The alternative sigma factor {sigma}B of Staphylococcus aureus controls the expression of a variety of genes, including virulence determinants and global regulators. Genetic manipulations and ...transcriptional start point (TSP) analyses showed that the sigB operon is transcribed from at least two differentially controlled promoters: a putative {sigma}A-dependent promoter, termed sigBp1, giving rise to a 3.6-kb transcript covering sa2059-sa2058-rsbU-rsbV-rsbW-sigB, and a {sigma}B-dependent promoter, sigBp3, initiating a 1.6-kb transcript covering rsbV-rsbW-sigB. TSP and promoter-reporter gene fusion experiments indicated that a third promoter, tentatively termed sigBp2 and proposed to lead to a 2.5-kb transcript, including rsbU-rsbV-rsbW-sigB, might govern the expression of the sigB operon. Environmental stresses, such as heat shock and salt stress, induced a rapid response within minutes from promoters sigBp1 and sigBp3. In vitro, the sigBp1 promoter was active in the early growth stages, while the sigBp2 and sigBp3 promoters produced transcripts throughout the growth cycle, with sigBp3 peaking around the transition state between exponential growth and stationary phase. The amount of sigB transcripts, however, did not reflect the concentration of {sigma}B measured in cell extracts, which remained constant over the entire growth cycle. In a guinea pig cage model of infection, sigB transcripts were as abundant 2 and 8 days postinoculation as values found in vitro, demonstrating that sigB is indeed transcribed during the course of infection. Physical interactions between staphylococcal RsbU-RsbV, RsbV-RsbW, and RsbW-{sigma}B were inferred from a yeast (Saccharomyces cerevisiae) two-hybrid approach, indicating the presence of a partner-switching mechanism in the {sigma}B activation cascade similar to that of Bacillus subtilis. The finding that overexpression of RsbU was sufficient to trigger an immediate and strong activation of {sigma}B, however, signals a relevant difference in the regulation of {sigma}B activation between B. subtilis and S. aureus in the cascade upstream of RsbU.PUBLICATION ABSTRACT
We study the possibility that at least one of the two pentaquark structures recently reported by LHCb can be described as a compact pentaquark state, and we give predictions for new channels that can ...be studied by the experimentalists if this hypothesis is correct. We use very general arguments dictated by symmetry considerations, in order to describe the pentaquark states within a group theory approach. A complete classification of all possible states and quantum numbers, that can be useful both to the experimentalists, for new finding, or to theoretical model builders, are given, without the introduction of any particular dynamical model. Some prediction are finally given using a Guersey-Radicati inspired mass formula. We reproduce the mass and the quantum numbers of the lightest pentaquark state reported by LHCb ( 3/2^-), with a parameter free mass formula, fixed on the well established baryons. We predict others pentaquark resonances (giving their masses, and suggesting possible decay channels) which belong to the same multiplet of the lightest one.Finally, we compute the partial decay widths for all the predicted pentaquark resonances.
ABSTRACT
Objective: To evaluate to what extent an inefficient statistical model affects the study of genetic factors in extra-intestinal manifestations of Crohn's disease (CD) and how clinical ...predictions can be improved using more adequate techniques.
Materials: Extra-intestinal manifestations were studied in 152 CD patients. Three sets of variables were considered: (1) disease characteristics – presentation, behavior, location; (2) generic risk factors – age, gender, smoke and familiarity; and (3) genetic polymorphisms of the NOD2, CD14, TNF, IL12B, and IL1RN genes, whose involvement in CD is known or suspected.
Methods: Six statistical classifiers and data mining models were applied: (1) logistic regression as a benchmark; (2) generalized additive model; (3) projection pursuit regression; (4) linear discriminant analysis, (5) quadratic discriminant analysis; (6) artificial neural networks one-layer feed forward. Models were selected using the Akaike Information criterion and their accuracy was compared with several indexes.
Results: Extra-intestinal manifestations occurred in 75 patients. The model with clinical variables only selected familiarity, gender, presentation, and behavior as significantly associated with extra-intestinal manifestations, whereas when the genetic factors were also included familiarity was no longer significant, being replaced by the NOD2, TNF, and IL12B single nucleotide polymorphisms. The projection pursuit regression performed best in predicting individual outcomes (Kappa statistics 0.078 SE 0.09 without and 0.108 SE 0.075 with genetic information). One-layer artificial neural networks did not show any particular improvement in terms of model accuracy over non-linear techniques.
Conclusions: The correct identification of factors associated with extra-intestinal symptoms in CD, in particular the genetic ones, is highly dependent on the model chosen for the analysis. By using the most sophisticated statistical models, the accuracy of prediction can be strengthened by 10–64%, compared with linear regression.
Cystic fibrosis (CF) is a progressive genetic disease caused by mutations in the gene that produces the CF transmembrane conductance regulator (CFTR) protein. The malfunction of the CFTR protein ...causes a thick buildup of mucus in the lungs that clogs the airways and traps bacteria, thus leading to infections, extensive lung damage and respiratory failure. Micro-delivery systems are currently being investigated as an efficient way to cross the viscous and complex architecture of the CF mucus. In this study, we produced synthetic and natural microparticles (MPs) based on poly(dl‑lactide‑co‑glycolide) (PLGA) or gellan gum through tailored water/oil emulsion procedures. Morphological and physico-chemical characterizations were carried out on both classes of MPs showing particles having diameters within suitable ranges to reach the CF airways. In vitro biocompatibility tests were also performed on both MPs using a human lung cancer cell line (A549) demonstrating that treatment with MPs induces no cytotoxic effects. Both classes of MPs were loaded with a mucolytic agent (N‑acetyl cysteine, NAC) and their release kinetics evaluated using high performance liquid chromatography (HPLC). The analysis pointed out that the amount of NAC released from MPs resulted in a dose-dependent increment, with a rapid release kinetic to satisfy the requirement for inducing an early mucus degradation. Finally, mucolytic action of NAC-loaded MPs was evaluated in an artificial sputum model through its rheological analysis obtaining the lowest viscosity profile after the addition of drug-loaded MPs. Taken together, gained results allowed us to select suitable MPs as potential drug targeting platforms having a mucolytic action for CF treatment.
The response of mesangial cells to a phlogistic challenge includes cell proliferation and mesangial matrix expansion. Cell proliferation is a highly regulated process which includes enhancing factors ...such as cyclins, cyclin dependent kinases, and inhibitory proteins, such as p27(kip1). The aim of the study was to evaluate the effects of Mycophenolate mofetil (MMF), and roscovitine (R), on the cell cycle regulatory system when administered in the florid phase of the experimental model of mesangial proliferative nephritis induced by the anti Thy-1 antigen monoclonal antibody. Three days after nephritis induction, different groups were given MMF and R. Rats treated with MMF or R showed a slight decrease in mesangial proliferation and matrix expansion. Samples of cortical tissue were tested by 'real time' RT-PCR in order to study gene expression of cyclins B, D1, D2, D3, E, and the cyclin inhibitor p27(kip1). Localization of mRNA was evaluated by in situ hybridization. Real time RT-PCR analysis showed a significant decrease in cyclins B, D1, D2, and D3 in rats treated with either MMF or R as compared to controls. Both MMF and R treatment induced a significant increase in p27(kip1) mRNA expression. In situ hybridization showed a mesangial-endothelial expression pattern in glomeruli. The number of labelled cells per glomerulus, the number of positive glomeruli in each examined slide as well as cyclin D2 and D3 signal intensity was significantly lower in rats treated with MMF or R as compared to controls, whereas MMF or R treatment up-regulated p27(kip1) mRNA expression. Immunohistochemical evaluation of p27(kip1) aimed to examine the influence of MMF or R on protein expression confirmed up-regulation.
Summary
Accumulating evidence indicates that B cells may undergo sequential rearrangements at the light chain loci, despite already expressing light chain receptors. This phenomenon may occur in the ...bone marrow and, perhaps, in germinal centers. As immunoglobulin (Ig)κ light chains usually rearrange before Igλ light chains, we analysed, by polymerase chain reaction, the Igκ locus of bone marrow mononuclear cells from 29 patients with Igλ myeloma to identify earlier recombinations in marrow plasma cells. The results demonstrated that Igκ alleles were inactivated via the kappa‐deleting element, presumably prior to Vκ‐Jκ rearrangement, in many cases. Eighteen alleles (16 myeloma clones, 55%) showed Vκ–Jκ rearrangements, with increased utilization of 5‵ distant Vκ and 3′ distant Jκ gene segments (Jκ4, 56%), an indication of multiple sequential rearrangements. In‐frame, potentially functional Vκ–Jκ rearrangements were found in approximately one‐third of available rearrangements (as expected by chance), each one in different myeloma clones: three were germline encoded, while one had several nucleotide substitutions, suggesting inactivation after the onset of somatic hypermutation. Three of four potentially functional Vκ–Jκ rearrangements involved Vκ4–1, a segment considered to be associated with autoimmunity. These findings provide insights into the regulation of light chain rearrangements and support the view that B cells may occasionally undergo sequential light chain rearrangements after the onset of somatic hypermutation.
Nowadays the particle physics has entered an era where high precision calculations are required in order to compare the theoretical predictions with the experimental data. In this paper, we ...explicitly compute the virtual contributions for the space-like one-jet processes, \(\procgg,\procqq,\procH\) and \(\procee\) within the auxiliary parton method. Our results, which are expected to play an important role in high precision description of small \(x\) physics, explicitly confirm the conjecture developed in Ref. \cite{vanHameren:2022mtk}, thus helping to bridge the gap between lowest order calculations and NLO corrections within hybrid \(k_T\)-factorization scheme.
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