Structural Organization and Energization of Iron Acquisition Systems in Staphylococcal Membranes

New antimicrobial strategies to prevent bacterial infections are urgently needed due to the increase in antibiotic resistances in pathogens. Iron is an essential trace metal that needs to be acquired by bacteria for proliferation and infection. Thus, targeting bacterial iron acquisition systems might represent a promising antibacterial strategy. In the human body free iron is actively limited, which is referred to as “nutritional immunity”. To overcome these limitations, staphylococci have several iron uptake systems. The staphylococcal pathogens Staphylococcus aureus and Staphylococcus lugdunensis acquire hemoglobin-derived heme using their iron-regulated surface determinant (Isd) system. The molecular mechanism of heme extraction and its guidance over the staphylococcal cell well is well understood. In contrast, heme transport across the membrane is less well understood and was subject of this thesis. Using protein interaction studies and growth analyses, we demonstrated that the ATPase FhuC energizes the Isd membrane transporter in S. aureus. Interestingly, FhuC is already known to energize the siderophore uptake transporters Fhu, Hts and Sir in S. aureus. In contrast, we found that S. lugdunensis encodes the ATPase isdL in its isd locus and does not depend on FhuC for heme transport. In addition, S. lugdunensis encodes an ABC transporter from the energy coupling factor type (ECF), and we show the system to accept heme from numerous hemoproteins independently from the Isd system. Moreover, we could show that S. lugdunensis uses the same transport systems as S. aureus for siderophore uptake, namely Hts, Sir, Fhu and Sst, all energized by FhuC. Furthermore, we could show that appropriate formation of functional membrane microdomains (FMM) and the scaffolding protein FloA are necessary for the function of the Isd system in both S. aureus and S. lugdunensis. Using co-immunoprecipitation, we detected direct interaction between FloA and the permease IsdF and deletion mutants of floA showed a growth deficit with hemoglobin as sole iron source. Our experiments show novel links between membrane structuring processes and nutrient acquisition in bacterial pathogens. Thus, FMM/FloA inhibition might represent a new strategy to treat staphylococcal infections by sensitizing the pathogens to host nutritional immunity mechanisms

An ECF-type transporter scavenges heme to overcome iron-limitation in Staphylococcus lugdunensis

Energy-coupling factor type transporters (ECF) represent trace nutrient acquisition systems. Substrate binding components of ECF-transporters are membrane proteins with extraordinary affinity, allowing them to scavenge trace amounts of ligand. A number of molecules have been described as substrates of ECF-transporters, but an involvement in iron-acquisition is unknown. Host-induced iron limitation during infection represents an effective mechanism to limit bacterial proliferation. We identified the iron-regulated ECF-transporter Lha in the opportunistic bacterial pathogen Staphylococcus lugdunensis and show that the transporter is specific for heme. The recombinant substrate-specific subunit LhaS accepted heme from diverse host-derived hemoproteins. Using isogenic mutants and recombinant expression of Lha, we demonstrate that its function is independent of the canonical heme acquisition system Isd and allows proliferation on human cells as sources of nutrient iron. Our findings reveal a unique strategy of nutritional heme acquisition and provide the first example of an ECF-transporter involved in overcoming host-induced nutritional limitation

Integration of clinical parameters and CT-based radiomics improves machine learning assisted subtyping of primary hyperaldosteronism

ObjectivesThe aim of this study was to investigate an integrated diagnostics approach for prediction of the source of aldosterone overproduction in primary hyperaldosteronism (PA).Methods269 patients from the prospective German Conn Registry with PA were included in this study. After segmentation of adrenal glands in native CT images, radiomic features were calculated. The study population consisted of a training (n = 215) and a validation (n = 54) cohort. The k = 25 best radiomic features, selected using maximum-relevance minimum-redundancy (MRMR) feature selection, were used to train a baseline random forest model to predict the result of AVS from imaging alone. In a second step, clinical parameters were integrated. Model performance was assessed via area under the receiver operating characteristic curve (ROC AUC). Permutation feature importance was used to assess the predictive value of selected features.ResultsRadiomics features alone allowed only for moderate discrimination of the location of aldosterone overproduction with a ROC AUC of 0.57 for unilateral left (UL), 0.61 for unilateral right (UR), and 0.50 for bilateral (BI) aldosterone overproduction (total 0.56, 95% CI: 0.45-0.65). Integration of clinical parameters into the model substantially improved ROC AUC values (0.61 UL, 0.68 UR, and 0.73 for BI, total 0.67, 95% CI: 0.57-0.77). According to permutation feature importance, lowest potassium value at baseline and saline infusion test (SIT) were the two most important features.ConclusionIntegration of clinical parameters into a radiomics machine learning model improves prediction of the source of aldosterone overproduction and subtyping in patients with PA

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV

Search for supersymmetry in events with one lepton and multiple jets in proton-proton collisions at root s=13 TeV

Peer reviewe

Measurement of the top quark forward-backward production asymmetry and the anomalous chromoelectric and chromomagnetic moments in pp collisions at √s = 13 TeV

Abstract The parton-level top quark (t) forward-backward asymmetry and the anomalous chromoelectric (d̂ t) and chromomagnetic (μ̂ t) moments have been measured using LHC pp collisions at a center-of-mass energy of 13 TeV, collected in the CMS detector in a data sample corresponding to an integrated luminosity of 35.9 fb−1. The linearized variable AFB(1) is used to approximate the asymmetry. Candidate t t ¯ events decaying to a muon or electron and jets in final states with low and high Lorentz boosts are selected and reconstructed using a fit of the kinematic distributions of the decay products to those expected for t t ¯ final states. The values found for the parameters are AFB(1)=0.048−0.087+0.095(stat)−0.029+0.020(syst),μ̂t=−0.024−0.009+0.013(stat)−0.011+0.016(syst), and a limit is placed on the magnitude of | d̂ t| < 0.03 at 95% confidence level. [Figure not available: see fulltext.

Measurement of the top quark mass using charged particles in pp collisions at root s=8 TeV

Peer reviewe

Measurement of t(t)over-bar normalised multi-differential cross sections in pp collisions at root s=13 TeV, and simultaneous determination of the strong coupling strength, top quark pole mass, and parton distribution functions

Peer reviewe