A biased MC for muon production for beam-dump experiments

The search for feebly-interacting new-physics particles in the MeV-GeV mass range often involves high-intensity beams dumped into thick heavy targets. The challenge of evaluating the expected backgrounds for these searches from first principles is limited by the CPU time needed to generate the shower induced by the primary beam. We present a Monte Carlo biasing method allowing a three orders of magnitude increase in the efficiency for the simulation of the muon production in a 400 GeV$/c$ proton beam-dump setup. At the same time, this biasing method is maintaining nearly every feature of a simulation from first principles

Identification of two novel LDLR variants by Next Generation Sequencing

Introduction. Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C). Targeted Next Generation Sequencing (NGS) is a new opportunity to expand the existing pathogenic variants (PVs) spectrum associated to FH. Our aim was to report a diagnostic NGS-based approach to detect variants associated to FH.Methods. We report two patients: a 48-year-old Asian woman, without known history of hypercholesterolemia and a 46-year-old Caucasian man, with childhood hypercholesterolemia.Results. An effective NGS-based pipeline, FH-Devyser kit/Amplicon Suite, beginning from sequencing to data analysis, did not identify known PVs in the LDLR, APOB, APOE, LDLRAP1, STAP1 and PCSK9 genes, but revealed two novel LDLR variants (c.1564A>T, p.Ile522Phe and c.1688C>T, p.Pro563Leu).Discussion and conclusions. This study showed that an effective NGS-based pipeline led to a definitive diagnosis in two FH families, allowing to plan their therapeutic treatment. Although the functional consequence of the two LDLR variants needs to be assessed in vitro, the in silico analysis and high preservation of the two amino acid positions observed in the LDLR protein, across different animal species, suggest that both variants are deleterious

Assessing the pathogenicity of BRCA1/2 variants of unknown significance: Relevance and challenges for breast cancer precision medicine

IntroductionBreast cancer (BC) is the leading cause of cancer-related death in women worldwide. Pathogenic variants in BRCA1 and BRCA2 genes account for approximately 50% of all hereditary BC, with 60-80% of patients characterized by Triple Negative Breast Cancer (TNBC) at an early stage phenotype. The identification of a pathogenic BRCA1/2 variant has important and expanding roles in risk-reducing surgeries, treatment planning, and familial surveillance. Otherwise, finding unclassified Variants of Unknown Significance (VUS) limits the clinical utility of the molecular test, leading to an “imprecise medicine”.MethodsWe reported the explanatory example of the BRCA1 c.5057A>C, p.(His1686Pro) VUS identified in a patient with TNBC. We integrated data from family history and clinic-pathological evaluations, genetic analyses, and bioinformatics in silico investigations to evaluate the VUS classification.ResultsOur evaluation posed evidences for the pathogenicity significance of the investigated VUS: 1) association of the BRCA1 variant to cancer-affected members of the family; 2) absence of another high-risk mutation; 3) multiple indirect evidences derived from gene and protein structural analysis.DiscussionIn line with the ongoing efforts to uncertain variants classification, we speculated about the relevance of an in-depth assessment of pathogenicity of BRCA1/2 VUS for a personalized management of patients with BC. We underlined that the efficient integration of clinical data with the widest number of supporting molecular evidences should be adopted for the proper management of patients, with the final aim of effectively guide the best prognostic and therapeutic paths

AML1/ETO Oncoprotein Is Directed to AML1 Binding Regions and Co-Localizes with AML1 and HEB on Its Targets

A reciprocal translocation involving chromosomes 8 and 21 generates the AML1/ETO oncogenic transcription factor that initiates acute myeloid leukemia by recruiting co-repressor complexes to DNA. AML1/ETO interferes with the function of its wild-type counterpart, AML1, by directly targeting AML1 binding sites. However, transcriptional regulation determined by AML1/ETO probably relies on a more complex network, since the fusion protein has been shown to interact with a number of other transcription factors, in particular E-proteins, and may therefore target other sites on DNA. Genome-wide chromatin immunoprecipitation and expression profiling were exploited to identify AML1/ETO-dependent transcriptional regulation. AML1/ETO was found to co-localize with AML1, demonstrating that the fusion protein follows the binding pattern of the wild-type protein but does not function primarily by displacing it. The DNA binding profile of the E-protein HEB was grossly rearranged upon expression of AML1/ETO, and the fusion protein was found to co-localize with both AML1 and HEB on many of its regulated targets. Furthermore, the level of HEB protein was increased in both primary cells and cell lines expressing AML1/ETO. Our results suggest a major role for the functional interaction of AML1/ETO with AML1 and HEB in transcriptional regulation determined by the fusion protein

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Searches for Lepton Flavour and Lepton Number violation in K+K^+ decays

The latest results on searches for Lepton Flavour and Lepton Number violation in K+→π∓μ±e+ and K+→π−l+l+ with l=(μ,e) decays at the NA62 experiment at CERN SPS are presented, improving on previous limits

Recent results from the NA62 experiment

The NA62 experiment at CERN SPS designed to measure the branching ratio of the ultra-rare $K^+ \rightarrow \pi^+ \nu \bar{\nu}$ decay using a decay-in-flight technique, collected data from 2016 to 2018. The analysis of the full 2018 data set is presented here, corresponding to a total number of kaon decays of about $2.62\times10^{12}$ , the largest data set so far collected. The combination with 2016-2017 data set is also reported. In addition the latest results from other searches are briefly presented

Search for an invisible vector boson from π 0 decays at NA62

The search for an invisible vector boson from $\pi^0$ decays at the NA62 experiment at CERN Super Proton Syncrotron (SPS) is discussed. Within the proposed models for physics beyond the SM, hidden sectors consisting of new, light, weakly-coupled particles are a particularly compelling possibility. Thanks to the high beam intensity, the extremely good performance of the photon detection systems, particle identification system and the detectors timing, NA62 is suited to search for these new particles. Here the search for a dark photon from $\pi^0$ decays using the $k^{+}\rightarrow \pi^+\pi ^0$, $\pi^0\rightarrow A^1\gamma$  decay chain is illustrated. The result from the analysis of a sub-sample of 2016 data is reported, corresponding to 1% of the full statistics collected in 2016-2018. A new upper limit on the $\pi^0\rightarrow A^1\gamma$  branching ratio has been set as a function of the dark photon mass, thus producing a new upper limit on the dark photon coupling parameter

Search for Lepton Number and Flavor violation in K decays at the NA62 experiment

The elementary particles and their interactions find their better description in the Standard Model. Nevertheless there are open theoretical and experimental issues which are not explained by the SM. For this reason nowadays particle physics experiments are focused on searches of New Physics (NP) effects. The work presented in this thesis has been carried out using the data collected at the NA62 experiment at CERN. Its main goal is to measure the Flavor Changing Neutral Current decay, K+ → π+ ν ν̄ , with an accuracy of same level of the theoretical prediction in order to both test the SM and search for NP. Thanks to the high-intensity setup, the trigger system flexibility, and detector performance NA62 is suitable for searching NP effects from different scenarios. The study presented aims at contributing to new physics searches looking for Lepton Number and Flavor violations in charged kaon decays, focusing on the K+ → π+μ+e- , K+ → π+μ-e+ and K+ → π-μ+e+ channels. The analysis has been performed blinding the signal region, defined as the region around the K mass in the three tracks invariant mass spectrum. The results have been obtained analyzing 17 x 1010 kaon decays from 2016 and 2017 data taking. In this work the selection criteria developed are presented. The performance of method for the multi-tracks vertex reconstruction and of the particle identification procedure are shown and a study of all possible background sources is also presented. The estimated Single Event Sensitivity and the preliminary results obtained with the Rolke-Lopetz method show improvements on the present experimental limits in the K+ → π+μ-e+ and K+ → π-μ+e+ channels, while for K+ → π+μ+e- more statistics is needed.(SC - Sciences) -- UCL, 201

First results for searches of exotic decays with NA62 in beam-dump mode

Searches for visible decays of exotic mediators can be performed by the NA62 experiment, when running in “beam-dump” mode. The analysis presented in this work, focuses on in-flight decays of dark photons to $\mu^{+}\mu^{-}$ pairs, using the data collected in 2021, corresponding to more than $10^{17}$ dumped protons