Protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3) is highly expressed in a variety of cancers, where it promotes tumor cell migration and metastasis leading to poor prognosis. Despite its clinical ...significance, small molecule inhibitors of PRL-3 are lacking. Here, we screened 1443 FDA-approved drugs for their ability to inhibit the activity of the PRL phosphatase family. We identified five specific inhibitors for PRL-3 as well as one selective inhibitor of PRL-2. Additionally, we found nine drugs that broadly and significantly suppressed PRL activity. Two of these broad-spectrum PRL inhibitors, Salirasib and Candesartan, blocked PRL-3-induced migration in human embryonic kidney cells with no impact on cell viability. Both drugs prevented migration of human colorectal cancer cells in a PRL-3 dependent manner and were selective towards PRLs over other phosphatases. In silico modeling revealed that Salirasib binds a putative allosteric site near the WPD loop of PRL-3, while Candesartan binds a potentially novel targetable site adjacent to the CX
R motif. Inhibitor binding at either of these sites is predicted to trap PRL-3 in a closed conformation, preventing substrate binding and inhibiting function.
Fasciolosis caused by Fasciola hepatica, is the most prevalent parasitic disease in dairy cattle from the northern region of Cajamarca, Peru. The control of this parasite is based on the use of ...Triclabendazole (TCBZ), a drug that has been used for more than fifteen years in this area. Recent studies, however, have reported a lack of clinical efficacy after treating dairy cattle. This research was aimed to determine the efficacy of TCBZ in a clinical trial. Eleven dairy cows all positive to F. hepatica identified by presence of eggs in feces, were treated with TCBZ (Fasinex® 10%) at 12mg/kg body weight. Fourteen and thirty days after treatment, the animals were analyzed for F. hepatica eggs in their feces by the fecal egg count reduction test. The results found show an overall efficacy of 31.05% and 13. 63% (14 and 30 days post treatment, respectively). Furthermore, an in vivo efficacy test was conducted in sheep with metacercariae obtained from eggs isolated from a cow clinically resistant to TCBZ. Eleven sheep divided in two groups, a control group with no treatment (n=5) and a treated group (n=6) were all infected with two hundred metacercariae. One hundred and six days after infection all the animals demonstrated F. hepatica eggs in their feces, confirming the presence of adult parasites in their livers. The animals were then treated with TCBZ (Fasinex® 10%) at 10mg/kg body weight. Fifteen days later, the animals were sacrificed and the number of F. hepatica in their livers counted. The results of this experiment showed an efficacy of the flukicide of 25.2% confirming the resistance to TCBZ of the F. hepatica isolated from dairy cattle in Cajamarca, Peru.
Abstract The full data set of the NEMO-3 experiment has been used to measure the half-life of the two-neutrino double beta decay of $$^{100}$$ 100 Mo to the ground state of $$^{100}$$ 100 Ru, ...$$T_{1/2} = \left 6.81 \pm 0.01\,\left( \text{ stat }\right) ^{+0.38}_{-0.40}\,\left( \text{ syst }\right) \right \times 10^{18}$$ T1/2=6.81±0.01stat-0.40+0.38syst×1018 year. The two-electron energy sum, single electron energy spectra and distribution of the angle between the electrons are presented with an unprecedented statistics of $$5\times 10^5$$ 5×105 events and a signal-to-background ratio of $$\sim $$ ∼ 80. Clear evidence for the Single State Dominance model is found for this nuclear transition. Limits on Majoron emitting neutrinoless double beta decay modes with spectral indices of $$\mathrm{n}=2,3,7$$ n=2,3,7 , as well as constraints on Lorentz invariance violation and on the bosonic neutrino contribution to the two-neutrino double beta decay mode are obtained.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this work, the enzymatic cocktail produced by
Pleurotus djamor
fungi extracted at pH of 4.8 and 5.3 was employed for castor cake solid-state treatment. Proximal, X-ray powder diffraction and ...scanning electron microscopy analysis of the pristine castor cake were carried out. First,
Pleurotus djamor
stain was inoculated in castor cake for the enzymatic production and the enzymatic activity was determined. The maximum enzymatic activity was identified at days 14 (65.9 UI/gss) and 11 (140.3 UI/gss) for the enzymatic cocktail obtained at pH 5.3 and 4.8, respectively. Then, the enzymatic cocktail obtained at the highest enzymatic activity days was employed directly over castor cake. Lignin was degraded throughout incubation time achieving a 47 and 45% decrease for the cocktail produced at pH 4.8 and 5.3, correspondingly. These results were corroborated by the SEM and XRD analysis where a higher porosity and xylan degradation were perceived throughout the enzymatic treatment.
Background:
Between 2008 and 2017, EDF has progressively replaced its old Personal Contamination Monitors (PCM) with a new generation to strengthen the control of the workers at the exit of the ...restricted controlled areas. One of the novelties of the new PCM generation is the introduction of gamma channels which, coupled to the beta channel, allows a more reliable and more precise measurement. The new PCM also includes a better monitoring of the C2 portals alarms triggering system, a greater detection surface to minimize the dead zone and carries out morphological compensation to take into account the attenuation of the gamma background by the body. This new PCM is very efficient and capable of detecting low contamination activities. The sensitivity of this monitoring system is such that the solid progeny of
222
Rn deposited on clothes (such as the
214
Pb and the
214
Po) could in some cases be detected and triggered the C2 portals alarm.
Objective:
In order to quantify the impact of radon (
222
Rn) and its progeny on the C2 portals triggers, a specific study has been conducted. Beyond the physical aspect, several purposes are targeted: (1) to provide quantitative explanations about the C2 alarms attributed to radon and determine which channels are more affected by the
222
Rn progeny; (2) to determine the existence of a relation between C2 alarms and high
222
Rn volume activity; (3) to optimize practices at the exit of the Restricted Controlled Areas (RCA), for example, adapt waiting time before control in PCM. The study consisted in measuring the activity of radon progeny deposited on several types of suits used in EDF Nuclear Power Plants (NPPs). To assess the impact of the
222
Rn, several factors have been studied such as the
222
Rn exposure time, the
222
Rn concentration and the nature of textile fibers constituting clothes. For this study, several facilities from the Laboratoire de Physique des deux infinis de Bordeaux (LP2i Bordeaux) have been used, including a
222
Rn emanation standard source and various emanation chambers between 60 L and 750 L. A specific calibration method to characterize radon progenies deposited has been developed (see Sects. 2.4 and 3). The
222
Rn concentration in the sample exposure environment is verified both using a commercial (see Sects. 2.4 and 3) and experimental high sensitivity radon detectors. The measurements of the
222
Rn progeny on clothes are made immediately after exposure by gamma spectrometry control on a High Purity Germanium (HPGe) detector. This experiment has been carried out at the PRISNA measurement platform (Plateforme Régionale Interdisciplinaire de Spectrométrie Nucléaire en Aquitaine) located in LP2I Bordeaux.
Conclusions:
In this study, several phenomena have been highlighted for a better understanding of the C2 portal triggering. We validate that in presence of
222
Rn volume concentration activity lower than 300 Bq/m
3
, an alarm in beta channels of C2 portals can be triggered because of the presence of the radon progeny on clothes. The triggering of the gamma channels could appear only if the volume concentration activity of radon is higher than 3000 Bq/m
3
. The results obtained in this study could led to optimize and harmonize the practices at the exit of Restricted Controlled Area (RCA) like adapt waiting time before control in PCM.
Several efforts are ongoing for the development of spherical gaseous time projection chamber detectors for the observation of rare phenomena such as weakly interacting massive particles or neutrino ...interactions. The proposed detector, thanks to its simplicity, low energy threshold and energy resolution, could be used to observe the ββ0ν process i.e. the neutrinoless double beta decay. In this work, a specific setup is presented for the measurement of ββ0ν on 50 kg of 136Xe. The different backgrounds are studied, demonstrating the possibility to reach a total background per year in the detector mass at the level of 2 events per year. The obtained results are competitive with the present generation of experiments and could represent the first step of a more ambitious roadmap including the ββ0ν search with different gases with the same detector and therefore the same background sources. The constraints in terms of detector constructions and material purity are also addressed, showing that none of them represents a show stopper for the proposed experimental setup.
Tritium is released abundantly to the environment by nuclear power plants (NPP), as a product of neutron capture by hydrogen and deuterium. In normal running conditions, released cooling waters may ...contain levels of tritium close to or even larger than the maximum authorised limit for human consumption (drinking and irrigation). The European Council Directive 2013/51/Euratom requires a maximum level of tritium in water for human consumption lower than 100 Bq=L. Current monitoring of tritium activity in water by liquid scintillating method takes about two days and can only be carried out in a dedicated laboratory. This system is not appropriate for real time monitoring. At present, there exists no available detector device with enough sensitivity to monitor waters for human consumption with high enough sensitivity. The goal of the TRITIUM project is to build a tritium monitor capable to measure tritium activities with detection limit close to 100Bq=L, using instrumentation technique developed in recent years for Nuclear and Particle Physics, such as scintillating fibres and silicon photomultipliers (SiPM). In this paper the current status of the TRITIUM project is presented and he results of first prototypes are discussed. A detector system based on scintillating fibers read out either photomultiplier tubes (PMTs) or silicon photomultiplier (SiPM) arrays is under development and will be installed in the vicinity of Almaraz nuclear power plant (Cáceres, Spain) by the fourth term of 2019.
Protein tyrosine phosphatases (PTP) have emerged as targets in diseases characterized by aberrant phosphorylations such as cancers. The activity of the phosphatase of regenerating liver 3, PRL3, has ...been linked to several oncogenic and metastatic pathways, particularly in breast, ovarian, colorectal, and blood cancers. Development of small molecules that directly target PRL3, however, has been challenging. This is partly due to the lack of structural information on how PRL3 interacts with its inhibitors. Here, computational methods are used to bridge this gap by evaluating the druggability of PRL3. In particular, web-based pocket prediction tools, DoGSite3 and FTMap, were used to identify binding pockets using structures of PRL3 currently available in the Protein Data Bank. Druggability assessment by molecular dynamics simulations with probes was also performed to validate these results and to predict the strength of binding in the identified pockets. While several druggable pockets were identified, those in the closed conformation show more promise given their volume and depth. These two pockets flank the active site loops and roughly correspond to pockets predicted by molecular docking in previous papers. Notably, druggability simulations predict the possibility of low nanomolar affinity inhibitors in these sites implying the potential to identify highly potent small molecule inhibitors for PRL3. Putative pockets identified here can be leveraged for high-throughput virtual screening to further accelerate the drug discovery against PRL3 and development of PRL3-directed therapeutics.
•The phosphatase of regenerating liver 3, PRL3, is a significant target in several cancers and in metastasis.•There is a critical need to identify inhibitors of PRL3 with potential to be developed as antineoplastic drugs or migrastatics.•Several putative druggable pockets are identified using a combination of computational tools which can be leveraged in virtual drug screens or structure-based drug design.•Druggability simulations predict theoretical high-affinity binding sites.
R2D2 TPC: first Xenon results Bouet, R.; Busto, J.; Cecchini, V. ...
Journal of instrumentation,
10/2023, Letnik:
18, Številka:
10
Journal Article
Recenzirano
Abstract
Radial time projection chambers (TPC), already employed in
the search for rare phenomena such as light Dark Matter candidate,
could provide a new detection approach for the search of
...neutrinoless double beta decay (
ββ
0
ν
). The assessment of
the performances of such a detector for
ββ
0
ν
search is
indeed the goal of the Rare Decays with Radial Detector (R2D2)
R&D. Promising results operating a spherical TPC with argon up to
1 bar have been published in 2021. Supplementary measurements were
recently taken extending the gas pressure range up to 3 bar. In
addition, a comparison between two detector geometries, namely
spherical (SPC for spherical proportional counter) and cylindrical
(CPC for cylindrical proportional counter), was performed. Using a
relatively simple gas purification system the CPC detector was also
operated with xenon at 1 bar: an energy resolution of 1.4%
full-width at half-maximum was achieved for drift distances up to
17 cm. Much lower resolution was observed with the SPC. These
results are presented in this article.
Spherical time projection chambers (TPC), also known as spherical proportional counters, are employed in the search for rare phenomena, such as light Dark Matter candidates. The spherical TPC ...exhibits a number of essential features, making it a promising candidate for the search of neutrinoless double beta decay (ββ0ν). A tonne-scale spherical TPC experiment could cover a region of parameter space relevant for the inverted mass hierarchy with a few years of data taking. In this direction, the major R&D goal of the R2D2 effort is the demonstration of the required energy resolution. First results from an argon-filled prototype detector are reported, demonstrating an energy resolution of 1.1% FWHM for 5.3 MeV α tracks in the 0.2 to 1.1 bar pressure range. This is a major milestone in terms of energy resolution, paving the way for further studies with xenon gas, and the possible use of this technology for ββ0ν searches.
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