k-Spectra of weakly-c-Balanced Words

A word $u$ is a scattered factor of $w$ if $u$ can be obtained from $w$ by deleting some of its letters. That is, there exist the (potentially empty) words $u_1,u_2,..., u_n$, and $v_0,v_1,..,v_n$ such that $u = u_1u_2...u_n$ and $w = v_0u_1v_1u_2v_2...u_nv_n$. We consider the set of length-$k$ scattered factors of a given word w, called here $k$-spectrum and denoted \ScatFact_k(w). We prove a series of properties of the sets \ScatFact_k(w) for binary strictly balanced and, respectively, $c$-balanced words $w$, i.e., words over a two-letter alphabet where the number of occurrences of each letter is the same, or, respectively, one letter has $c$-more occurrences than the other. In particular, we consider the question which cardinalities n= |\ScatFact_k(w)| are obtainable, for a positive integer $k$, when $w$ is either a strictly balanced binary word of length $2k$, or a $c$-balanced binary word of length $2k-c$. We also consider the problem of reconstructing words from their $k$-spectra

National Programme for Radiation Safety Research

Vuoden 2013 tutkimuslaitosuudistuksen myötä kansallista työnjakoa säteilyturvallisuuden tutkimuksessa on nyt tarkasteltu uudelleen. Suomeen perustetaan yliopistojen, korkeakoulujen ja STUKin välinen tutkimusyhteenliittymä. Yhteenliittymän työn pohjaksi on laadittu säteilyturvallisuuden tutkimusohjelma, jonka tavoitteena on kuvata tutkimustarpeet ja varmistaa korkeatasoinen kansallinen osaaminen ja tietopohja säteilyturvallisuudessa ja turvata kansallisten viranomaisten tiedon saanti. Säteilyturvallisuus kattaa sekä ionisoivan säteilyn että ionisoimattoman säteilyn. Keskeisiä tiedon tarpeita liittyy seuraaviin aiheisiin: - Säteily ja terveys: säteilyn terveyshaitat ja vaikutusmekanismit, lääketieteellinen säteilyn käyttö, potilasturvallisuus ja turvalliset hoito‐ ja diagnostiikkakäytännöt, työntekijöiden turvallisuus, riskitietoisuus ja –käyttäytyminen - Säteily ympäristössä: radonturvallinen rakentaminen, radioaktiivisten aineiden kulkeutuminen ympäristössä, elintarvikkeiden pitoisuudet ja niiden kautta tapahtuva altistuminen, vaikutukset eliökuntaan; kansalliset erityispiirteet - Säteilyuhkiin ja onnettomuuksiin varautuminen: onnettomuusvalmius ja turvajärjestelyt - Mittaukset ja teknologiat säteilyturvallisuudessa: metrologiaan ja dosimetriaan liittyvät innovaatiot, säteily‐ ja ydinturvallisuutta palvelevat sovellukset, ohjelmistot ja laitteet. Säteilyturvallisuus kattaa laajan kirjon tieteenaloja, aina säteily‐ ja ydinfysiikasta biolääketieteisiin, ympäristötieteisiin, tekniikkaan ja yhteiskunta‐ ja käyttäytymistieteisiin. Kotimaisista yliopistoista löytyy vahvaa tieteenalojen osaamista, ja tämä osaaminen saatetaan entistä paremmin mukaan yhteiskunnan tarpeista lähtevään säteilyturvallisuuden tutkimukseen. STUK suuntaa oman tutkimus‐ ja kehittämistoimintansa suoraan valvontaa ja valmiutta sekä turvajärjestelyjä tukeviin aiheisiin ja selvityksiin. Yliopistojen panosta tarvitaan erityi‐sesti laajoissa hankkeissa ja perustutkimusta ja soveltavaa tutkimusta edellyttävissä aiheissa, jotka liittyvät riskinarviointiin, teknologiseen kehittämiseen ja riskien hallintaan. STUK on ollut keskeisesti mukana luomassa eurooppalaisia tutkimusagendoja ja tutkimuksen yhteenliittymiä Euratom‐ohjelmassa. Tavoitteena on liittää kansallinen säteilyturvallisuuden ohjelma eurooppalaisiin säteilyturvallisuusalan ohjelmiin. Säteilyturvallisuustutkimuksen uudelleen järjestely edellyttää ohjelmaluonteista rahoitusta, jolla pystytään turvaamaan pitkäjänteinen osaamisen ylläpito ja kehittäminen monitietei‐sellä, koko yhteiskuntaa palvelevalla tutkimussaralla. STUK on aiemmin melko ketterästi pystynyt vastaamaan muiden viranomaisten ja hallinnonalojen säteilyturvallisuutta koskeviin kansallisiin kehittämistarpeisiin sekä antamaan asiantuntijatukea kansainvälisellä tasolla. Jatkossa rahoitusta yhteiskunnan kannalta merkittäviin tietotarpeisiin tulee osoittaa joko ministeriöiden oman tutkimusrahoituksen tai tutkimuslaitosuudistuksen yhteydessä perustettujen uusien rahoitusvälineiden, Valtioneuvoston kanslian selvitys‐ ja tutkimustoiminnan ja Suomen Akatemian strategisen tutkimuksen neuvoston kautta. Kansallisen sätei‐lyturvallisuustutkimuksen ohjelman linkittäminen H2020‐ohjelmaan ja kansainvälisistä tutkimusresursseista hyötyminen edellyttää kansallista vastinrahoitusta EU‐tutkimuksessa

Combined Effects of Thrombosis Pathway Gene Variants Predict Cardiovascular Events

The genetic background of complex diseases is proposed to consist of several low-penetrance risk loci. Addressing this complexity likely requires both large sample size and simultaneous analysis of different predisposing variants. We investigated the role of four thrombosis genes: coagulation factor V (F5), intercellular adhesion molecule 1 (ICAM1), protein C (PROC), and thrombomodulin (THBD) in cardiovascular diseases. Single allelic gene variants and their pair-wise combinations were analyzed in two independently sampled population cohorts from Finland. From among 14,140 FINRISK participants (FINRISK-92, n = 5,999 and FINRISK-97, n = 8,141), we selected for genotyping a sample of 2,222, including 528 incident cardiovascular disease (CVD) cases and random subcohorts totaling 786. To cover all known common haplotypes (>10%), 54 single nucleotide polymorphisms (SNPs) were genotyped. Classification-tree analysis identified 11 SNPs that were further analyzed in Cox's proportional hazard model as single variants and pair-wise combinations. Multiple testing was controlled by use of two independent cohorts and with false-discovery rate. Several CVD risk variants were identified: In women, the combination of F5 rs7542281 × THBD rs1042580, together with three single F5 SNPs, was associated with CVD events. Among men, PROC rs1041296, when combined with either ICAM1 rs5030341 or F5 rs2269648, was associated with total mortality. As a single variant, PROC rs1401296, together with the F5 Leiden mutation, was associated with ischemic stroke events. Our strategy to combine the classification-tree analysis with more traditional genetic models was successful in identifying SNPs—acting either in combination or as single variants—predisposing to CVD, and produced consistent results in two independent cohorts. These results suggest that variants in these four thrombosis genes contribute to arterial cardiovascular events at population level

Synchronizing automata with a letter of deficiency 2

AbstractWe present two infinite series of synchronizing automata with a letter of deficiency 2 whose shortest reset words are longer than those for synchronizing automata obtained by a straightforward modification of Černý’s construction

Thirty-One Novel Biomarkers as Predictors for Clinically Incident Diabetes

The prevalence of diabetes is increasing in all industrialized countries and its prevention has become a public health priority. However, the predictors of diabetes risk are insufficiently understood. We evaluated, whether 31 novel biomarkers could help to predict the risk of incident diabetes.The biomarkers were evaluated primarily in the FINRISK97 cohort (n = 7,827; 417 cases of clinically incident diabetes during the follow-up). The findings were replicated in the Health 2000 cohort (n = 4,977; 179 cases of clinically incident diabetes during the follow-up). We used Cox proportional hazards models to calculate the relative risk of diabetes, after adjusting for the classic risk factors, separately for each biomarker. Next, we assessed the discriminatory ability of single biomarkers using receiver operating characteristic curves and C-statistics, integrated discrimination improvement (IDI) and net reclassification improvement (NRI). Finally, we derived a biomarker score in the FINRISK97 cohort and validated it in the Health 2000 cohort. A score consisting of adiponectin, apolipoprotein B, C-reactive protein and ferritin almost doubled the relative risk of diabetes in the validation cohort (HR per one standard deviation increase 1.88, p = 2.8 e-5). It also improved discrimination of the model (IDI = 0.0149, p<0.0001) and reclassification of diabetes risk (NRI = 11.8%, p = 0.006). Gender-specific analyses suggested that the best score differed between men and women. Among men, the best results were obtained with the score of four biomarkers: adiponectin, apolipoprotein B, ferritin and interleukin-1 receptor antagonist, which gave an NRI of 25.4% (p<0.0001). Among women, the best score included adiponectin, apolipoprotein B, C-reactive protein and insulin. It gave an NRI of 13.6% (p = 0.041).We identified novel biomarkers that were associated with the risk of clinically incident diabetes over and above the classic risk factors. This gives new insights into the pathogenesis of diabetes and may help with targeting prevention and treatment

Risk Alleles of USF1 Gene Predict Cardiovascular Disease of Women in Two Prospective Studies

Upstream transcription factor 1 (USF1) is a ubiquitously expressed transcription factor controlling several critical genes in lipid and glucose metabolism. Of some 40 genes regulated by USF1, several are involved in the molecular pathogenesis of cardiovascular disease (CVD). Although the USF1 gene has been shown to have a critical role in the etiology of familial combined hyperlipidemia, which predisposes to early CVD, the gene's potential role as a risk factor for CVD events at the population level has not been established. Here we report the results from a prospective genetic–epidemiological study of the association between the USF1 variants, CVD, and mortality in two large Finnish cohorts. Haplotype-tagging single nucleotide polymorphisms exposing all common allelic variants of USF1 were genotyped in a prospective case-cohort design with two distinct cohorts followed up during 1992–2001 and 1997–2003. The total number of follow-up years was 112,435 in 14,140 individuals, of which 2,225 were selected for genotyping based on the case-cohort study strategy. After adjustment for conventional risk factors, we observed an association of USF1 with CVD and mortality among females. In combined analysis of the two cohorts, female carriers of a USF1 risk haplotype had a 2-fold risk of a CVD event (hazard ratio [HR] 2.02; 95% confidence interval [CI] 1.16–3.53; p = 0.01) and an increased risk of all-cause mortality (HR 2.52; 95% CI 1.46–4.35; p = 0.0009). A putative protective haplotype of USF1 was also identified. Our study shows how a gene identified in exceptional families proves to be important also at the population level, implying that allelic variants of USF1 significantly influence the prospective risk of CVD and even all-cause mortality in females

Assessment of causality of natriuretic peptides and atrial fibrillation and heart failure : a Mendelian randomization study in the FINRISK cohort

Aims Natriuretic peptides are extensively studied biomarkers for atrial fibrillation (AF) and heart failure (HF). Their role in the pathogenesis of both diseases is not entirely understood and previous studies several single-nucleotide poly-morphisms (SNPs) at the NPPA-NPPB locus associated with natriuretic peptides have been identified. We investigated the causal relationship between natriuretic peptides and AF as well as HF using a Mendelian randomization approach. Methods and results N-terminal pro B-type natriuretic peptide (NT-proBNP) (N= 6669), B-type natriuretic peptide (BNP) (N= 6674), and mid-regional pro atrial natriuretic peptide (MR-proANP) (N= 6813) were measured in the FINRISK 1997 cohort. N=30 common SNPs related to NT-proBNP, BNP, and MR-proANP were selected from studies. We performed six Mendelian randomizations for all three natriuretic peptide biomarkers and for both outcomes, AF and HF, separately. Polygenic risk scores (PRSs) based on multiple SNPs were used as genetic instrumental variable in Mendelian randomizations. Polygenic risk scores were significantly associated with the three natriuretic peptides. Polygenic risk scores were not significantly associated with incident AF nor HF. Most cardiovascular risk factors showed significant confounding percentages, but no association with PRS. A causal relation except for small causal betas is unlikely. Conclusion In our Mendelian randomization approach, we confirmed an association between common genetic variation at the NPPA-NPPB locus and natriuretic peptides. A strong causal relationship between natriuretic peptides and incidence of AF as well as HF at the community-level was ruled out. Therapeutic approaches targeting natriuretic peptides will therefore very likely work through indirect mechanisms.Peer reviewe

Diabetes status-related differences in risk factors and mediators of heart failure in the general population:results from the MORGAM/BiomarCaRE consortium

Background: The risk of heart failure among diabetic individuals is high, even under tight glycemic control. The correlates and mediators of heart failure risk in individuals with diabetes need more elucidation in large population-based cohorts with long follow-up times and a wide panel of biologically relevant biomarkers. Methods: In a population-based sample of 3834 diabetic and 90,177 non-diabetic individuals, proportional hazards models and mediation analysis were used to assess the relation of conventional heart failure risk factors and biomarkers with incident heart failure. Results: Over a median follow-up of 13.8 years, a total of 652 (17.0%) and 5524 (6.1%) cases of incident heart failure were observed in participants with and without diabetes, respectively. 51.4% were women and the mean age at baseline was 48.7 (standard deviation [SD] 12.5) years. The multivariable-adjusted hazard ratio (HR) for heart failure among diabetic individuals was 2.70 (95% confidence interval, 2.49–2.93) compared to non-diabetic participants. In the multivariable-adjusted Cox models, conventional cardiovascular disease risk factors, such as smoking (diabetes: HR 2.07 [1.59–2.69]; non-diabetes: HR 1.85 [1.68–2.02]), BMI (diabetes: HR 1.30 [1.18–1.42]; non-diabetes: HR 1.40 [1.35–1.47]), baseline myocardial infarction (diabetes: HR 2.06 [1.55–2.75]; non-diabetes: HR 2.86 [2.50–3.28]), and baseline atrial fibrillation (diabetes: HR 1.51 [0.82–2.80]; non-diabetes: HR 2.97 [2.21–4.00]) had the strongest associations with incident heart failure. In addition, biomarkers for cardiac strain (represented by nT-proBNP, diabetes: HR 1.26 [1.19–1.34]; non-diabetes: HR 1.43 [1.39–1.47]), myocardial injury (hs-TnI, diabetes: HR 1.10 [1.04–1.16]; non-diabetes: HR 1.13 [1.10–1.16]), and inflammation (hs-CRP, diabetes: HR 1.13 [1.03–1.24]; non-diabetes: HR 1.29 [1.25–1.34]) were also associated with incident heart failure. In general, all these associations were equally strong in non-diabetic and diabetic individuals. However, the strongest mediators of heart failure in diabetes were the direct effect of diabetes status itself (relative effect share 43.1% [33.9–52.3] and indirect effects (effect share 56.9% [47.7-66.1]) mediated by obesity (BMI, 13.2% [10.3–16.2]), cardiac strain/volume overload (nT-proBNP, 8.4% [-0.7–17.4]), and hyperglycemia (glucose, 12.0% [4.2–19.9]). Conclusions: The findings suggest that the main mediators of heart failure in diabetes are obesity, hyperglycemia, and cardiac strain/volume overload. Conventional cardiovascular risk factors are strongly related to incident heart failure, but these associations are not stronger in diabetic than in non-diabetic individuals. Active measurement of relevant biomarkers could potentially be used to improve prevention and prediction of heart failure in high-risk diabetic patients