Induction of optical activity in di- and triaryl stereodynamic chromophoric probes

Wydział ChemiiChiralność, dotycząca obiektów i makro- i mikroskopowych, stanowi jedno z najbardziej fundamentalnych zjawisk warunkujących chociażby życie na Ziemi. Celem mojej rozprawy doktorskiej było opracowanie multichromoforowych sond i wykorzystanie ich w detekcji chiralności dioli, alkoholi II-rzędowych oraz amin I-rzędowych. Przede wszystkim zamierzałem wykazać i zrozumieć mechanizm indukcji aktywności optycznej w chiralnych układach typu induktor–reporter. W tym celu posłużyłem się komplementarnymi metodami (m.in. spektroskopiami ECD i NMR czy obliczeniami DFT). Efektem moich badań było otrzymanie sond chromoforowych o zróżnicowanej konstytucji i zakresie spektralnym. Umożliwiają one dogodne badania strukturalne nawet „trudnych” związków chiralnych, a więc takich, które charakteryzują się bardzo małym zróżnicowaniem podstawników centrum stereogenicznego. Poza opracowanymi sondami chromoforowymi stanowiącymi precyzyjne, wydajne oraz użyteczne narzędzia do badań stereochemicznych istotnym rezultatem moich badań było zaproponowanie mechanizmów chirogenezy. Wykazałem bowiem, że przeniesienie chiralności od centrum stereogenicznego do osi chiralnej przebiega w sposób efektywny w przypadku induktorów nawet o bardzo małym zróżnicowaniu strukturalnym. To właśnie jest wyróżnikiem opracowanych przeze mnie układów na tle innych sond chromoforowych opisanych w literaturze.Chirality of macro- and microscopic objects is a phenomenon of a paramount significance for the life on earth. The aim of my dissertation was to develop multichromophoric probes suitable for chirality sensing of diols, secondary alcohols, and primary amines. Above all, I intended to demonstrate and understand mechanism of optical activity induction in chiral inductor-reporter systems with the aid of complementary methods (i.e. ECD and NMR spectroscopy, DTF calculations). The result of my research was the preparation of structurally diverse chromophoric probes varying in spectral range and thus, making them suitable for convenient structural studies of “demanding” inductors characterized by negligible differences in substituents near the stereogenic centre. Apart from the described chromophoric probes which are precise, efficient, and convenient tools for stereochemical analysis the essential effect of my research was the proposition of the mechanism of chirogenesis. I proved that the chirality transmission from stereogenic centre to chiral axis is efficient even for inductor molecules of limited structural diversity. This is the feature that distinguishes probes that I have developed from other until now described reporter molecules

Round Compression for Parallel Matching Algorithms

For over a decade now we have been witnessing the success of {\em massive parallel computation} (MPC) frameworks, such as MapReduce, Hadoop, Dryad, or Spark. One of the reasons for their success is the fact that these frameworks are able to accurately capture the nature of large-scale computation. In particular, compared to the classic distributed algorithms or PRAM models, these frameworks allow for much more local computation. The fundamental question that arises in this context is though: can we leverage this additional power to obtain even faster parallel algorithms? A prominent example here is the {\em maximum matching} problem---one of the most classic graph problems. It is well known that in the PRAM model one can compute a 2-approximate maximum matching in $O(\log{n})$ rounds. However, the exact complexity of this problem in the MPC framework is still far from understood. Lattanzi et al. showed that if each machine has $n^{1+\Omega(1)}$ memory, this problem can also be solved $2$-approximately in a constant number of rounds. These techniques, as well as the approaches developed in the follow up work, seem though to get stuck in a fundamental way at roughly $O(\log{n})$ rounds once we enter the near-linear memory regime. It is thus entirely possible that in this regime, which captures in particular the case of sparse graph computations, the best MPC round complexity matches what one can already get in the PRAM model, without the need to take advantage of the extra local computation power. In this paper, we finally refute that perplexing possibility. That is, we break the above $O(\log n)$ round complexity bound even in the case of {\em slightly sublinear} memory per machine. In fact, our improvement here is {\em almost exponential}: we are able to deliver a $(2+\epsilon)$-approximation to maximum matching, for any fixed constant $\epsilon>0$, in $O((\log \log n)^2)$ rounds

Mechanism of action of hypomethylating agents in myelodysplastic syndromes

Hipermetylacja DNA odgrywa znaczącą rolę w procesie onkogenezy, zwłaszcza w patogeneziezespołów mielodysplastycznych (MDS). Leki o działaniu hipometylującym DNA prowadzą doaktywacji genów supresorowych i regulujących cykl komórkowy, stanowiąc przykład terapiiepigenetycznej. Obecnie w leczeniu MDS stosuje się dwa leki o działaniu hipometylującymDNA — azacytydynę i decytabinę. Leki te, zastosowane w małych dawkach, wpływają nametylację kwasów nukleinowych poprzez hamowanie metylotransferazy DNA. W badaniachrandomizowanych wykazano, że znacząco poprawiają wyniki leczenia chorych na MDS,a azacytydyna wydłuża ich przeżycie. Azacytydyna jest obecnie zalecana w leczeniu MDS z grupypośredniego i wysokiego ryzyka u chorych niekwalifikujących się do leczenia z zastosowaniemallogenicznego przeszczepienia krwiotwórczych komórek macierzystych (allo-HSCT). Ważnymmechanizmem działania leków hipometylujących jest możliwość indukowania reakcji „przeszczepprzeciwko białaczce” po allo-HSCT, poprzez nasilanie ekspresji antygenów HLA-DRi antygenów białaczkowych na powierzchni komórek nowotworowych. Dokładne mechanizmydziałania leków hipometylujących nie są jeszcze poznane. Znaczenie dla odpowiedzi klinicznejma prawdopodobnie metabolizm wewnątrzkomórkowy tych leków. Poszukuje się biomarkerówmolekularnych, które pozwolą na przewidywanie skuteczności terapii.DNA hypermethylation is an important process in oncogenesis, especially in patogenesis ofmyelodysplastic syndrome (MDS). DNA hypomethylation is associated with inducing reexpressionof epigenetically silenced suppressor genes. Two hypomethylating agents are currentlyused in the treatment of patients with MDS: azacitidine and decitabine. Therapy with thosedrugs, administered in low doses, results in DNA demethylation through the inhibition ofDNA methyltransferase. It is confirmed in randomized trials, that hypomethylating drugs improve outcome of selected patients with MDS. Azacitidine is proved to prolong survival ofpatients with MDS, and currently is recommended for treatment of patients from theintermediate and high risk group who are not eligible for allogeneic hematopoietic stem celltransplantation (allo-HSCT). Hypomethylating agents appear to induce leukemic celldifferentiation and to increase expression of HLA-DR antigens and other leukemia-associatedantigens, which can increase graft versus leukemia effect after allo-HSCT. Detailed mechanismof action of hypomethylating agents is not known. Clinical response is probably related tocellular metabolism of those drugs. Molecular biomarkers should be found to predict therapyresponses and patients outcome

Trends for beta-blockers use in a large cohort of Polish hypertensive patients — Pol-Fokus Study

Background Beta-blockers remain one of the most frequently prescribed antihypertensive drug classes. The aim of the analysis was to evaluate characteristics of patients treated with beta-blockers and factors associated with the treatment of beta-blockers. Material and methods We analysed the data from the large cross-sectional study evaluating 12,375 patients treated for hypertension for at least one year. Results Overall, 7080 patients (57.2% of the whole group) were treated with beta-blockers. The rate of use of beta-blockers was higher in patients with diabetes (62.9 vs 55.6%), coronary artery disease (72.2 vs 46.4%), previous myocardial infarction (82.3 vs 54.1%), heart failure (73.1 vs 53.3%) and arrhythmias (73.1 vs 51.1%) than in patients without those conditions (all comparisons p < 0.001). Beta-blockers were used less frequently among patients with asthma/COPD than without asthma/COPD (54.0 vs 58.0%; p = 0.017). In patients aged 40 years and less, the compelling indications for these agents were found only in 21.7% of patients. In patients aged 40–65 years, none of compelling indications was found in 41.3% of patients. In patients 65 years or more, the most frequent compelling indications were coronary artery disease, previous myocardial infarction and heart failure, which were present in 70.1% of patients. Conclusions High utilization rate of beta-blockers in patients with hypertension, only second to renin-angiotensin blockers, has been shown. In middle age and, especially, in older patients it might reflect high cardiovascular burden of those patients, including coexistence of established cardiac disease. In younger patients beta-blockers are used more frequently with none of the compelling indications present

Study of the serum copper levels in patients with major depressive disorder

Copper may be involved in the pathophysiology of depression. Clinical data on this issue are very limited and not conclusive. The purpose of the study was to determine the copper concentration in the serum of patients with major depressive disorder and to discuss its potential clinical usefulness as a biomarker of the disease. A case–control clinical study included 69 patients with current depressive episode, 45 patients in remission and 50 healthy volunteers. Cu concentration was measured by electrothermal atomic absorption spectrometry (ETAAS). The mean serum copper level in depressed patients was slightly lower (by 11 %; not statistically significant) than in the control group. Furthermore, there was no significant difference in Cu(2+) concentration between depressive episode and remission, nor between remission and control group. In the remission group were observed significant correlations between copper levels and the average number of relapses over the past years or time of remission. There was no correlation between serum copper and severity of depression, as measured by HDRS and MADRS. The obtained results showed no significant differences between the copper concentration in the blood serum of patients (both with current depressive episode and in remission) and healthy volunteers, as well as the lack of correlations between the copper level in the active stage of the disease and clinical features of the population. Our study is the first conducted on such a large population of patients, so the results may be particularly important and reliable source of knowledge about the potential role of copper in depression

The serum magnesium concentration as a potential state marker in patients with unipolar affective disorder

Aim. The growing body of evidence suggests that magnesium levels can serve as a marker of major depressive disorder (MDD), but findings from clinical trials remain inconclusive. The aim of the presented study was to determine the magnesium concentration in serum of patients with MDD (in the active stage of the disease or in remission) and to analyze the role of magnesium levels as a potential marker of the disease. Methods. Sixty-nine patients with current depressive episode, 45 patients in remission and 50 healthy volunteers were enrolled into the case-control study. The magnesium concentration was measured by flame atomic absorption spectrometry (FAAS). Results. The mean serum magnesium concentration of patients in the depressed phase was significantly higher, compared to the control group. Moreover, magnesium levels of patients in the remission were not significantly different from the concentrations recorded in the healthy volunteers. There was also a positive correlation between the magnesium levels and the severity of depression measured by the Hamilton Rating Scale for Depression (HDRS) and the Montgomery-Asberg Depression Rating Scale (MADRS). Conclusions. The obtained results may suggest a role of magnesium as a state marker reflecting the pathophysiological changes underlying MDD and accompanying severe depressive episodes

The serum concentration of magnesium as a potential state marker in patients with diagnosis of bipolar disorder

Aim. Few scientific reports indicate changes in the concentration of magnesium in the blood of patients with bipolar disorder (BD). So far very little studies concerning these issues have been conducted. Therefore, the aim of this study was to evaluate the serum magnesium level in patients with bipolar disorder (in different phases of the disease) in comparison to healthy volunteers. Methodology. The study included 129 patients (58 subjects in depressive episode, 23 in manic episode and 48 patients in remission) with the diagnosis of bipolar disorder type I or II. The control group consisted of 50 healthy people. Magnesium concentration was measured using flame atomic absorption spectrometry (FAAS). Results. Patients with a current depressive or manic/hypomanic episode had statistically significantly elevated serum magnesium levels compared to healthy volunteers. Moreover, a positive correlation between the duration of the manic/hypomanic episode and the relapse frequency in the last year was observed. The concentration of magnesium in patients in remission was unchanged in relation to the control group. Conclusions. Presented findings suggest a role of serum magnesium level as a potential state marker, reflecting the pathophysiological changes associated with acute episodes of bipolar disorder

Zinc and copper concentration do not differentiate bipolar disorder from major depressive disorder

Aim. The aim of this study was to compare the zinc and copper concentration in the group of patients with bipolar disorder (BD) and major depressive disorder (MDD). Method. 110 patients with the diagnosis of BD and 114 with MDD were qualified to the study. To assess the levels of microelements, the flame atomic absorption spectrometry (FAAS) was used in the case of zinc and the electrothermal atomic absorption spectrometry (ET AAS) was used in the case of copper. Results. There were no differences between concentration of zinc and copper in remission and depressive phase between patients with BD and MDD. Additionally, there were also no statistically significant differences in comparisons including type I and II, early or late phase of BD and MDD. Conclusions. The lack of differences in zinc and copper concentrations between patients with bipolar disorder and major depressive disorder might indicate that those disorders have similar etiology