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Defects in cellular proteostasis and mitochondrial function drive many aspects of infertility, cancer, and other age-related diseases. All of these conditions rely on quiescent cells, such as oocytes and adult stem cells, that reduce their activity and remain dormant as part of their roles in tissue homeostasis, reproduction, and even cancer recurrence. Using a multi-organism approach, we show that dynamic shifts in the ubiquitin proteasome system drive mitochondrial remodeling during cellular quiescence. In contrast to the commonly held view that the ubiquitin-proteasome system (UPS) is primarily regulated by substrate ubiquitination, we find that increasing proteasome number and their recruitment to mitochondria support mitochondrial respiratory quiescence (MRQ). GSK3 triggers proteasome recruitment to the mitochondria by phosphorylating outer membrane proteins, such as VDAC, and suppressing mitochondrial fatty acid oxidation. This work defines a process that couples dynamic regulation of UPS activity to coordinated shifts in mitochondrial metabolism in fungi, Drosophila , and mammals during quiescence. Dynamic regulation of cellular proteostasis is linked to the metabolic state of quiescent cells in vivo. Here, the authors show, in multiple organisms, that shifts in the ubiquitin-proteome system are coupled to mitochondrial metabolic changes and subsequent respiratory quiescence.

In this work, we report on the sensitivity potential of complementary muon-on-target experiments to new physics using a scalar boson benchmark model associated with charged lepton flavor violation. The NA64 μ experiment at CERN uses a 160-GeV energy muon beam with an active target to search for excess events with missing energy and momentum as a probe of new physics. At the same time, the proton beam at Fermilab, which is used to produce the neutrino beam for the Deep Underground Neutrino Experiment (DUNE), will also produce a high-intensity muon beam dumped in an absorber. Combined with the liquid argon near detector, the system could be used to search for similar scalar boson particles with a lower-energy but higher-intensity beam. We find that both NA64 μ and DUNE could cover new, unexplored parts of the parameter space of the same benchmark model, providing a complementary way to search for new physics.

In this study, we demonstrate the potential of the NA64 experiment at CERN SPS to search for New Physics processes involving e → μ transitions after the collision of 100 GeV electrons with target nuclei. A new Dark Sector leptonic portal in which a scalar boson φ could be produced in the lepton-flavor-changing bremsstrahlung-like reaction, e N → μ N φ , is used as benchmark process. In this work, we develop a realistic Monte Carlo simulation of the NA64 experimental setup implementing the differential and total production cross-section computed at exact tree-level and applying the Weiszäcker–Williams phase space approximation. Using this framework, we investigate the main background sources and calculate the expected sensitivity of the experiment. The results indicate that with minor setup optimization, NA64 can probe a large fraction of the available parameter space compatible with the muon g - 2 anomaly and the Dark Matter relic predictions in the context of a new Dark Sector leptonic portal with 10 11 EOT. This result paves the way to the exploration of lepton-flavour-changing transitions in NA64.

In this work, we report on the sensitivity potential of complementary muon-on-target experiments to new physics using a scalar boson benchmark model associated with charged lepton flavor violation. The NA64 [Formula omitted] experiment at CERN uses a 160-GeV energy muon beam with an active target to search for excess events with missing energy and momentum as a probe of new physics. At the same time, the proton beam at Fermilab, which is used to produce the neutrino beam for the Deep Underground Neutrino Experiment (DUNE), will also produce a high-intensity muon beam dumped in an absorber. Combined with the liquid argon near detector, the system could be used to search for similar scalar boson particles with a lower-energy but higher-intensity beam. We find that both NA64 [Formula omitted] and DUNE could cover new, unexplored parts of the parameter space of the same benchmark model, providing a complementary way to search for new physics.

We report the results of a search for a new vector boson (A′) decaying into two dark matter particles χ1χ2 of different mass. The heavier χ2 particle subsequently decays to χ1 and an off-shell Dark Photon A′∗→e+e-. For a sufficiently large mass splitting, this model can explain in terms of new physics the recently confirmed discrepancy observed in the muon anomalous magnetic moment at Fermilab. Remarkably, it also predicts the observed yield of thermal dark matter relic abundance. A detailed Monte-Carlo simulation was used to determine the signal yield and detection efficiency for this channel in the NA64 setup. The results were obtained re-analyzing the previous NA64 searches for an invisible decay A′→χχ¯ and axion-like or pseudo-scalar particles a→γγ. With this method, we exclude a significant portion of the parameter space justifying the muon g-2 anomaly and being compatible with the observed dark matter relic density for A′ masses from 2me up to 390 MeV and mixing parameter ε between 3×10-5 and 2×10-2.

Rapidly proliferating cells such as cancer cells and embryonic stem cells rely on a specialized metabolic program known as aerobic glycolysis, which supports biomass production from carbohydrates. The fruit fly Drosophila melanogaster also utilizes aerobic glycolysis to support the rapid growth that occurs during larval development. Here we use singular value decomposition analysis of modENCODE RNA-seq data combined with GC-MS-based metabolomic analysis to analyze the changes in gene expression and metabolism that occur during Drosophila embryogenesis, spanning the onset of aerobic glycolysis. Unexpectedly, we find that the most common pattern of co-expressed genes in embryos includes the global switch to glycolytic gene expression that occurs midway through embryogenesis. In contrast to the canonical aerobic glycolytic pathway, however, which is accompanied by reduced mitochondrial oxidative metabolism, the expression of genes involved in the tricarboxylic cycle (TCA cycle) and the electron transport chain are also upregulated at this time. Mitochondrial activity, however, appears to be attenuated, as embryos exhibit a block in the TCA cycle that results in elevated levels of citrate, isocitrate, and α-ketoglutarate. We also find that genes involved in lipid breakdown and β-oxidation are upregulated prior to the transcriptional initiation of glycolysis, but are downregulated before the onset of larval development, revealing coordinated use of lipids and carbohydrates during development. These observations demonstrate the efficient use of nutrient stores to support embryonic development, define sequential metabolic transitions during this stage, and demonstrate striking similarities between the metabolic state of late-stage fly embryos and tumor cells.

As cells transition between periods of growth and quiescence, their metabolic demands change. During this transition, cells must coordinate changes in mitochondrial function with the induction of biosynthetic processes. Mitochondrial metabolism and nucleotide biosynthesis are key rate-limiting factors in regulating early growth. However, it remains unclear what coordinates these mechanisms in developmental systems. Here, we show that during quiescence, as mitochondrial activity drops, nucleotide breakdown increases. However, at fertilization, mitochondrial oxidative metabolism and nucleotide biosynthesis are coordinately activated to support early embryogenesis. We have found that the serine/threonine kinase GSK3 is a key factor in coordinating mitochondrial metabolism with nucleotide biosynthesis during transitions between quiescence and growth. Silencing GSK3 in quiescent oocytes causes increased levels of mitochondrial activity and a shift in the levels of several redox metabolites. Interestingly, silencing GSK3 in quiescent oocytes also leads to a precocious induction of nucleotide biosynthesis in quiescent oocytes. Taken together, these data indicate that GSK3 functions to suppress mitochondrial oxidative metabolism and prevent the premature onset of nucleotide biosynthesis in quiescent eggs. These data reveal a key mechanism that coordinates mitochondrial function and nucleotide synthesis with fertilization.

A bstract Thermal light dark matter (LDM) with particle masses in the 1 MeV–1 GeV range could successfully explain the observed dark matter abundance as a relic from the primordial Universe. In this picture, a new feeble interaction acts as a “portal” between the Standard Model and LDM particles, allowing for the exploration of this paradigm at accelerator experiments. In the last years, the “missing energy” experiment NA64 e at CERN SPS (Super Proton Synchrotron) has set world-leading constraints in the vector-mediated LDM parameter space, by exploiting a 100 GeV electron beam impinging on an electromagnetic calorimeter, acting as an active target. In this paper, we report a detailed description of the analysis of a preliminary measurement with a 70 GeV/c positron beam at NA64 e , performed during summer 2023 with an accumulated statistics of 1 . 596 × 10 10 positrons on target (hereafter referred to as e + OT). This data set was analyzed with the primary aim of evaluating the performance of the NA64 e detector with a lower energy positron beam, towards the realization of the post-LS3 program. The analysis results, other than additionally probing unexplored regions in the LDM parameter space, provide valuable information towards the future NA64 e positron campaign.

Recently, the ATOMKI experiment has reported new evidence for the excess of e + e - events with a mass ∼ 17 MeV in the nuclear transitions of 4 He, that they previously observed in measurements with 8 Be. These observations could be explained by the existence of a new vector X 17 boson. So far, the search for the decay X 17 → e + e - with the NA64 experiment at the CERN SPS gave negative results. Here, we present a new technique that could be implemented in NA64 aiming to improve the sensitivity and to cover the remaining X 17 parameter space. If a signal-like event is detected, an unambiguous observation is achieved by reconstructing the invariant mass of the X 17 decay with the proposed method. To reach this goal an optimization of the X 17 production target, as well as an efficient and accurate reconstruction of two close decay tracks, is required. A dedicated analysis of the available experimental data making use of the trackers information is presented. This method provides independent confirmation of the NA64 published results [ 1 ], validating the tracking procedure. The detailed Monte Carlo study of the proposed setup and the background estimate show that the goal of the proposed search is feasible.

The search of New Physics through Dark Sectors is an exciting possibility to explain, among others, the origin of Dark Matter. Within this context, the sensitivity study of a given experiment and its design optimization are key points in estimating its potential for discovery. In this proceeding we present the fully GEANT4 -compatible Monte Carlo simulation package for production and propagation of Dark Matter particles, DMG4 . In particular, we discuss the implementation of production cross-sections in its GEANT4 -independent sub-package, DarkMatter, and the latest DMG4 release, including a finer application programming interface to GEANT4 . We also cover its recent developments with faster and more accurate cross-section computations, sampling methods, extended energy range, as well as the expansion of the package to B − L and semi-visible models. We finally discuss the improvements in the simulations of New Physics processes specific to muon beams.