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At least 1,063 records · Page 59

Three-Dimensional Normal Human Neutral Progenitor Tissue-Like Assemblies: A Model for Persistent Varicella-Zoster Virus Infection and Platform to Study Oxidate Stress and Damage in Multiple Hit Scenarios

The environment of space results in a multitude of challenges to the human physiology that present barriers to extended habitation and exploration. Over 40 years of investigation to define countermeasures to address space flight adaptation has left gaps in our knowledge regarding mitigation strategies partly due to the lack of investigative tools, monitoring strategies, and real time diagnostics to understand the central causative agent(s) responsible for physiologic adaptation and maintaining homeostasis. Spaceflight-adaptation syndrome is the combination of space environmental conditions and the synergistic reaction of the human physiology. Our work addresses the role of oxidative stress and damage (OSaD) as a negative and contributing Risk Factor (RF) in the following areas of combined spaceflight related dysregulation: i) radiation induced cellular damage [1], [2] ii) immune impacts and the inflammatory response [3], [4] and iii) varicella zoster virus (VZV) reactivation [5]. Varicella-zoster (VZV)/Chicken Pox virus is a neurotropic human alphaherpes virus resulting in varicella upon primary infection, suppressed by the immune system becomes latent in ganglionic neurons, and reactivates under stress events to re-express in zoster and possibly shingles. Our laboratory has developed a complex three-dimensional (3D) normal human neural tissue model that emulates several characteristics of the human trigeminal ganglia (TG) and allows the study of combinatorial experimentation which addresses, simultaneously, OSaD associated with Spaceflight adaptation and habitation [6]. By combining the RFs of microgravity, radiation, and viral infection we will demonstrate that living in the space environment leads to significant physiological consequences for the peripheral and subsequently the central nervous system (PNS, CNS) associated with OSaD generation and consequentially endangers long-duration and exploration-class missions.

Goodwin, Thomas J.↗

Entry and Disposition of Zika Virus Immune Complexes in a Tissue Culture Model of the Maternal-Fetal Interface

Zika virus (ZIKV) infections have been associated with an increased incidence of severe microcephaly and other neurodevelopmental disorders in newborn babies. Passive immunization with anti-ZIKV neutralizing antibodies has the potential to become a feasible treatment or prophylaxis option during pregnancy. Prior to clinical use, such antibodies should be assessed for their ability to block ZIKV passage to the fetus. We used human placental and mammalian cell monolayers that express FcRn and laboratory preparations of anti-ZIKV antibodies as a model system to investigate the disposition of ZIKV/antibody immune complexes (ICs) at the maternal-fetal interface. We further characterized solution properties of the ICs to evaluate whether these are related to in vitro effects. We found that both ZIKV and ZIKV envelope glycoprotein can enter and passage through epithelial cells, especially those that overexpress FcRn. In the presence of ZIKV antibodies, Zika virus entry was bimodal, with reduced entry at the lowest (0.3–3 ng/mL) and highest (µg/mL) antibody concentrations. Intermediate concentrations attenuated inhibition or enhanced viral entry. With respect to anti-ZIKV antibodies, we found that their degradation was accelerated when presented as ICs containing increased amounts of ZIKV immunogen. Of the two monoclonal antibodies tested, the preparation with higher aggregation also exhibited higher degradation. Our studies confirm that intact Zika virus and its envelope immunogen have the potential to enter and be transferred across placental and other epithelial cells that express FcRn. Presence of anti-ZIKV IgG antibodies can either block or enhance cellular entry, with the antibody concentration playing a complex role in this process. Physicochemical properties of IgG antibodies can influence their degradation in vitro.

60 APPLIED LIFE SCIENCES↗

Green’s Function Perspective on the Nonlinear Density Response of Quantum Many-Body Systems

We derive equations of motion for higher order density response functions using the theory of thermodynamic Green’s functions. We also derive expressions for the higher order generalized dielectric functions and polarization functions. Moreover, we relate higher order response functions and higher order collision integrals within the Martin–Schwinger hierarchy. We expect our results to be highly relevant to the study of a variety of quantum many-body systems such as matter under extreme temperatures, densities, and pressures.

Density Functional Theory↗

Anaerobic methane oxidation coupled to manganese reduction by members of the Methanoperedenaceae

Abstract Anaerobic oxidation of methane (AOM) is a major biological process that reduces global methane emission to the atmosphere. Anaerobic methanotrophic archaea (ANME) mediate this process through the coupling of methane oxidation to different electron acceptors, or in concert with a syntrophic bacterial partner. Recently, ANME belonging to the archaeal family Methanoperedenaceae (formerly known as ANME-2d) were shown to be capable of AOM coupled to nitrate and iron reduction. Here, a freshwater sediment bioreactor fed with methane and Mn(IV) oxides (birnessite) resulted in a microbial community dominated by two novel members of the Methanoperedenaceae, with biochemical profiling of the system demonstrating Mn(IV)-dependent AOM. Genomic and transcriptomic analyses revealed the expression of key genes involved in methane oxidation and several shared multiheme c-type cytochromes (MHCs) that were differentially expressed, indicating the likely use of different extracellular electron transfer pathways. We propose the names “Candidatus Methanoperedens manganicus” and “Candidatus Methanoperedens manganireducens” for the two newly described Methanoperedenaceae species. This study demonstrates the ability of members of the Methanoperedenaceae to couple AOM to the reduction of Mn(IV) oxides, which suggests their potential role in linking methane and manganese cycling in the environment.

54 ENVIRONMENTAL SCIENCES↗

Laser beam pointing stabilization using analog position-sensitive diodes

Laser wire scanners have been used for ion beam profile and emittance measurements at the Spallation Neutron Source linear accelerator. Due to propagation distances exceeding 100 m, reliable measurements require laser beam stabilization, previously accomplished with a feedback control loop using a digital camera as a position sensor [Hardin et al., Opt. Express 19, 2874 (2011)]. Here, this paper presents an upgraded pointing stabilization system utilizing analog position-sensitive diodes (PSDs) as the position detector, optimized with an optical diffuser. The new system significantly surpasses the previous system by offering an order-of-magnitude improvement in radiation tolerance and a bandwidth limited only by the burst repetition rate of the laser beam. Operating with a 60-Hz burst mode laser, the new system effectively suppresses laser beam drifts up to 30 Hz, compared to the previous system’s 4 Hz limit. In addition, the amplitude of spectral components below 0.1 Hz was reduced by a factor of more than 100, which is over seven times greater than was achieved by the previous system.

Data acquisition↗

Detecting hidden layers from spreading dynamics on complex networks

When dealing with spreading processes on networks it can be of the utmost importance to test the reliability of data and identify potential unobserved spreading paths. In this paper we address these problems and propose methods for hidden layer identification and reconstruction. We also explore the interplay between difficulty of the task and the structure of the multilayer network describing the whole system where the spreading process occurs. Our methods stem from an exact expression for the likelihood of a cascade in the susceptible-infected model on an arbitrary graph. We then show that by imploring statistical properties of unimodal distributions and simple heuristics describing joint likelihood of a series of cascades one can obtain an estimate of both existence of a hidden layer and its content with success rates far exceeding those of a null model. Furthermore, we conduct our analyses on both synthetic and real-world networks providing evidence for the viability of the approach presented.

97 MATHEMATICS AND COMPUTING↗

Mycorrhizal effector PaMiSSP10b alters polyamine biosynthesis in Eucalyptus root cells and promotes root colonization

Summary Pathogenic microbes are known to manipulate the defences of their hosts through the production of secreted effector proteins. More recently, mutualistic mycorrhizal fungi have also been described as using these secreted effectors to promote host colonization. Here we characterize a mycorrhiza‐induced small secreted effector protein of 10 kDa produced by the ectomycorrhizal fungus Pisolithus albus , PaMiSSP10b. We demonstrate that PaMiSSP10b is secreted from fungal hyphae, enters the cells of its host, Eucalyptus grandis, and interacts with an S‐adenosyl methionine decarboxylase (AdoMetDC) in the polyamine pathway. Plant polyamines are regulatory molecules integral to the plant immune system during microbial challenge. Using biochemical and transgenic approaches we show that expression of PaMiSSP10b influences levels of polyamines in the plant roots as it enhances the enzymatic activity of AdoMetDC and increases the biosynthesis of higher polyamines. This ultimately favours the colonization success of P. albus . These results identify a new mechanism by which mutualistic microbes are able to manipulate the host´s enzymatic pathways to favour colonization.

Plett, Jonathan M.↗

Multifactorial genetic control and magnesium levels govern the production of a Streptomyces antibiotic with unusual cell density dependence

Streptomyces bacteria are renowned both for their antibiotic production capabilities and for their cryptic metabolic potential. Their metabolic repertoire is subject to stringent genetic control, with many of the associated biosynthetic gene clusters being repressed by the conserved nucleoid-associated protein Lsr2. In an effort to stimulate new antibiotic production in wild Streptomyces isolates, we leveraged the activity of an Lsr2 knockdown construct and successfully enhanced antibiotic production in the wild Streptomyces isolate WAC07094. We determined that this new activity stemmed from increased levels of the angucycline-like family member saquayamycin. Saquayamycin has both antibiotic and anti-cancer activities, and intriguingly, beyond Lsr2-mediated repression, we found saquayamycin production was also suppressed at high density on solid or in liquid growth media; its levels were greatest in low-density cultures. This density-dependent control was exerted at the level of the cluster-situated regulatory gene sqnR and was mediated in part through the activity of the PhoRP two-component regulatory system, where deleting phoRP led to both constitutive antibiotic production and sqnR expression. This suggests that PhoP functions to repress the expression of sqnR at high cell density. We further discovered that magnesium supplementation could alleviate this density dependence, although its action was independent of PhoP. Finally, we revealed that the nitrogen-responsive regulators GlnR and AfsQ1 could relieve the repression exerted by Lsr2 and PhoP. Intriguingly, we found that this low density-dependent production of saquayamycin was not unique to WAC07094; saquayamycin production by another wild isolate also exhibited low-density activation, suggesting that this spatial control may serve an important ecological function in their native environments.

59 BASIC BIOLOGICAL SCIENCES↗

Safety in Artificial Intelligence: Challenges and Opportunities for the U.S. National Labs and Beyond

This report discusses the importance of the critical and underexplored topic of artificial intelligence (AI) safety, as highlighted during the “Strategy Alignment on AI Safety” workshop convened at Lawrence Livermore National Laboratory (LLNL) in April 2024. Through a summary of keynote talks, panel discussions, and breakout sessions, world-leading AI safety experts from academic, industry, national labs, and government agencies clearly agree on the need for and importance of large-scale investments for research and capabilities in AI safety. With the field innovating at unprecedented rates, there is increasing urgency to develop novel evaluation methodologies that allow full considerations of risks/threats of AI technologies in different domains. Quantitative metrics and effective methodologies that can evaluate and audit the “safeness” of how a given AI technology is trained, deployed, or regulated are, at best, nascent for certain scenarios or, more commonly, nonexistent. This maturation gap presents the possibility of serious threats to national security, and further inaction may have serious consequences. Additionally, the gap between the public’s and research community’s perceptions of AI risks/rewards is significant. While numerous voices from the AI community have expressed concern that the risks could be so high that future AI systems could inflict extinction-level damage to humanity if deployed incorrectly, the public largely is aware only of risk in low-impact scenarios. This discrepancy highlights the crucial need for researchers to articulate to governmental bodies what, why, and when various AI risks matter as part of motivating funding requests. Thus, the call to action for this community is to pursue AI safety as a “Big Science” project on a scale comparable to the Manhattan Project. High risks and high payoffs are on the table, but safe AI is a fast-moving target, and large-scale investments are needed to guide development of this technology in a responsible way. We highlight the need for a multilayered solution combining the development of new methods and algorithmic approaches to mitigate threats with an active participation of the government(s) in setting high industry standards and regulations based on state-of-the-art technology. The U.S. Department of Energy (DOE) national laboratories have served as leading institutions for scientific innovation in the U.S. for more than 70 years. Drawing on their expertise in the AI community and their history of safeguarding critical and sensitive information, and as we look to the future, national labs are the best choice for evaluating and safeguarding AI technologies.

97 MATHEMATICS AND COMPUTING↗

Sex- and age-specific aspects of human peripheral T-cell dynamics

Background: The diversity of the antigenic T cell receptor (TCR) repertoire clonally expressed on T lymphocytes is a key element of the adaptive immune system protective functions. A decline in diversity in the older adults is associated with health deterioration. This diversity is generated by the rearrangement of TRB genes coding for TCR chains during lymphocyte differentiation in the thymus, but is essentially maintained by peripheral T lymphocytes proliferation for most of life. Deep sequencing of rearranged TRB genes from blood cells allows the monitoring of peripheral T cell repertoire dynamics. We analysed two aspects of rearranged TRB diversity, related to T lymphocyte proliferation and to the distribution of the T cell clone size, in a collection of repertoires obtained from 1 to 74 years-old donors. Results: Our results show that peripheral T lymphocytes expansion differs according to the recombination status of their TRB loci. Their proliferation rate changes with age, with different patterns in men and women. T cell clone size becomes more heterogeneous with time, and, in adults, is always more even in women. Importantly, a longitudinal analysis of TRB repertoires obtained at ten years intervals from individual men and women confirms the findings of this cross-sectional study. Conclusions: Peripheral T lymphocyte proliferation partially depends on their thymic developmental history. The rate of proliferation of T cells differing in their TRB rearrangement status is different in men and women before the age of 18 years old, but similar thereafter.

59 BASIC BIOLOGICAL SCIENCES↗

Two-body linear guidance matrices

Analytical expressions for two-body linear guidance matrices in velocity dependent coordinate system for variant motion equation solutions

COORDINATE SYSTEM↗

Gas-flow restrictor

Gas flow restrictor is described, consisting of predetermined length and size of capillary tubing to control flow rate of carrier gas into gas chromatograph of flow rate of sample gas into mass spectrometer inlet system. Length and inner diameter of capillary tubing was estimated with mathematical expressions for viscous flow.

Bastien, G. J.↗

Polarization phenomena in multiphoton ionization of atoms

The theory of multiphoton ionization for an atomic system of arbitrary complexity is developed using a density matrix formalism. An expression is obtained which determines the differential N-photon ionization cross section as a function of the polarization states of the target atom and the incident radiation. The parameters which characterize the photoelectron angular distribution are related to the general reduced matrix elements for the N-photon transition. Two-photon ionization of unpolarized atoms is treated as an illustration of the use of the theory. The dependence of the multiphoton ionization cross section on the polarization state of the incident radiation, which has been observed in two- and three-photon ionization of Cs, is accounted for by the theory. Finally, the photoelectron spin polarization produced by the multiphoton ionization of unpolarized atoms, like the analogous polarization resulting from single-photon ionization, is found to depend on the circular polarization of the incident radiation.

Jacobs, V. L.↗

Polarization phenomena in multiphoton ionization of atoms.

The theory of multiphoton ionization for an atomic system of arbitrary complexity is developed using a density matrix formalism. An expression is obtained which determines the differential N-photon ionization cross section as a function of the polarization states of the target atom and the incident radiation. The parameters which characterize the photo-electron angular distribution are related to the general reduced matrix elements for the N-photon transition. Two-photon ionization of unpolarized atoms is treated as an illustration of the use of the theory. The dependence of the multiphoton ionization cross section on the polarization state of the incident radiation, which has been observed in two- and three-photon ionization of Cs, is accounted for by the theory. Finally, the photoelectron spin polarization produced by the multiphoton ionization of unpolarized atoms, like the analogous polarization resulting from single-photon ionization, is found to depend on the circular polarization of the incident radiation.

Jacobs, V. L.↗

Stress intensity factors of composite orthotropic plates containing periodic buffer strips

The fracture problem of laminated plates which consist of bonded orthotropic layers is studied. The fields equations for an elastic orthotropic body are transformed to give the displacement and stress expressions for each layer or strip. The unknown functions in these expressions are found by satisfying the remaining boundary and continuity conditions. A system of singular integral equations is obtained from the mixed boundary conditions. The singular behavior around the crack tip and at the bimaterial interface is studied. The stress intensity factors are computed for various material combinations and various crack geometries. The results are discussed and are compared with those for isotropic materials.

Delale, F.↗

Theory of flux anisotropies in a guiding center plasma

Assuming time stationarity of the one-particle distribution function f on the scale of the bounce motion of particles in a magnetic field, the paper expands the Vlasov equation through O(epsilon) in the adiabatic parameter epsilon, which is the ratio of particle gyroradius to scale length of the magnetic field. Since f is directly proportional to particle flux differential in kinetic energy and solid angle, f is in principle measurable in space experiments, and the present analysis is tailored to be explicitly applicable to space problems. It is shown that the usual expression for the electric field which produces plasma corotation in an axisymmetric system such as a dipole also holds for any nonaxisymmetric but rigidly rotating magnetic field pattern, provided the observed magnetic field is used in place of the dipole field. The analysis is applied to the electric field in a rigidly corotating magnetosphere.

Birmingham, T. J.↗