In-vivo brain neuroimaging provides a gateway for integrating biological and clinical biomarkers of Alzheimer's disease.

PURPOSE OF REVIEW: Only 5% of the Alzheimer's cases are explained by genetic mutations, whereas the remaining 95% are sporadic. The pathophysiological mechanisms underlying sporadic Alzheimer's disease are not well understood, suggesting a complex multifactorial cause. This review summarizes the recent findings on research aiming to show how biomarkers can be used for revealing the underlying mechanisms of preclinical stage Alzheimer's disease and help in their diagnosis. RECENT FINDINGS: The undisputed successful publicly accessible repositories provide longitudinal brain images, clinical, genetic and proteomic information of Alzheimer's disease. By combining with increasingly sophisticated data analysis methods, it is a great opportunity for searching new biomarkers. Innovative studies validated theoretical models of disease progression demonstrating the sequential ordering of well-established biomarkers. Novel observations shed light on the interaction between biomarkers to confirm that disease progression is related to multiple pathological factors. A typical example is the tau-associated neuronal toxicity that can be additionally potentiated by amyloid β peptides. To increase further the complexity, studies report specific impact of common genetic variants that can be traced from childhood through middle age up to the symptomatic onset of Alzheimer's disease. SUMMARY: The discovery of efficient therapies to prevent the disease or modify the progression of disease requires a more thorough understanding of the underlying biological processes. Neuroimaging, genetic and proteomic biomarkers for Alzheimer's disease are critically discussed and proposed to be included in clinical descriptions and diagnostic guidelines.

Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.

Stromal fibroblast senescence has been linked to ageing-associated cancer risk. However, density and proliferation of cancer-associated fibroblasts (CAFs) are frequently increased. Loss or downmodulation of the Notch effector CSL (also known as RBP-Jκ) in dermal fibroblasts is sufficient for CAF activation and ensuing keratinocyte-derived tumours. We report that CSL silencing induces senescence of primary fibroblasts from dermis, oral mucosa, breast and lung. CSL functions in these cells as a direct repressor of multiple senescence- and CAF-effector genes. It also physically interacts with p53, repressing its activity. CSL is downmodulated in stromal fibroblasts of premalignant skin actinic keratosis lesions and squamous cell carcinomas, whereas p53 expression and function are downmodulated only in the latter, with paracrine FGF signalling as the probable culprit. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effectors and promotes stromal and cancer cell expansion. The findings support a CAF activation-stromal co-evolution model under convergent CSL-p53 control.

Improvements in the Assessment of Bacterial Viability and Killing

It is axiomatic that our planet is extensively inhabited by diverse micro-organisms such as bacteria, yet the absolute diversity of different bacterial species is widely held to be unknown. Different bacteria can be found from the depths of the oceans to the top of the mountains; even the air is more or less colonized by bacteria. Most bacteria are either harmless or even advantageous to human beings but there are also bacteria, which can cause severe infectious diseases or spoil the supplies intended for human consumption. Therefore, it is vitally important not only to be able to detect and enumerate bacteria but also to assess their viability and possible harmfulness. Whilst the growth of bacteria is remarkably fast under optimum conditions and easy to detect by cultural methods, most bacteria are believed to lie in stationary phase of growth in which the actual growth is ceased and thus bacteria may simply be undetectable by cultural techniques. Additionally, several injurious factors such as low and high temperature or deficiency of nutrients can turn bacteria into a viable but non-culturable state (VBNC) that cannot be detected by cultural methods. Thereby, various noncultural techniques developed for the assessment of bacterial viability and killing have widely been exploited in modern microbiology. However, only a few methods are suitable for kinetic measurements, which enable the real-time detection of bacterial growth and viability. The present study describes alternative methods for measuring bacterial viability and killing as well as detecting the effects of various antimicrobial agents on bacteria on a real-time basis. The suitability of bacterial (lux) and beetle (luc) luciferases as well as green fluorescent protein (GFP) to act as a marker of bacterial viability and cell growth was tested. In particular, a multiparameter microplate assay based on GFP-luciferase combination as well as a flow cytometric measurement based on GFP-PI combination were developed to perform divergent viability analyses. The results obtained suggest that the antimicrobial activities of various drugs against bacteria could be successfully measured using both of these methods. Specifically, the data reliability of flow cytometric viability analysis was notably improved as GFP was utilized in the assay. A fluoro-luminometric microplate assay enabled kinetic measurements, which significantly improved and accelerated the assessment of bacterial viability compared to more conventional viability assays such as plate counting. Moreover, the multiparameter assay made simultaneous detection of GFP fluorescence and luciferase bioluminescence possible and provided extensive information about multiple cellular parameters in single assay, thereby increasing the accuracy of the assessment of the kinetics of antimicrobial activities on target bacteria.

Proportionality and Party Success in Europe

This thesis consists of four articles and an introductory section. The main research questions in all the articles are about proportionality and party success in Europe, at European, national or district levels. Proportionality in this thesis denotes the proximity of seat shares parties receive compared to their respective vote shares, after the electoral system’s allocation process. This proportionality can be measured through numerous indices that illustrate either the overall proportionality of an electoral system or a particular election. The correspondence of a single party’s seat shares to its vote shares can also be measured. The overall proportionality is essential in three of the articles (1, 2 and 4), where the system’s performance is studied by means of plots. In article 3, minority party success is measured by advantage-ratios that reveal single party’s winnings or losses in the votes to seat allocation process. The first article asks how proportional are the European parliamentary (EP) electoral systems, how do they compare with results gained from earlier studies and how do the EP electoral systems treat different sized parties. The reasons for different outcomes are looked for in explanations given by traditional electoral studies i.e. electoral system variables. The countries studied (EU15) apply electoral systems that vary in many important aspects, even though a certain amount of uniformity has been aspired to for decades. Since the electoral systems of the EP elections closely resemble the national elections, the same kinds of profiles emerge as in the national elections. The electoral systems indeed treat the parties differentially and six different profile types can be found. The counting method seems to somewhat determine the profile group, but the strongest variables determining the shape of a countries’ profile appears to be the average district magnitude and number of seats allocated to each country. The second article also focuses on overall proportionality performance of an electoral system, but here the focus is on the impact of electoral system changes. I have developed a new method of visualizing some previously used indices and some new indices for this purpose. The aim is to draw a comparable picture of these electoral systems’ changes and their effects. The cases, which illustrate this method, are four elections systems, where a change has occurred in one of the system variables, while the rest remained unchanged. The studied cases include the French, Greek and British European parliamentary systems and the Swedish national parliamentary system. The changed variables are electoral type (plurality changed to PR in the UK), magnitude (France splitting the nationwide district into eight smaller districts), legal threshold (Greece introducing a three percent threshold) and counting method (d’Hondt was changed to modified Sainte-Laguë in Sweden). The radar plots from elections after and before the changes are drawn for all country cases. When quantifying the change, the change in the plots area that is created has also been calculated. Using these radar plots we can observe that the change in electoral system type, magnitude, and also to some extent legal threshold had an effect on overall proportionality and accessibility for small parties, while the change between the two highest averages counting method had none. The third article studies the success minority parties have had in nine electoral systems in European heterogeneous countries. This article aims to add more motivation as to why we should care how different sized parties are treated by the electoral systems. Since many of the parties that aspire to represent minorities in European countries are small, the possibilities for small parties are highlighted. The theory of consociational (or power-sharing) democracy suggests that, in heterogeneous societies, a proportional electoral system will provide the fairest treatment of minority parties. The OSCE Lund Recommendations propose a number of electoral system features, which would improve minority representation. In this article some party variables, namely the unity of the minority parties and the geographical concentration of the minorities were included among possible explanations. The conclusions are that the central points affecting minority success were indeed these non-electoral system variables rather than the electoral system itself. Moreover, the size of the party was a major factor governing success in all the systems investigated; large parties benefited in all the studied electoral systems. In the fourth article the proportionality profiles are again applied, but this time to district level results in Finnish parliamentary elections. The level of proportionality distortion is also studied by way of indices. The average magnitudes during the studied periodrange from 7.5 to 26.2 in the Finnish electoral districts and this opens up unequal opportunities for parties in different districts and affects the shape of the profiles. The intra-country case allows the focus to be placed on the effect of district magnitude, since all other electoral systems are kept constant in an intra-country study. The time span in the study is from 1962 to 2007, i.e. the time that the districts have largely been the same geographically. The plots and indices tell the same story, district magnitude and electoral alliances matter. The district magnitude is connected to the overall proportionality of the electoral districts according to both indices, and the profiles are, as expected, also closer to perfect proportionality in large districts. Alliances have helped some small parties to gain a much higher seat share than their respective vote share and these successes affect some of the profiles. The profiles also show a consistent pattern of benefits for the small parties who ally with the larger parties.

A role for homologous recombination proteins in cell cycle regulation.

Eukaryotic cells respond to DNA breaks, especially double-stranded breaks (DSBs), by activating the DNA damage response (DDR), which encompasses DNA repair and cell cycle checkpoint signaling. The DNA damage signal is transmitted to the checkpoint machinery by a network of specialized DNA damage-recognizing and signal-transducing molecules. However, recent evidence suggests that DNA repair proteins themselves may also directly contribute to the checkpoint control. Here, we investigated the role of homologous recombination (HR) proteins in normal cell cycle regulation in the absence of exogenous DNA damage. For this purpose, we used Chinese Hamster Ovary (CHO) cells expressing the Fluorescent ubiquitination-based cell cycle indicators (Fucci). Systematic siRNA-mediated knockdown of HR genes in these cells demonstrated that the lack of several of these factors alters cell cycle distribution, albeit differentially. The knock-down of MDC1, Rad51 and Brca1 caused the cells to arrest in the G2 phase, suggesting that they may be required for the G2/M transition. In contrast, inhibition of the other HR factors, including several Rad51 paralogs and Rad50, led to the arrest in the G1/G0 phase. Moreover, reduced expression of Rad51B, Rad51C, CtIP and Rad50 induced entry into a quiescent G0-like phase. In conclusion, the lack of many HR factors may lead to cell cycle checkpoint activation, even in the absence of exogenous DNA damage, indicating that these proteins may play an essential role both in DNA repair and checkpoint signaling.

Uncertainties in 4pi-gamma coincidence counting

The 4πβ-γ coincidence counting method and its close relatives are widely used for the primary standardization of radioactivity. Both the general formalism and specific implementation of these methods have been well-documented. In particular, previous papers contain the extrapolation equations used for various decay schemes, methods for determining model parameters and, in some cases, tabulated uncertainty budgets. Two things often lacking from experimental reports are both the rationale for estimating uncertainties in a specific way and the details of exactly how a specific component of uncertainty was estimated. Furthermore, correlations among the components of uncertainty are rarely mentioned. To fill in these gaps, the present article shares the best-practices from a few practitioners of this craft. We explain and demonstrate with examples of how these approaches can be used to estimate the uncertainty of the reported massic activity. We describe uncertainties due to measurement variability, extrapolation functions, dead-time and resolving-time effects, gravimetric links, and nuclear and atomic data. Most importantly, a thorough understanding of the measurement system and its response to the decay under study can be used to derive a robust estimate of the measurement uncertainty.

A chromosomal insertion toolbox for promoter probing, mutant complementation and pathogenicity studies in Ralstonia solanacearum

We describe here the construction of a delivery system for stable and directed insertion of gene constructs in a permissive chromosomal site of the bacterial wilt pathogen Ralstonia solanacearum. The system consists of a collection of suicide vectors the Ralstonia chromosome (pRC) series that carry an integration element flanked by transcription terminators and two sequences of homology to the chromosome of strain GMI1000, where the integration element is inserted through a double recombination event. Unique restriction enzyme sites and a GATEWAY cassette enable cloning of any promoter::gene combination in the integration element. Variants endowed with different selectable antibiotic resistance genes and promoter::gene combinations are described. We show that the system can be readily used in GMI1000 and adapted to other R. solanacearum strains using an accessory plasmid. We prove that the pRC system can be employed to complement a deletion mutation with a single copy of the native gene, and to measure transcription of selected promoters in monocopy both in vitro and in planta. Finally, the system has been used to purify and study secretion type III effectors. These novel genetic tools will be particularly useful for the construction of recombinant bacteria that maintain inserted genes or reporter fusions in competitive situations (i.e., during plant infection).

On evaluating the accuracy and biological plausibility of diffusion MRI tractograms

In diffusion MRI, traditional tractography algorithms do not recover truly quantitative tractograms and the structural connectivity has to be estimated indirectly by counting the number of fiber tracts or averaging scalar maps along them. Recently, global and efficient methods have emerged to estimate more quantitative tractograms by combining tractography with local models for the diffusion signal, like the Convex Optimization Modeling for Microstructure Informed Tractography (COMMIT) framework. In this abstract, we show the importance of using both (i) proper multi-compartment diffusion models and (ii) adequate multi-shell acquisitions, in order to evaluate the accuracy and the biological plausibility of the tractograms.

Bat assemblages in the Nietoperek bat reserve (Western Poland) and their conservation strategies

Międzyrzecz Fortified Front, were Natura 2000 site PLH080003 Nietoperek is situated, was built by the Germans in the 1930s and during the World War II. It is composed of above ground bunkers connected by underground tunnels of ca. 32 km total length. Nietoperek is the eighth largest bats hibernation site in EU. Monthly censuses were carried out from October to April during three consecutive winter seasons (2011/12 – 2013/14) in area covering ca. 30% of the undergrounds. The aims of the study were: (1) to describe changes in numbers of each species in the course of hibernation season, (2) to suggest deadlines for counting particular bat species to obtain maximal numbers and (3) to describe negative impact of tourism on hibernating bats. The results will be useful for restriction of winter tourism in Nietoperek. The total number of bats observed during the study was 37869 individuals of 9 species. Because of difficulties in distinguishing without handling M. mystacinus and M. brandtii were treated as one group. M. myotis constituted from 53% (first season) to 64% (last season) of all hibernating bats. The maximal numbers of individuals were observed in November (first two seasons) and in December (third season). M. daubentonii constituted from 27% (first season) to 21% (last season) and M. nattereri from 10% (first season) to 11% (second season) of all bats. During the three seasons the maximal numbers of M. daubentonii and M. nattereri were observed in November and December respectively. B. barbastellus and P. auritus constituted from 4% (first season) to 2% (last season) of the multi species colony. The maximal numbers of B. barbastellus were observed in January and P. auritus in January (first and second seasons) and in December (third season). Results indicated that the best period for counting maximal numbers of M. myotis and M. daubentonii is November, for M. nattereri is December and for B. barbastellus and P. auritus is January. The study undertaken in the part visited by tourists in winter (total length of 900 m) proved negative effect caused by human disturbance with 23% decline of total bat numbers.

Poorly differentiated clusters (PDC) in colorectal cancer: what is and ought to be known.

BACKGROUND: The counting of poorly differentiated clusters of 5 or more cancer cells lacking a gland-like structure in a tumor mass has recently been identified among the histological features predictive of poor prognosis in colorectal cancer. MAIN BODY: Poorly differentiated clusters can easily be recognized in the histological sections of colorectal cancer routinely stained with haematoxylin and eosin. Despite some limitations related to specimen fragmentation, counting can also be assessed in endoscopic biopsies. Based on the number of poorly differentiated clusters that appear under a microscopic field of a ×20 objective lens (i.e., a microscopic field with a major axis of 1 mm), colorectal cancer can be graded into malignancies as follows: tumors with <5 clusters as grade 1, tumors with 5 to 9 clusters as grade 2, and tumors with ≥10 clusters as grade 3. High poorly differentiated cluster counts are significantly associated with peri-neural and lympho-vascular invasion, the presence of nodal metastases or micrometastases, as well as shorter overall and progression free survival to colorectal cancer. CONCLUSION: The morphological aspects and clinical relevance of poorly differentiated clusters counting in colorectal cancer are discussed in this review.

Optical Encryption using Photon-Counting Polarimetric Imaging

We present a polarimetric-based optical encoder for image encryption and verification. A system for generating random polarized vector keys based on a Mach-Zehnder configuration combined with translucent liquid crystal displays in each path of the interferometer is developed. Polarization information of the encrypted signal is retrieved by taking advantage of the information provided by the Stokes parameters. Moreover, photon-counting model is used in the encryption process which provides data sparseness and nonlinear transformation to enhance security. An authorized user with access to the polarization keys and the optical design variables can retrieve and validate the photon-counting plain-text. Optical experimental results demonstrate the feasibility of the encryption method.

Tailored Jeffamine molecular tools for ordering mesoporous Silica

Herein, we report the formation of organized mesoporous silica materials prepared from a novel nonionic gemini surfactant, myristoyl-end capped Jeffamine, synthesized from a polyoxyalkyleneamine (ED900). The behavior of the modified Jeffamine in water was first investigated. A direct micellar phase (L1) and a hexagonal (H1) liquid crystal were found. The structure of the micelles was investigated from the SAXS and the analysis by Generalized Indirect Fourier Transformation (GIFT), which show that the particles are globular of coreshell type. The myristoyl chains, located at the ends of the amphiphile molecule are assembled to form the core of the micelles and, as a consequence, the molecules are folded over on themselves. Mesoporous materials were then synthesized from the self-assembly mechanism. The recovered materials were characterized by SAXS measurements, nitrogen adsorptiondesorption analysis, transmission and scanning electron microscopy. The results clearly evidence that by modifying the synthesis parameters, such as the surfactant/silica precursor molar ratio and the hydrothermal conditions, one can control the size and the nanostructuring of the resulting material. It was observed that, the lower the temperature of the hydrothermal treatment, the better the mesopore ordering.

Magnetic and transport properties of InGaAs quantum wells with Mn

In the present work structural, magnetic and transport properties of InGaAs quantum wells (QW) prepared by MBE with an remote Mn layer are investigated. By means of high-resolution X-ray diffractometry the structure of the samples is analyzed. It is shown that Mn ions penetrate into the QW. Influence of the thickness of GaAs spacer and annealing at 286 ºС on the properties of the system is shown. It is shown that annealing of the samples led to Mn activation and narrowing of the Mn layer. Substantial role of 2D holes in ferromagnetic ordering in Mn layer is shown. Evidence for that is observation of maximum at 25 – 55 K on the resistivity temperature dependence. Position of maximum, which is used for quantitative assessment of the Curie temperature, correlates with calculations of the Curie temperature for structures with indirect interaction via 2D holes’ channel. Dependence of the Curie temperature on the spacer thickness shows, that creation of applicable spintronic devices needs high-precision equipment to manufacture extra fine structures. The magnetotransport measurements show that charge carrier mobility is very low. This leads to deficiency of the anomalous Hall effect. At the same time, magnetic field dependences of the magnetization at different temperatures demonstrate that systems are ferromagnetically ordered. These facts, most probably, give evidence of presence of the ferromagnetic MnAs clusters.

Winner-Loser Performance and Macroeconomic Effects during three last Economic Crises in Finnish Stock Market

The main purpose of this thesis is to investigate winner-loser performance when financial markets are facing crisis. This is examined through the idea that does the prior loser portfolios outperform the prior winner portfolios during the three major crises: The depression of the 1990s, the IT-Bubble and the Subprime -crisis. Firstly, the winner and loser portfolios superiority is counted by using the cumulative excess returns from the examination period. The portfolios were formed by counting the excess returns and locating them in to the order of superiority. The excess returns are counted by using one year pre-data before the actual examination period. The results of this part did not support the results of De Bondt & Thaler’s (1985) paper. Secondly, it is investigated how the Finnish and the US macroeconomic factors are seen to be affecting the stock market valuation in Finnish Stock Markets during economic crises. This is done to explain better the changes in the successes of the winner-loser performance. The crises included different amount of selected macro factors. Two latest crises involved as well few selected US macro factors. Exclusively the IT-Bubble -crisis had the most statistically significant results with the US factors. Two other crises did not receive statistically significant results. An extra research was produced to study do the US macro factors impact more significantly on Finnish stock exchange after lags. The selected lags were three, six, nine and twelve months. Three and six month lagged US macro factors during the IT-Bubble -crisis improved the results. The extra research did not improve the results of the Subprime -crisis.

Quantum-to-classical crossover in full counting statistics

The reduction of quantum scattering leads to the suppression of shot noise. In this Letter, we analyze the crossover from the quantum transport regime with universal shot noise to the classical regime where noise vanishes. By making use of the stochastic path integral approach, we find the statistics of transport and the transmission properties of a chaotic cavity as a function of a system parameter controlling the crossover. We identify three different scenarios of the crossover.