Half-life Limit Research Articles

Supramolecular nanoparticle loaded with bilirubin enhances cartilage protection and alleviates osteoarthritis via modulating oxidative stress and inflammatory responses

Osteoarthritis (OA) is a chronic inflammation that gradually leads to cartilage degradation. Prolonged chondrocyte oxidative stress contributes to the development of diseases, including chondrocyte apoptosis, cartilage matrix degradation, and aggravation of articular cartilage damage. Bilirubin (BR) possesses strong antioxidant properties by scavenging reactive oxygen species (ROS) and potent protection effects against inflammation. However, its insolubility and short half-life limit its clinical use. Therefore, we developed a supramolecular system of ε-polylysine (EPL) conjugated by β-cyclodextrin (β-CD) on the side chain, and bilirubin was loaded via host-guest interactions, which resulted in the self-assemble of this system into bilirubin-loaded polylysine-β-cyclodextrin nanoparticle (PB) with improving solubility while reducing toxicity and prolonging medication action time. To explore PB's potential pharmacological mechanisms on OA, we established in vitro and in vivo OA models. PB exerted ROS-scavenging proficiency and anti-apoptotic effects on rat chondrocytes by activating the Nrf2-HO-1/GPX4 signaling pathway. Additionally, PB reprogrammed the cartilage microenvironment by regulating the NF-κB signaling pathway to maintain chondrocyte function. Animal experiments further confirmed that PB had excellent scavenging ability for ROS and inflammatory factors related to charge adsorption with cartilage as well as long retention ability. Together, this work suggests that PB has superior protective abilities with beneficial effects on OA, indicating its great potential for intervention therapy targeting chondrocytes.

Safe Application of 75% Trifloxystrobin-Tebuconazole as Water-Dispersible Granules in Paddy Based on Residue and Dietary Risk Assessment.

The present study describes the development of a highly effective approach for determining the residue distribution and dissipation of trifloxystrobin and tebuconazole, and their risk assessment in brown rice, husk, straw, and grain using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The current study provides considerable novel information regarding the safe utilization of a mixture of trifloxystrobin and tebuconazole in paddy production. The samples demonstrated a range of mean recoveries between 72% and 86%, with a 1.1-9.2% relative standard deviation (RSD). The limits of quantification (LOQ) and half-lives (t1/2) for brown rice, husk, straw, and grain were, respectively, established to be 0.001-0.01 mg/kg and 4.1-7.7 days. The concentrations of terminal residues in the brown rice, husk, straw, and grain were, respectively, found to be 0.02-0.05, 0.03-0.11, 0.02-0.07, and 0.02-0.05 mg/kg after being treated twice at 168.75 g a.i./ha with 21 and 28 days of pre-harvest intervals (PHIs). Trifloxystrobin and tebuconazole presented a non-negligible chronic risk to human subjects, as evidenced by a risk quotient (RQ) value of less than 1.

DECM based dusal-responsive vascular graft with enzyme-controlled adenine release for long-term patency

Rapid occlusion is the culprit leading to implantation failure of biological blood vessels. Although adenosine is a clinical-proven drug to overcome the problem, its short half-life and turbulent burst-release limit its direct application. Thus, a pH/temperature dual-responsive blood vessel possessed controllable long-term adenosine secretion was constructed based on acellular matrix via compact crosslinking by oxidized chondroitin sulfate (OCSA) and functionalized with apyrase and acid phosphatase. These enzymes, as adenosine micro-generators, controlled the adenosine release amount by “real-time-responding” to acidity and temperature of vascular inflammation sites. Additionally, the macrophage phenotype was switched from M1 to M2, and related factors expression proved that adenosine release was effectively regulated with the severity of inflammation. What's more, the ultra-structure for degradation resisting and endothelialization accelerating was also preserved by their “double-crosslinking”. Therefore, this work suggested a new feasible strategy providing a bright future of long-term patency for transplanted blood vessels.

Final Result of the Majorana Demonstrator’s Search for Neutrinoless Double- β Decay in Ge76

The Majorana Demonstrator searched for neutrinoless double-β decay (0νββ) of ^{76}Ge using modular arrays of high-purity Ge detectors operated in vacuum cryostats in a low-background shield. The arrays operated with up to 40.4kg of detectors (27.2kg enriched to ∼88% in ^{76}Ge). From these measurements, the Demonstrator has accumulated 64.5kg yr of enriched active exposure. With a world-leading energy resolution of 2.52keV FWHM at the 2039keV Q_{ββ} (0.12%), we set a half-life limit of 0νββ in ^{76}Ge at T_{1/2}>8.3×10^{25} yr (90%C.L.). This provides a range of upper limits on m_{ββ} of (113-269)meV (90%C.L.), depending on the choice of nuclear matrix elements.

Search for the Majorana Nature of Neutrinos in the Inverted Mass Ordering Region with KamLAND-Zen.

The KamLAND-Zen experiment has provided stringent constraints on the neutrinoless double-beta (0νββ) decay half-life in ^{136}Xe using a xenon-loaded liquid scintillator. We report an improved search using an upgraded detector with almost double the amount of xenon and an ultralow radioactivity container, corresponding to an exposure of 970kgyr of ^{136}Xe. These new data provide valuable insight into backgrounds, especially from cosmic muon spallation of xenon, and have required the use of novel background rejection techniques. We obtain a lower limit for the 0νββ decay half-life of T_{1/2}^{0ν}>2.3×10^{26} yr at 90%C.L., corresponding to upper limits on the effective Majorana neutrino mass of 36-156meV using commonly adopted nuclear matrix element calculations.

Final results on the 0nu beta beta decay half-life limit of ^{100}Mo from the CUPID-Mo experiment

The CUPID-Mo experiment to search for 0nu beta beta decay in ^{100}Mo has been recently completed after about 1.5 years of operation at Laboratoire Souterrain de Modane (France). It served as a demonstrator for CUPID, a next generation 0nu beta beta decay experiment. CUPID-Mo was comprised of 20 enriched hbox {Li}_{{2}}^{100}hbox {MoO}_4 scintillating calorimeters, each with a mass of sim 0.2 kg, operated at sim 20 mK. We present here the final analysis with the full exposure of CUPID-Mo (^{100}Mo exposure of 1.47 hbox {kg} times hbox {year}) used to search for lepton number violation via 0nu beta beta decay. We report on various analysis improvements since the previous result on a subset of data, reprocessing all data with these new techniques. We observe zero events in the region of interest and set a new limit on the ^{100}Mo 0nu beta beta decay half-life of T_{1/2}^{0nu }> {1.8}times 10^{24} year (stat. + syst.) at 90% CI. Under the light Majorana neutrino exchange mechanism this corresponds to an effective Majorana neutrino mass of left<m_{beta beta }right> <~{(0.28{-}0.49)} eV, dependent upon the nuclear matrix element utilized.

Double Beta Decay: A Shell Model Approach

Studies of weak interaction in nuclei are important tools for testing different aspects of the fundamental symmetries of the Standard Model. Neutrinoless double beta decay offers an unique venue of investigating the possibility that neutrinos are Majorana fermions and that the lepton number conservation law is violated. Here, I use a shell model approach to calculate the nuclear matrix elements needed to extract the lepton-number-violating parameters of a few nuclei of experimental interest from the latest experimental lower limits of neutrinoless double beta decay half-lives. The analysis presented here could reveal valuable information regarding the dominant neutrinoless double beta decay mechanism if experimental half-life data become available for different isotopes. A complementary shell model analysis of the two-neutrino double beta decay nuclear matrix elements and half-lives is also presented.

Design and Characterization of a Natural Arf-GEFs Inhibitor Prodrug CHNQD-01255 with Potent Anti-Hepatocellular Carcinoma Efficacy In Vivo.

Brefeldin A (BFA), a well-known natural Arf-GEFs inhibitor, is effective against hepatocellular carcinoma (HCC), while the poor solubility, serious toxicity, and short half-life limit its potential. Herein, distinct corresponding prodrugs of BFA, including esters 1-15, carbonates 16-24 and 30-32, and carbamates 25-29, were synthesized and evaluated. CHNQD-01255 (16) with improved aqueous solubility (15-20 mg/mL) demonstrated favorable pharmacokinetic profiles. It behaved as expected by undergoing rapid conversion to BFA in vivo, and achieved sufficient high plasma exposure, prolonged half-life, as well as the improved bioavailability of BFA (F = 18.96%). Meanwhile, CHNQD-01255 significantly suppressed tumor growth (TGI = 61.0%) at a dose of 45 mg/kg (p.o.) in the xenograft model. Notably, the improved safety profile of CHNQD-01255 (MTD > 750 mg/kg, p.o.) was confirmed to be superior to that of BFA (MTD < 506 mg/kg). Overall, CHNQD-01255 may serve as a safe and effective new anti-HCC prodrug.

Neutrino masses and mass hierarchy: evidence for the normal hierarchy

The latest cosmological constraints on the sum of neutrino masses, in combination with the latest laboratory measurements on oscillations, provide “decisive” Bayesian evidence for the normal neutrino mass hierarchy. We show that this result holds across very different prior alternatives by exploring two extremes on the range of prior choices. In fact, while the specific numerical value for the Evidence depends on the choice of prior, the Bayesian odds remain greater than 140:1 across very different prior choices. For Majorana neutrinos this has important implications for the upper limit of the neutrino-less double beta decay half life and thus for the technology and resources needed for future double beta decay experiments.

Enrichment of 150Nd for neutrinoless double-beta decay detection

A 562 nm–627 nm–597 nm three-step resonant photoionization scheme has been studied using the density matrix formalism for the enrichment of 150Nd in weighable quantities for the neutrinoless double-beta decay detection. The effect of bandwidth of the excitation laser and charge exchange collisions, on the production rates and degree of enrichment has also been studied. Optimum conditions for the efficient enrichment of 150Nd isotope have been derived. It has been shown that it might be possible to produce 50 kg of 66% enriched 150Nd isotope in about five months (16 h/day) using the conditions derived through this investigation. This enables to reach the 0νββ decay half-life limit of ≈ 1.8 × 1025 year for the 150Nd isotope.

Investigation on Rare Nuclear Processes in Hf Nuclides

In this work, a review of recent studies concerning rare nuclear processes in Hf isotopes is presented. In particular, the investigations using HP-Ge spectrometry and Hf-based crystal scintillators are focused; the potentiality and the results of the “source = detector” approach are underlined. In addition, a short introduction concerning the impact of such kind of research in the context of astroparticle and nuclear physics is pointed out. In particular, the study of α decay and double beta decay of 174Hf, 176Hf, 177Hf, 178Hf, 179Hf, 180Hf isotopes either to the ground state or to the lower bounded levels have been discussed. The observation of α decay of 174Hf isotope to the ground state with a T1/2=7.0(1.2)×1016 y is reported and discussed. No decay was detected for α decay of 174Hf isotope at the first excited level of daughter and of 176Hf, 177Hf, 178Hf, 179Hf, 180Hf isotopes either to the ground state or to the lower bounded levels. The T1/2 lower limits for these decays are at the level of 1016–1020 y. Nevertheless, the T1/2 lower limits for the transitions of 176Hf→172Yb (0+→0+) and 177Hf→173Yb (7/2−→5/2−) are near to the theoretical predictions, giving hope to their observation in the near future. All the other experimental limits (∼1016–1020 y) are absolutely far from the theoretical expectations. The experiments investigating the 2ϵ and ϵβ+ processes in 174Hf are also reported; the obtained half-life limits are set at the level of 1016–1018 y. Moreover, we estimate the T1/2 of 2ν2ϵ of 174Hf decay at the level of (0.3–6) × 1021 y (at now the related measured lower limit is 7.1×1016 y).

New results on search for 2β decay processes in 106Cd using 106CdWO4 scintillator

Preliminary researches on double beta decay transitions in 106Cd were carried out using a cadmium tungstate scintillator enriched in 106Cd at 66% (106CdWO4, mass 215.4 g), in coincidence (anticoincidence) with two CdWO4 scintillation detectors composed of natural Cd. The detector system is inserted in the DAMA/R&D setup, placed in the Gran Sasso National Laboratory of the INFN (LNGS, Italy). The contaminations which appear in the different materials of the experimental apparatus were simulated using Monte Carlo coding. New calculations of half-life limits have been done for various double beta decay channels of 106Cd and are of order of lim 10−10 yr. These results were derived by means of the analysis of the data accumulated for 467 days. The preliminary estimation on for the positron-emitting electron capture with two neutrinos emission in 106Cd is equal to 1.5 10 yr, which is close to the theoretical forecasts for this process, 10−10 yr.

Constraints on partial half-lives of Ce136 and Ce138 double electron captures

The gamma-ray emissions from a radiopure cerium-bromide crystal with a mass of 4381 g were measured for a total of 497.4 d by means of high-resolution gamma-ray spectrometry in the HADES underground laboratory at a depth of 500 m.w.e. A search for 0/2nee and 0/2neb+ double beta decay transitions of Ce-136 and Ce-138 was performed using Bayesian analysis techniques. No signals were observed for a total of 35 investigated decay modes. 90% credibility limits were set in the order of 1e18-1e19 a. Existing constraints from a cerium oxide powder measurement were tested with a different cerium compound and half-life limits could be improved for most of the decay modes. The most likely accessible decay mode of the Ce-136 2nee transition into the 0+1 state of Ba-136 results in a new best 90% credibility limit of 5.0e18 a.

Synergistic Effect of L-Carnosine and Hyaluronic Acid in Their Covalent Conjugates on the Antioxidant Abilities and the Mutual Defense against Enzymatic Degradation.

Hyaluronic acid (Hy) is a natural linear polymer that is widely distributed in different organisms, especially in the articular cartilage and the synovial fluid. During tissue injury due to oxidative stress, Hy plays an important protective role. All the beneficial properties of Hy make the polymer attractive for many biomedical uses; however, the low stability and short biological half-life limit Hy application. To overcome these problems, the addition of small antioxidant molecules to Hy solution has been employed to protect the molecular integrity of Hy or delay its degradation. Carnosine (β-alanyl-L-histidine, Car) protects cells from the damage due to the reactive species derived from oxygen (ROS), nitrogen (RNS) or carbonyl groups (RCS). Car inhibits the degradation of hyaluronan induced by free radical processes in vitro but, like Hy, the potential protective action of Car is drastically hampered by the enzymatic hydrolysis in vivo. Recently, we conjugated Hy to Car and the derivatives (HyCar) showed protective effects in experimental models of osteoarthritis and rheumatoid arthritis in vivo. Here we report the antioxidant activity exerted by HyCar against ROS, RNS and RCS. Moreover, we tested if the covalent conjugation between Hy and Car inhibits the enzymatic hydrolysis of the polymer and the dipeptide backbone. We found that the antioxidant properties and the resistance to the enzymatic hydrolysis of Hy and Car are greatly improved by the conjugation.

New results from the CUORE experiment

The Cryogenic Underground Observatory for Rare Events (CUORE) is the first bolometric experiment searching for neutrino-less double-beta (0[Formula: see text]) decay that has been able to reach the one-ton scale. The detector, located at the Laboratori Nazionali del Gran Sasso in Italy, consists of an array of 988 TeO2 crystals arranged in a compact cylindrical structure of 19 towers. Following the completion of the detector construction in August 2016, CUORE began its first physics data run in 2017 at a base temperature of about 10 mK. Following multiple optimization campaigns in 2018, CUORE is currently in stable operating mode. In 2019, CUORE released its second result of the search for 0[Formula: see text] corresponding to a TeO2 exposure of 372.5 kg[Formula: see text]⋅[Formula: see text]yr and a median exclusion sensitivity to a 130Te 0[Formula: see text] decay half-life of [Formula: see text] yr. We find no evidence for 0[Formula: see text] decay and set a 90% C.I. Bayesian lower limit of [Formula: see text] yr on the 130Te 0[Formula: see text] decay half-life. We present the current status of CUORE’s search for 0[Formula: see text]. We give an update of the CUORE background model and the measurement of the 130Te two neutrino double-beta (2[Formula: see text]) decay half-life. Eventually, we show the preliminary results on half-life limits from the analysis of 130Te 0[Formula: see text] and 2[Formula: see text] decay to the first 0[Formula: see text] excited state of [Formula: see text]Xe.

Search for rare alpha and double beta decays of Yb isotopes to excited levels of daughter nuclei

A search for alpha and double beta decays of ytterbium isotopes was performed with an ultra low-background high purity germanium detector at Gran Sasso Underground Laboratory (Italy). A 194.7 g Yb_2(C_2O_4)_3 powder sample was measured for 11.3 days with a total Yb exposure of 1.25 kgtimes day. Half-life limits for alpha -decay modes of ^{168}mathrm Yb, ^{170}mathrm Yb, ^{171}mathrm Yb, ^{172}mathrm Yb, ^{173}mathrm Yb, ^{174}mathrm Yb and ^{176}mathrm Yb into the first excited states have been obtained between 6times 10^{14} years and 2times 10^{16} years. These are the first experimental constraints of these decay modes. Double electron capture of ^{168}mathrm Yb and double beta decay of ^{176}mathrm Yb into the first excited 2^+ and 0^+ states could be excluded with limits between 1times 10^{14} years to 8times 10^{16} years. This improves the experimental information on some of the decay modes compared to previous constraints.

Dark Matter Search with the Nuclear Isomer 180mTa

There is compelling cosmological and astrophysical evidence of dark matter comprising 27% of the energy budget of the Universe. However, dark matter has never been observed in direct detection experiments. The long-time favorite model of Weakly Interacting Massive Particles saw a large experimental effort with steady progress over recent decades. Since also these large-scale searches remain unsuccessful to date, it is compelling to look at more exotic dark matter models which can be constrained with new approaches and much less scientific resources. Using nuclear isomers is one of these approaches. 180m Ta is the rarest known isotope with the longest-lived meta-stable state whose partial half-life limits are on the order of 1014016 yr. We investigate how strongly interacting dark matter and inelastic dark dark matter collides with 180m Ta, leading to its de-excitation. The energy stored in the meta-stable state is released in the transition, which becomes the signature for thermalized dark matter in a well-shielded underground experiment.We report on a direct detection experiment searching for these dark-matter-induced decay signatures which has further constrained the open parameter space. We also propose an indirect geochemical experiment to search for decay products of 180mTa in tantalum minerals accumulated over 1 billion years.

Dual mechanistic TRAIL nanocarrier based on PEGylated heparin taurocholate and protamine which exerts both pro-apoptotic and anti-angiogenic effects

The selective cytotoxicity of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) to cancer cells but not to normal cells makes it an attractive candidate for cancer therapeutics. However, the disadvantages of TRAIL such as physicochemical instability and short half-life limit its further clinical applications. In this study, TRAIL was encapsulated into a novel anti-angiogenic nanocomplex for both improved drug distribution at the tumor site and enhanced anti-tumor efficacy. A nanocomplex was prepared firstly by entrapping TRAIL into PEG-low molecular weight heparin-taurocholate conjugate (LHT7), which is previously known as a potent angiogenesis inhibitor. Then, protamine was added to make a stable form of nanocomplex (PEG-LHT7/TRAIL/Protamine) by exerting electrostatic interactions. We found that entrapping TRAIL into the nanocomplex significantly improved both pharmacokinetic properties and tumor accumulation rate without affecting the tumor selective cytotoxicity of TRAIL. Furthermore, the anti-tumor efficacy of nanocomplex was highly augmented (73.77±4.86%) compared to treating with only TRAIL (18.49 ± 19.75%), PEG-LHT7/Protamine (47.84 ± 14.20%) and co-injection of TRAIL and PEG-LHT7/Protamine (56.26 ± 9.98%). Histological analysis revealed that treatment with the nanocomplex showed both anti-angiogenic efficacy and homogenously induced cancer cell apoptosis, which suggests that accumulated TRAIL and LHT7 in tumor tissue exerted their anti-tumor effects synergistically. Based on this study, we suggest that PEG-LHT7/Protamine complex is an effective nanocarrier of TRAIL for enhancing drug distribution as well as improving anti-tumor efficacy by exploiting the synergistic mechanism of anti-angiogenesis.

Brief Review of the Results Regarding the Possible Underlying Mechanisms Driving the Neutrinoless Double Beta Decay

Since the experimental discovery of neutrino oscillations, the search for the neutrinoless double beta (0νββ) decay has intensified greatly, as this particular decay mode, if experimentally discovered, could offer a testing ground for Beyond Standard Model (BSM) theories related to the yet hidden fundamental properties of neutrinos and the possibility of violating of some fundamental symmetries. In this work we make a brief review of the nuclear matrix elements and phase space factors calculations performed mainly by our group. Next, using these calculations and the most recent experimental half-life limits, we revise the constraints on the BSM parameters violating the lepton number corresponding to four mechanisms that could contribute to 0νββ decay. Finally, using the values obtained for the BSM parameters from one of the most sensitive double-beta decay experiments, we provide a comparison with the sensitivities of other experiments.

Development of Stable Chimeric IL-15 for Trans-Presentation by the Antigen Presenting Cells.

IL-15 is one of the important biologics considered for vaccine adjuvant and treatment of cancer. However, a short half-life and poor bioavailability limit its therapeutic potential. Herein, we have structured IL-15 into a chimeric protein to improve its half-life enabling greater bioavailability for longer periods. We have covalently linked IL-15 with IgG2 base to make the IL-15 a stable chimeric protein, which also increased its serum half-life by 40 fold. The dimeric structure of this kind of IgG based biologics has greater stability, resistance to proteolytic cleavage, and less frequent dosing schedule with minimum dosage for achieving the desired response compared to that of their monomeric forms. The structured chimeric IL-15 naturally forms a dimer, and retains its affinity for binding to its receptor, IL-15Rβ. Moreover, with the focused action of the structured chimeric IL-15, antigen-presenting cells (APC) would transpresent chimeric IL-15 along with antigen to the T cell, that will help the generation of quantitatively and qualitatively better antigen-specific memory T cells. In vitro and in vivo studies demonstrate the biological activity of chimeric IL-15 with respect to its ability to induce IL-15 signaling and modulating CD8+ T cell response in favor of memory generation. Thus, a longer half-life, dimeric nature, and anticipated focused transpresentation by APCs to the T cells will make chimeric IL-15 a super-agonist for memory CD8+ T cell responses.