Structural Health Monitoring (SHM) based on Lamb wave propagation is a promising technology to optimize maintenance costs, enlarge service life and improve safety of aircrafts. A large quantity of data is collected during all the life cycle of the structure under monitoring and must be analysed in real time. We propose here to use 1D-CNN to estimate the severity and the localisation of a damage with the signals measured on a composite structure monitored with piezoelectric transducers (PZT). Two architectures have been tested: one takes for input the difference of the time signals of two different states and the second takes for inputs temporal damage indexes. Those simple networks with a few layers predict with high precision the position and the severity of a damage in a composite plate. The evaluations on different cases show the robustness to simulated manufacturing uncertainties and noise. An evaluation on experimental measurement shows promising results to localise a damage on a real plate with a CNN trained with numerical data.
The last decade has seen mRNA modification emerge as a new layer of gene expression regulation. The Fat mass and obesity-associated protein (FTO) was the first identified eraser of N6-methyladenosine (m6A) adducts, the most widespread modification in eukaryotic messenger RNA. This discovery, of a reversible and dynamic RNA modification, aided by recent technological advances in RNA mass spectrometry and sequencing has led to the birth of the field of epitranscriptomics. FTO crystallized much of the attention of epitranscriptomics researchers and resulted in the publication of numerous, yet contradictory, studies describing the regulatory role of FTO in gene expression and central biological processes. These incongruities may be explained by a wide spectrum of FTO substrates and RNA sequence preferences: FTO binds multiple RNA species (mRNA, snRNA and tRNA) and can demethylate internal m6A in mRNA and snRNA, N6,2'-O-dimethyladenosine (m6Am) adjacent to the mRNA cap, and N1-methyladenosine (m1A) in tRNA. Here, we review current knowledge related to FTO function in healthy and cancer cells. In particular, we emphasize the divergent role(s) attributed to FTO in different tissues and subcellular and molecular contexts.
Maturation of the HIV-1 viral particles shortly after budding is required for infectivity. During this process, the Pr55Gag precursor undergoes a cascade of proteolytic cleavages, and whilst the structural rearrangements of the viral proteins are well understood, the concomitant maturation of the genomic RNA (gRNA) structure is unexplored, despite evidence that it is required for infectivity. To get insight into this process, we systematically analysed the interactions between Pr55Gag or its maturation products (NCp15, NCp9 and NCp7) and the 5' gRNA region and their structural consequences, in vitro. We show that Pr55Gag and its maturation products mostly bind at different RNA sites and with different contributions of their two zinc knuckle domains. Importantly, these proteins have different transient and permanent effects on the RNA structure, the late NCp9 and NCp7 inducing dramatic structural rearrangements. Altogether, our results reveal the distinct contributions of the different Pr55Gag maturation products on the gRNA structural maturation.
Recently, the inhibitory CD94/NKG2A receptor has joined the group of immune checkpoints (ICs) and its expression has been documented in NK cells and CD8+ T lymphocytes in several cancers and some infectious diseases. In colorectal cancer (CRC), we previously reported that NKG2A+ tumor-infiltrating lymphocytes (TILs) are predominantly CD8+ αβ T cells and that CD94 overexpression and/or its ligand HLA-E were associated with a poor prognosis. This study aimed to thoroughly characterize the NKG2A+ CD8+ TIL subpopulation and document the impact of NKG2A on anti-tumor responses in CRC. Our findings highlight new features of this subpopulation: (i) enrichment in colorectal tumors compared to paired normal colonic mucosa, (ii) their character as tissue-resident T cells and their majority terminal exhaustion status, (iii) co-expression of other ICs delineating two subgroups differing mainly in the level of NKG2A expression and the presence of PD-1, (iv) high functional avidity despite reduced proliferative capacity and finally (v) inhibition of anti-tumor reactivity that is overcome by blocking NKG2A. From a clinical point of view, these results open a promising alternative for immunotherapies based on NKG2A blockade in CRC, which could be performed alone or in combination with other IC inhibitors, adoptive cell transfer or therapeutic vaccination.
Transcription and processing of 45S rRNAs in the nucleolus are keystones of ribosome biogenesis. While these processes are severely impacted by stress conditions in multiple species, primarily upon heat exposure, we lack information about the molecular mechanisms allowing sessile organisms without a temperature-control system, like plants, to cope with such circumstances. We show that heat stress disturbs nucleolar structure, inhibits pre-rRNA processing and provokes imbalanced ribosome profiles in Arabidopsis thaliana plants. Notably, the accuracy of transcription initiation and cleavage at the primary P site in the 5'ETS (5' External Transcribed Spacer) are not affected but the levels of primary 45S and 35S transcripts are, respectively, increased and reduced. In contrast, precursors of 18S, 5.8S and 25S RNAs are rapidly undetectable upon heat stress. Remarkably, nucleolar structure, pre-rRNAs from major ITS1 processing pathway and ribosome profiles are restored after returning to optimal conditions, shedding light on the extreme plasticity of nucleolar functions in plant cells. Further genetic and molecular analysis to identify molecular clues implicated in these nucleolar responses indicate that cleavage rate at P site and nucleolin protein expression can act as a checkpoint control towards a productive pre-rRNA processing pathway.
COVID-19 has caused unprecedented disruption to previously settled everyday routines, prompting a period of forced experimentation as people have adjusted to rapid changes in their private and working lives. For discussions regarding consumption, this period of experimentation has been interesting, as the apparent instability has disturbed the ongoing trajectory of consumption practices, and with it has created possibilities for transition toward sustainability. In this article, we examine food practices (e.g., food shopping, preparation, and eating) in seven countries (France, Germany, Italy, Netherlands, Norway, UK, and Vietnam) to assess what we can learn to accelerate transitions toward sustainable consumption. Grounded in a practice theoretical approach, our empirical analysis shows how disruption of everyday routines has generated socio-materially bounded experimentation. We demonstrate commonalities across contexts in how lockdown measures have restricted the performance of previously taken-for-granted practices. We also show diversity in experimentation as food consumption is entangled in other everyday practices. Our study, on one hand, portrays how adaptation of food practices allows disruption to be managed, demonstrating creativity in working within and around restrictions to continue to provide services for everyday life. On the other hand, we reveal that the capacity of experimentation is not evenly distributed among people and this variation helps in identifying the wider socio-material conditions that constrain and enable opportunities for readjustment. Understanding disparities that affect experimentation (e.g., integration of food practices with work and caring practices) is informative when thinking about how to stimulate sustainability transformations in food practices and provides critical reflections on strategies to enable sustainable consumption.
The Large Hadron Collider beauty (LHCb) experiment at CERN is undergoing an upgrade in preparation for the Run 3 data collection period at the Large Hadron Collider (LHC). As part of this upgrade, the trigger is moving to a full software implementation operating at the LHC bunch crossing rate. We present an evaluation of a CPU-based and a GPU-based implementation of the first stage of the high-level trigger. After a detailed comparison, both options are found to be viable. This document summarizes the performance and implementation details of these options, the outcome of which has led to the choice of the GPU-based implementation as the baseline.
Background Recent multicenter studies identified COVID-19 as a risk factor for invasive pulmonary aspergillosis (IPA). However, no large multicenter study has compared the incidence of IPA between COVID-19 and influenza patients. Objectives To determine the incidence of putative IPA in critically ill SARS-CoV-2 patients, compared with influenza patients. Methods This study was a planned ancillary analysis of the coVAPid multicenter retrospective European cohort. Consecutive adult patients requiring invasive mechanical ventilation for > 48 h for SARS-CoV-2 pneumonia or influenza pneumonia were included. The 28-day cumulative incidence of putative IPA, based on Blot definition, was the primary outcome. IPA incidence was estimated using the Kalbfleisch and Prentice method, considering extubation (dead or alive) within 28 days as competing event. Results A total of 1047 patients were included (566 in the SARS-CoV-2 group and 481 in the influenza group). The incidence of putative IPA was lower in SARS-CoV-2 pneumonia group (14, 2.5%) than in influenza pneumonia group (29, 6%), adjusted cause-specific hazard ratio (cHR) 3.29 (95% CI 1.53–7.02, p = 0.0006). When putative IPA and Aspergillus respiratory tract colonization were combined, the incidence was also significantly lower in the SARS-CoV-2 group, as compared to influenza group (4.1% vs. 10.2%), adjusted cHR 3.21 (95% CI 1.88–5.46, p < 0.0001). In the whole study population, putative IPA was associated with significant increase in 28-day mortality rate, and length of ICU stay, compared with colonized patients, or those with no IPA or Aspergillus colonization. Conclusions Overall, the incidence of putative IPA was low. Its incidence was significantly lower in patients with SARS-CoV-2 pneumonia than in those with influenza pneumonia. Clinical trial registration The study was registered at ClinicalTrials.gov, number NCT04359693 .
Background The recent rise in cultivation-independent genome sequencing has provided key material to explore uncharted branches of the Tree of Life. This has been particularly spectacular concerning the Archaea , projecting them at the center stage as prominently relevant to understand early stages in evolution and the emergence of fundamental metabolisms as well as the origin of eukaryotes. Yet, resolving deep divergences remains a challenging task due to well-known tree-reconstruction artefacts and biases in extracting robust ancient phylogenetic signal, notably when analyzing data sets including the three Domains of Life. Among the various strategies aimed at mitigating these problems, divide-and-conquer approaches remain poorly explored, and have been primarily based on reconciliation among single gene trees which however notoriously lack ancient phylogenetic signal. Results We analyzed sub-sets of full supermatrices covering the whole Tree of Life with specific taxonomic sampling to robustly resolve different parts of the archaeal phylogeny in light of their current diversity. Our results strongly support the existence and early emergence of two main clades, Cluster I and Cluster II, which we name Ouranosarchaea and Gaiarchaea , and we clarify the placement of important novel archaeal lineages within these two clades. However, the monophyly and branching of the fast evolving nanosized DPANN members remains unclear and worth of further study. Conclusions We inferred a well resolved rooted phylogeny of the Archaea that includes all recently described phyla of high taxonomic rank. This phylogeny represents a valuable reference to study the evolutionary events associated to the early steps of the diversification of the archaeal domain. Beyond the specifics of archaeal phylogeny, our results demonstrate the power of divide-and-conquer approaches to resolve deep phylogenetic relationships, which should be applied to progressively resolve the entire Tree of Life.
Recording electric field evolution in single-shot with THz bandwidth is needed in science including spectroscopy, plasmas, biology, chemistry, Free-Electron Lasers, accelerators, and material inspection. However, the potential application range depends on the possibility to achieve sub-picosecond resolution over a long time window, which is a largely open problem for single-shot techniques. To solve this problem, we present a new conceptual approach for the so-called spectral decoding technique, where a chirped laser pulse interacts with a THz signal in a Pockels crystal, and is analyzed using a grating optical spectrum analyzer. By borrowing mathematical concepts from photonic time stretch theory and radio-frequency communication, we deduce a novel dual-output electro-optic sampling system, for which the input THz signal can be numerically retrieved—with unprecedented resolution—using the so-called phase diversity technique. We show numerically and experimentally that this approach enables the recording of THz waveforms in single-shot over much longer durations and/or higher bandwidth than previous spectral decoding techniques. We present and test the proposed DEOS (Diversity Electro-Optic Sampling) design for recording 1.5 THz bandwidth THz pulses, over 20 ps duration, in single-shot. Then we demonstrate the potential of DEOS in accelerator physics by recording, in two successive shots, the shape of 200 fs RMS relativistic electron bunches at European X-FEL, over 10 ps recording windows. The designs presented here can be used directly for accelerator diagnostics, characterization of THz sources, and single-shot Time-Domain Spectroscopy.
Effective and rapid effusive crisis response is necessary to mitigate the risks associated with lava flows that could threaten or inundate inhabited or visited areas. At Piton de la Fournaise (La Réunion, France), well-established protocols between Observatoire Volcanologique du Piton de la Fournaise - Institut de Physique du Globe de Paris (OVPF-IPGP) and civil protection, and between scientists of a multinational array of institutes, allow effective tracking of eruptive crises and hazard management embracing all stakeholders. To assess the outstanding needs for such responses Tsang and Lindsay (J Appl Volcanol 9:9, 2020) applied a gap analysis to assess research gaps in terms of preparedness, response and recovery at 11 effusive centers, including Piton de la Fournaise. For Piton de la Fournaise, their gap analysis implied widespread gaps in the state of knowledge. However, their work relied on incomplete and erroneous data and methods, resulting in a gap analysis that significantly underrepresented this state of knowledge. We thus here re-build a correct database for Piton de la Fournaise, properly define the scope of an appropriate gap analysis, and provide a robust gap analysis, finding that there are, actually, very few gaps for Piton de la Fournaise. This is a result of the existence of a great quantity of published work in the peer-reviewed literature, as well as frequent reports documenting event impact in the local press and observatory reports. At Piton de la Fournaise, this latter (observatory-based) resource is largely due to the efforts of OVPF-IPGP who have a wealth of experience having responded to 81 eruptions since its creation in 1979 through the end of September 2021. Although welcome and necessary, especially if it is made by a group of scientists outside the local management of the volcanic risk (i.e., a neutral group), such gap analysis need to be sure to fully consider all available peer-reviewed literature, as well as newspaper reports, observatory releases and non-peer-reviewed eruption reports, so as to be complete and correct. Fundamentally, such an analysis needs to consider the information collected and produced by the volcano observatory charged with handling surveillance operations and reporting duties to civil protection for the volcano under analysis. As a very minimum, to ensure that a necessarily comprehensive and complete treatment of the scientific literature has been completed, we recommend that a third party expert, who is a recognized specialist in terms of research at the site considered, reviews and checks the material used for the gap analysis before final release of recommendations. Supplementary information: The online version contains supplementary material available at 10.1186/s13617-021-00111-w.
We investigate the collective mode response of the iron-based superconductor Ba 1− x K x Fe 2 As 2 using intense terahertz (THz) light. In the superconducting state a THz Kerr signal is observed and assigned to nonlinear THz coupling to superconducting degrees of freedom. The polarization dependence of the THz Kerr signal is remarkably sensitive to the coexistence of a nematic order. In the absence of nematic order the C 4 symmetric polarization dependence of the THz Kerr signal is consistent with a coupling to the Higgs amplitude mode of the superconducting condensate. In the coexisting nematic and superconducting state the signal becomes purely nematic with a vanishing C 4 symmetric component, signaling the emergence of a superconducting collective mode activated by nematicity.
Background Clinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent. Cognitive composite scores are often used as endpoints but are lacking in genetic FTD. We aimed to create cognitive composite scores for genetic frontotemporal dementia (FTD) as well as recommendations for recruitment and duration in clinical trial design. Methods A standardized neuropsychological test battery covering six cognitive domains was completed by 69 C9orf72 , 41 GRN , and 28 MAPT mutation carriers with CDR® plus NACC-FTLD ≥ 0.5 and 275 controls. Logistic regression was used to identify the combination of tests that distinguished best between each mutation carrier group and controls. The composite scores were calculated from the weighted averages of test scores in the models based on the regression coefficients. Sample size estimates were calculated for individual cognitive tests and composites in a theoretical trial aimed at preventing progression from a prodromal stage (CDR® plus NACC-FTLD 0.5) to a fully symptomatic stage (CDR® plus NACC-FTLD ≥ 1). Time-to-event analysis was performed to determine how quickly mutation carriers progressed from CDR® plus NACC-FTLD = 0.5 to ≥ 1 (and therefore how long a trial would need to be). Results The results from the logistic regression analyses resulted in different composite scores for each mutation carrier group (i.e. C9orf72 , GRN , and MAPT ). The estimated sample size to detect a treatment effect was lower for composite scores than for most individual tests. A Kaplan-Meier curve showed that after 3 years, ~ 50% of individuals had converted from CDR® plus NACC-FTLD 0.5 to ≥ 1, which means that the estimated effect size needs to be halved in sample size calculations as only half of the mutation carriers would be expected to progress from CDR® plus NACC FTLD 0.5 to ≥ 1 without treatment over that time period. Discussion We created gene-specific cognitive composite scores for C9orf72 , GRN , and MAPT mutation carriers, which resulted in substantially lower estimated sample sizes to detect a treatment effect than the individual cognitive tests. The GENFI-Cog composites have potential as cognitive endpoints for upcoming clinical trials. The results from this study provide recommendations for estimating sample size and trial duration.
The accurate simulation of additional interactions at the ATLAS experiment for the analysis of proton–proton collisions delivered by the Large Hadron Collider presents a significant challenge to the computing resources. During the LHC Run 2 (2015–2018), there were up to 70 inelastic interactions per bunch crossing, which need to be accounted for in Monte Carlo (MC) production. In this document, a new method to account for these additional interactions in the simulation chain is described. Instead of sampling the inelastic interactions and adding their energy deposits to a hard-scatter interaction one-by-one, the inelastic interactions are presampled, independent of the hard scatter, and stored as combined events. Consequently, for each hard-scatter interaction, only one such presampled event needs to be added as part of the simulation chain. For the Run 2 simulation chain, with an average of 35 interactions per bunch crossing, this new method provides a substantial reduction in MC production CPU needs of around 20%, while reproducing the properties of the reconstructed quantities relevant for physics analyses with good accuracy.
Ubiquitylation is one of the most common post-translational modifications (PTMs) of proteins that frequently targets substrates for proteasomal degradation. However it can also result in non-proteolytic events which play important functions in cellular processes such as intracellular signaling, membrane trafficking, DNA repair and cell cycle. Emerging evidence demonstrates that dysfunction of non-proteolytic ubiquitylation is associated with the development of multiple human diseases. In this review, we summarize the current knowledge and the latest concepts on how non-proteolytic ubiquitylation pathways are involved in cellular signaling and in disease-mediating processes. Our review, may advance our understanding of the non-degradative ubiquitylation process.
We review the field of collisionless numerical simulations for the large-scale structure of the Universe. We start by providing the main set of equations solved by these simulations and their connection with General Relativity. We then recap the relevant numerical approaches: discretization of the phase-space distribution (focusing on N -body but including alternatives, e.g., Lagrangian submanifold and Schrödinger–Poisson) and the respective techniques for their time evolution and force calculation (direct summation, mesh techniques, and hierarchical tree methods). We pay attention to the creation of initial conditions and the connection with Lagrangian Perturbation Theory. We then discuss the possible alternatives in terms of the micro-physical properties of dark matter (e.g., neutralinos, warm dark matter, QCD axions, Bose–Einstein condensates, and primordial black holes), and extensions to account for multiple fluids (baryons and neutrinos), primordial non-Gaussianity and modified gravity. We continue by discussing challenges involved in achieving highly accurate predictions. A key aspect of cosmological simulations is the connection to cosmological observables, we discuss various techniques in this regard: structure finding, galaxy formation and baryonic modelling, the creation of emulators and light-cones, and the role of machine learning. We finalise with a recount of state-of-the-art large-scale simulations and conclude with an outlook for the next decade.
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