95 research outputs found
Cells exhibiting strong p16INK4a promoter activation in vivo display features of senescence
The activation of cellular senescence throughout the lifespan promotes tumor suppression, whereas the persistence of senescent cells contributes to aspects of aging. This theory has been limited, however, by an inability to identify and isolate individual senescent cells within an intact organism. Toward that end, we generated a murine reporter strain by “knocking-in” a fluorochrome, tandem-dimer Tomato (tdTom), into exon 1α of the p16 INK4a locus. We used this allele (p16 tdTom ) for the enumeration, isolation, and characterization of individual p16 INK4a -expressing cells (tdTom + ). The half-life of the knocked-in transcript was shorter than that of the endogenous p16 INK4a mRNA, and therefore reporter expression better correlated with p16 INK4a promoter activation than p16 INK4a transcript abundance. The frequency of tdTom + cells increased with serial passage in cultured murine embryo fibroblasts from p16 tdTom/+ mice. In adult mice, tdTom + cells could be readily detected at low frequency in many tissues, and the frequency of these cells increased with aging. Using an in vivo model of peritoneal inflammation, we compared the phenotype of cells with or without activation of p16 INK4a and found that tdTom + macrophages exhibited some features of senescence, including reduced proliferation, senescence-associated β-galactosidase (SA-β-gal) activation, and increased mRNA expression of a subset of transcripts encoding factors involved in SA-secretory phenotype (SASP). These results indicate that cells harboring activation of the p16 INK4a promoter accumulate with aging and inflammation in vivo, and display characteristics of senescence
APPLICATION OF URETHRAL STENT IN CHILDREN WITH URETHRAL STRICTURE, EARLY OUTCOMES
Background. Urethral stricture is one of the most common complications after urethroplasty. And nowadays a growing number of congenital urethral diseases is observed. It is obvious that there is a huge amount of urethroplasty needed all over the world. Material and Methods. 15 patients with urethral strictures were included in the conducted prospective research. All patients underwent a complex urology investigation consisted of uroflowmetry, urethrography and urethroscopy. Most of strictures were located in penile urethra, their length varied from 1 to 5 mm. All patients enrolled in the study had the only single stricture. After investigation internal visual urethrotomy was performed with one-time stenting using individual prepared titanium nickelide stent. Stent was in urethra for 14–21 days. It had been evacuated from urethra and uroflowmetry, urethrography and urethroscopy were performed. Results and discussion. All patients have good result of uroflowmetry in the postoperative period. The results of urethrography and urethroscopy have also showed that there were no urethral strictures. The longest follow-up has lasted for 3 years. The efficiency of treatment is 93 %. The repeated procedure was required in one case. Any complications of this way of urethral stricture’s treatment haven’t occurred. Nowadays laser urethrotomy is known to have a success rate about 84 %, but follow-up period is still rather short. And also it is estimated that 65 % of all children with direct vision urethrotomy had a recurrence of the stricture in 5 years. It is hoped that the announced way of treatment of urethral stricture will be very perspective and will help to solve such significant problem in pediatric urology as urethral stricture. Conclusions. Stenting of urethra after internal visual urethrotomy has good outcomes, and seems to be a very perspective minimally invasive way of treatment of urethral stricture
Josephson effect in double-barrier superconductor-ferromagnet junctions
We study the Josephson effect in ballistic double-barrier SIFIS planar
junctions, consisting of bulk superconductors (S), a clean metallic ferromagnet
(F), and insulating interfaces (I). We solve the scattering problem based on
the Bogoliubov--de Gennes equations and derive a general expression for the dc
Josephson current, valid for arbitrary interfacial transparency and Fermi wave
vectors mismatch (FWVM). We consider the coherent regime in which quasiparticle
transmission resonances contribute significantly to the Andreev process. The
Josephson current is calculated for various parameters of the junction, and the
influence of both interfacial transparency and FWVM is analyzed. For thin
layers of strong ferromagnet and finite interfacial transparency, we find that
coherent (geometrical) oscillations of the maximum Josephson current are
superimposed on the oscillations related to the crossover between 0 and
states. For the same case we find that the temperature-induced
transition occurs if the junction is very close to the crossovers at zero
temperature.Comment: 13 pages, 6 figure
TLR9 Agonist Protects Mice from Radiation-Induced Gastrointestinal Syndrome
Radiation-induced gastrointestinal syndrome (RIGS) is due to the clonogenic loss of crypt cells and villi depopulation, resulting in disruption of mucosal barrier, bacterial invasion, inflammation and sepsis. Intestinal macrophages could recognize invading bacterial DNA via TLR9 receptors and transmit regenerative signals to the neighboring crypt. We therefore investigated whether systemic administration of designer TLR9 agonist could ameliorate RIGS by activating TLR9.Male C57Bl6 mice were distributed in four experimental cohorts, whole body irradiation (WBI) (8.4-10.4 Gy), TLR9 agonist (1 mg/kg s.c.), 1 h pre- or post-WBI and TLR9 agonist+WBI+iMyd88 (pretreatment with inhibitory peptide against Myd88). Animals were observed for survival and intestine was harvested for histological analysis. BALB/c mice with CT26 colon tumors in abdominal wall were irradiated with 14 Gy single dose of whole abdominal irradiation (AIR) for tumor growth study.Mice receiving pre-WBI TLR9 agonist demonstrated improvement of survival after 10.4 Gy (p<0.03), 9.4 Gy (p<0.008) and 8.4 Gy (p<0.002) of WBI, compared to untreated or iMyd88-treated controls. Post-WBI TLR9 agonist mitigates up to 8.4 Gy WBI (p<0.01). Histological analysis and xylose absorption test demonstrated significant structural and functional restitution of the intestine in WBI+TLR9 agonist cohorts. Although, AIR reduced tumor growth, all animals died within 12 days from RIGS. TLR9 agonist improved the survival of mice beyond 28 days post-AIR (p<0.008) with significant reduction of tumor growth (p<0.0001).TLR9 agonist treatment could serve both as a prophylactic or mitigating agent against acute radiation syndrome and also as an adjuvant therapy to increase the therapeutic ratio of abdominal Radiation Therapy for Gastro Intestinal malignancies
Small molecule compounds targeting the p53 pathway: are we finally making progress?
Loss of function of p53, either through mutations in the gene or through mutations to other members of the pathway that inactivate wild-type p53, remains a critically important aspect of human cancer development. As such, p53 remains the most commonly mutated gene in human cancer. For these reasons, pharmacologic activation of the p53 pathway has been a highly sought after, yet unachieved goal in developmental therapeutics. Recently progress has been made not only in the discovery of small molecules that target wild-type and mutant p53, but also in the initiation and completion of the first in-human clinical trials for several of these drugs. Here, we review the current literature of drugs that target wild-type and mutant p53 with a focus on small-molecule type compounds. We discuss common means of drug discovery and group them according to their common mechanisms of action. Lastly, we review the current status of the various drugs in the development process and identify newer areas of p53 tumor biology that may prove therapeutically useful
The neutron and its role in cosmology and particle physics
Experiments with cold and ultracold neutrons have reached a level of
precision such that problems far beyond the scale of the present Standard Model
of particle physics become accessible to experimental investigation. Due to the
close links between particle physics and cosmology, these studies also permit a
deep look into the very first instances of our universe. First addressed in
this article, both in theory and experiment, is the problem of baryogenesis ...
The question how baryogenesis could have happened is open to experimental
tests, and it turns out that this problem can be curbed by the very stringent
limits on an electric dipole moment of the neutron, a quantity that also has
deep implications for particle physics. Then we discuss the recent spectacular
observation of neutron quantization in the earth's gravitational field and of
resonance transitions between such gravitational energy states. These
measurements, together with new evaluations of neutron scattering data, set new
constraints on deviations from Newton's gravitational law at the picometer
scale. Such deviations are predicted in modern theories with extra-dimensions
that propose unification of the Planck scale with the scale of the Standard
Model ... Another main topic is the weak-interaction parameters in various
fields of physics and astrophysics that must all be derived from measured
neutron decay data. Up to now, about 10 different neutron decay observables
have been measured, much more than needed in the electroweak Standard Model.
This allows various precise tests for new physics beyond the Standard Model,
competing with or surpassing similar tests at high-energy. The review ends with
a discussion of neutron and nuclear data required in the synthesis of the
elements during the "first three minutes" and later on in stellar
nucleosynthesis.Comment: 91 pages, 30 figures, accepted by Reviews of Modern Physic
Fundamental Symmetries, Neutrons, and Neutrinos (FSNN): Whitepaper for the 2023 NSAC Long Range Plan
This whitepaper presents the research priorities decided on by attendees of
the 2022 Town Meeting for Fundamental Symmetries, Neutrons and Neutrinos, which
took place December 13-15, 2022 in Chapel Hill, NC, as part of the Nuclear
Science Advisory Committee (NSAC) 2023 Long Range Planning process. A total of
275 scientists registered for the meeting. The whitepaper makes a number of
explicit recommendations and justifies them in detail
Different Effect of Proteasome Inhibition on Vesicular Stomatitis Virus and Poliovirus Replication
Proteasome activity is an important part of viral replication. In this study, we examined the effect of proteasome inhibitors on the replication of vesicular stomatitis virus (VSV) and poliovirus. We found that the proteasome inhibitors significantly suppressed VSV protein synthesis, virus accumulation, and protected infected cells from toxic effect of VSV replication. In contrast, poliovirus replication was delayed, but not diminished in the presence of the proteasome inhibitors MG132 and Bortezomib. We also found that inhibition of proteasomes stimulated stress-related processes, such as accumulation of chaperone hsp70, phosphorylation of eIF2α, and overall inhibition of translation. VSV replication was sensitive to this stress with significant decline in replication process. Poliovirus growth was less sensitive with only delay in replication. Inhibition of proteasome activity suppressed cellular and VSV protein synthesis, but did not reduce poliovirus protein synthesis. Protein kinase GCN2 supported the ability of proteasome inhibitors to attenuate general translation and to suppress VSV replication. We propose that different mechanisms of translational initiation by VSV and poliovirus determine their sensitivity to stress induced by the inhibition of proteasomes. To our knowledge, this is the first study that connects the effect of stress induced by proteasome inhibition with the efficiency of viral infection
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