Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis.

Cholesterol crystals (CC) play an essential role in the formation of atherosclerotic plaques. CC activate the classical and the alternative complement pathways, but the role of the lectin pathway is unknown. We hypothesized that the pattern recognition molecules (PRMs) from the lectin pathway bind CC and function as an upstream innate inflammatory signal in the pathophysiology of atherosclerosis. We investigated the binding of the PRMs mannose-binding lectin (MBL), ficolin-1, ficolin-2, and ficolin-3, the associated serine proteases, and complement activation products to CC in vitro using recombinant proteins, specific inhibitors, as well as deficient and normal sera. Additionally, we examined the deposition of ficolin-2 and MBL in human carotid plaques by immunohistochemistry and fluorescence microscopy. The results showed that the lectin pathway was activated on CC by binding of ficolin-2 and MBL in vitro, resulting in activation and deposition of complement activation products. MBL bound to CC in a calcium-dependent manner whereas ficolin-2 binding was calcium-independent. No binding was observed for ficolin-1 or ficolin-3. MBL and ficolin-2 were present in human carotid plaques, and binding of MBL to CC was confirmed in vivo by immunohistochemistry, showing localization of MBL around CC clefts. Moreover, we demonstrated that IgM, but not IgG, bound to CC in vitro and that C1q binding was facilitated by IgM. In conclusion, our study demonstrates that PRMs from the lectin pathway recognize CC and provides evidence for an important role for this pathway in the inflammatory response induced by CC in the pathophysiology of atherosclerosis

C-reactive protein binds to cholesterol crystals and co-localizes with the terminal complement complex in human atherosclerotic plaques

Inflammation is a part of the initial process leading to atherosclerosis and cholesterol crystals (CC), found in atherosclerotic plaques, which are known to induce complement activation. The pentraxins C-reactive protein (CRP), long pentraxin 3 (PTX3), and serum amyloid P component (SAP) are serum proteins associated with increased risk of cardiovascular events and these proteins have been shown to interact with the complement system. Whether the pentraxins binds to CC and mediate downstream complement-dependent inflammatory processes remains unknown. Binding of CRP, PTX3, and SAP to CC was investigated in vitro by flow cytometry and fluorescence microscopy. CRP, PTX3, and SAP bound to CC in a concentration-dependent manner. CRP and PTX3 interacted with the complement pattern recognition molecule C1q on CC by increasing the binding of both purified C1q and C1q in plasma. However, CRP was the strongest mediator of C1q binding and also the pentraxin that most potently elevated C1q-mediated complement activation. In a phagocytic assay using whole blood, we confirmed that phagocytosis of CC is complement dependent and initiated by C1q-mediated activation. The pathophysiological relevance of the in vitro observations was examined in vivo in human atherosclerotic plaques. CRP, PTX3, and SAP were all found in atherosclerotic plaques and were located mainly in the cholesterol-rich necrotic core, but co-localization with the terminal C5b-9 complement complex was only found for CRP. In conclusion, this study identifies CRP as a strong C1q recruiter and complement facilitator on CC, which may be highly relevant for the development of atherosclerosis

JUNO Conceptual Design Report

The Jiangmen Underground Neutrino Observatory (JUNO) is proposed to determine the neutrino mass hierarchy using an underground liquid scintillator detector. It is located 53 km away from both Yangjiang and Taishan Nuclear Power Plants in Guangdong, China. The experimental hall, spanning more than 50 meters, is under a granite mountain of over 700 m overburden. Within six years of running, the detection of reactor antineutrinos can resolve the neutrino mass hierarchy at a confidence level of 3-4$\sigma$, and determine neutrino oscillation parameters $\sin^2\theta_{12}$, $\Delta m^2_{21}$, and $|\Delta m^2_{ee}|$ to an accuracy of better than 1%. The JUNO detector can be also used to study terrestrial and extra-terrestrial neutrinos and new physics beyond the Standard Model. The central detector contains 20,000 tons liquid scintillator with an acrylic sphere of 35 m in diameter. $\sim$17,000 508-mm diameter PMTs with high quantum efficiency provide $\sim$75% optical coverage. The current choice of the liquid scintillator is: linear alkyl benzene (LAB) as the solvent, plus PPO as the scintillation fluor and a wavelength-shifter (Bis-MSB). The number of detected photoelectrons per MeV is larger than 1,100 and the energy resolution is expected to be 3% at 1 MeV. The calibration system is designed to deploy multiple sources to cover the entire energy range of reactor antineutrinos, and to achieve a full-volume position coverage inside the detector. The veto system is used for muon detection, muon induced background study and reduction. It consists of a Water Cherenkov detector and a Top Tracker system. The readout system, the detector control system and the offline system insure efficient and stable data acquisition and processing.Comment: 328 pages, 211 figure

Software and hardware development for the next-generation liquid scintillator detectors JUNO and OSIRIS

Large liquid scintillator~(LS) detectors are acknowledged instruments in the field of neutrino physics. Based on various successful experiments, reporting the currently best limits on several parameters of neutrino flavor oscillations, a new generation of detectors with several tens of kilotons of LS are under consideration. The Jiangmen Underground Neutrino Observatory~(JUNO) is a 20 kiloton LS detector, that is fully funded and under construction in China. Its main goal is the determination of the neutrino mass ordering~(MO) through a precision measurement of the reactor electron anti-neutrino spectrum. The first part of this thesis discusses the underlying theory of neutrino flavor oscillations, the JUNO detector design and how neutrinos of various sources can be detected with this instrument. The focus is laid on a correlated background for the inverse beta decay~(IBD) measurement of reactor anti-neutrinos, which stems from cosmic muons. When they traverse the detector, the muons can create unstable radioisotopes, which decay after a short time in a (beta + n) channel. In order to identify and reject this background, it is paramount to know the track of the muon precisely. For this purpose, a novel muon reconstruction algorithm is developed and tested in this work. It is based on the geometric model of the intersection of the first-light front with the PMT array. The track parameters are optimized in a likelihood fit based on probability density functions produced with a detailed detector simulation. In addition, a simulation of the full readout electronics is performed to yield the best estimate of the performance on real data. Excluding the edge of the CD, the muon track's distance from the detector center DeltaD can be determined with an uncertainty of 5 cm and its direction with 0.3°. The impact on the detector's exposure by a muon veto based on this reconstruction was also studied. Compared to a perfect knowledge of each muon track, the developed method only creates an additional 4 % of loss in exposure. In the second part, a pre-detector for JUNO is investigated. OSIRIS is a standalone, 20 ton LS detector, that will be used to monitor the radiopurity of the cleaned LS before it is filled into JUNO.In the scope of this work, a detailed detector simulation based on C++11 and Geant4 is developed. It is then used to determine the sensitivity of the detector to its main physics goal: the identification of Bi-Po coincidences from the decay chains of U-238 and Th-232 in the LS. Furthermore, a calibration campaign for OSIRIS is studied. Under consideration of the available hardware, the decision is made to utilize an automated calibration unit~(ACU) from the Daya Bay collaboration. The energy range of 0.5 - 3 MeV will be calibrated by exposing the detector simultaneously to Cs-137, Zn-65, and Co-60 in a single capsule. With different vertical positions on a fixed radial distance r = 120 cm from the detector's center, its non-uniformity can be properly sampled. Timing calibration of the PMTs with an accuracy of~0.1 ns is realized with a 430 nm LED, that can be deployed along the same vertical axis

Forecasting employment using sentiment scores from news

Maģistra darbs pielieto ekonomisko ziņu noskaņojuma indeksu, lai atrisinātu paradoksu starp nepieciešamību pēc biežākām makroekonomisko prognožu atjauninājumiem un nepietiekamu attiecīgo rādītāju atjaunošanas biežumu. Izmantojot modernākas datu zinātnes metodes, tika iegūts ikdienu ziņu noskaņojuma indekss, lai izpētītu, vai ziņu noskaņojums ir piemērots, prognozējot nodarbinātības dinamiku Dānijā, un uzlabotu prognozes precizitāti modelī. Analīze rāda, ka pastāv statistiska saistība starp nodarbinātības dinamiku un ziņu noskaņojumu, un ka noskaņojuma rādītāju izmantošana var palielināt nodarbinātības datu prognozēšanas precizitāti īsos prognozēšanas periodos.The thesis is seeking to solve a paradox between the need for more frequent macroeconomic forecasts and inadequate updates of relevant indicators with the aid of economic news. Using advanced data science methods, the thesis extracted sentiment scores from numerous relevant day-to-day economic news, to investigate whether news sentiment is applicable in predicting employment levels in Denmark and improve forecast accuracy in the model. The analysis shows that a statistical relationship does exist between employment levels and news sentiments and using sentiment scores can increase forecast accuracy of employment data on short forecasting horizons