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At least 145 records · Page 8

Multi-scale signaling and tumor evolution in high-grade gliomas

Although genomic anomalies in glioblastoma (GBM) have been well studied for over a decade, its 5-year survival rate remains lower than 5%. We seek to expand the molecular landscape of high-grade glioma, composed of IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma, by integrating proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with genomic and transcriptomic measurements to uncover multi-scale regulatory interactions governing tumor development and evolution. Applying 14 proteogenomic and metabolomic platforms to 228 tumors (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 at recurrence, plus 18 normal brain samples and 14 brain metastases as comparators, reveals heterogeneous upstream alterations converging on common downstream events at the proteomic and metabolomic levels and changes in protein-protein interactions and glycosylation site occupancy at recurrence. Recurrent genetic alterations and phosphorylation events on PTPN11 map to important regulatory domains in three dimensions, suggesting a central role for PTPN11 signaling across high-grade gliomas.

60 APPLIED LIFE SCIENCES↗

Progressive Climate Change on Titan: Implications for Habitability

Titan's landscape is profoundly shaped by its atmosphere and comparable in magnitude perhaps with only the Earth and Mars amongst the worlds of the Solar System. Like the Earth, climate dictates the intensity and relative roles of fluvial and aeolian activity from place to place and over geologic time. Thus Titan's landscape is the record of climate change. We have investigated three broad classes of Titan climate evolution hypotheses (Steady State, Progressive, and Cyclic), regulated by the role, sources, and availability of methane. We favor the Progressive hypotheses, which we will outline here, then discuss their implication for habitability.

implication for habitability↗

Probing Mechanism of Evolution of Simple Genomes

Our overarching goal is to discover how the structure of the genotypic space of RNA polymers affects their ability to evolve. Specifically, we will address several fundamental questions that, so far, have remained largely unanswered. Was the genotypic space explored globally or only locally? Was the outcome of early evolution predictable or was it, instead, govern by chance? What was the role of neutral mutations in the evolution of increasing complex systems? As the first step, we study the problem in the example of RNA ligases. We obtain the complete, empirical fitness landscapes for short ligases and examine possible evolutionary paths for RNA molecules that are sufficiently long to preclude exhaustive search of the genotypic space.

Evolution↗

Characterizing Early Damage Evolution in CMCs

Silicon carbide / silicon carbide ceramic matrix composites (SiC/SiC CMCs) are structural ceramics that are well-suited for the extreme environment conditions of space and aerospace applications largely due to their low weight, creep resistance, damage tolerance, and high specific strength. In CMCs, the initiation and accumulation of damage depends on characteristics of the constituent landscape including porosity, interfacial properties, and geometric distribution of CMC constituents. In order to accurately predict the lifetimes of these advanced composites, it is critical to understand the evolution of damage and to characterize which early damage mechanisms subsequently lead to crack coalescence and macroscopic failure. In this study, SiC/SiC minicomposites are characterized through an experimental approach combining acoustic emission (AE) with tensile testing in-SEM (scanning electron microscope), in order to examine early damage initiation (below the proportional limit) and its evolution at room temperature. The approach provides insight into the relative activity of early damage mechanisms in CMCs at both the surface and subsurface levels and sheds light on the impact of fabrication choices on the evolution of damage to final failure. The potential application of this combined approach towards the characterization of damage in SiC/SiC CMCs under more complex testing conditions will also be discussed.

damage evolution↗

Phase-field modeling of solid-state metathesis reactions with the charge neutrality constraint

In this work, we present a phase-field model that captures the evolution of ionic concentrations and phase fractions during solid-state metathesis (SSM) reactions where diffusion limits the rate of transformation. The evolution of the mole fraction of each ion is obtained via governing equations that describe the reduction of a free energy, which includes an energy landscape with local minima located at compositions corresponding to stable products. We utilized two Lagrange multipliers to impose constraints of electroneutrality as well as on the sum of mole fractions, which were then eliminated to derive set of two partial differential equations that describe the dynamics of the mole fraction evolution. From these governing equations, the expressions for effective mobilities for the cations and the anions were obtained. We first study the effect of mobilities of ions on the reaction kinetics, using a simple model considering the ions with an identical absolute value of charge numbers. The simulation results show that the overall characteristic mobility, defined as the sum of the two effective ionic mobilities, provides an excellent measure of the rate at which reaction progresses and that the ratio of the effective mobilities of the anions and the cations signifies the manner by which the reaction progresses. We then generalize the model to consider ions with different charge numbers and tuned the mobility of ions based on their diffusion coefficients reported in the literature and experimental data from a thin-film experiment for the synthesis of FeS 2 to demonstrate the capability of the model to predict the phase evolution during SSM reactions. In particular, the simulation predicts nonplanar phase evolution, which is recently observed in thin-film reactions for the synthesis of FeS 2 via transmission electron microscopy. The approach can serve as a basis for models for phase transformations in other multiphase ionic mixtures, such as in all-solid-state batteries and in ionic liquids.

36 MATERIALS SCIENCE↗

Invasion and rapid adaptation of guppies ( Poecilia reticulata ) across the Hawaiian Archipelago

How much does natural selection, as opposed to genetic drift, admixture, and gene flow, contribute to the evolution of invasive species following introduction to a new environment? Here we assess how evolution can shape biological invasions by examining population genomic variation in non-native guppies (Poecilia reticulata) introduced to the Hawaiian Islands approximately a century ago. By examining 18 invasive populations from four Hawaiian islands and four populations from the native range in northern South America, we reconstructed the history of introductions and evaluated population structure as well as the extent of ongoing gene flow across watersheds and among islands. Patterns of differentiation indicate that guppies have developed significant population structure, with little natural or human-mediated gene flow having occurred among populations following introduction. Demographic modeling and admixture graph analyses together suggest that guppies were initially introduced to O‘ahu and Maui and then translocated to Hawai‘i and Kaua‘i. We detected evidence for only one introduction event from the native range, implying that any adaptive evolution in introduced populations likely utilized the genetic variation present in the founding population. Environmental association tests accounting for population structure identified loci exhibiting signatures of adaptive variation related to predators and landscape characteristics but not nutrient regimes. When paired with high estimates of effective population sizes and detectable population structure, the presence of environment-associated loci supports the role of natural selection in shaping contemporary evolution of Hawaiian guppy populations. Our findings indicate that local adaptation may engender invasion success, particularly in species with life histories that facilitate rapid evolution. Finally, evidence of low gene flow between populations suggests that removal could be an effective approach to control invasive guppies across the Hawaiian archipelago.

59 BASIC BIOLOGICAL SCIENCES↗

Protoplast fusion in Bacillus species produces frequent, unbiased, genome-wide homologous recombination

Abstract In eukaryotes, fine-scale maps of meiotic recombination events have greatly advanced our understanding of the factors that affect genomic variation patterns and evolution of traits. However, in bacteria that lack natural systems for sexual reproduction, unbiased characterization of recombination landscapes has remained challenging due to variable rates of genetic exchange and influence of natural selection. Here, to overcome these limitations and to gain a genome-wide view on recombination, we crossed Bacillus strains with different genetic distances using protoplast fusion. The offspring displayed complex inheritance patterns with one of the parents consistently contributing the major part of the chromosome backbone and multiple unselected fragments originating from the second parent. Our results demonstrate that this bias was in part due to the action of restriction–modification systems, whereas genome features like GC content and local nucleotide identity did not affect distribution of recombination events around the chromosome. Furthermore, we found that recombination occurred uniformly across the genome without concentration into hotspots. Notably, our results show that species-level genetic distance did not affect genome-wide recombination. This study provides a new insight into the dynamics of recombination in bacteria and a platform for studying recombination patterns in diverse bacterial species.

59 BASIC BIOLOGICAL SCIENCES↗

Towards chloroplastic nanofactories: formation of proteinaceous scaffolds for metabolic engineering

The evolution of eukaryotic lipid-bound organelles allows for specialized metabolism to occur within spatially distinct metabolic landscapes within the same cell. However, this strategy of compartmentalization is not unique to eukaryotic organisms. Many bacteria, spread across 45 different phyla, contain loci that encode for specialized bacterial microcompartments (BMCs) (Sutter et al., 2021). The formation of a BMC involves self-assembly from three families of shell proteins to form the outer shell membrane, in addition to the encapsulation of an enzymatic core packaged within the lumen of a BMC (Kerfeld et al., 2018). These proteinaceous organelles provide a competitive growth advantage by enabling organisms to process inaccessible substrates by sequestering metabolic intermediates (i.e. aldehydes) that would otherwise be toxic within the cytoplasm. While BMCs perform specific metabolic functions in their native organism, synthetic, empty BMC shells can form without the requirement of native cargo inside (Doron and Kerfeld, 2024). This provides a transferable and tunable platform of protein scaffolding for guiding metabolic engineering within a host organism of choice (Raba and Kerfeld, 2022).

59 BASIC BIOLOGICAL SCIENCES↗

Woody Plant Transformation: Current Status, Challenges, and Future Perspectives

Woody plants, comprising forest and fruit tree species, provide essential ecological and economic benefits to society. Their genetic improvement is challenging due to long generation intervals and high heterozygosity. Genetic transformation, which combines targeted DNA delivery with plant regeneration from transformed cells, offers a powerful alternative to accelerating their domestication and improvement. Agrobacterium tumefaciens, Rhizobium rhizogenes, and particle bombardment have been widely used for DNA delivery into a wide variety of explants, including leaves, stems, hypocotyls, roots, and embryos, with regeneration occurring via direct organogenesis, callus-mediated organogenesis, somatic embryogenesis, or hairy root formation. Despite successes, conventional approaches are hampered by low efficiency, genotype dependency, and a reliance on challenging tissue culture. This review provides a critical analysis of the current landscape in woody plant transformation, moving beyond a simple summary of techniques to evaluate the co-evolution of established platforms with disruptive technologies. Key advances among these include the use of developmental regulators to engineer regeneration, the rise in in planta systems to bypass tissue culture, and the imperative for DNA-free genome editing to meet regulatory and public expectations. By examining species-specific breakthroughs in key genera, including Populus, Malus, Citrus, and Pinus, this review highlights a paradigm shift from empirical optimization towards rational, predictable engineering of woody plants for a sustainable future.

Agrobacterium tumefaciens↗

Coupled land surface/hydrologic/atmospheric models

The topics covered include the following: prototype land cover characteristics data base for the conterminous United States; surface evapotranspiration effects on cumulus convection and implications for mesoscale models; the use of complex treatment of surface hydrology and thermodynamics within a mesoscale model and some related issues; initialization of soil-water content for regional-scale atmospheric prediction models; impact of surface properties on dryline and MCS evolution; a numerical simulation of heavy precipitation over the complex topography of California; representing mesoscale fluxes induced by landscape discontinuities in global climate models; emphasizing the role of subgrid-scale heterogeneity in surface-air interaction; and problems with modeling and measuring biosphere-atmosphere exchanges of energy, water, and carbon on large scales.

Pielke, Roger↗

The implementation of the Human Exploration Demonstration Project (HEDP), a systems technology testbed

The Human Exploration Demonstration Project (HEDP) is an ongoing task at the NASA's Ames Research Center to address the advanced technology requirements necessary to implement an integrated working and living environment for a planetary surface habitat. The integrated environment consists of life support systems, physiological monitoring of project crew, a virtual environment work station, and centralized data acquisition and habitat systems health monitoring. The HEDP is an integrated technology demonstrator, as well as an initial operational testbed. There are several robotic systems operational in a simulated planetary landscape external to the habitat environment, to provide representative work loads for the crew. This paper describes the evolution of the HEDP from initial concept to operational project; the status of the HEDP after two years; the final facilities composing the HEDP; the project's role as a NASA Ames Research Center systems technology testbed; and the interim demonstration scenarios that have been run to feature the developing technologies in 1993.

Rosen, Robert↗

Price equation captures the role of drug interactions and collateral effects in the evolution of multidrug resistance

Bacterial adaptation to antibiotic combinations depends on the joint inhibitory effects of the two drugs (drug interaction [DI]) and how resistance to one drug impacts resistance to the other (collateral effects [CE]). Here we model these evolutionary dynamics on two-dimensional phenotype spaces that leverage scaling relations between the drug-response surfaces of drug-sensitive (ancestral) and drug-resistant (mutant) populations. We show that evolved resistance to the component drugs – and in turn, the adaptation of growth rate – is governed by a Price equation whose covariance terms encode geometric features of both the two-drug-response surface (DI) in ancestral cells and the correlations between resistance levels to those drugs (CE). Within this framework, mean evolutionary trajectories reduce to a type of weighted gradient dynamics, with the drug interaction dictating the shape of the underlying landscape and the collateral effects constraining the motion on those landscapes. We also demonstrate how constraints on available mutational pathways can be incorporated into the framework, adding a third key driver of evolution. Our results clarify the complex relationship between drug interactions and collateral effects in multidrug environments and illustrate how specific dosage combinations can shift the weighting of these two effects, leading to different and temporally explicit selective outcomes.

Gjini, Erida↗

Entropic control of the free-energy landscape of an archetypal biomolecular machine

Biomolecular machines are complex macromolecular assemblies that utilize thermal and chemical energy to perform essential, multistep, cellular processes. Despite possessing different architectures and functions, an essential feature of the mechanisms of action of all such machines is that they require dynamic rearrangements of structural components. Surprisingly, biomolecular machines generally possess only a limited set of such motions, suggesting that these dynamics must be repurposed to drive different mechanistic steps. Although ligands that interact with these machines are known to drive such repurposing, the physical and structural mechanisms through which ligands achieve this remain unknown. Using temperature-dependent, single-molecule measurements analyzed with a time-resolution-enhancing algorithm, here, we dissect the free-energy landscape of an archetypal biomolecular machine, the bacterial ribosome, to reveal how its dynamics are repurposed to drive distinct steps during ribosome-catalyzed protein synthesis. Specifically, we show that the free-energy landscape of the ribosome encompasses a network of allosterically coupled structural elements that coordinates the motions of these elements. Moreover, we reveal that ribosomal ligands which participate in disparate steps of the protein synthesis pathway repurpose this network by differentially modulating the structural flexibility of the ribosomal complex (i.e., the entropic component of the free-energy landscape). Here, we propose that such ligand-dependent entropic control of free-energy landscapes has evolved as a general strategy through which ligands may regulate the functions of all biomolecular machines. Such entropic control is therefore an important driver in the evolution of naturally occurring biomolecular machines and a critical consideration for the design of synthetic molecular machines.

Science & Technology - Other Topics↗

ALPS: The Age-Layered Population Structure for Reducing the Problem of Premature Convergence

To reduce the problem of premature convergence we define a new attribute of an individual, its age, and propose the Age-Layered Population Structure (ALPS), in which age is used to restrict competition and breeding between members of the population. ALPS differs from a typical EA by segregating individuals into different age-layers by their age - a measure of how long the genetic material has been in the population - and by regularly replacing all individuals in the bottom layer with randomly generated ones. The introduction of new, randomly generated individuals at regular intervals results in an EA that is never completely converged and is always looking at new parts of the fitness landscape. By using age to restrict competition and breeding search is able to develop promising young individuals without them being dominated by older ones. We demonstrate the effectiveness of the ALPS algorithm on an antenna design problem in which evolution with ALPS produces antennas more than twice as good as does evolution with two other types of EAs. Further analysis shows that the ALPS model does allow the offspring of newly generated individuals to move the population out of mediocre local-optima to better parts of the fitness landscape.

Hornby, Gregory S.↗

Reduced meiotic recombination in rhesus macaques and the origin of the human recombination landscape

Characterizing meiotic recombination rates across the genomes of nonhuman primates is important for understanding the genetics of primate populations, performing genetic analyses of phenotypic variation and reconstructing the evolution of human recombination. Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primates in biomedical research. We constructed a high-resolution genetic map of the rhesus genome based on whole genome sequence data from Indian-origin rhesus macaques. The genetic markers used were approximately 18 million SNPs, with marker density 6.93 per kb across the autosomes. We report that the genome-wide recombination rate in rhesus macaques is significantly lower than rates observed in apes or humans, while the distribution of recombination across the macaque genome is more uniform. These observations provide new comparative information regarding the evolution of recombination in primates.

59 BASIC BIOLOGICAL SCIENCES↗

The Evolution of Volatile Memory Forensics

The collection and analysis of volatile memory is a vibrant area of research in the cybersecurity community. The ever-evolving and growing threat landscape is trending towards fileless malware, which avoids traditional detection but can be found by examining a system’s random access memory (RAM). Additionally, volatile memory analysis offers great insight into other malicious vectors. It contains fragments of encrypted files’ contents, as well as lists of running processes, imported modules, and network connections, all of which are difficult or impossible to extract from the file system. For these compelling reasons, recent research efforts have focused on the collection of memory snapshots and methods to analyze them for the presence of malware. However, to the best of our knowledge, no current reviews or surveys exist that systematize the research on both memory acquisition and analysis. We fill that gap with this novel survey by exploring the state-of-the-art tools and techniques for volatile memory acquisition and analysis for malware identification. For memory acquisition methods, we explore the trade-offs many techniques make between snapshot quality, performance overhead, and security. For memory analysis, we examined the traditional forensic methods used, including signature-based methods, dynamic methods performed in a sandbox environment, as well as machine learning-based approaches. We summarize the currently available tools, and suggest areas for more research.

Nyholm, Hannah↗

“Multiagent” Screening Improves Directed Enzyme Evolution by Identifying Epistatic Mutations

Enzyme evolution has enabled numerous advances in biotechnology and synthetic biology, yet still requires many iterative rounds of screening to identify optimal mutant sequences. This is due to the sparsity of the fitness landscape, which is caused by epistatic mutations that only offer improvements when combined with other mutations. We report an approach that incorporates diverse substrate analogues in the screening process, where multiple substrates act like multiple agents navigating the fitness landscape, identifying epistatic mutant residues without a need for testing the entire combinatorial search space. We initially validate this approach by engineering a malonyl-CoA synthetase and identify numerous epistatic mutations improving activity for several diverse substrates. The majority of these mutations would have been missed upon screening for a single substrate alone. We expect that this approach can accelerate a wide array of enzyme engineering programs.

60 APPLIED LIFE SCIENCES↗