The discovery of microRNAs (miRNAs) and their critical role in genetic control opened new avenues in understanding of various biological processes including immune cell lineage commitment, ...differentiation, proliferation and apoptosis. However, a given miRNA may have hundreds of different mRNA targets and a target might be regulated by multiple miRNAs, thus the characterisation of dysregulated miRNA expression profiles could give a better insight into the development of immunological disturbances in autoimmune diseases. The aim of our study was to examine the changes in miRNA expression profiles in patients with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS). Eight SLE patients, 8 pSS patients and 7 healthy subjects were enrolled in the investigation. MiRNAs were isolated from peripheral blood mononuclear cells, and expression patterns were determined with Illumina next-generation sequencing technology. Since the immunopathogenesis of pSS and SLE encompasses pronounced B cell hyperactivity along with specific autoantibody production, we paid a special attention on the association between miRNA expression levels and altered peripheral B cell distribution. In SLE patients 135, while in pSS patients 26 miRNAs showed altered expression. Interestingly, the 25 miRNAs including miR-146a, miR-16 and miR-21, which were over-expressed in pSS patients, were found to be elevated in SLE group, as well. On the contrary, we observed the down-regulation of miR-150-5p, which is a novel and unique finding in pSS. Levels of several miRNAs over-expressed in SLE, were not changed in pSS, such as miR-148a-3p, miR-152, miR-155, miR-223, miR-224, miR-326 and miR-342. Expression levels of miR-223-5p, miR-150-5p, miR-155-5p and miR-342-3p, which miRNAs are potentially linked to B cell functions, showed associations with the B cell proportions within peripheral blood mononuclear cells. The observed differences in miRNA expression profiles and the better understanding of immune regulatory mechanisms of miRNAs may help to elucidate the pathogenesis of SLE and pSS.
The discovery of the nephrogenic systemic fibrosis (NSF) and its link with the in vivo dissociation of certain Gd(III)-based contrast agents (CAs) applied in the magnetic resonance imaging (MRI) ...induced a still growing research to replace the compromised agents with safer alternatives. In recent years, several ligands were designed to exploit the luminescence properties of the lanthanides, containing structurally constrained aromatic moieties, which may form rigid Gd(III) complexes. One of these ligands is (1,10-phenanthroline-2,9-diyl)bis(methyliminodiacetic acid) (H4FENTA) designed and synthesized to sensitize Eu(III) and Tb(III) luminescence. Our results show that the conditional stability of the Gd(FENTA)− chelate calculated for physiological pH (pGd = 19.7) is similar to those determined for Gd(DTPA)2– (pGd = 19.4) and Gd(DOTA)− (pGd = 20.1), routinely used in the clinical practice. The Gd(FENTA)− complex is remarkably inert with respect to its dissociation (t 1/2 = 872 days at pH = 7 and 25 °C); furthermore, its relaxivity values determined at different field strengths and temperatures (e.g., r 1p = 4.3 mM–1s–1at 60 MHz and 37 °C) are ca. one unit higher than those of Gd(DTPA)2– (r 1p = 3.4 mM–1 s–1) and Gd(DOTA)− (r 1p = 3.1 mM–1 s–1) under the same conditions. Moreover, significant improvement on the relaxivity was observed in the presence of serum proteins (r 1p = 6.9 mM–1 s–1 at 60 MHz and 37 °C). The luminescence lifetimes recorded in H2O and D2O solutions indicate the presence of a water molecule (q = 1) in the inner sphere of the complex directly coordinated to the metal ion, possessing a relatively high water exchange rate (k ex 298 = 29(2) × 106 s–1). The acceleration of the water exchange can be explained by the steric compression around the water binding site due to the rigid structure of the complex, which was supported by DFT calculations. On the basis of these results, ligands containing a phenanthroline platform have great potential in the design of safer Gd(III) agents for MRI.
Until the recent years, substances containing radioactive 61Cu were strongly considered as potential positron-emitting radiopharmaceuticals for use in positron emission tomography (PET) applications; ...however, due to their suitably long half-life, and generator-independent and cost-effective production, they seem to be economically viable for human imaging. Since malignant melanoma (MM) is a major public health problem, its early diagnosis is a crucial contributor to long-term survival, which can be achieved using radiolabeled α-melanocyte-stimulating hormone analog NAPamide derivatives. Here, we report on the physicochemical features of a new CB-15aneN5-based Cu(II) complex (Cu(KFTGdiac)−) and the ex vivo and in vivo characterization of its NAPamide conjugate. The rigid chelate possesses prompt complex formation and suitable inertness (t 1/2 = 18.4 min in 5.0 M HCl at 50 °C), as well as excellent features in the diagnosis of B16–F10 melanoma tumors (T/M(SUVs) (in vivo): 12.7, %ID/g: 6.6 ± 0.3, T/M (ex vivo): 22).
The role of spirituality in health and disease is a complex and emerging area of research. Incorporating spirituality into the bio-psycho-social model of health and disease leading to the ...bio-psycho-social-spiritual model provides a more comprehensive framework. In this context, chronic disorders like primary Sjögren's syndrome (pSS) are of interest due to their intricate interactions between biological, psychological, and spiritual factors. This study explored the relationship between spirituality, immune parameters, and disease activity in pSS patients. Data from 108 patients were analyzed, including self-assessed spirituality (answering to direct questions and completing the Spiritual Transcendence Scale), immunological parameters and disease activity scores. The findings revealed several associations. Individuals with spiritual attitudes or engaged in regular prayer/meditation showed lower serum levels of autoantibodies specific to pSS and lower disease activity scores. Spiritual engagement was also linked to decreased perceived skin and tracheal dryness, suggesting potential benefits for physical symptoms. These findings suggest that spirituality may play a significant role in modulating immune responses and disease activity in pSS patients. The study underscores the importance of considering spirituality as an integral part of the holistic approach to health and disease, further expanding the understanding of the interconnectedness of biological, psychological, and spiritual dimensions.
Predictions for cold nuclear matter effects on charged hadrons, identified light hadrons, quarkonium and heavy flavor hadrons, Drell–Yan dileptons, jets, photons, gauge bosons and top quark pairs ...produced in p+Pb collisions at sNN=8.16 TeV are compiled and, where possible, compared to each other. Predictions of the normalized ratios of p+Pb to p+p cross sections are also presented for most of the observables, providing new insights into the expected role of cold nuclear matter effects. In particular, the role of nuclear parton distribution functions on particle production can now be probed over a wider range of phase space than ever before.
Age-related changes of the immune system lead to an increased morbidity and mortality due to enhanced vulnerability to infectious diseases and malignancies. Recent studies revealed the important ...effects of physical activity on immune functions, which may largely depend on the type of exercise, its intensity and duration. However, limited information is available regarding the immunological effects of sport activities in older ages. The aim of our study was to examine the changes in a wide spectrum of lymphocyte subtypes after regular workout among healthy elderly individuals. We enrolled 29 elderly women with sedentary lifestyle (mean age: 67.03 ± 3.74 years) to take part in a 6-week long functional conditioning gymnastic exercise program. The percentages of peripheral natural killer (NK), NKT cells, T and B lymphocyte subtypes (early-/late-activated T, naïve and memory T, cytotoxic T (Tc), T-helper (Th)1, Th2, Th17, T regulatory type 1 (Tr1), CD4
CD127
CD25
Treg, as well as naïve and memory B cells) were determined by flow cytometry. Evaluation of the changes in functional capability of Treg cells was based on
functional assays. At the end of exercise program, in parallel with improvements in body composition and physical performance, significant changes in naïve and memory lymphocyte ratios were observed. Importantly, levels of naïve Tc cells elevated, ratios of effector memory Tc cells decreased and distribution of memory B cells rearranged as well. Additionally, proportions of late-activated HLA-DR
T cells increased, while percentages of anti-inflammatory interleukin (IL)-10 producing Tr1 cells, as well as immunosuppressive CD4
CD127
CD25
Treg cells decreased following the exercise workout. Changes observed after the regular exercise program indicate an improvement in the age-related redistribution of certain naïve and memory cell proportions and a retuned immune regulation in older ages.
Expected Shortfall (ES), the average loss above a high quantile, is the current financial regulatory market risk measure. Its estimation and optimization are highly unstable against sample ...fluctuations and become impossible above a critical ratio r=N/T, where N is the number of different assets in the portfolio, and T is the length of the available time series. The critical ratio depends on the confidence level α, which means we have a line of critical points on the α−r plane. The large fluctuations in the estimation of ES can be attenuated by the application of regularizers. In this paper, we calculate ES analytically under an ℓ1 regularizer by the method of replicas borrowed from the statistical physics of random systems. The ban on short selling, i.e., a constraint rendering all the portfolio weights non-negative, is a special case of an asymmetric ℓ1 regularizer. Results are presented for the out-of-sample and the in-sample estimator of the regularized ES, the estimation error, the distribution of the optimal portfolio weights, and the density of the assets eliminated from the portfolio by the regularizer. It is shown that the no-short constraint acts as a high volatility cutoff, in the sense that it sets the weights of the high volatility elements to zero with higher probability than those of the low volatility items. This cutoff renormalizes the aspect ratio r=N/T, thereby extending the range of the feasibility of optimization. We find that there is a nontrivial mapping between the regularized and unregularized problems, corresponding to a renormalization of the order parameters.
Abstract MicroRNAs (miRNAs) are single-stranded, endogenous non-coding small RNAs, ranging from 18 to 25 nucleotides in length. Growing evidence suggests that miRNAs are essential in regulating gene ...expression, cell development, differentiation and function. Autoimmune diseases are a family of chronic systemic inflammatory diseases. Recent findings on miRNA expression profiles have been suggesting their role as biomarkers in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome. In this review, we summarize the characteristics of miRNAs and their functional role in the immune system and autoimmune diseases including systemic lupus erythematosus, primary Sjögren's syndrome, rheumatoid arthritis, systemic sclerosis, multiple sclerosis and psoriasis; moreover, we depict the advantages of miRNAs in modern diagnostics.
Numerous anti-cancer drugs perturb thymidylate biosynthesis and lead to genomic uracil incorporation contributing to their antiproliferative effect. Still, it is not yet characterized if uracil ...incorporations have any positional preference. Here, we aimed to uncover genome-wide alterations in uracil pattern upon drug treatments in human cancer cell line models derived from HCT116. We developed a straightforward U-DNA sequencing method (U-DNA-Seq) that was combined with in situ super-resolution imaging. Using a novel robust analysis pipeline, we found broad regions with elevated probability of uracil occurrence both in treated and non-treated cells. Correlation with chromatin markers and other genomic features shows that non-treated cells possess uracil in the late replicating constitutive heterochromatic regions, while drug treatment induced a shift of incorporated uracil towards segments that are normally more active/functional. Data were corroborated by colocalization studies
dSTORM microscopy. This approach can be applied to study the dynamic
nature of genomic uracil.
Gradient-based optimization using algorithmic derivatives can be a useful technique to improve engineering designs with respect to a computer-implemented objective function. Likewise, uncertainty ...quantification through computer simulations can be carried out by means of derivatives of the computer simulation. However, the effectiveness of these techniques depends on how 'well-linearizable' the software is. In this study, we assess how promising derivative information of a typical proton computed tomography (pCT) scan computer simulation is for the aforementioned applications.
This study is mainly based on numerical experiments, in which we repeatedly evaluate three representative computational steps with perturbed input values. We support our observations with a review of the algorithmic steps and arithmetic operations performed by the software, using debugging techniques.
The model-based iterative reconstruction (MBIR) subprocedure (at the end of the software pipeline) and the Monte Carlo (MC) simulation (at the beginning) were piecewise differentiable. However, the observed high density and magnitude of jumps was likely to preclude most meaningful uses of the derivatives. Jumps in the MBIR function arose from the discrete computation of the set of voxels intersected by a proton path, and could be reduced in magnitude by a 'fuzzy voxels' approach. The investigated jumps in the MC function arose from local changes in the control flow that affected the amount of consumed random numbers. The tracking algorithm solves an inherently non-differentiable problem.
Besides the technical challenges of merely applying AD to existing software projects, the MC and MBIR codes must be adapted to compute smoother functions. For the MBIR code, we presented one possible approach for this while for the MC code, this will be subject to further research. For the tracking subprocedure, further research on surrogate models is necessary.
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