Double minutes (dmin), homogeneously staining regions, and ring chromosomes are vehicles of gene amplification in cancer. The underlying mechanism leading to their formation as well as their ...structure and function in acute myeloid leukemia (AML) remain mysterious. We combined a range of high-resolution genomic methods to investigate the architecture and expression pattern of amplicons involving chromosome band 8q24 in 23 cases of AML (AML-amp). This revealed that different MYC-dmin architectures can coexist within the same leukemic cell population, indicating a step-wise evolution rather than a single event origin, such as through chromothripsis. This was supported also by the analysis of the chromothripsis criteria, that poorly matched the model in our samples. Furthermore, we found that dmin could evolve toward ring chromosomes stabilized by neocentromeres. Surprisingly, amplified genes (mainly PVT1) frequently participated in fusion transcripts lacking a corresponding DNA template. We also detected a significant overexpression of the circular RNA of PVT1 (circPVT1) in AML-amp cases versus AML with a normal karyotype. Our results show that 8q24 amplicons in AML are surprisingly plastic DNA structures with an unexpected association to novel fusion transcripts and circular RNAs.
RES-NOVA is a newly proposed experiment for detecting neutrinos from astrophysical sources, mainly Supernovae, using an array of cryogenic detectors made of PbWO
4
crystals produced from ...archaeological Pb. This unconventional material, characterized by intrinsic high radiopurity, enables low-background levels in the region of interest for the neutrino detection via Coherent Elastic neutrino-Nucleus Scattering (CE
ν
NS). This signal lies at the detector energy threshold,
O
(1 keV), and it is expected to be hidden by naturally occurring radioactive contaminants of the crystal absorber. Here, we present the results of a radiopurity assay on a 0.84 kg PbWO
4
crystal produced from archaeological Pb operated as a cryogenic detector. The crystal internal radioactive contaminations are:
232
Th <40
μ
Bq/kg,
238
U <30
μ
Bq/kg,
226
Ra 1.3 mBq/kg and
210
Pb 22.5 mBq/kg. We also present a background projection for the final experiment and possible mitigation strategies for further background suppression. The achieved results demonstrate the feasibility of realizing this new class of detectors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Core-collapse Supernovae (SNe) are one of the most energetic events in the Universe, during which almost all the star’s binding energy is released in the form of neutrinos. These particles are direct ...probes of the processes occurring in the stellar core and provide unique insights into the gravitational collapse. RES-NOVA will revolutionize how we detect neutrinos from astrophysical sources, by deploying the first ton-scale array of cryogenic detectors made from archaeological lead. Pb offers the highest neutrino interaction cross-section via coherent elastic neutrino-nucleus scattering (CEνNS). Such process will enable RES-NOVA to be equally sensitive to all neutrino flavours. For the first time, we propose the use archaeological Pb as sensitive target material in order to achieve an ultra-low background level in the region of interest (O(1 keV)). All these features make possible the deployment of the first cm-scale neutrino telescope for the investigation of astrophysical sources. In this contribution, we will characterize the radiopurity level and the performance of a small-scale proof-of-principle detector of RES-NOVA, consisting in a PbWO4 crystal made from archaeological-Pb operated as cryogenic detector.
•RES-NOVA: first-proposed cryogenic detector made from archaeological lead for background suppression.•Coherent elastic neutrino-nucleus scattering: innovative way to detect neutrinos from astrophysical sources.•Radiopurity level measured on kg-scale prototype allows supernovae neutrino detection.
Abstract
The CRESST experiment searches for dark matter induced nuclear recoils inside CaWO
4
based cryogenic calorimeters at the Laboratori Nazionali del Gran Sasso (LNGS) in Italy. To identify ...reliably a potential signal, a precise understanding of its background budget is crucial. An important background category could be “cosmogenics”: radionuclides produced via interactions with cosmic rays, mainly during the crystal production at surface facilities. Albeit CaWO
4
is a well-established calorimetric material, no systematic study of its susceptibility for cosmic activation existed so far. In this contribution, we will first report the exposure profile of CRESST’s in-house grown TUM93 crystal to cosmic rays. Then we will identify the most prominent cosmogenics via AcTIVIA calculations. Afterwards we discuss the expected background spectrum based on Geant4 simulations and compare it to measurements.
The relation between co- and post-translational protein folding and aggregation in the cell is poorly understood. Here, we employ a combination of fluorescence anisotropy decays in the frequency ...domain, fluorescence-detected solubility assays, and NMR spectroscopy to explore the role of the ribosome in protein folding within a biologically relevant context. First, we find that a primary function of the ribosome is to promote cotranslational nascent-protein solubility, thus supporting cotranslational folding even in the absence of molecular chaperones. Under these conditions, however, only a fraction of the soluble expressed protein is folded and freely tumbling in solution. Hence, the ribosome alone is insufficient to guarantee quantitative formation of the native state of the apomyoglobin (apoMb) model protein. Right after biosynthesis, nascent chains encoding apoMb emerge from the ribosomal exit tunnel and undergo a crucial irreversible post-translational kinetic partitioning between further folding and aggregation. Mutational analysis in combination with protein-expression kinetics and NMR show that nascent proteins can attain their native state only when the relative rates of soluble and insoluble product formation immediately upon release from the ribosome are tilted in favor of soluble species. Finally, the outcome of the above immediately post-translational kinetic partitioning is much more sensitive to amino acid sequence perturbations than the native fold, which is rather mutation-insensitive. Hence, kinetic channeling of nascent-protein conformation upon release from the ribosome may be a major determinant of evolutionary pressure.
Proteins are particularly prone to aggregation immediately after release from the ribosome, and it is therefore important to elucidate the role of chaperones during these key steps of protein life. ...The Hsp70 and trigger factor (TF) chaperone systems interact with nascent proteins during biogenesis and immediately post-translationally. It is unclear, however, whether these chaperones can prevent formation of soluble and insoluble aggregates. Here, we address this question by monitoring the solubility and structural accuracy of globin proteins biosynthesized in an Escherichia coli cell-free system containing different concentrations of the bacterial Hsp70 and TF chaperones. We find that Hsp70 concentrations required to grant solubility to newly synthesized proteins are extremely sensitive to client-protein sequence. Importantly, Hsp70 concentrations yielding soluble client proteins are insufficient to prevent formation of soluble aggregates. In fact, for some aggregation-prone protein variants, avoidance of soluble-aggregate formation demands Hsp70 concentrations that exceed cellular levels in E. coli. In all, our data highlight the prominent role of soluble aggregates upon nascent-protein release from the ribosome and show the limitations of the Hsp70 chaperone system in the case of highly aggregation-prone proteins. These results demonstrate the need to devise better strategies to prevent soluble-aggregate formation upon release from the ribosome.
Abstract
In the past few years, attention has been drawn to the fact that a precision analysis of two-neutrino double beta decay (2
υββ
) allows the study of interesting physics cases like the ...emission of Majoron bosons and possible Lorentz symmetry violation. These processes modify the summed-energy distribution of the two electrons emitted in 2
υββ
. CUPID is a next-generation experiment aiming to exploit
100
Mo-enriched scintillating Li
2
MoO
4
crystals, operating as cryogenic calorimeters. Given the relatively fast half-life of
100
Mo 2
υββ
and the large exposure that can be reached by CUPID, we expect to measure with very high precision the
100
Mo 2
υββ
spectrum shape, reaching great sensitivities in the search for distortions induced by the physics beyond the Standard Model. In this contribution, we present the CUPID exclusion sensitivity for such New Physics processes, as well as the preliminary projected background of CUPID.
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