A common sense approach to consequence analysis at a large DOE site

The primary objective of the Probabilistic Safety Assessment (PSA) at the U. S. Department of Energy (DOE) Savannah River Site (SRS) is to quantify health and economic risks posed by K Reactor operation to the nearby offsite and onsite areas from highly unlikely severe accidents. The overall risk analyses have also been instrumental as defensible bases for analyzing existing safety margins of the restart configuration; determining component, human action, and engineering system vulnerabilities; comparing measures of risk to DOE and commercial guidelines; and prioritizing risk-significant improvements. The key final phase of these probabilistic risk calculations, a third level of analysis or Level 3 PSA, requires the determination of the conditional consequences to onsite workers and the DOE reservation facilities, given low-probability, postulated fuel-melting accidents with accompanying atmospheric releases have occurred. A modified version of the commercial reactor-based MACCS 1.5 code, MACCS/ON, is used in the context of the SRS PSA to perform the consequence determinations. The updated code is applicable to other large DOE sites for risk analyses of facility operations, and is compatible with proposed modifications planned by code developers, Sandia National Laboratories

Drop-on-demand metal jetting of pure copper: On the interaction of molten metal with ceramic and metallic substrates

Copper, renowned for its exceptional electrical and thermal conductivity at a low cost, holds great promise in electronic applications. While additive manufacturing of copper has attracted interest, the exploration of applying Drop-on-demand Metal Jetting (DoD-MJ) to 3D print pure copper remains uncharted. To fill this research gap, we employed an in-house DoD-MJ platform, MetalJet, to generate Cu microdroplets and deposit them onto ceramic and metallic substrates, a first-time achievement in this research context. Our study demonstrates the successful generation of uniform Cu microdroplets, emphasising the pivotal role of oxygen content control in preventing nozzle-level reactions, a factor that can disrupt droplet formation. Both alumina and aluminium nitride substrates exhibited poor wettability with molten Cu droplets, and no interface formed between these surfaces due to thermodynamically unfavourable reactions. Nevertheless, the irregular surface of alumina displayed an interesting capability to enable the adhesion of Cu droplets to the substrate through an interlocking mechanism. Lastly, the electrical resistivity of MetalJet printed pillars was measured as low as 6.75×10-8Ωm without any post-treatment, offering exciting possibilities for applications in 3D electronics

From impact to solidification in drop-on-demand metal additive manufacturing using MetalJet

Drop-on-demand metal jetting is a promising additive manufacturing (AM) technology that is gaining interest due to its capability to directly print complex single and multi-material components at high resolutions. It also has key advantages over other metal AM techniques, such as avoiding powder handling and extensive post-processing. In this method, parts are built via spatially controlled deposition of individual molten droplets onto a substrate. Therefore, the success of the process entirely depends on the behaviour of these single droplets from deposition to solidification including their interactions with the substrate, which is scarcely investigated to date. To fill this research gap, the in-house MetalJet platform was used to investigate the spreading and solidification of metallic micro-droplets at low Weber numbers. This was undertaken onto various substrates using a range of jetting and substrate temperatures through an integrated experimental, analytical, and computational approach. This study reports that increasing the substrate temperature enhanced the diffusion between the droplet and substrate, hence improving the bonding. Moreover, ripples forming on a droplet’s periphery during solidification disappeared at elevated substrate temperatures, resulting in improved inter-droplet bonding. Furthermore, the significant role of the substrate wettability and thermal properties, which control the droplet’s dynamics and solidification behaviour, respectively, is elucidated. This highlights the importance of substrate material selection using this technology. The results presented in this article underpin the optimal process conditions under which the 3D structures produced with this technology can exhibit reliable integrity and consistency. This represents a step forward in the direct metal printing of high resolution functional multi-material components

FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease

Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for therapy. We identified a subset of luminal A primary breast tumors that give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2-). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that FGFR4 likely participates in this subtype switching. To evaluate this, we developed 2 FGFR4 genomic signatures using a patient-derived xenograft (PDX) model treated with an FGFR4 inhibitor, which inhibited PDX growth in vivo. Bulk tumor gene expression analysis and single-cell RNA sequencing demonstrated that the inhibition of FGFR4 signaling caused molecular switching. In the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohort, FGFR4-induced and FGFR4-repressed signatures each predicted overall survival. Additionally, the FGFR4-induced signature was an independent prognostic factor beyond subtype and stage. Supervised analysis of 77 primary tumors with paired metastases revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4- induced signature also predicted site-specific metastasis for lung, liver, and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting treatment options for FGFR4-positive patients, whose high expression is not caused by mutation or amplification

Team dynamics in emergency surgery teams: results from a first international survey

Background: Emergency surgery represents a unique context. Trauma teams are often multidisciplinary and need to operate under extreme stress and time constraints, sometimes with no awareness of the trauma\u2019s causes or the patient\u2019s personal and clinical information. In this perspective, the dynamics of how trauma teams function is fundamental to ensuring the best performance and outcomes. Methods: An online survey was conducted among the World Society of Emergency Surgery members in early 2021. 402 fully filled questionnaires on the topics of knowledge translation dynamics and tools, non-technical skills, and difficulties in teamwork were collected. Data were analyzed using the software R, and reported following the Checklist for Reporting Results of Internet E-Surveys (CHERRIES). Results: Findings highlight how several surgeons are still unsure about the meaning and potential of knowledge translation and its mechanisms. Tools like training, clinical guidelines, and non-technical skills are recognized and used in clinical practice. Others, like patients\u2019 and stakeholders\u2019 engagement, are hardly implemented, despite their increasing importance in the modern healthcare scenario. Several difficulties in working as a team are described, including the lack of time, communication, training, trust, and ego. Discussion: Scientific societies should take the lead in offering training and support about the abovementioned topics. Dedicated educational initiatives, practical cases and experiences, workshops and symposia may allow mitigating the difficulties highlighted by the survey\u2019s participants, boosting the performance of emergency teams. Additional investigation of the survey results and its characteristics may lead to more further specific suggestions and potential solutions

Modelling Jets, Tori and Flares in Pulsar Wind Nebulae

In this contribution we review the recent progress in the modelling of Pulsar Wind Nebulae (PWN). We start with a brief overview of the relevant physical processes in the magnetosphere, the wind-zone and the inflated nebula bubble. Radiative signatures and particle transport processes obtained from 3D simulations of PWN are discussed in the context of optical and X-ray observations. We then proceed to consider particle acceleration in PWN and elaborate on what can be learned about the particle acceleration from the dynamical structures called GwispsG observed in the Crab nebula. We also discuss recent observational and theoretical results of gamma-ray flares and the inner knot of the Crab nebula, which had been proposed as the emission site of the flares. We extend the discussion to GeV flares from binary systems in which the pulsar wind interacts with the stellar wind from a companion star. The chapter concludes with a discussion of solved and unsolved problems posed by PWN

Genomic–transcriptomic evolution in lung cancer and metastasis

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis

Sarco(endo)plasmic reticulum calcium pumps: recent advances in our understanding of structure/function and biology (Review)

This review examines the structure and function of the sarco(endo)plasmic reticulum calcium pump (SERCA1a) in the light of the recent publication of the 2.6 resolution structure of this protein, and looks at the increasing awareness of the key role played by SERCAs in calcium signalling. The roles played by the calcium pump isoforms, SERCA1a/b, SERCA2a/b and SERCA3a/b/c in cellular function are discussed, and the modulation of SERCA activity by phospholamban, sarcolipin and other modulatory influences is examined. The recent discoveries of human SERCA mutations leading to disease states is reviewed, and the insights into SERCA function using transgenic approaches are outlined