Serum proteomics to detect early changes in type 1 diabetes and carotid atherosclerosis

The detection of early markers is the key issue in predicting the outcome of inflammatory diseases such as type 1 diabetes and atherosclerosis. Whilst biochemical testing approaches have improved prediction of inflammatory diseases, validated biomarkers with better diagnostic specificities are still needed. Currently, majority of the disease-related proteomics studies have focused on their endpoints. The work presented in this thesis includes the first comprehensive proteomics analyses on serum samples collected from two unique Finnish longitudinal cohorts, namely The Diabetes Prediction and Prevention Project (DIPP) and The Cardiovascular Risk in Young Finns Study (YFS), to identify early markers associated with type 1 diabetes and carotid atherosclerosis. Using mass spectrometry (MS)-based quantitative serum proteomics, profiling was carried out to the study temporal variation in pre-diabetic samples and early markers of plaque formation with the T1D and YFS cohorts, respectively. The analyses revealed consistent differences in the abundance of a number of proteins in subjects having an ongoing asymptomatic changes, several of which are functionally relevant to the disease process. Taken together, the discovered markers are candidates for further validation studies in an independent cohorts and may be used to characterize an increased risk, progression and early onset of these diseases.Tyypin 1 diabeteksen ja ateroskleroosin kehittymiseen liittyvät varhaiset muutokset seerumiproteomissa Yksi keskeinen haaste tulehduksellisten sairauksien, kuten tyypin 1 diabeteksen ja ateroskleroosin, ennustamisessa on varhaisten tautimarkkerien löytäminen. Vaikka erilaiset biokemialliset testit ovat jo parantaneet tulehdusperäisten sairauksien ennustamista, uusia tarkempia biomarkkereita tarvitaan edelleen. Tästä huolimatta monissa näiden alojen proteomiikkatöissä on nykyisin keskitytty sairastumishetken tutkimiseen. Tämän väitöskirjatyön aikana olemme tehneet laajamittaiset proteomiikka-analyysit seeruminäytteille, jotka on kerätty osana kahta ainutlaatuista suomalaista seurantatutkimusta: DIPP-tutkimusta (tyypin 1 diabeteksen ennustaminen ja ennaltaehkäisy) ja YFS-tutkimusta (sydän- ja verisuonitautien riski nuorilla suomalaisilla). Näissä tutkimuksissa seerumiproteomiikkaa hyödynnettiin ensimmistä kertaa varhaisten tyypin 1 diabetes- ja ateroskleroosimarkkerien etsimiseen. Tutkimme tyypin 1 diabeteksen kehittymiseen ja ateroskleroottisten plakkien muodostumiseen liittyviä muutoksia seerumin proteomiprofiileissa massaspektrometriaan perustuvan kvantitatiivisen proteomiikan avulla. Nämä analyysit paljastivat johdonmukaisia eroja lukuisissa proteiineissa myöhemmin sairastuneiden oireettomien henkilöiden ja terveinä pysyneiden kontrollien välillä. Monet näistä proteiineista saattavat myös liittyä olennaisesti tautien kehittymiseen. Tutkimuksissamme löydetyt markkerit tarjoavat lähtökohdan tuleville validointitutkimuksille, ja niitä voitaisiin tulevaisuudessa käyttää yksilön kohonneen sairastumisriskin, taudin etenemisen sekä taudin varhaisen puhkeamisen kartoittamiseen

Stable isotope studies on granulites from the high grade terrain of Southern India

Fluid inclusion and petrologic characteristics of South India granulites and their bearing on the sources of metamorphic fluids are discussed. This paper served as a review and an introduction to the next paper by D. Jackson. Jackson presented carbon isotope data from gases extracted from fluid inclusions in South Indian granulites. The uniformly low Delta C-13 values (minus 10 plus or minus 2 per mil) and the greater abundance of CO2 in the incipient charnockites are suggestive of fluid influx from an externally buffered reservoir

Characteristics and carbon stable isotopes of fluids in the Southern Kerala granulites and their bearing on the source of CO2

Carbon dioxide-rich inclusions commonly occur in the banded charnockites and khondalites of southern Kerala as well as in the incipient charnockites formed by desiccation of gneisses along oriented zones. The combined high density fluid inclusion isochores and the range of thermometric estimates from mineral assemblages indicate entrapment pressures in the range of 5.4 to 6.1 Kbar. The CO2 equation of state barometry closely compares with the 5 plus or minus 1 Kbar estimate from mineral phases for the region. The isochores for the high density fluid inclusions in all the three rock types pass through the P-T domain recorded by phase equilibria, implying that carbon dioxide was the dominating ambient fluid species during peak metamorphic conditions. In order to constrain the source of fluids and to evaluate the mechanism of desiccation, researchers undertook detailed investigations of the carbon stable isotope composition of entrapped fluids. Researchers report here the results of preliminary studies in some of the classic localities in southern Kerala namely, Ponmudi, Kottavattom, Manali and Kadakamon

Paramagnetic magnetization signals and curious metastable behaviour in field-cooled magnetization of a single crystal of superconductor 2H-NbSe2

We present here some newer characteristics pertaining to paramagnetic Meissner effect like response in a single crystal of the low Tc superconducting compound 2H-NbSe2 via a detailed study of effects of perturbation on the field-cooled magnetization response. In the temperature range, where an anomalous paramagnetic magnetization occurs, the field-cooled magnetization response is found to be highly metastable: it displays a curious tendency to switch randomly from a given paramagnetic value to a diamagnetic or to a different paramagnetic value, when the system is perturbed by an impulse of an externally applied ac field. The new facets revealed in a single crystal of 2H-NbSe2 surprisingly bear a marked resemblance with the characteristics of magnetization behaviour anticipated for the giant vortex states with multiple flux quanta predicted to occur in mesoscopic-sized superconducting specimen and possible transitions amongst such states.Comment: 12 pages, 9 figures, submitted to Journal of Physics: Condensed Matte

Regulation of u-PAR gene expression by H2A.Z is modulated by the MEK–ERK/AP-1 pathway

The urokinase receptor (u-PAR) which is largely regulated at the transcriptional level has been implicated in tumor progression. In this study, we explored the epigenetic regulation of u-PAR and showed that the histone variant H2A.Z negatively regulates its expression in multiple cell lines. Chromatin immunoprecipitation assays revealed that H2A.Z was enriched at previously characterized u-PAR-regulatory regions (promoter and a downstream enhancer) and dissociates upon activation of gene expression by phorbol ester (PMA). Using specific chemical and dominant negative expression constructs, we show that the MEK–ERK signaling pathway terminating at AP-1 transcription factors intersects with the epigenetic control of u-PAR expression by H2A.Z. Furthermore, we demonstrate that two other AP-1 targets (MMP9 gene and miR-21 microRNA) are also H2A.Z regulated. In conclusion, our work demonstrates that (i) the expression of two genes and a microRNA all implicated in tumor progression are directly regulated by H2A.Z and (ii) MEK–ERK signaling terminating at AP-1 intersects with the epigenetic control of target gene expression by H2A.Z

CARVE: Practical Security-Focused Software Debloating Using Simple Feature Set Mappings

Software debloating is an emerging field of study aimed at improving the security and performance of software by removing excess library code and features that are not needed by the end user (called bloat). Software bloat is pervasive, and several debloating techniques have been proposed to address this problem. While these techniques are effective at reducing bloat, they are not practical for the average user, risk creating unsound programs and introducing vulnerabilities, and are not well suited for debloating complex software such as network protocol implementations. In this paper, we propose CARVE, a simple yet effective security-focused debloating technique that overcomes these limitations. CARVE employs static source code annotation to map software features source code, eliminating the need for advanced software analysis during debloating and reducing the overall level of technical sophistication required by the user. CARVE surpasses existing techniques by introducing debloating with replacement, a technique capable of preserving software interoperability and mitigating the risk of creating an unsound program or introducing a vulnerability. We evaluate CARVE in 12 debloating scenarios and demonstrate security and performance improvements that meet or exceed those of existing techniques.Comment: 8 pages, 4 figures, 2 tables, 1 appendi