Aharonov-Bohm Effect in Cyclotron and Synchrotron Radiations

We study the impact of Aharonov-Bohm solenoid on the radiation of a charged particle moving in a constant uniform magnetic field. With this aim in view, exact solutions of Klein-Gordon and Dirac equations are found in the magnetic-solenoid field. Using such solutions, we calculate exactly all the characteristics of one-photon spontaneous radiation both for spinless and spinning particle. Considering non-relativistic and relativistic approximations, we analyze cyclotron and synchrotron radiations in detail. Radiation peculiarities caused by the presence of the solenoid may be considered as a manifestation of Aharonov-Bohm effect in the radiation. In particular, it is shown that new spectral lines appear in the radiation spectrum. Due to angular distribution peculiarities of the radiation intensity, these lines can in principle be isolated from basic cyclotron and synchrotron radiation spectraComment: 38 pages, LaTex fil

Semiclassical Effects Induced by Aharonov-Bohm Interaction Between a Cosmic String and a Scalar Field

In the context of the vacuum polarization effect, we consider the backreaction of the energy-momentum tensor of a charged scalar field on the background metric of a cosmic string carrying a magnetic flux $\Phi$. Working within the semiclassical approach to the Einstein eqs. we find the first-order (in $\hbar$) metric associated to the magnetic flux cosmic string. We show that the contribution to the vacuum polarization effect coming from the Aharonov-Bohm interaction is larger than the one coming from the non-trivial gravitational interaction.Comment: 13 pages, no figures, accepted for publication in Phys. Letters

Acceleration of CRISPR/Cas9-Mediated Editing at Multiple Sites in the <i>Saccharomyces cerevisiae</i> Genome

The application of the CRISPR/Cas9-based genome editing technique to the yeast Saccharomyces cerevisiae has made it possible to simultaneously modify several sites, particularly to integrate several expression cassettes. The existing methods provide high efficiency for such modifications; however, common protocols include several preparatory steps, namely, the construction of an intermediate Cas9-expressing strain, the assembly of a plasmid bearing several single guide RNA (sgRNA) expression cassettes, and the surrounding integrated DNA fragments with long flanks for recombination with target loci. Since these preparatory steps are time consuming and may not be desirable in some types of experiments, we explored the possibility of multiple integration without these steps. We have demonstrated that it is possible to skip them simultaneously and integrate up to three expression cassettes into separate sites by transforming the recipient strain with the Cas9 expression plasmid, three differently marked sgRNA plasmids, and three donor DNAs flanked with short (70 bp) arms for recombination. This finding increases the flexibility of choosing the optimal experimental design for multiple editing of the genome of S. cerevisiae and can significantly accelerate such experiments

Multiple pathways for the formation of the γ-glutamyl peptides γ-glutamyl-valine and γ- glutamyl-valyl-glycine in Saccharomyces cerevisiae.

The role of glutathione (GSH) in eukaryotic cells is well known. The biosynthesis of this γ-glutamine tripeptide is well studied. However, other γ-glutamyl peptides were found in various sources, and the pathways of their formation were not always clear. The aim of the present study was to determine whether Saccharomyces cerevisiae can produce γ-glutamyl tripeptides other than GSH and to identify the pathways associated with the formation of these peptides. The tripeptide γ-Glu-Val-Gly (γ-EVG) was used as a model. Wild-type yeast cells were shown to produce this peptide during cultivation in minimal synthetic medium. Two different biosynthetic pathways for this peptide were identified. The first pathway consisted of two steps. In the first step, γ-Glu-Val (γ-EV) was produced from glutamate and valine by the glutamate-cysteine ligase (GCL) Gsh1p or by the transfer of the γ-glutamyl group from GSH to valine by the γ-glutamyltransferase (GGT) Ecm38p or by the (Dug2p-Dug3p)2 complex. In the next step, γ-EV was combined with glycine by the glutathione synthetase (GS) Gsh2p. The second pathway consisted of transfer of the γ-glutamyl residue from GSH to the dipeptide Val-Gly (VG). This reaction was carried out mainly by the (Dug2p-Dug3p)2 complex, whereas the GGT Ecm38p did not participate in this reaction. The contribution of each of these two pathways to the intracellular pool of γ-EVG was dependent on cultivation conditions. In this work, we also found that Dug1p, previously identified as a Cys-Gly dipeptidase, played an essential role in the hydrolysis of the dipeptide VG in yeast cells. It was also demonstrated that γ-EV and γ-EVG could be effectively imported from the medium and that γ-EVG was imported by Opt1p, known to be a GSH importer. Our results demonstrated that γ-glutamyl peptides, particularly γ-EVG, are produced in yeast as products of several physiologically important reactions and are therefore natural components of yeast cells

Engineering Escherichia coli for autoinducible production of L-valine: An example of an artificial positive feedback loop in amino acid biosynthesis.

Artificial metabolically regulated inducible expression systems are often used for the production of essential compounds. In most cases, the application of such systems enables regulating the expression of an entire group of genes in response to any internal signal such as an aerobic/anaerobic switch, a transition to stationary phase, or the exhausting of essential compounds. In this work, we demonstrate an example of another type of artificial autoinducible module, denoted a positive feedback module. This positive feedback module generates an inducer molecule that in turn enhances its own synthesis, promoting an activation signal. Due to the use of acetolactate, an intermediate of the L-valine biosynthetic pathway, as a specific inducer molecule, we realized a positive feedback loop in the biosynthetic pathway of branched chain amino acids. Such positive feedback was demonstrated to improve the production of a target compound

First Successful Experience of Organ-Preserving Endoscopic Surgical Treatment for Upper Urinary Tract Urothelial Carcinoma

Transition cell cancer of the upper urinary tract accounts for about 5% of all urothelial tumors. Monofocal localization of the tumor is more common. The simultaneous bilateral position of the lesion is extremely rare, and according to a large Swedish study led by Holmang et al. covers less than 1.6% of all cases. Radical nephroureterectomy with bladder resection is the gold standard for the treatment of transition cell cancer of upper urinary tract. The analysis of 1,462 patients (992 males and 470 females) treatment results shows no positive progress in clinical outcomes during last three decades, despite the advances in both medical science and technology. Hall with co-authors have conducted multi-factor analysis of the treatment results for 30-year period and noted that Upper Urinary Tract Urothelial Carcinoma (UTUC) relapse frequency depends on the tumor stage and the type of surgical treatment. Moreover, the tumor relapse rate is significantly high in case of organ-preserving surgical approach. Implementation of robotic nephroureterectomy has not also allowed improving sufficiently the treatment results. Nephroureterectomy in case of urothelial cancer of the only or single-functional kidney inevitably leads to program lifetime hemodialysis, which itself increases mortality rate from the non-oncological cause

Relapse-Free Survival and PD-L1 Expression in First High- and Low-Grade Relapsed Luminal, Basal and Double-Negative P53-Mutant Non-Muscular Invasive Bladder Cancer Depending on Previous Chemo- and Immunotherapy

The goal of this study was to assess how PD-L1 expression in tissue specimens of patients with main molecular subtypes of NMIBC (luminal, basal and double-negative p53-mutant) associates with relapsed-free survival in dependence on the tumor grade and prior treatment of primary bladder cancer. PD-L1 expressions on the membrane of neoplastic and CD8+ immune cells were assessed in tumor specimens (n = 240) of primary and relapsed luminal, basal and double-negative p53-mutant NMIBC. Association between relapse-free survival and PD-L1 expression was estimated for high- and low-grade relapsed NMIBC according to previous treatment and their molecular profile, using the Kaplan&ndash;Meier method, and assessed by using the log-rank test. Potential confounders were adjusted by Cox regression models. In a group of patients who underwent only TUR without intravesical therapy, there were significant differences in relapse time between high- and low-grade tumors in basal and luminal molecular subtypes; for basal relapsed carcinoma, RFS was shorter in cases where tumors were less malignant. Both intravesical mitomycin and Bacillus Calmette&ndash;Guerin (BCG) therapy significantly extended the time of recurrence of low-grade luminal and basal bladder malignancies with no intergroup differences in double-negative NMIBC. PD-L1 expression status was associated with RFS for luminal relapsed NMIBCs in the group without previous frontline intervention, and with RFS in the group of patients with luminal relapsed bladder cancer previously utilized BCG. Obtained results may be considered as a promising approach for further clinical implementation

Relapse-Free Survival and PD-L1 Expression in First High- and Low-Grade Relapsed Luminal, Basal and Double-Negative P53-Mutant Non-Muscular Invasive Bladder Cancer Depending on Previous Chemo- and Immunotherapy

The goal of this study was to assess how PD-L1 expression in tissue specimens of patients with main molecular subtypes of NMIBC (luminal, basal and double-negative p53-mutant) associates with relapsed-free survival in dependence on the tumor grade and prior treatment of primary bladder cancer. PD-L1 expressions on the membrane of neoplastic and CD8+ immune cells were assessed in tumor specimens (n = 240) of primary and relapsed luminal, basal and double-negative p53-mutant NMIBC. Association between relapse-free survival and PD-L1 expression was estimated for high-and low-grade relapsed NMIBC according to previous treatment and their molecular profile, using the Kaplan–Meier method, and assessed by using the log-rank test. Potential confounders were adjusted by Cox regression models. In a group of patients who underwent only TUR without intravesical therapy, there were significant differences in relapse time between high-and low-grade tumors in basal and luminal molecular subtypes; for basal relapsed carcinoma, RFS was shorter in cases where tumors were less malignant. Both intravesical mitomycin and Bacillus Calmette–Guerin (BCG) therapy significantly extended the time of recurrence of low-grade luminal and basal bladder malignancies with no intergroup differences in double-negative NMIBC. PD-L1 expression status was associated with RFS for luminal relapsed NMIBCs in the group without previous frontline intervention, and with RFS in the group of patients with luminal relapsed bladder cancer previously utilized BCG. Obtained results may be considered as a promising approach for further clinical implementation. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Expression of p53 protein associates with anti-pd-l1 treatment response on human-derived xenograft model of gata3/cr5/6-negative recurrent nonmuscular invasive bladder urothelial carcinoma

Background: The possible involvement of p53 signaling, FGFR3 expression, and FGFR3 mutation rates in the prediction of the NMIBC anti-PD-L1 treatment response needs to be clarified. The main aim of our study was to explore predictive value of p53 expression, FGFR3 expression, and its gene mutation status for the therapeutic success of anti-PD-L1 treatment in the patient-derived murine model of recurrent high-PD-L1(+) GATA3(-)/CR5/6(-) high-grade and low-grade NMIBC. Methods: twenty lines of patient-derived xenografts (PDXs) of relapsed high-PD-L1(+) double-negative NMIBC were developed, of which 10 lines represented high-grade tumors and the other ones—low-grade bladder cancer. Acceptors of each grade-related branch received specific anti-PD-L1 antibodies. Animals’ survival, tumor-doubling time, and remote metastasis were followed during the post-interventional period. PD-L1, GATA3, CR5/6, and p53 protein expressions in engrafted tumors were assessed by immunohistochemistry. The FGFR3 expression and FGFR3 mutations in codons 248 and 249 were detected by real-time polymerase chain reaction. Results: The expression of p53 protein is an independent factor affecting the animals’ survival time [HR = 0.036, p = 0.031] of anti-PD-L1-treated mice with low-grade high-PD-L1(+) double-negative NMIBC PDX. The FGFR3 expression and FGFR3 mutation rate have no impact on the anti-PD-L1 treatment response in the interventional groups. Conclusions: p53 expression may be considered as a prognostic factor for the anti-PD-L1 treatment efficacy of low-grade high-PD-L1-positive GATA3(-)/CR5/6(-)relapsed noninvasive bladder cancer. © 2021 by the authors. Licensee MDPI, Basel, Switzerland