GALADRIEL: A facility for advancing engineering science relevant to rep-rated high energy density physics and inertial fusion energy experiments.

Many current and upcoming laser facilities used to study high-energy-density (HED) physics and inertial fusion energy (IFE) support operating at high rep-rates (HRRs) of ∼0.1-10 Hz, yet many diagnostics, target-fielding strategies, and data storage methods cannot support this pace of operation. Therefore, established experimental paradigms must change for the community to progress toward rep-rated operation. To this end, we introduce the General Atomics LAboratory for Developing Rep-rated Instrumentation and Experiments with Lasers, or GALADRIEL, to serve as a test bed for developing and benchmarking the engineering science advancements required for HRR experiments. GALADRIEL was constructed from the ground up around a commercial 1 TW (∼25 mJ in ∼25 fs at 800 nm) laser with diverse experimental applications in mind. Assembly of the basic framework of GALADRIEL concluded with commissioning shots generating ∼1-4 MeV electrons via laser-wakefield acceleration (LWFA) using a nitrogen gas jet. Subsequent LWFA experiments operated at 1 Hz, utilized instrument feedback for optimization, and stored all data in a custom-built NoSQL database system. From this database called MORIA, or the MOngodb Repository for Information Archiving, data are retrievable via individual files or en masse by query requests defined by the user. GALADRIEL focuses on outstanding questions in engineering science, including targetry, diagnostics, data handling, environmental and materials studies, analysis and machine learning algorithm development, and feedback control systems. GALADRIEL fills a niche presently missing in the US-based user-facility community by providing a flexible experimental platform to address problems in engineering science relevant to rep-rated HED and IFE experiments.

Laboratory evidence of the nonresonant streaming instability in the formation of quasiparallel collisionless shocks at high Alfvénic Mach number.

We present an experimental investigation of the formation stage of a collisionless shock when the flow velocity is aligned with an ambient magnetic field utilizing laser-driven, super-Alfvénic plasma flows. As the flows interact, electromagnetic streaming instabilities develop. Proton deflectometry is used to visualize these electromagnetic fluctuations indicating the development of the ion-Weibel instability and the nonresonant instability. Hybrid simulations also show growth of the nonresonant instability and suggest that it provides an efficient source of dissipation for a shock.

DASCore: a Python Library for Distributed Fiber Optic Sensing.

In the past decade, distributed acoustic sensing (DAS) has enabled many new monitoring applications in diverse fields including hydrocarbon exploration and extraction; induced, local, regional, and global seismology; infrastructure and urban monitoring; and several others. However, to date, the open-source software ecosystem for handling DAS data is relatively immature. Here we introduce DASCore, a Python library for analyzing, visualizing, and managing DAS data. DASCore implements an object-oriented interface for performing common data processing and transformations, reading and writing various DAS file types, creating simple visualizations, and managing file system-based DAS archives. DASCore also integrates with other Python-based tools which enable the processing of massive data sets in cloud environments. DASCore is the foundational package for the broader DAS data analysis ecosystem (DASDAE), and as such its main goal is to facilitate the development of other DAS libraries and applications.

Pristine Photopolymerizable Gelatin Hydrogels: A Low-Cost and Easily Modifiable Platform for Biomedical Applications.

The study addresses the challenge of temperature sensitivity in pristine gelatin hydrogels, widely used in biomedical applications due to their biocompatibility, low cost, and cell adhesion properties. Traditional gelatin hydrogels dissolve at physiological temperatures, limiting their utility. Here, we introduce a novel method for creating stable hydrogels at 37 °C using pristine gelatin through photopolymerization without requiring chemical modifications. This approach enhances consistency and simplifies production and functionalization of the gelatin with bioactive molecules. The stabilization mechanism involves the partial retention of the triple-helix structure of gelatin below 25 °C, which provides specific crosslinking sites. Upon activation by visible light, ruthenium (Ru) acts as a photosensitizer that generates sulphate radicals from sodium persulphate (SPS), inducing covalent bonding between tyrosine residues and "locking" the triple-helix conformation. The primary focus of this work is the characterization of the mechanical properties, swelling ratio, and biocompatibility of the photopolymerized gelatin hydrogels. Notably, these hydrogels supported better cell viability and elongation in normal human dermal fibroblasts (NHDFs) compared to GelMA, and similar performance was observed for human pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). As a proof of concept for functionalization, gelatin was modified with selenous acid (GelSe), which demonstrated antioxidant and antimicrobial capacities, particularly against E. coli and S. aureus. These results suggest that pristine gelatin hydrogels, enhanced through this new photopolymerization method and functionalized with bioactive molecules, hold potential for advancing regenerative medicine and tissue engineering by providing robust, biocompatible scaffolds for cell culture and therapeutic applications.

A customizable data management framework for high-repetition-rate high-energy-density science.

The high-energy-density (HED) physics community is moving toward a new paradigm of high-repetition-rate (HRR) operation. To fully leverage the scientific power of HRR HED facilities, all of the components of each subsystem (laser, targetry, and performance diagnostics) must be connected and synchronized in a reliable and robust manner while the data acquired are tagged and archived in real time. To this end, GA has begun developing a generalized NoSQL-database framework, the MongoDB repository for information and archiving. An organizational strategy has been developed that shifts HED data organization from a shot-based to a diagnostic-based approach in order to increase archival and retrieval efficiency that lends itself to optimization applications. This work is a first step in pushing HRR HED science toward data management solutions that emphasize machine actionability and aim to stimulate community engagement to define data standards in HED science.

Challenges for assessment of cohabiting stocks of argentine shortfin squid Illex argentinus using parasites as biological tags.

The Argentine shortfin squid Illex argentinus is one of the most important commercial species for the Argentine fisheries. The understanding of its stock structure is therefore necessary to ensure fishery sustainability and, given the relevance of squids in the regional food web, for biodiversity conservation. An overlap between parasitology and fisheries lies in the use of parasites as biological tags to identify the stock composition of exploited resources, however, the efficiency of this methodology has been questioned for stock assessment in cephalopods. In this work, the value of parasite assemblages of I. argentinus to discriminate between the co-occurring summer spawning stock (SSS) and south patagonic stock (SPS) in a mixing area over the Patagonian continental shelf during summer was evaluated for two cohorts. Five shortfin squid samples corresponding to SSS and SPS were examined for metazoan parasites. The squid size affected the parasite assemblage similarities, conversely, no gender effect on the infracommunities was observed. Multivariate analysis evidenced similarity in parasite assemblage composition and structure between both stocks captured in the mixing area on the same date. This similarity was related to the presence of short-lived trophically transmitted parasites, which are associated with their recently consumed food items and, indirectly, to the oceanographic conditions. The same set of host and environmental variables were identified as the most probable causes of the temporal variability observed in parasite assemblages between SPS cohorts and even intra-cohort. Despite the value of parasites as tags for discriminating squid stocks may have little value when cohabiting stocks are analysed, their variability could serve as a valuable indicator of environmental conditions. The use of parasites as biological tags to discriminate stocks needs to be verified at different spatiotemporal scales, including samples from other non-sympatric stocks in the analyses.

Simulation of the THF hydrate-water interfacial free energy from computer simulation.

In this work, the tetrahydrofuran (THF) hydrate-water interfacial free energy is determined at 500 bar, at one point of the univariant two-phase coexistence line of the THF hydrate, by molecular dynamics simulation. The mold integration-host methodology, an extension of the original mold integration technique to deal with hydrate-fluid interfaces, is used to calculate the interfacial energy. Water is described using the well-known TIP4P/Ice model, and THF is described using a rigid version of the TraPPE model. We have recently used the combination of these two models to accurately describe the univariant two-phase dissociation line of the THF hydrate in a wide range of pressures from computer simulation [Algaba et al., J. Chem. Phys. 160, 164718 (2024)]. The THF hydrate-water interfacial free energy predicted in this work is compared with the only experimental data available in the literature. The value obtained, 27(2) mJ/m2, is in excellent agreement with the experimental data taken from the literature, 24(8) mJ/m2. To the best of our knowledge, this is the first time that the THF hydrate-water interfacial free energy is predicted from computer simulation. This work confirms that the mold integration technique can be used with confidence to predict the solid-fluid interfaces of complex structures, including hydrates that exhibit sI and sII crystallographic structures.

Automatic segmentation and classification of Papanicolaou-stained cells and dataset for oral cancer detection.

BACKGROUND AND OBJECTIVE: Papanicolaou staining has been successfully used to assist early detection of cervix cancer for several decades. We postulate that this staining technique can also be used for assisting early detection of oral cancer, which is responsible for about 300,000 deaths every year. The rational for such claim includes two key observations: (i) nuclear atypia, i.e., changes in volume, shape, and staining properties of the cell nuclei can be linked to rapid cell proliferation and genetic instability; and (ii) Papanicolaou staining allows one to reliably segment cells' nuclei and cytoplasms. While Papanicolaou staining is an attractive tool due to its low cost, its interpretation requires a trained pathologist. Our goal is to automate the segmentation and classification of morphological features needed to evaluate the use of Papanicolaou staining for early detection of mouth cancer. METHODS: We built a convolutional neural network (CNN) for automatic segmentation and classification of cells in Papanicolaou-stained images. Our CNN was trained and evaluated on a new image dataset of cells from oral mucosa consisting of 1,563 Full HD images from 52 patients, annotated by specialists. The effectiveness of our model was evaluated against a group of experts. Its robustness was also demonstrated on five public datasets of cervical images captured with different microscopes and cameras, and having different resolutions, colors, background intensities, and noise levels. RESULTS: Our CNN model achieved expert-level performance in a comparison with a group of three human experts on a set of 400 Papanicolaou-stained images of the oral mucosa from 20 patients. The results of this experiment exhibited high Interclass Correlation Coefficient (ICC) values. Despite being trained on images from the oral mucosa, it produced high-quality segmentation and plausible classification for five public datasets of cervical cells. Our Papanicolaou-stained image dataset is the most diverse publicly available image dataset for the oral mucosa in terms of number of patients. CONCLUSION: Our solution provides the means for exploring the potential of Papanicolaou-staining as a powerful and inexpensive tool for early detection of oral cancer. We are currently using our system to detect suspicious cells and cell clusters in oral mucosa slide images. Our trained model, code, and dataset are available and can help practitioners and stimulate research in early oral cancer detection.

Image perception and reception in wordless picture books: Eye movements of children with intellectual disabilities.

Wordless picture books enhance comprehension and vocabulary growth and motivate children with intellectual disabilities (ID) to participate in literary activities. However, the reception of picture books can be challenging because deliberate selective attention processes and recognition of the image's meaning are often delayed. Examining eye movements may help explore these cognitive processes. Therefore, we examined eye movements in 29 children with mild and moderate ID as they explored a wordless picture book, presented on a screen and compared them to 14 typically developing children using a Tobii Pro X3-120 eye tracker. The findings showed that children with moderate ID had shorter fixation duration, fixated less often, and revisited regions of interest less frequently. Our results suggest that children with moderate ID have greater difficulties in selectively directing their attention toward regions of visual input with a high level of informativeness and expend less cognitive effort to understand their meaning.

ß-amyloid monomer scavenging by an anticalin protein prevents neuronal hyperactivity in mouse models of Alzheimer's Disease.

Hyperactivity mediated by synaptotoxic ß-amyloid (Aß) oligomers is one of the earliest forms of neuronal dysfunction in Alzheimer's disease. In the search for a preventive treatment strategy, we tested the effect of scavenging Aß peptides before Aß plaque formation. Using in vivo two-photon calcium imaging and SF-iGluSnFR-based glutamate imaging in hippocampal slices, we demonstrate that an Aß binding anticalin protein (Aß-anticalin) can suppress early neuronal hyperactivity and synaptic glutamate accumulation in the APP23xPS45 mouse model of ß-amyloidosis. Our results suggest that the sole targeting of Aß monomers is sufficient for the hyperactivity-suppressing effect of the Aß-anticalin at early disease stages. Biochemical and neurophysiological analyses indicate that the Aß-anticalin-dependent depletion of naturally secreted Aß monomers interrupts their aggregation to neurotoxic oligomers and, thereby, reverses early neuronal and synaptic dysfunctions. Thus, our results suggest that Aß monomer scavenging plays a key role in the repair of neuronal function at early stages of AD.

Phase-State-Dependent Silica Nanoparticle Uptake of Giant Unilamellar Vesicles.

We quantify endocytosis-like nanoparticle (NP) uptake of model membranes as a function of temperature and, therefore, phase state. As model membranes, we use giant unilamellar vesicles (GUV) consisting of 1,2-dipentadecanoyl-sn-glycero-3-phosphocholine (15:0 PC). Time-series micrographs of the vesicle shrinkage show uptake rates that are a highly nonlinear function of temperature. A global maximum appears close to the main structural phase transition at T = Tm + 3 K = 37 °C and a minor peak at the pretransition T = Tp = 22 °C. The quality of linear fits to the shrinkage, and thus uptake kinetics, reveals a deviation from the linear trend at the vesicle shrinkage peaks. Taking values for the bending modulus as a function of temperature from literature and Helfrich's model allows us to draw qualitative conclusions on the membrane tension and the adhesion of the NP to the membrane as a function of temperature. These findings provide valuable insights into the dynamic interplay between temperature, membrane phase transitions, and NP uptake, shedding light on the complex behavior of biological membranes.

Kinetic Resolution of Epimeric Proteins Enables Stereoselective Chemical Mutagenesis.

Chemical mutagenesis via dehydroalanine (Dha) is a powerful method to tailor protein structure and function, allowing the site-specific installation of post-translational modifications and non-natural functional groups. Despite the impressive versatility of this method, applications have been limited, as products are formed as epimeric mixtures, whereby the modified amino acid is present as both the desired l-configuration and a roughly equal amount of the undesired d-isomer. Here, we describe a simple remedy for this issue: removal of the d-isomer via proteolysis using a d-stereoselective peptidase, alkaline d-peptidase (AD-P). We demonstrate that AD-P can selectively cleave the d-isomer of epimeric residues within histone H3, GFP, Ddx4, and SGTA, allowing the installation of non-natural amino acids with stereochemical control. Given the breadth of modifications that can be introduced via Dha and the simplicity of our method, we believe that stereoselective chemoenzymatic mutagenesis will find broad utility in protein engineering and chemical biology applications.

Evolving patterns and clinical outcome of genetic studies performed at diagnosis in acute myeloid leukemia patients: Real life data from the PETHEMA Registry.

BACKGROUND: There are no studies assessing the evolution and patterns of genetic studies performed at diagnosis in acute myeloid leukemia (AML) patients. Such studies could help to identify potential gaps in our present diagnostic practices, especially in the context of increasingly complex procedures and classifications. METHODS: The REALMOL study (NCT05541224) evaluated the evolution, patterns, and clinical impact of performing main genetic and molecular studies performed at diagnosis in 7285 adult AML patients included in the PETHEMA AML registry (NCT02607059) between 2000 and 2021. RESULTS: Screening rates increased for all tests across different time periods (2000-2007, 2008-2016, and 2017-2021) and was the most influential factor for NPM1, FLT3-ITD, and next-generation sequencing (NGS) determinations: NPM1 testing increased from 28.9% to 72.8% and 95.2% (p < .001), whereas FLT3-ITD testing increased from 38.1% to 74.1% and 95.9% (p < .0001). NGS testing was not performed between 2000-2007 and only reached 3.5% in 2008-2016, but significantly increased to 72% in 2017-2021 (p < .001). Treatment decision was the most influential factor to perform karyotype (odds ratio [OR], 6.057; 95% confidence interval [CI], 4.702-7.802), and fluorescence in situ hybridation (OR, 2.273; 95% CI, 1.901-2.719) studies. Patients ≥70 years old or with an Eastern Cooperative Oncology Group ≥2 were less likely to undergo these diagnostic procedures. Performing genetic studies were associated with a favorable impact on overall survival, especially in patients who received intensive chemotherapy. CONCLUSIONS: This unique study provides relevant information about the evolving landscape of genetic and molecular diagnosis for adult AML patients in real-world setting, highlighting the increased complexity of genetic diagnosis over the past 2 decades.

High repetition-rate foam targetry for laser-plasma interaction experiments: Concept and preliminary results.

Foam targets have gained considerable importance over the last decade in laser-matter interaction. They find widespread applications such as in inertial confinement fusion and secondary sources for particles and radiation. At the same time, the advent of high repetition-rate laser systems, be they short-pulse in the tens of femtosecond regime or in the kilo-Joule nanosecond regime, calls for equally high repetition rate targetry systems. A well-established repetition-rate targetry system is the tape target. In this article, we present the successful marriage of a tape target delivery system with 3D-printed foam targets produced by two photon polymerization.

Rapid Peptide Cyclization Inspired by the Modular Logic of Nonribosomal Peptide Synthetases.

Nonribosomal cyclic peptides (NRcPs) are structurally complex natural products and a vital pool of therapeutics, particularly antibiotics. Their structural diversity arises from the ability of the multidomain enzyme assembly lines, nonribosomal peptide synthetases (NRPSs), to utilize bespoke nonproteinogenic amino acids, modify the linear peptide during elongation, and catalyze an array of cyclization modes, e.g., head to tail, side chain to tail. The study and drug development of NRcPs are often limited by a lack of easy synthetic access to NRcPs and their analogues, with selective macrolactamization being a major bottleneck. Herein, we report a generally applicable chemical macrocyclization method of unprecedented speed and selectivity. Inspired by biosynthetic cyclization, it combines the deprotected linear biosynthetic precursor peptide sequence with a highly reactive C-terminus to produce NRcPs and analogues in minutes. The method was applied to several NRcPs of varying sequences, ring sizes, and cyclization modes including rufomycin, colistin, and gramicidin S with comparable success. We thus demonstrate that the linear order of modules in NRPS enzymes that determines peptide sequence encodes the key structural information to produce peptides conformationally biased toward macrocyclization. To fully exploit this conformational bias synthetically, a highly reactive C-terminal acyl azide is also required, alongside carefully balanced pH and solvent conditions. This allows for consistent, facile cyclization of exceptional speed, selectivity, and atom efficiency. This exciting macrolactamization method represents a new enabling technology for the biosynthetic study of NRcPs and their development as therapeutics.

Population Dynamics is a Cancer Driver.

Most tissues are continuously renovated through the division of stem cells and the death of old or damaged cells, which is known as cell turnover rate (CTOR). Despite being in steady state, tissues have different population dynamics and leading to diverse clonality levels. Here, we propose and test that cell population dynamics can be a cancer driver. We employed the evolutionary software esiCancer to show that CTOR, within a range comparable to what is observed in human tissues, can amplify the risk of a mutation due to ancestral selection (ANSEL). In a high CTOR tissue, a mutated ancestral cell is likely to be selected and persist over generations, which leads to a scenario of elevated ANSEL profile, characterized by few niches of large clones, which does not occur in low CTOR. We found that CTOR is significantly associated with the risk of developing cancer, even when correcting for mutation load, indicating that population dynamics per se is a cancer driver. This concept is central to understanding cancer risk and for the design of new therapeutic interventions that minimize the contribution of ANSEL in cancer growth.

Boredom due to being over- or under-challenged in mathematics: A latent profile analysis.

BACKGROUND: Recent research on boredom suggests that it can emerge in situations characterized by over- and under-challenge. In learning contexts, this implies that high boredom may be experienced both by low- and high-achieving students. AIMS: This research aimed to explore the existence and prevalence of boredom due to being over- and under-challenged in mathematics, for which empirical evidence is lacking. SAMPLE: We employed a sample of 1.407 students (fifth to ninth graders) from all three secondary school tracks (lower, middle and upper) in Bavaria (Germany). METHODS: Boredom was assessed via self-report and achievement via a standardized mathematics test. We used latent profile analysis to identify groups characterized by different levels of boredom and achievement, and we additionally examined gender and school track as group membership predictors. RESULTS: Results revealed four distinct groups, of which two showed considerably high boredom. One was coupled with low achievement on the test (i.e. 'over-challenged group', 13% of the total sample), and one was coupled with high achievement (i.e. 'under-challenged group', 21%). Furthermore, we found a low boredom and high achievement (i.e. 'well-off group', 27%) and a relatively low boredom low achievement group (i.e. 'indifferent group', 39%). Girls were overrepresented in the over-challenged group, and students from the upper school track were underrepresented in the under-challenged group. CONCLUSION: Our research emphasizes the need to openly discuss and further investigate boredom due to being over- and under-challenged.

FRET Sensor-Modified Synthetic Hydrogels for Real-Time Monitoring of Cell-Derived Matrix Metalloproteinase Activity using Fluorescence Lifetime Imaging.

Matrix remodeling plays central roles in a range of physiological and pathological processes and is driven predominantly by the activity of matrix metalloproteinases (MMPs), which degrade extracellular matrix (ECM) proteins. Our understanding of how MMPs regulate cell and tissue dynamics is often incomplete as in vivo approaches are lacking and many in vitro strategies cannot provide high-resolution, quantitative measures of enzyme activity in situ within tissue-like 3D microenvironments. Here, we incorporate a Förster resonance energy transfer (FRET) sensor of MMP activity into fully synthetic hydrogels that mimic many properties of the native ECM. We then use fluorescence lifetime imaging to provide a real-time, fluorophore concentration-independent quantification of MMP activity, establishing a highly accurate, readily adaptable platform for studying MMP dynamics in situ. MCF7 human breast cancer cells encapsulated within hydrogels highlight the detection of MMP activity both locally, at the sub-micron level, and within the bulk hydrogel. Our versatile platform may find use in a range of biological studies to explore questions in the dynamics of cancer metastasis, development, and tissue repair by providing high-resolution, quantitative and in situ readouts of local MMP activity within native tissue-like environments.

Molecular Insights into the Wettability and Adsorption of Acid Gas-Water Mixture.

Sequestration of acid gas in geological formations is a disposal method with potential economic and environmental benefits. The process is governed by variables such as gas-water interfacial tension, wetting transition, and gas adsorption into water, among other things. However, the influence of the pressure and temperature on these parameters is poorly understood. This study investigates these parameters using coarse-grained molecular dynamics (CG-MD) simulations and density gradient theory (DGT). Simulations were carried out at 313.15 K and a pressure range of 0-15 MPa. A comparison was made against H2S-water systems to clarify the effects of adsorption on interfacial tension due to vapor-liquid-liquid equilibrium. The predicted H2S-water interfacial tension and phase densities by CG-MD and DGT matched the experimental values well. The adsorption can be quantified via the Gibbs Adsorption function Γ12, which correlated well with the three-phase transition. On the one hand, pressure increments below the three-phase transition revealed a significant adsorption of H2S. On the other hand, above the three-phase transition, the Gibbs Adsorption capacity remained constant, which indicated a saturation of H2S at the water surface due to liquid-liquid equilibrium. Finally, H2S behaves markedly differently in wetting transition, rather than the involved for CO2 to different molecular layers beneath the surface of aqueous solutions. In this respect, H2S is represented by a first-order wetting transition while CO2 presents a critical wetting. Finally, it has also been found that the preferential adsorption of H2S over the H2O interface is greater if compared to that of CO2, due to its strong interaction with water. In fact, we have also demonstrated that CO2 under triphasic conditions strongly influences the wetting of the ternary system.

Modeling oceanic sedimentary methane hydrate growth through molecular dynamics simulation.

The crystallization process of methane hydrates in a confined geometry resembling seabed porous silica sedimentary conditions has been studied using molecular dynamics simulations. With this objective in mind, a fully atomistic quartz silica slit pore has been designed, and the temperature stability of a methane hydrate crystalline seed in the presence of water and guest molecule methane has been analyzed. NaCl ion pairs have been added in different concentrations, simulating salinity conditions up to values higher than average oceanic conditions. The structure obtained when the hydrate crystallizes inside the pore is discussed, paying special attention to the presence of ionic doping inside the hydrate and the subsequent induced structural distortion. The shift in the hydrate stability conditions due to the increasing water salinity is discussed and compared with the case of unconfined hydrate, concluding that the influence of the confinement geometry and pore hydrophilicity produces a larger deviation in the confined hydrate phase equilibria.