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This work presents statistical models of the variability of plasma in the topside ionosphere based on observations made by the European Space Agency’s (ESA) Swarm satellites. The models were developed in the “Swarm Variability of Ionospheric Plasma” (Swarm-VIP) project within the European Space Agency’s Swarm+4D-Ionosphere framework. The configuration of the Swarm satellites, their near-polar orbits and the data products developed, enable studies of the spatial variability of the ionosphere at multiple scale sizes. The statistical modelling technique of Generalised Linear Modelling (GLM) was used to create models of both the electron density and measures of the variability of the plasma structures at horizontal spatial scales between 20 km and 100 km. Despite being developed using the Swarm data, the models provide predictions that are independent of these data. Separate models were created for low, middle, auroral and polar latitudes. The models make predictions based on heliogeophysical variables, which act as proxies for the solar and geomagnetic processes. The first and most significant term in the majority of the models was a proxy for solar activity. The most common second term varied with the latitudinal region. This was the Solar Zenith Angle (SZA) in the polar region, a measure of latitude in the auroral region, solar time in the mid-latitude region and a measure of latitude in the equatorial region. Other, less significant terms in the models covered a range of proxies for the solar wind, geomagnetic activity and location. In this paper, the formulation, optimisation and evaluation of these models are discussed. The models show very little bias, with a mean error of zero to two decimal places in 14 out of 20 cases. The models capture some, but not all, of the trends present in the data, with Pearson correlation coefficients of up to 0.75 between the observations and the model predictions. The models also capture some, but not all, of the variability of the ionospheric plasma, as indicated by the precision, which ranged between 0.20 and 0.83. The addition of the thermospheric density as an explanatory variable in the models improved the precision in the polar and auroral regions. It is suggested that, if the thermosphere could be observed at a higher spatial resolution, then even more of the variability of the plasma structures could be captured by statistical models. The formulation and optimisation of the models are presented in this paper. The capability of the model in reproducing the expected climatological features of the topside ionosphere, in supporting GNSS-based ionospheric observations and the performance of the model against the Thermosphere-Ionosphere-Electrodynamics General Circulation Model (TIE-GCM), are provided in a companion paper (Spogli L et al. 2024. J Space Weather Space Clim https://doi.org/10.1051/swsc/2024003).

Statistical models of the variability of plasma in the topside ionosphere based on the Swarm data have been developed in the “Swarm Variability of Ionospheric Plasma” (Swarm-VIP) project within the European Space Agency’s Swarm+4D-Ionosphere framework. The models can predict the electron density, its gradients for three horizontal spatial scales – 20, 50 and 100 km – along the North-South direction and the level of the density fluctuations. Despite being developed by leveraging on Swarm data, the models provide predictions that are independent of these data, having a global coverage, fed by various parameters and proxies of the helio-geophysical conditions. Those features make the Swarm-VIP models useful for various purposes, which include the possible support for already available ionospheric models and proxy of the effect of ionospheric irregularities of the medium scales that affect the signals emitted by Global Navigation Satellite Systems (GNSS). The formulation, optimisation and validation of the Swarm-VIP models are reported in Paper 1 (Wood et al. 2024. J Space Weather Space Clim. in press). This paper describes the performance assessment of the models, by addressing their capability to reproduce the known climatological variability of the modelled quantities, and the ionospheric weather as depicted by ground-based GNSS, as a proxy for the ionospheric effect on GNSS signals. Additionally, we demonstrate that, under certain conditions, the model can better reproduce the ionospheric variability than a physics-based model, namely the Thermosphere-Ionosphere-Electrodynamics General Circulation Model (TIE-GCM).

BACKGROUND: Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood. METHODS: We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF. RESULTS: We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving CSK (C-terminal Src kinase) as the strongest candidate for ibrutinib-induced AF. Cardiac-specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3-8.7; P

Acute bacterial endocarditis is a rapid, difficult to manage, and frequently lethal disease. Potent antibiotics often cannot efficiently kill Staphylococcus aureus that colonizes the hearts valves. S. aureus relies on virulence factors to evade therapeutics and the hosts immune response, usurping the hosts clotting system by activating circulating prothrombin with staphylocoagulase and von Willebrand factor-binding protein. An insoluble fibrin barrier then forms around the bacterial colony, shielding the pathogen from immune cell clearance. Targeting virulence factors may provide previously unidentified avenues to better diagnose and treat endocarditis. To tap into this unused therapeutic opportunity, we codeveloped therapeutics and multimodal molecular imaging to probe the host-pathogen interface. We introduced and validated a family of small-molecule optical and positron emission tomography (PET) reporters targeting active thrombin in the fibrin-rich environment of bacterial colonies. The imaging agents, based on the clinical thrombin inhibitor dabigatran, are bound to heart valve vegetations in mice. Using optical imaging, we monitored therapy with antibodies neutralizing staphylocoagulase and von Willebrand factor-binding protein in mice with S. aureus endocarditis. This treatment deactivated bacterial defenses against innate immune cells, decreased in vivo imaging signal, and improved survival. Aortic or tricuspid S. aureus endocarditis in piglets was also successfully imaged with clinical PET/magnetic resonance imaging. Our data map a route toward adjuvant immunotherapy for endocarditis and provide efficient tools to monitor this drug class for infectious diseases.

Abstract Parabens (PBs) are a group of substances commonly used in industry. They also pollute the environment, penetrate into living organisms and adversely affect various internal organs. During this study, the degree of exposure of people living in Olsztyn, a city in north eastern Poland, to selected parabens most often used in industry was studied. The chemicals under investigation included: methyl paraben—MePB, ethyl paraben—EtPB, propyl paraben—PrPB, benzyl paraben BePB and butyl paraben -BuPB. To this aim, hair samples collected from the scalps of 30 volunteers were analyzed using a liquid chromatography–mass spectrometry technique. All PBs studied were present in a high percentage of analyzed samples (from 76.7% in the case of BePB to 100% in the case of MePB and PrPB). The mean concentration levels were 4425.3 pg/mg for MeBP, 704.0 pg/mg for EtPB, 825.7 pg/mg for PrPB, 135.2 pg/mg for BePB and 154.5 pg/mg for BuPB. Significant differences in PB concentration levels between particular persons were visible. On the other hand, gender, age and artificial hair coloring did not cause statistically significant differences in PB levels. Obtained results have clearly indicated that people living in north eastern Poland are exposed to various PBs, and therefore these substances may affect their health status. However, the evaluation of PBs influence on human health requires further research.

© 2017 The Author(s). Patients with short bowel syndrome lack sufficient functional intestine to sustain themselves with enteral intake alone. Transplantable vascularized bioengineered intestine could restore nutrient absorption. Here we report the engineering of humanized intestinal grafts by repopulating decellularized rat intestinal matrix with human induced pluripotent stem cell-derived intestinal epithelium and human endothelium. After 28 days of in vitro culture, hiPSC-derived progenitor cells differentiate into a monolayer of polarized intestinal epithelium. Human endothelial cells seeded via native vasculature restore perfusability. Ex vivo isolated perfusion testing confirms transfer of glucose and medium-chain fatty acids from lumen to venous effluent. Four weeks after transplantation to RNU rats, grafts show survival and maturation of regenerated epithelium. Systemic venous sampling and positron emission tomography confirm uptake of glucose and fatty acids in vivo. Bioengineering intestine on vascularized native scaffolds could bridge the gap between cell/tissue-scale regeneration and whole organ-scale technology needed to treat intestinal failure patients.

Abstract Background 3-Ketosteroid Δ1-dehydrogenases (KSTDs) are the enzymes involved in microbial cholesterol degradation and modification of steroids. They catalyze dehydrogenation between C1 and C2 atoms in ring A of the polycyclic structure of 3-ketosteroids. KSTDs substrate spectrum is broad, even though most of them prefer steroids with small substituents at the C17 atom. The investigation of the KSTD’s substrate specificity is hindered by the poor solubility of the hydrophobic steroids in aqueous solutions. In this paper, we used 2-hydroxpropyl-β-cyclodextrin (HBC) as a solubilizing agent in a study of the KSTDs steady-state kinetics and demonstrated that substrate bioavailability has a pivotal impact on enzyme specificity. Results Molecular dynamics simulations on KSTD1 from Rhodococcus erythropolis indicated no difference in ΔGbind between the native substrate, androst-4-en-3,17-dione (AD; − 8.02 kcal/mol), and more complex steroids such as cholest-4-en-3-one (− 8.40 kcal/mol) or diosgenone (− 6.17 kcal/mol). No structural obstacle for binding of the extended substrates was also observed. Following this observation, our kinetic studies conducted in the presence of HBC confirmed KSTD1 activity towards both types of steroids. We have compared the substrate specificity of KSTD1 to the other enzyme known for its activity with cholest-4-en-3-one, KSTD from Sterolibacterium denitrificans (AcmB). The addition of solubilizing agent caused AcmB to exhibit a higher affinity to cholest-4-en-3-one (Ping-Pong bi bi KmA = 23.7 μM) than to AD (KmA = 529.2 μM), a supposedly native substrate of the enzyme. Moreover, we have isolated AcmB isoenzyme (AcmB2) and showed that conversion of AD and cholest-4-en-3-one proceeds at a similar rate. We demonstrated also that the apparent specificity constant of AcmB for cholest-4-en-3-one (kcat/KmA = 9.25∙106 M−1 s−1) is almost 20 times higher than measured for KSTD1 (kcat/KmA = 4.71∙105 M−1 s−1). Conclusions We confirmed the existence of AcmB preference for a substrate with an undegraded isooctyl chain. However, we showed that KSTD1 which was reported to be inactive with such substrates can catalyze the reaction if the solubility problem is addressed.

Background: Host immune response is a critical component in tumorigenesis and immune escape. Radiation is widely used for glioblastoma (GBM) and can induce marked tissue inflammation and substantially alter host immune response. However, the role of myeloperoxidase (MPO), a key enzyme in inflammation and host immune response, in tumorigenesis after radiotherapy is unclear. In this study, we aimed to determine how post-radiation MPO activity influences GBM and outcome. Methods: We injected C57BL/6J or MPO-knockout mice with 005 mouse GBM stem cells intracranially. To observe MPO's effects on post-radiation tumor progression, we then irradiated the head with 10 Gy unfractionated and treated the mice with a specific MPO inhibitor, 4-aminobenzoic acid hydrazide (ABAH), or vehicle as control. We performed semi-quantitative longitudinal molecular MRI, enzymatic assays and flow cytometry to assess changes in inflammatory response and tumor size, and tracked survival. We also performed cell culture experiments in murine and human GBM cells to determine the effect of MPO on these cells. Results: Brain irradiation increased the number of monocytes/macrophages and neutrophils, and boosted MPO activity by ten-fold in the glioma microenvironment. However, MPO inhibition dampened radiation-induced inflammation, demonstrating decreased MPO-specific signal on molecular MRI and attenuated neutrophil and inflammatory monocyte/macrophage recruitment to the glioma. Compared to saline-treated mice, both ABAH-treated and MPO-knockout mice had accelerated tumor growth and reduced survival. We further confirmed that MPO decreased tumor cell viability and proliferation in cell cultures. Conclusion: Local radiation to the brain initiated an acute systemic inflammatory response with increased MPO-carrying cells both in the periphery and the GBM, resulting in increased MPO activity in the tumor microenvironment. Inhibition or absence of MPO activity increased tumor growth and decreased host survival, revealing that elevated MPO activity after radiation has an anti-tumor role.

One of the main challenges is the question how sustainable development assumptions can be implemented in practice better and more effectively. This paper explores the relation between sustainable development trends and experience economy, with its main aim to describe links of those two ideas. The authors hypothesized that there is relation between sustainable development and experience economy since both ideas have common goals and are a counterweight to the concept of mass consumption. The aim of the study is to prove that the concept of experience economics along with its conscious design in an enterprise can counteract growing consumerism. In order to verify this hypothesis and achieve the main aim, the author used triangulation methods combining desk research and qualitative research. The main research result is that designing experience in organisations will be an important trend that will allow to meet the current challenges not only economic, social but also ecological. It is a very good time for designers for using their creativity in many different branches of industry.

Abstract Background Patient-derived xenograft (PDX) mouse models of cancer have been recognized as better mouse models that recapitulate the characteristics of original malignancies including preserved tumor heterogeneity, lineage hierarchy, and tumor microenvironment. However, common challenges of PDX models are the significant time required for tumor expansion, reduced tumor take rates, and higher costs. Here, we describe a fast, simple, and cost-effective method of expanding PDX of pancreatic ductal adenocarcinoma (PDAC) in mice. Methods We used two established frozen PDAC PDX tissues (derived from two different patients) and implanted them subcutaneously into SCID mice. After tissues reached 10–20 mm in diameter, we performed survival surgery on each mouse to harvest 90–95% of subcutaneous PDX (incomplete resection), allowing the remaining 5–10% of PDX to continue growing in the same mouse. Results We expanded three consecutive passages (P1, P2, and P3) of PDX in the same mouse. Comparing the times required for in vivo expansion, P2 and P3 (expanded through incomplete resection) grew 26-60% faster than P1. Moreover, such expanded PDX tissues were successfully implanted orthotopically into mouse pancreases. Within 20 weeks using only 14 mice, we generated sufficient PDX tissue for future implantation of 200 mice. Our histology study confirmed that the morphologies of cancer cells and stromal structures were similar across all three passages of subcutaneous PDX and the orthotopic PDX and were reflective of the original patient tumors. Conclusions Taking advantage of incomplete resection of tumors associated with high local recurrence, we established a fast method of PDAC PDX expansion in mice.

Nicosulfuron is a herbicide used for plant protection. This paper presents the results of research on the physicochemical properties of three herbicidal preparations containing nicosulfuron as the active substance by measuring and comparing its concentration by the chromatographic method. These preparations are in the form of a concentrated suspension intended for dilution with water, and due to the fact that nicosulfuron contained in the tested preparations is sensitive to water quality, while checking the physicochemical properties of the preparations, a dispersion for soft (pH: 5–7) and hard (pH: 8–9) water was also determined. It is important to note that high content of mineral salts in water may have a negative effect on the biological activity of the substance. In addition, the use of herbicides does not only apply to the use of appropriate dilutions, which are effective and not harmful to the environment. However, it is also important to consider specific farmer and equipment used, so that the preparation is easy to use and does not adversely affect the kit used for spraying. This study has shown that depending on the preparation used based on the amount of active substance 40 g/l, the amount of nicosulfuron varies. The test indicators in the form of pH and density are similar, while during the tested dispersion, differences depending on the tested water were observed (sediments were observed in only one preparation tested). Differences depending on the occurrence of sediments in the water used, both at 0 and 24 h, are signaling in favor of the soft water. Therefore, it is important to assess the hardness of the water, which in turn guarantees a reduction of the amount of deposits and protection of agricultural equipment used for spraying.

Fullerene derivatives offer great scope for modification of the basic molecule, often called a buckyball. In recent years, they have been the subject of numerous studies, in particular in terms of their applications, including in solar cells. Here, the properties of four recently synthesized fullerene C60 derivatives were examined regarding their optical properties and the efficiency of the charge transfer process, both in fullerene derivatives themselves and in their heterojunctions with poly (3-hexylthiophene). Optical absorption, electron spin resonance (ESR), and time-resolved photoluminescence (TRPL) techniques were applied to study the synthesized molecules. It was shown that the absorption processes in fullerene derivatives are dominated by absorption of the fullerene cage and do not significantly depend on the type of the derivative. It was also found by ESR and TRPL studies that asymmetrical, dipole-like derivatives exhibit stronger light-induced charge transfer properties than their symmetrical counterparts. The observed inhomogeneous broadening of the ESR lines indicated a large disorder of all polymer–fullerene derivative blends. The density functional theory was applied to explain the results of the optical absorption experiments.