Metody výzkumu fotofyziky fotosensibilizátorů s aplikací na thiazolyl-porfyriny

Název práce: Metody výzkumu fotofyziky fotosensibilizátorů s aplikací na thiazolyl- porfyriny Autor: Marek Scholz Katedra: Katedra chemické fyziky a optiky Vedoucí diplomové práce: RNDr. Roman Dědic, Ph.D. e-mail vedoucího: [email protected] Abstrakt: Fotodynamická terapie onkologických a dalších závažných onemocnění je prudce se rozvíjející léčebnou metodou. Principem jejího účinku je generace vy- soce reaktivního singletního kyslíku a volných radikálů přenosem excitační energie z molekul tzv. fotosensibilizátorů, které se selektivně usazují v postižené tkáni a při léčbě jsou excitovány lokálním ozářením příslušné tkáně. Vzniklé reaktivní formy molekul potom způsobí apoptózu nebo nekrózu postižených buněk a tím i likvidaci postižené tkáně. Zásadním článkem ve vývoji fotodynamických metod je příprava účinných a biologicky kompatibilních fotosensibilizačních barviv spolu s jejich následnou podrobnou fotofyzikální charakterizací. Práce se zaměřuje na vysvětlení nejpoužívanějších metod výzkumu fotofyziky fotosensibilizátorů a je- jich aplikaci na nově syntetizovaná fotosensibilizační barviva: thiazolyl-porfyriny. Byly použity metody absorpční a fluorescenční spektroskopie, časově a...Title: Methods of Study of Photosensitizer-photophysics with Application on Thiazolyl-porphyrins Author: Marek Scholz Department: Department of Chemical Physics and Optics Supervisor: RNDr. Roman Dědic, Ph.D. Supervisor's e-mail address: [email protected] Abstract: Photodynamic therapy for oncologic and various chronic diseases is a rapidly emerging method of treatment. It is based on the production of highly reactive singlet oxygen and free radicals by excitation energy transfer from the molecules of photosensitizers. Photosensitizers are preferentially accumulated in the target tissues and locally illuminated. This way produced reactive species cause apoptosis or necrosis of the cells leading to the desired therapeutic effect. Synthesis and subsequent photophysical characterization of photosensitizing dyes is a fundamental part of the development of photodynamic methods. The main aim of the work is to explain the most widely used methods of photophysical study of photosensitizers and apply them to new synthesized photosensitizers: thiazolyl-porphyrins. Methods of absorption and fluorescence spectroscopy, flash- photolysis, time- and spectral-resolved detection of luminescence, optoacoustic spectroscopy and other spectroscopic methods were used. Thiazolyl-porphyrins proved to be promising new...Katedra chemické fyziky a optikyDepartment of Chemical Physics and OpticsFaculty of Mathematics and PhysicsMatematicko-fyzikální fakult

Metody výzkumu fotofyziky fotosensibilizátorů s aplikací na thiazolyl-porfyriny

Název práce: Metody výzkumu fotofyziky fotosensibilizátorů s aplikací na thiazolyl- porfyriny Autor: Marek Scholz Katedra: Katedra chemické fyziky a optiky Vedoucí diplomové práce: RNDr. Roman Dědic, Ph.D. e-mail vedoucího: [email protected] Abstrakt: Fotodynamická terapie onkologických a dalších závažných onemocnění je prudce se rozvíjející léčebnou metodou. Principem jejího účinku je generace vy- soce reaktivního singletního kyslíku a volných radikálů přenosem excitační energie z molekul tzv. fotosensibilizátorů, které se selektivně usazují v postižené tkáni a při léčbě jsou excitovány lokálním ozářením příslušné tkáně. Vzniklé reaktivní formy molekul potom způsobí apoptózu nebo nekrózu postižených buněk a tím i likvidaci postižené tkáně. Zásadním článkem ve vývoji fotodynamických metod je příprava účinných a biologicky kompatibilních fotosensibilizačních barviv spolu s jejich následnou podrobnou fotofyzikální charakterizací. Práce se zaměřuje na vysvětlení nejpoužívanějších metod výzkumu fotofyziky fotosensibilizátorů a je- jich aplikaci na nově syntetizovaná fotosensibilizační barviva: thiazolyl-porfyriny. Byly použity metody absorpční a fluorescenční spektroskopie, časově a...Title: Methods of Study of Photosensitizer-photophysics with Application on Thiazolyl-porphyrins Author: Marek Scholz Department: Department of Chemical Physics and Optics Supervisor: RNDr. Roman Dědic, Ph.D. Supervisor's e-mail address: [email protected] Abstract: Photodynamic therapy for oncologic and various chronic diseases is a rapidly emerging method of treatment. It is based on the production of highly reactive singlet oxygen and free radicals by excitation energy transfer from the molecules of photosensitizers. Photosensitizers are preferentially accumulated in the target tissues and locally illuminated. This way produced reactive species cause apoptosis or necrosis of the cells leading to the desired therapeutic effect. Synthesis and subsequent photophysical characterization of photosensitizing dyes is a fundamental part of the development of photodynamic methods. The main aim of the work is to explain the most widely used methods of photophysical study of photosensitizers and apply them to new synthesized photosensitizers: thiazolyl-porphyrins. Methods of absorption and fluorescence spectroscopy, flash- photolysis, time- and spectral-resolved detection of luminescence, optoacoustic spectroscopy and other spectroscopic methods were used. Thiazolyl-porphyrins proved to be promising new...Department of Chemical Physics and OpticsKatedra chemické fyziky a optikyFaculty of Mathematics and PhysicsMatematicko-fyzikální fakult

Progress in plasma research at IPJ and IPPLM, Poland

The most important results of theoretical and experimental studies of plasmas, which have been achieved at the IPJ in Swierk and IPPLM in Warsaw recently, are presented. Studies of physical phenomena in PF discharges, development of diagnostic techniques and research on new plasma technologies, as performed at IPJ, have been summarized. Studies of dense magnetized plasmas, investigation of physics and applications of laser-produced plasmas; and research on the development of advanced diagnostic techniques for the EURATOM fusion program, as performed at IPPLM, are also described

Agdc1p - a gallic acid decarboxylase involved in the degradation of tannic acid in the yeast Blastobotrys (Arxula) adeninivorans

Tannins and hydroxylated aromatic acids, such as gallic acid (3,4,5-trihydroxybenzoic acid), are plant secondary metabolites which protect plants against herbivores and plant-associated microorganisms. Some microbes, such as the yeast Arxula adeninivorans are resistant to these antimicrobial substances and are able to use tannins and gallic acid as carbon sources. In this study, the Arxula gallic acid decarboxylase (Agdc1p) which degrades gallic acid to pyrogallol was characterized and its function in tannin catabolism analyzed. The enzyme has a higher affinity for gallic acid (Km -0.7 ± 0.2 mM, kcat -42.0 ± 8.2 s-1) than to protocatechuic acid (3,4-dihydroxybenzoic acid) (Km -3.2 ± 0.2 mM, kcat -44.0 ± 3.2 s-1). Other hydroxylated aromatic acids, such as 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid and 2,5-dihydroxybenzoic acid are not gallic acid decarboxylase substrates. A. adeninivorans G1212/YRC102-AYNI1-AGDC1, which expresses the AGDC1 gene under the control of the strong nitrate inducible AYNI1 promoter achieved a maximum gallic acid decarboxylase activity of 1064.4 U/l and 97.5 U/g of dry cell weight in yeast grown in minimal medium with nitrate as nitrogen source and glucose as carbon source. In the same medium, gallic acid decarboxylase activity was not detected for the control strain G1212/YRC102 with AGDC1 expression under the control of the endogenous promoter. Gene expression analysis showed that AGDC1 is induced by gallic acid and protocatechuic acid. In contrast to G1212/YRC102-AYNI1-AGDC1 and G1212/YRC102, A. adeninivorans G1234 [δagdc1] is not able to grow on medium with gallic acid as carbon source but can grow in presence of protocatechuic acid. This confirms that Agdc1p plays an essential role in the tannic acid catabolism and could be useful in the production of catechol and cis, cis-muconic acid. However, the protocatechuic acid catabolism via Agdc1p to catechol seems to be not the only degradation pathway

Formation of cristae and crista junctions in mitochondria depends on antagonism between Fcj1 and Su e/g

Crista junctions (CJs) are important for mitochondrial organization and function, but the molecular basis of their formation and architecture is obscure. We have identified and characterized a mitochondrial membrane protein in yeast, Fcj1 (formation of CJ protein 1), which is specifically enriched in CJs. Cells lacking Fcj1 lack CJs, exhibit concentric stacks of inner membrane in the mitochondrial matrix, and show increased levels of F1FO–ATP synthase (F1FO) supercomplexes. Overexpression of Fcj1 leads to increased CJ formation, branching of cristae, enlargement of CJ diameter, and reduced levels of F1FO supercomplexes. Impairment of F1FO oligomer formation by deletion of its subunits e/g (Su e/g) causes CJ diameter enlargement and reduction of cristae tip numbers and promotes cristae branching. Fcj1 and Su e/g genetically interact. We propose a model in which the antagonism between Fcj1 and Su e/g locally modulates the F1FO oligomeric state, thereby controlling membrane curvature of cristae to generate CJs and cristae tips

Identification and prediction of Parkinson's disease subtypes and progression using machine learning in two cohorts.

The clinical manifestations of Parkinson's disease (PD) are characterized by heterogeneity in age at onset, disease duration, rate of progression, and the constellation of motor versus non-motor features. There is an unmet need for the characterization of distinct disease subtypes as well as improved, individualized predictions of the disease course. We used unsupervised and supervised machine learning methods on comprehensive, longitudinal clinical data from the Parkinson's Disease Progression Marker Initiative (n = 294 cases) to identify patient subtypes and to predict disease progression. The resulting models were validated in an independent, clinically well-characterized cohort from the Parkinson's Disease Biomarker Program (n = 263 cases). Our analysis distinguished three distinct disease subtypes with highly predictable progression rates, corresponding to slow, moderate, and fast disease progression. We achieved highly accurate projections of disease progression 5 years after initial diagnosis with an average area under the curve (AUC) of 0.92 (95% CI: 0.95 ± 0.01) for the slower progressing group (PDvec1), 0.87 ± 0.03 for moderate progressors, and 0.95 ± 0.02 for the fast-progressing group (PDvec3). We identified serum neurofilament light as a significant indicator of fast disease progression among other key biomarkers of interest. We replicated these findings in an independent cohort, released the analytical code, and developed models in an open science manner. Our data-driven study provides insights to deconstruct PD heterogeneity. This approach could have immediate implications for clinical trials by improving the detection of significant clinical outcomes. We anticipate that machine learning models will improve patient counseling, clinical trial design, and ultimately individualized patient care

The unexpected resurgence of Weyl geometry in late 20-th century physics

Weyl's original scale geometry of 1918 ("purely infinitesimal geometry") was withdrawn by its author from physical theorizing in the early 1920s. It had a comeback in the last third of the 20th century in different contexts: scalar tensor theories of gravity, foundations of gravity, foundations of quantum mechanics, elementary particle physics, and cosmology. It seems that Weyl geometry continues to offer an open research potential for the foundations of physics even after the turn to the new millennium.Comment: Completely rewritten conference paper 'Beyond Einstein', Mainz Sep 2008. Preprint ELHC (Epistemology of the LHC) 2017-02, 92 pages, 1 figur

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. Findings: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14–1·83) and the presence of either LPA SNP (1·88, 1·40–2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81–1·11 and either LPA SNP 1·10, 0·92–1·31) or cardiovascular mortality (0·99, 0·81–1·2 and 1·13, 0·90–1·40, respectively) or in the validation studies. Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. Funding: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny

Association of Factor V Leiden with Subsequent Atherothrombotic Events:A GENIUS-CHD Study of Individual Participant Data

BACKGROUND: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. METHODS: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. RESULTS: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. CONCLUSIONS: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population

Subsequent Event Risk in Individuals with Established Coronary Heart Disease:Design and Rationale of the GENIUS-CHD Consortium

BACKGROUND: The "GENetIcs of sUbSequent Coronary Heart Disease" (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD. METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185,614 participants with either acute coronary syndrome, stable CHD or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS: Enrollment into the individual studies took place between 1985 to present day with duration of follow up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (HR 1.15 95% CI 1.14-1.16) per 5-year increase, male sex (HR 1.17, 95% CI 1.13-1.21) and smoking (HR 1.43, 95% CI 1.35-1.51) with risk of subsequent CHD death or myocardial infarction, and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and non-genetic determinants of subsequent event risk in individuals with established CHD, in order to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators