Secondary mechanisms of anti-HER2 resistance in breast cancer: NF1 as an actionable target

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Improving SPLIT-STED super-resolution imaging with tunable depletion and excitation power

Abstract The SPLIT approach is a simple and efficient way to improve the spatial resolution of a super-resolved STED multi-dimensional image, i.e. a STED image in which an additional dimension encodes spatial information. Recently, we have demonstrated that the SPLIT can be applied to multidimensional STED images obtained with tunable depletion power. In this SPLIT-STED implementation, the additional dimension is represented by the depletion power, a parameter that can be easily tuned on any STED microscope. In this work, we introduce a modified implementation in which we tune also the excitation power. The tuning of the excitation power is used to modulate the number of photons collected for each STED image. We show that the modified SPLIT-STED method produces an improvement of spatial resolution for very different tuning patterns of the excitation intensity, improving the versatility of the SPLIT-STED approach. Interestingly, we find that the extent of photobleaching can be modulated by the excitation pattern, as it depends on the simultaneous impact of high STED and excitation powers. Thus, the tuning of the excitation power can improve applicability of the method to live cell imaging, potentially minimizing the photobleaching of the fluorophores and the phototoxicity on the biological samples during a SPLIT-STED acquisition. We apply the modified SPLIT-STED method to super-resolution imaging of nuclear periphery, in both fixed and live cells

The Coiled-coil Domain Is the Structural Determinant for Mammalian Homologues of Drosophila Sina-mediated Degradation of Promyelocytic Leukemia Protein and Other Tripartite Motif Proteins by the Proteasome

Mammalian homologues of Drosophila Seven in Absentia (SIAHs) target for proteasome-mediated degradation several factors involved in cell growth and tumorigenesis. Here we show that SIAH-1/2 binds and targets for proteasome-mediated degradation the putative tumor suppressor and tripartite motif (TRIM) family member PML, leading to the loss of its transcriptional co-activating properties and a reduction in the number of endogenous PML nuclear bodies. Association with PML requires the substrate-binding domain (SBD) of SIAH-1/2 through an interacting surface apparently distinct from those predicted by the structural studies, or shown experimentally to mediate binding to SIAH-associated factors. Within PML, the coiled-coil domain is required for Siah- and proteasome-mediated degradation, and deletions of regions critical for the integrity of this region impair the ability of Siah to trigger PML-RAR degradation. Fusion of the coiled-coil domain to heterologous proteins resulted in the capacity of mSiah-2 to target their degradation. All of the TRIM proteins tested were degraded upon mSiah-2 overexpression. Finally, we show that the fusion protein PML-RAR (that retains the coiled-coil domain), which causes acute promyelocytic leukemias, is also a potential substrate of mSiah-2. As a result of mSiah-2 overexpression and subsequent degradation of the fusion protein, the arrest in hematopoietic differentiation because of expression of PML-RAR is partially rescued. These results identify PML and other TRIMs as new factors post-translationally regulated by SIAH and involve the coiled-coil region of PML and of other SIAH substrates as a novel structural determinant for targeted degradation

Obesity is a risk factor for acute promyelocytic leukemia: evidence from population and cross-sectional studies and correlation with FLT3 mutations and polyunsaturated fatty acid metabolism.

Obesity correlates with hematologic malignancies including leukemias, but risk of specific leukemia subtypes like acute promyelocytic leukemia and underlying molecular mechanisms are poorly understood. We explored multiple datasets for correlation between leukemia, body mass index (BMI) and molecular features. In a population-based study (n=5.2 million), we correlated BMI with promyelocytic leukemia, and other acute myeloid, lymphoid or other leukemias. In cross-sectional studies, we tested BMI deviation in promyelocytic leukemia trial cohorts from that expected based on national surveys. We explored The Cancer Genome Atlas for transcriptional signatures and mutations enriched in promyelocytic leukemia and/or obesity, and confirmed a correlation between body mass and FLT3 mutations in promyelocytic leukemia cohorts by logistic regression. In the population-based study, hazard ratio per 5 kg/m2 increase was: promyelocytic leukemia 1.44 (95%CI: 1.0-2.08), non-promyelocytic acute myeloid leukemias 1.17 (95%CI: 1.10-1.26), lymphoid leukemias 1.04 (95%CI: 1.0-1.09), other 1.10 (95%CI: 1.04-1.15). In cross-sectional studies, body mass deviated significantly from that expected (Italy: P<0.001; Spain: P=0.011; USA: P<0.001). Promyelocytic leukemia showed upregulation of polyunsaturated fatty acid metabolism genes. Odds of FLT3 mutations were higher in obese acute myeloid leukemias (odds ratio=2.4, P=0.007), whether promyelocytic or not, a correlation confirmed in the pooled promyelocytic leukemia cohorts (OR=1.22, 1.05-1.43 per 5 kg/m2). These results strengthen the evidence for obesity as a bona fide risk factor for myeloid leukemias, and in particular APL. FLT3 mutations and polyunsaturated fatty acid metabolism may play a previously under-appreciated role in obesity-associated leukemogenesis

Real-time Monitoring for the Next Core-Collapse Supernova in JUNO

Core-collapse supernova (CCSN) is one of the most energetic astrophysical events in the Universe. The early and prompt detection of neutrinos before (pre-SN) and during the SN burst is a unique opportunity to realize the multi-messenger observation of the CCSN events. In this work, we describe the monitoring concept and present the sensitivity of the system to the pre-SN and SN neutrinos at the Jiangmen Underground Neutrino Observatory (JUNO), which is a 20 kton liquid scintillator detector under construction in South China. The real-time monitoring system is designed with both the prompt monitors on the electronic board and online monitors at the data acquisition stage, in order to ensure both the alert speed and alert coverage of progenitor stars. By assuming a false alert rate of 1 per year, this monitoring system can be sensitive to the pre-SN neutrinos up to the distance of about 1.6 (0.9) kpc and SN neutrinos up to about 370 (360) kpc for a progenitor mass of 30$M_{\odot}$ for the case of normal (inverted) mass ordering. The pointing ability of the CCSN is evaluated by using the accumulated event anisotropy of the inverse beta decay interactions from pre-SN or SN neutrinos, which, along with the early alert, can play important roles for the followup multi-messenger observations of the next Galactic or nearby extragalactic CCSN.Comment: 24 pages, 9 figure

Solar neutrino physics with JUNO: analysis strategy and sensitivity studies for Be7, pep, and CNO neutrinos

The JUNO experiment, currently under construction in Jiangmen (China), is a 20 kt multi-purpose liquid scintillator detector. Although it was originally designed for neutrino mass ordering determination, thanks to its large target mass and excellent energy resolution (3% at 1 MeV), JUNO has the potential to provide solar neutrino measurement with an accuracy highly competitive with respect to the current state-of-the-art in the solar neutrino field. The purpose of this poster is to describe the main driving factors for JUNO sensitivity focusing on the so-called intermediate energy solar neutrinos: Be7, pep, and CNO neutrinos. Since the success of the analysis relies on a good understanding of the detector, the complete simulation of the expected signal and background components will be discussed. The analysis was carried out accounting for all the possible sources of backgrounds with different foreseeable level of contaminants, and including thoroughly the electronic response of the detector. The software framework developed to perform the sensitivity studies and the final results will be presented, proving that JUNO will substantially improve the existing measurements on intermediate energy neutrinos

Data analysis strategy used for the detection of CNO solar neutrinos with Borexino

Borexino is a large liquid scintillator experiment located at the underground INFN Laboratori Nazionali del Gran Sasso, in Italy. It was designed and built with the primary goal of real-time detection of low energy solar neutrinos, and in more than ten years of data taking it has measured all the neutrino fluxes produced in the proton-proton chain, i.e. the main fusion process accounting for 99% of the energy production in the Sun. Recently, after improvements and developments in both hardware and software, Borexino has provided the first observation of solar neutrinos emitted from the subdominant Carbon-Nitrogen-Oxygen (CNO) fusion cycle. All the crucial steps of the analysis strategy adopted to disentangle the signal of CNO neutrinos from backgrounds present in the detector will be described in this article