetilise info põhjal ennustaks tema haigusriski. Käesolevas väitekirjas käsitleti komplekshaigusena teist tüüpi diabeeti (T2D), mis tekib kõrge veresuhkru taseme korral ning põhjustab õigeaegse ja korrektse ravi puudumisel tüsistusi. T2D teadaolevateks riskiteguriteks on kõrgem vanus, madal kehaline aktiivsus, liigne kaloraaž, madal sotsiaalmajanduslik staatus, suitsetamine ja alkoholi tarvitamine. Geneetilisi riskitegureid ja nende seoseid elustiili ning keskkondlike riskiteguritega on küll uuritud, aga haiguse keerukuse tõttu pole täpseid toimemehhanisme veel välja selgitatud. Seetõttu uuriti käesolevas väitekirjas inimese genoomi, et mõista, kuidas paremini kasutada geneetilist informatsiooni T2D riski prognoosimiseks. Selleks kasutati polügeenset riskiskoori (PRS), mis summeerib inimese haiguse tekke geneetilise riski ja mille abil tuvastatakse juba praegu kõrgesse T2D riskirühma kuuluvaid indiviide. Siiski on veel mitmeid vastakaid seisukohti praeguseks väljatöötatud PRS-ide geneetilise riski hindamises. Näiteks ei pruugi PRS-i ennustustäpsus olla piisav või seda ei ole võimalik arvutada iga indiviidi jaoks sarnaselt, kuna iga genoom on mõjutatud suure hulga riskitegurite poolt, mis võivad erinevates populatsioonides erineda. Käesoleva väitekirja teadusartiklitel põhinevad viis peatükki keskendusid personaliseeritud T2D ennetuse parendamisele geneetiliste meetodite kaudu, PRS-i metoodiliste piirangute käsitlemisele ning epigeneetiliste riskitegurite rolli uurimisele T2D korral. Esimeses peatükis valideeriti kahes suures Euroopa biopangas PRS-meetodina topeltkaalutud geneetiline riskiskoor. Teises peatükis töötati välja uued PRS-meetodid, et parandada PRS-i ülekantavust neile indiviididele, kelle esivanemad pärinevad erinevatest populatsioonidest, kelle genoomid olid segunenud ja keda oli tänu uudsete geneetiliste meetodite kasutamisele võimalik uurida. Kolmandas peatükis uuriti PRS-i ülekantavust kahe Euroopa populatsiooni vahel, kus genoomid võivad erineda mitmete populatsioonispetsiifiliste tegurite tõttu. Neljandas peatükis testiti metülatsiooniskooride (MS) seost T2D ja selle glükeemiliste endofenotüüpidega, et teha kindlaks, kas epigeneetilised mehhanismid vahendavad keskkonna ja geeni-keskkonna koosmõjusid T2D tekkes. Viiendas peatükis anti ülevaade genoomika valdkonna viimastest arengutest ning nende rakendamise võimalustest personaalmeditsiinis just Eesti Geenivaramu näitel. Töö tulemused näitasid, et topeltkaalutud GRS töötas paremini kui traditsiooniline GRS. Uued PRS-id, mis kasutasid geneetilise lookuse kindlast populatsioonist põlvnemise hindamise meetodit, parandasid komplekstunnuste prognoosimise täpsust hiljuti segunenud indiviidide puhul, kes varasemalt jäeti geneetilistest uuringutest välja, kuid uudse PRS meetodi tõttu on võimalik neid nüüd kaasata personaalmeditsiini uuringutesse. Uudne populatsioonistruktuuri korrigeerimisviis geneetilistes analüüsides ei parandanud PRS ülekantavust kahe Euroopa kohordi vahel ja isegi traditsioonilise lähenemisviisiga saadud PRS sisaldas populatsioonistruktuuri. MS-id näitasid, et epigeneetika on võimalik molekulaarne vahelüli, mis peegeldab keskkonna ja elustiili mõju T2D-le ja selle endofenotüüpidele. Töö tulemused näitavad komplekstunnuste ja -haiguste personaalse ennetuse täpsema ja laialdasema rakenduse võimalikkust, mis viib meid sammu lähemale personaalmeditsiinile eesmärgiga pikendada inimeste tervena elatud aastate arvu.In nowadays world, common complex diseases are among the top leading causes of death globally. These diseases result from many genetic and non-genetic (e.g. lifestyle and environment) factors and from interactions between them. Since such diseases have a high health burden for the affected individual and place a heavy load on the healthcare systems, scientists are searching for solutions to delay their onset or even better, to prevent them. Evidently, differences in genetic and non-genetic components result in variation in disease risk between individuals. Therefore, prevention of such complex diseases requires a personalized approach that uses each person’s genetic and non-genetic information to predict his or her disease risk. In the current thesis, type 2 diabetes (T2D) was used as a model example of a common complex disease, T2D occurs when the blood sugar levels are too high and results in severe health complications when appropriate and timely treatment is not guaranteed. Factors such as higher age, low physical activity, high calorie intake, low socioeconomic position, smoking, and alcohol consumption have already been established as risk factors for T2D. However, the contributions of genetic risk factors and their interactions with non-genetic risk factors have not been so well explored. Therefore, the current thesis zooms in on the human genome to understand how better to use genetic information for risk prediction of T2D, leveraging on recently developed polygenic risk score (PRS – a measure combining a person’s genetic risk for a disease) approaches. Such PRSs could already enable detection of the high-risk individuals for T2D according to their genetic composition at young ages before the onset of the disease. However, there are still several limitations regarding the use of a PRS in clinical practice as its performance does not reach to the estimated levels or it cannot be constructed for each individual in a similar way due to the population-specific risk factors, causing too low estimated risks when applied in non-Europeans or admixed individuals. Therefore, current thesis presents five chapters, which mainly focus on improving the personalized prediction via genetics, tackling the current methodological limitations for PRSs, plus investigating the role of epigenetic risk factors for T2D. In the first chapter, a PRS method (called doubly-weighted GRS) was validated in two European biobanks. In the second chapter, novel PRS methods were developed to improve the PRS transferability for individuals with admixed ancestry. In the third chapter, the PRS transferability issue was investigated on a finer-scale, that is, whether a principal component projection (a method to account for population structure) could mitigate the transferability issue between two European populations. In the fourth chapter, associations of methylation scores (MSs) with prevalent T2D and its glycemic endophenotypes were tested to see whether epigenetic mechanisms could represent environmental and gene-environment effects on top of the genetics. In the fifth chapter the latest advancements in the genomics field were discussed and how to apply these in the personalized medicine framework with the prime example of the Estonian Biobank. The findings of this thesis showed that the doubly-weighted GRS indeed performed better that the traditional GRS in both European biobanks. The novel PRSs, which used the information from the method estimating genetic ancestry in a specific genetic locus could improve the prediction for the recently admixed individuals. These PRS methods made it possible to include individuals and having them benefit from personalized prediction, who were previously just excluded from the genetic studies. The traditional population-specific principal components outperformed our approach. However, the resulting PRS still contained population structure. Lastly, MSs showed a promising trend towards representing the environmental triggers for T2D and its underlying traits. In summary, the doctoral thesis resulted in more accurate and broader application of personalized prediction for complex traits and diseases leading us a step closer to personalized medicine, which makes it easier to maintain health and to prolong healthy life years.https://www.ester.ee/record=b550890

Molecular interactions of ASPP1 and ASPP2 with the p53 protein family and the apoptotic promoters PUMA and Bax

The apoptosis stimulating p53 proteins, ASPP1 and ASPP2, are the first two common activators of the p53 protein family that selectively enable the latter to regulate specific apoptotic target genes, which facilitates yes yet unknown mechanisms for discrimination between cell cycle arrest and apoptosis. To better understand the interplay between ASPP- and p53-family of proteins we investigated the molecular interactions between them using biochemical methods and structure-based homology modelling. The data demonstrate that: (i) the binding of ASPP1 and ASPP2 to p53, p63 and p73 is direct; (ii) the C-termini of ASPP1 and ASPP2 interact with the DNA-binding domains of p53 protein family with dissociation constants, Kd, in the lower micro-molar range; (iii) the stoichiometry of binding is 1:1; (iv) the DNA-binding domains of p53 family members are sufficient for these protein–protein interactions; (v) EMSA titrations revealed that while tri-complex formation between ASPPs, p53 family of proteins and PUMA/Bax is mutually exclusive, ASPP2 (but not ASPP1) formed a complex with PUMA (but not Bax) and displaced p53 and p73. The structure-based homology modelling revealed subtle differences between ASPP2 and ASPP1 and together with the experimental data provide novel mechanistic insights

Two Models of Speculative Bubbles Dynamics for Cryptocurrency Prices

The problem of investing into a cryptocurrency market requires good understanding of the processes that regulate the price of the currency. In this paper we offer a view of the cryptocurrency market as an environment for realization of self-organized speculative schemes that result in the formation of a characteristic price bubble. We use a microscale, agent-based model to simulate the system behavior and derive a macroscale ordinary differential equation (ODE) model to estimate the price and the return rates observed in the simulated agent-based model. We provide a formula for the total risk of the system expressed as a sum of two independent components, one being characteristic of the price bubble and the other of the investor behavior