The CUORE Detector and Results Nutini, Irene; Adams, D. Q.; Alfonso, K. ...
Journal of low temperature physics,
2020/4, Letnik:
199, Številka:
1-2
Journal Article
Recenzirano
Odprti dostop
The cryogenic underground observatory for rare events (CUORE) is a cryogenic experiment searching for neutrinoless double beta decay (
0
ν
β
β
) of
130
Te
. The detector consists of an array of
988
...TeO
2
crystals arranged in a compact cylindrical structure of 19 towers. We report the CUORE initial operations and optimization campaigns. We then present the CUORE results on
0
ν
β
β
and
2
ν
β
β
decay of
130
Te
obtained from the analysis of the physics data acquired in 2017.
Latest Results from the CUORE Experiment Nutini, I.; Adams, D. Q.; Alfonso, K. ...
Journal of low temperature physics,
12/2022, Letnik:
209, Številka:
5-6
Journal Article
Recenzirano
Odprti dostop
The Cryogenic Underground Observatory for Rare Events (CUORE) is the first cryogenic experiment searching for
0
ν
β
β
decay that has been able to reach the one-tonne mass scale. The detector, located ...at the Laboratori Nazionali del Gran Sasso (LNGS) in Italy, consists of an array of 988
TeO
2
crystals arranged in a compact cylindrical structure of 19 towers. CUORE began its first physics data run in 2017 at a base temperature of about 10 mK and in April 2021 released its
3
rd
result of the search for
0
ν
β
β
, corresponding to a tonne-year of
TeO
2
exposure. This is the largest amount of data ever acquired with a solid state detector and the most sensitive measurement of
0
ν
β
β
decay in
130
Te
ever conducted . We present the current status of CUORE search for
0
ν
β
β
with the updated statistics of one tonne-yr. We finally give an update of the CUORE background model and the measurement of the
130
Te
2
ν
β
β
decay half-life and decay to excited states of
130
Xe
, studies performed using an exposure of 300.7 kg yr.
We report new results from the search for neutrinoless double-beta decay in $^{130}$Te with the CUORE detector. This search benefits from a four-fold increase in exposure, lower trigger thresholds ...and analysis improvements relative to our previous results. We observe a background of $(1.38\pm0.07)\cdot10^{-2}$ counts$/($keV$\cdot$kg$\cdot$yr$)$ in the $0\nu\beta\beta$ decay region of interest and, with a total exposure of 372.5 kg$\cdot$yr, we attain a median exclusion sensitivity of $1.7\cdot10^{25}$ yr. We find no evidence for $0\nu\beta\beta$ decay and set a $90\%$ CI Bayesian lower limit of $3.2\cdot10^{25}$ yr on the $^{130}$Te half-life for this process. In the hypothesis that $0\nu\beta\beta$ decay is mediated by light Majorana neutrinos, this results in an upper limit on the effective Majorana mass of 75-350 meV, depending on the nuclear matrix elements used.
The 1q21 amplification, which occurs in approximately 40% of de novo and 70% of relapsed MM, is among the most frequent chromosomal aberrations in multiple myeloma (MM) patients and is considered a ...very high-risk genetic feature that is especially correlated with disease progression and drug resistance.
To uncover novel 1q21 MM-critical genes, we first identified a list of 78 potential 1q21 drivers, which were located in the minimal common region of amplification of 254 MM samples and showed copy number-driven expression. These 78 candidates were then subjected to an shRNA screen to identify those genes involved in selective death and/or growth inhibition of MM cells carrying the 1q21 amplification.
Using this approach, we identified and functionally validated the Interleukin-2 enhancer binding factor 2 (ILF2) as one of key 1q21 amplification-specific genes.
ILF2 downregulation in 1q21-amplified MM cells resulted in multinucleated phenotypes and abnormal nuclear morphologies, findings that are consistent with the DNA damage-induced genomic instability that is associated with DNA repair defects that occur during cellular replication. Correspondingly, ILF2 downregulation was associated with a significant increase in the activation of the ATM (but not ATR or DNA-PK) pathway and accumulation of gH2AX foci, which are indicative of double-strand DNA breaks, and resulted in caspase 3-mediated apoptosis. Therefore, we sought to determine whether ILF2 is involved in the genome damage repair that occurs during cellular replication. To this end, we evaluated whether ILF2 depletion could affect the efficiency of non-homologous end joining (NHEJ) or homologous recombination (HR), the two major repair pathways in mammalian cells. We observed a profound impairment of HR in ILF2-depleted cells (p=0.038), whereas NHEJ was unaltered after ILF2 downregulation. Conversely, enforced ILF2 expression significantly enhanced HR efficiency in MM cells (p=0.008). To further support the role of ILF2 in the regulation of the DNA repair pathway in MM cells, we evaluated whether ILF2 downregulation increased MM sensitivity to DNA-damaging agents routinely used in the treatment of MM. Employing the interstrand crosslinker melphalan as an instigator of double-strand DNA breaks, we found that ILF2-depleted MM cells subjected to continuous melphalan treatment showed increased accumulation of γH2AX and apoptosis. Consistent with these findings, elevated ILF2 expression significantly correlated with poor survival in MM patients treated with high-dose melphalan followed by tandem autologous transplantation (n=256, p=0.01).
Mechanistically, mass spectrometry analysis showed that ILF2 interacted with numerous RNA binding proteins directly involved in the regulation of DNA damage response by modulating alternative splicing of specific pre-mRNAs. RNA-sequencing experiments confirmed that ILF2 depletion resulted in aberrant splicing of genes involved in the DNA repair pathway, including ERCC1, FANCD2, and EXO1. RNA immunoprecipitation sequencing experiments showed that ILF2 directly bound to transcripts involved in the regulation of the HR pathway, including components of BRCA1 protein complex. Furthermore, in an attempt to dissect the ILF2 protein interacting network involved in the DNA repair regulation in response to DNA damage activation, we found that ILF2 mediated drug resistance in a dose-dependent manner by modulating YB-1 nuclear localization and interaction with the splicing factor U2AF65 to promote mRNA processing and stabilization of DNA repair genes, including FANCD2 and EXO1, in response to DNA damage.
In conclusion, our study reveals an intimate relationship among 1q21 amplification, mRNA splicing, and DNA repair in the control of DNA damage response in MM.
Given that 1q21 amplification is one of the most frequent copy number alterations in cancer, synthetic lethality approaches based on targeting gain-of-functions associated with ILF2 may have a broad spectrum of applications to potentiate the sensitivity of cancer cells to chemotherapeutic agents.
Giuliani:Janssen: Research Funding; Celgene: Research Funding.
The CUORE experiment is a ton-scale array of
TeO
2
cryogenic bolometers located at the underground Laboratori Nazionali del Gran Sasso of Istituto Nazionale di Fisica Nucleare (INFN), in Italy. The ...CUORE detector consists of 988 crystals operated as source and detector at a base temperature of
∼
10
mK. Such cryogenic temperature is reached and maintained by means of a custom built cryogen-free dilution cryostat, designed with the aim of minimizing the vibrational noise and the environmental radioactivity. The primary goal of CUORE is the search for neutrinoless double beta decay of
130
Te
, but thanks to its large target mass and ultra-low background it is suitable for the study of other rare processes as well, such as the neutrinoless double beta decay of
128
Te
. This tellurium isotope is an attractive candidate for the search of this process, due to its high natural isotopic abundance of 31.75%. The transition energy at (866.7 ± 0.7) keV lies in a highly populated region of the energy spectrum, dominated by the contribution of the two-neutrino double beta decay of
130
Te
. As the first ton-scale infrastructure operating cryogenic
TeO
2
bolometers in stable conditions, CUORE is able to achieve a factor
>
10
higher sensitivity to the neutrinoless double beta decay of this isotope with respect to past direct experiments.
Abstract We report on a search for double beta decay of $$^{130}\hbox {Te}$$ 130Te to the first $$0^{+}$$ 0+ excited state of $$^{130}\hbox {Xe}$$ 130Xe using a $$9.8\,\hbox {kg}\cdot \hbox {yr}$$ ...9.8kg·yr exposure of $$^{130}\hbox {Te}$$ 130Te collected with the CUORE-0 experiment. In this work we exploit different topologies of coincident events to search for both the neutrinoless and two-neutrino double beta decay modes. We find no evidence for either mode and place lower bounds on the half-lives: $$T^{0\nu }_{0^+_1}>7.9\cdot 10^{23}\hbox {yr}$$ T01+0ν>7.9·1023yr and $$T^{2\nu }_{0^+_1}>2.4\cdot 10^{23}\hbox {yr}$$ T01+2ν>2.4·1023yr ($$90\%\,\hbox {CL}$$ 90%CL ). Combining our results with those obtained by the CUORICINO experiment, we achieve the most stringent constraints available for these processes: $$T^{0\nu }_{0^+_1}>1.4\cdot 10^{24}\hbox {yr}$$ T01+0ν>1.4·1024yr and $$T^{2\nu }_{0^+_1}>2.5\cdot 10^{23}\hbox {yr}$$ T01+2ν>2.5·1023yr ($$90\%\,\hbox {CL}$$ 90%CL ).
Steatotic mice are particularly susceptible to hepatic ischemia/reperfusion injury compared with their lean littermates. We have previously demonstrated that livers of mice having a spontaneous ...mutation in the leptin gene (ob/ob), resulting in global obesity and liver steatosis, are ATP depleted, are endotoxin sensitive, and do not survive (I/R) injury. We hypothesize that administration of an anti‐LPS monoclonal antibody (mAb) prior to initiation of I/R would be protective from that insult. Steatotic mice (ob/ob) were subjected to 15 min of ischemia via complete porta‐hepatis occlusion and varying lengths of reperfusion with or without pre‐treatment with an anti‐LPS mAb. There was 14–31% survival of isotype matched control mAb treated ob/ob mice after 15 min of ischemia and 24 h of reperfusion. In contrast, 75–83% of ob/ob mice pre‐treated with an anti‐LPS mAb prior to initiation of I/R survived both ischemia and 24 h of reperfusion. Furthermore, there was a decrease in ALT and circulating endotoxin levels when treated with an anti‐LPS mAb compared with control antibodies. Attenuation of the endotoxin load with anti‐LPS mAb, prior to initiation of I/R, was cytoprotective and improved survival. Consequently, these studies might offer a solution to the problems associated with using steatotic livers in clinical transplantation.
PDF
