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At least 667 records · Page 37

Control of Peptide Amphiphile Supramolecular Nanostructures by Isosteric Replacements

Supramolecular nanostructures with tunable properties can have applications in medicine, pharmacy, and biotechnology. In this work, we show that the self-assembly behavior of peptide amphiphiles (PAs) can be effectively tuned by replacing the carboxylic acids exposed to the aqueous media with isosteres, functionalities that share key physical or chemical properties with another chemical group. Transmission electron microscopy, atomic force microscopy, and small-angle X-ray scattering studies indicated that the nanostructure’s morphologies are responsive to the ionization states of the side chains, which are related to their pK a values. Circular dichroism studies revealed the effect of the isosteres on the internal arrangement of the nanostructures. The interactions between diverse surfaces and the nanostructures and the effect of salt concentration and temperature were assessed to further understand the properties of these self-assembled systems. These results indicate that isosteric replacements allow the pH control of supramolecular morphology by manipulating the pK a of the charged groups located on the nanostructure’s surface. Theoretical studies were performed to understand the morphological transitions that the nanostructures underwent in response to pH changes, suggesting that the transitions result from alterations in the Coulomb forces between PA molecules. Furthermore, this work provides a strategy for designing biomaterials that can maintain or change behaviors based on the pH differences found within cells and tissues.

36 MATERIALS SCIENCE↗

Structural basis for Marburg virus VP35-mediated immune evasion mechanisms

Filoviruses, marburgvirus (MARV) and ebolavirus (EBOV), are causative agents of highly lethal hemorrhagic fever in humans. MARV and EBOV share a common genome organization but show important differences in replication complex formation, cell entry, host tropism, transcriptional regulation, and immune evasion. Multifunctional filoviral viral protein (VP) 35 proteins inhibit innate immune responses. Recent studies suggest double-stranded (ds)RNA sequestration is a potential mechanism that allows EBOV VP35 to antagonize retinoic-acid inducible gene-I (RIG-I) like receptors (RLRs) that are activated by viral pathogen–associated molecular patterns (PAMPs), such as double-strandedness and dsRNA blunt ends. Here, we show that MARV VP35 can inhibit IFN production at multiple steps in the signaling pathways downstream of RLRs. The crystal structure of MARV VP35 IID in complex with 18-bp dsRNA reveals that despite the similar protein fold as EBOV VP35 IID, MARV VP35 IID interacts with the dsRNA backbone and not with blunt ends. Functional studies show that MARV VP35 can inhibit dsRNA-dependent RLR activation and interferon (IFN) regulatory factor 3 (IRF3) phosphorylation by IFN kinases TRAF family member-associated NFkb activator (TANK) binding kinase-1 (TBK-1) and IFN kB kinase e (IKKe) in cell-based studies. We also show that MARV VP35 can only inhibit RIG-I and melanoma differentiation associated gene 5 (MDA5) activation by double strandedness of RNA PAMPs (coating backbone) but is unable to inhibit activation of RLRs by dsRNA blunt ends (end capping). In contrast, EBOV VP35 can inhibit activation by both PAMPs. Insights on differential PAMP recognition and inhibition of IFN induction by a similar filoviral VP35 fold, as shown here, reveal the structural and functional plasticity of a highly conserved virulence factor.

Ramanan, Parameshwaran↗

Meeting the Challenges of Modern Transit through the Integration of Traditional Transit, On-Demand Micro-Transit Services and Vehicle Automation - A Case Study in Chandler, Arizona

Current technology trends of vehicle automation, electrification and on-demand transit are providing new tools to develop effective public mobility services, yet need to be balanced with traditional modes to serve the spectrum of demand effectively and efficiently. Automated vehicle transportation network company (TNC) services, better known as 'Robotaxis' are beginning to proliferate and scale across the US, with Waymo as the lead commercial entity. Chandler, AZ was the first fully automated deployment of Waymo technology. Chandler was also one of the first municipalities in Arizona to roll out micro-transit service to its citizens in 2022. At present the Chandler Flex micro-transit program is beginning to partner with Waymo to augment micro-transit services during peak demands, another first in the nation. However, the mix of services in Chandler relies not only on new technology, but also on traditional modes including fixed route transit and para-transit services. These are blended and balanced such that both old and new modes are applied within the context in which each excel. This presentation will provide background on the Chandler, AZ public mobility services, and the performance metrics that govern their use and selection within the spectrum of development and population density as well as socio-demographics within Chandler. Additionally, the behavioral response of the use of unmanned, automated vehicles employed to augment micro-transit is novel, the first in the nation - and initial feedback from public transit constituents in Chandler will be shared.

24 POWER TRANSMISSION AND DISTRIBUTION↗

Design and implementation of a medium speed communications interface and protocol for a low cost, refreshed display computer

The design and implementation of hardware and software systems involved in using a 40,000 bit/second communication line as the connecting link between an IMLAC PDS 1-D display computer and a Univac 1108 computer system were described. The IMLAC consists of two independent processors sharing a common memory. The display processor generates the deflection and beam control currents as it interprets a program contained in the memory; the minicomputer has a general instruction set and is responsible for starting and stopping the display processor and for communicating with the outside world through the keyboard, teletype, light pen, and communication line. The processing time associated with each data byte was minimized by designing the input and output processes as finite state machines which automatically sequence from each state to the next. Several tests of the communication link and the IMLAC software were made using a special low capacity computer grade cable between the IMLAC and the Univac.

Phyne, J. R.↗

The Global File System

The global file system (GFS) is a prototype design for a distributed file system in which cluster nodes physically share storage devices connected via a network-like fiber channel. Networks and network-attached storage devices have advanced to a level of performance and extensibility so that the previous disadvantages of shared disk architectures are no longer valid. This shared storage architecture attempts to exploit the sophistication of storage device technologies whereas a server architecture diminishes a device's role to that of a simple component. GFS distributes the file system responsibilities across processing nodes, storage across the devices, and file system resources across the entire storage pool. GFS caches data on the storage devices instead of the main memories of the machines. Consistency is established by using a locking mechanism maintained by the storage devices to facilitate atomic read-modify-write operations. The locking mechanism is being prototyped in the Silicon Graphics IRIX operating system and is accessed using standard Unix commands and modules.

Soltis, Steven R.↗

Including operational aspects in the planning of power systems with large amounts of variable generation: A review of modeling approaches

In the past, power system planning was based on meeting the load duration curve at minimum cost. The increasing share of variable generation (VG) makes operational constraints more important in the planning problem, and there is more and more interest in considering aspects such as sufficient ramping capability, sufficient reserve procurement, power system stability, storage behavior, and the integration of other energy sectors often through demand response assets. In VG integration studies, several methods have been applied to combine the planning and operational timescales. We present a four-level categorization for the modeling methods, in order of increasing complexity: (1a) investment model only, (1b) operational model only, (2) unidirectionally soft-linked investment and operational models, (3a) bidirectionally soft-linked investment and operational models, (3b) operational model with an investment update algorithm, and (4) co-optimization of investments and operation. The review shows that using a low temporal resolution or only few representative days will not suffice in order to determine the optimal generation portfolio. In addition, considering operational effects proves to be important in order to get a more optimal generation portfolio and more realistic estimations of system costs. However, operational details appear to be less significant than the temporal representation. Furthermore, the benefits and impacts of more advanced modeling techniques on the resulting generation capacity mix significantly depend on the system properties. Thus, the choice of the model should depend on the purpose of the study as well as on system characteristics.

24 POWER TRANSMISSION AND DISTRIBUTION↗

Multimodal framework for the joint analysis of single-cell RNA and T cell receptor sequencing data predicts T cell response to cancer immunotherapy

T cell states are prognostic in different cancer types. Recent technologies enable joint profiling of T cell RNA and T cell receptor (TCR) sequences at single-cell resolution. Here we present the TCR-RNA Integrating Model (TRIM), a multi-modal variational autoencoder framework that integrates RNA-TCR data and predicts T cell clonality and transcriptional states. TRIM learns a shared representation of the data conditioned on patient, tissue source, and treatment timepoint. We applied TRIM to three independent datasets that included T cells collected before and after checkpoint inhibitor treatment, sourced either from blood and tumor biopsies in patients with head and neck squamous cell carcinoma and colorectal cancer, or from tumor and adjacent tissue in a pan-cancer dataset. In all settings, TRIM accurately predicted intra-tumor T cell clonal expansion and transcriptional status based on T cells from blood or normal tissue before treatment, demonstrating its utility in modeling multimodal T cell data and predicting T cell response to treatment and disease progression.

60 APPLIED LIFE SCIENCES↗

CpG preconditioning regulates miRNA expression that modulates genomic reprogramming associated with neuroprotection against ischemic injury

CpG preconditioning reprograms the genomic response to stroke to protect the brain against ischemic injury. The mechanisms that underlie genomic reprogramming are incompletely understood. MicroRNAs (miRNA) are novel regulators of gene expression; however, their potential role in modulating gene responses produced by CpG preconditioning is unknown. We evaluated brain miRNA expression in response to CpG preconditioning prior to and following stroke using microarray. Importantly, we have gene expression data from previous gene microarrays under the same conditions and timepoints, which allowed integration of miRNA and gene expression data to specifically identify regulated miRNA gene targets. Statistical analysis revealed that the miRNA targets were enriched in our regulated gene population, implicating that miRNAs likely orchestrate this gene expression. CpG and saline treatment shared expression of many miRNAs and their gene targets correlate with damaging upregulation of inflammation and protective suppression of metabolism and excitotoxicity. Excitingly, miRNAs that were differentially regulated between CpG and saline treated animals associated with the upregulation of several neuroprotective genes, indicating that these miRNAs are involved in genomic reprogramming to increase protection. This data suggests that miRNAs regulate endogenous responses to stroke and that manipulation of these miRNAs may have the potential to acutely activate novel protective responses to stroke.

systems biology, microRNA, bioinformatics, stroke,↗

Sharing is caring: An extensive analysis of parameter-based transfer learning for the prediction of building thermal dynamics

In recent years deep neural networks have been proposed as a lightweight data-driven model to capture high-dimensional, nonlinear physical processes to predict building thermal responses. However, the need of a large amount of data for the training process of deep neural networks clashes with the potential limited data availability in most existing or new buildings. Transfer learning aims to enhance the performance of a target learner exploiting knowledge from related and similar environments. This study conducted a suite of experiments that leveraged 250 data-driven models based on a synthetic dataset of a building archetype to study the influence of data availability, energy efficiency level, occupancy and climate for the transfer process of thermal dynamics. The performance of the transfer learning process was compared against a classical machine learning approach. Here, the results suggest that building thermal dynamics can be effectively transferred under the same climatic conditions, increasing performance when dealing with different occupancy schedules, efficiency levels and low data availability. Furthermore, the paper compares the performance of both transfer learning and machine learning approaches in an online fashion, to support the implementation in real-world deployment.

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗

Metabolomic signatures of chronic kidney disease of diverse etiologies in the rats and humans

Chronic kidney disease (CKD) has emerged as a major public health problem worldwide. It frequently progresses to end-stage renal disease, which is related to very high cost and mortality. Novel biomarkers can provide insight into the novel mechanism, facilitate early detection, and monitor progression of CKD and its response to therapeutic interventions. To identify potential biomarkers, we applied an UPLC-HDMS together with univariate and multivariate statistical analyses using plasma samples from patients with CKD of diverse etiologies (100 sera in discovery set and 120 sera in validation set) and two different rat models of CKD. Using comprehensive screening and validation workflow, we identified a panel of seven metabolites that were shared by all patients and animals regardless of the underlying cause of CKD. These included ricinoleic acid, stearic acid, cytosine, LPA(16:0), LPA(18:2), 3-methylhistidine, and argininic acid. The combination of these seven biomarkers enabled the discrimination of patients with CKD from healthy subjects with a sensitivity of 83.3% and a specificity of 96.7%. In addition, these biomarkers accurately reflected improvements in renal function in response to the therapeutic interventions. Lastly, our results indicated that the identified biomarkers may improve the diagnosis of CKD and provide a novel tool for monitoring of the progression of disease and response to treatment in CKD patients.

5/6 nephrectomized rats↗

Graph-based optimization of epitope coverage for vaccine antigen design

Epigraph is a recently developed algorithm that enables the computationally efficient design of single or multi-antigen vaccines to maximize the potential epitope coverage for a diverse pathogen population. Potential epitopes are defined as short contiguous stretches of proteins, comparable in length to T-cell epitopes. This optimal coverage problem can be formulated in terms of a directed graph, with candidate antigens represented as paths that traverse this graph. Epigraph protein sequences can also be used as the basis for designing peptides for experimental evaluation of immune responses in natural infections to highly variable proteins. The epigraph tool suite also enables rapid characterization of populations of diverse sequences from an immunological perspective. Fundamental distance measures are based on immunologically relevant shared potential epitope frequencies, rather than simple Hamming or phylogenetic distances. Here, we provide a mathematical description of the epigraph algorithm, include a comparison of different heuristics that can be used when graphs are not acyclic, and we describe an additional tool we have added to the web-based epigraph tool suite that provides frequency summaries of all distinct potential epitopes in a population. Lastly, we also show examples of the graphical output and summary tables that can be generated using the epigraph tool suite and explain their content and applications.

60 APPLIED LIFE SCIENCES↗

The atmospheric effect of aerosols on future tropical cyclone frequency and precipitation in the Energy Exascale Earth System Model

This study uses experiments from the Energy Exascale Earth System Model (E3SM) to compare the influence on tropical cyclone (TC) activity of: (i) the atmospheric effect of aerosols under specified sea-surface temperatures (SSTs); and (ii) the net effect of greenhouse gases (GhGs) (including changes in SSTs). The experiments were performed using the CMIP6 Shared Socioeconomic Pathway SSP5-8.5 emissions scenario with GhG-induced SST warming specified and atmospheric aerosol effects simulated but without explicit ocean coupling. Insignificant changes in global TC frequency are found in response to the atmospheric effect of future aerosols and GhGs, as significant regional responses in TC frequency counteract each other. Future GhGs contribute to more frequent TCs in the North Atlantic, and reductions over the Northwestern Pacific and Southern Indian Ocean. The atmospheric effect of future aerosols drives more frequent TCs over the Northwestern Pacific and reductions over the Northeast Pacific and North Atlantic. Along with increases in TC intensity, global TC precipitation (TCP) is projected to increase by 52.8% (14.1%/K) due to the combined effect of future aerosols and GhGs. Although both forcings contribute to TCP increases (14.7–19.3% from reduced aerosols alone and 28.1–33.3% from increased GhGs alone), they lead to different responses in the spatial structure of TCP. TCP increases preferentially in the inner-core due to increased GhGs, whereas TCP decreases in the inner-core and increases in the outer-bands in response to the atmospheric effects of decreased aerosols. These changes are distinct from those caused by aerosol-induced SST changes, which have been considered in other studies.

54 ENVIRONMENTAL SCIENCES↗

When do different scenarios of projected electricity demand start to meaningfully diverge?

Resource adequacy studies look at balancing electricity supply and demand on 10- to 15-year time horizons while asset investment planning typically evaluates returns on 20- to 40-year time horizons. Projections of electricity demand are factored into the decision-making in both cases. Climate, energy policy, and socioeconomic changes are key uncertainties known to influence electricity demands, but their relative importance for demands over the next 10-40 years is unclear. The power sector would benefit from a better understanding of the need to characterize these uncertainties for resource adequacy and investment planning. In this study, we quantify when projected United States (U.S.) electricity demands start to meaningfully diverge in response to a range of climate, energy policy, and socioeconomic drivers. Here we use a wide yet plausible range of 21st century scenarios for the U.S. The projections span two population/economic growth scenarios (Shared Socioeconomic Pathways 3 and 5) and two climate/energy policy scenarios, one including climate mitigation policies and one without (Representative Concentration Pathways 4.5 and 8.5). Each climate/energy policy scenario has two warming levels to reflect a range of climate model uncertainty. We show that the socioeconomic scenario matters almost immediately – within the next 10 years, the climate/policy scenario matters within 25-30 years, and the climate model uncertainty matters only after 50+ years. This work can inform the power sector working to integrate climate change uncertainties into their decision-making.

29 ENERGY PLANNING, POLICY, AND ECONOMY↗

Coordinated frequency regulation among asynchronous AC grids with an MTDC system

With the increasing penetration level of renewable power, the power systems’ inertias are decreasing. To ensure that the frequency is above the threshold of the under frequency load shedding, one effective way is to share the spinning reserves among asynchronous AC grids through HVDC systems. In this paper, a coordinated frequency regulation scheme that enables spinning reserves sharing is proposed for such hybrid AC/DC grids. This scheme is a communication-free method that consists of the droop control, the inertia emulation control and the frequency safety control. The combined response of the three controls can increase not only the frequency nadir but also the settled frequency of the disturbed grid. In addition, the hysteresis comparators and the power injection limits are adopted in the frequency regulation scheme to reduce the coupling effect among AC grids. Thus, under small and harmless disturbance, the frequency regulation scheme will be inactive; the disturbance in strong AC grids would not affect the weak AC systems. The frequency regulation scheme coordinates well with the automatic generation control of the grids. Furthermore, the feasibility and effectiveness of the proposed frequency regulation scheme are verified through simulation studies.

24 POWER TRANSMISSION AND DISTRIBUTION↗

FREYA-a new Monte Carlo code for improved modeling of fission chains

A new simulation capability for modeling of individual fission events and chains and the transport of fission products in materials is presented. FREYA ( Fission Yield Event Yield Algorithm ) is a Monte Carlo code for generating fission events providing correlated kinematic information for prompt neutrons, gammas, and fragments. As a standalone code, FREYA calculates quantities such as multiplicity-energy, angular, and gamma-neutron energy sharing correlations. To study materials with multiplication, shielding effects, and detectors, we have integrated FREYA into the general purpose Monte Carlo code MCNP. This new tool will allow more accurate modeling of detector responses including correlations and the development of SNM detectors with increased sensitivity.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗

Life Cycle Analysis of Kidney Gene Expression in Male F344 Rats

Age is a predisposing condition for susceptibility to chronic kidney disease and progression as well as acute kidney injury that may arise due to the adverse effects of some drugs. Age-related differences in kidney biology, therefore, are a key concern in understanding drug safety and disease progression. We hypothesize that the underlying suite of genes expressed in the kidney at various life cycle stages will impact susceptibility to adverse drug reactions. Therefore, establishing changes in baseline expression data between these life stages is the first and necessary step in evaluating this hypothesis. Untreated male F344 rats were sacrificed at 2, 5, 6, 8, 15, 21, 78, and 104 weeks of age. Kidneys were collected for histology and gene expression analysis. Agilent whole-genome rat microarrays were used to query global expression profiles. An ANOVA (p,0.01) coupled with a fold-change.1.5 in relative mRNA expression, was used to identify 3,724 unique differentially expressed genes (DEGs). Principal component analyses of these DEGs revealed three major divisions in life-cycle renal gene expression. K-means cluster analysis identified several groups of genes that shared age-specific patterns of expression. Pathway analysis of these gene groups revealed age-specific gene networks and functions related to renal function and aging, including extracellular matrix turnover, immune cell response, and renal tubular injury. Large age-related changes in expression were also demonstrated for the genes that code for qualified renal injury biomarkers KIM-1, Clu, and Tff3. These results suggest specific groups of genes that may underlie age-specific susceptibilities to adverse drug reactions and disease. This analysis of the basal gene expression patterns of renal genes throughout the life cycle of the rat will improve the use of current and future renal biomarkers and inform our assessments of kidney injury and disease.

59 BASIC BIOLOGICAL SCIENCES↗

Human RNome Project draft human RNome sequence of GM12878, B-cell line, obtained by mass-spectrometry sequencing, long-read sequencing and short-read sequencing.

Here we report the first draft of the human RNome sequence, a reference map of RNA chemical modifications in a human B-cell line. RNA carries a diverse repertoire of chemical modifications that regulate gene expression, cellular function, and responses to physiological and pathological cues. Yet, unlike the genome, no reference map of RNA modifications is available for any human cell. To generate this resource, the Human RNome Project Consortium analyzed a shared RNA preparation from the well-characterized GM12878 B-cell line using short-read sequencing, long-read direct RNA sequencing, and mass spectrometry, generating more than 7.1 billion sequencing reads spanning approximately 1.2 trillion nucleotides. The resulting maps of the human RNome reveal that RNA modifications are organized according to function, transcript architecture, and cellular identity. Modifications concentrate at functional centers of ribosomal and transfer RNAs, follow the canonical topology of N6-methyladenosine in coding transcripts, and form coordinated hotspots in immune regulatory genes. This first reference human RNome provides a foundation for understanding how RNA chemistry shapes cellular identity, human disease, and the development of RNA-based therapeutics.

59 BASIC BIOLOGICAL SCIENCES↗

A Detailed Study of the Most Relaxed SPT-selected Galaxy Clusters: Properties of the Cool Core and Central Galaxy

We present a multi-wavelength analysis of the four most relaxed clusters in the South Pole Telescope 2500 deg 2 survey, which lie at 0.55 < z < 0.75. This study, which utilizes new, deep data from Chandra and Hubble, along with ground-based spectroscopy from Gemini and Magellan, improves significantly on previous studies in both depth and angular resolution, allowing us to directly compare to clusters at z~0. We find that the temperature, density, and entropy profiles of the intracluster medium (ICM) are very similar among the four clusters, and share similar shapes to clusters at z~0. Specifically, we find no evidence for deviations from self similarity in the temperature profile over the radial range 10kpc < r < 1Mpc, implying that the processes responsible for preventing runaway cooling over the past >6 Gyr are, at least roughly, preserving self similarity. We find typical metallicities of ~0.3 Zsun in the bulk of the ICM, rising to ~0.5 Zsun in the inner ~100 kpc, and reaching ~1 Zsun at r < 10kpc. This central excess is similar in magnitude to what is observed in the most relaxed clusters at z~0, suggesting that both the global metallicity and the central excess that we see in cool core clusters at z~0 were in place very early in the cluster lifetime and, specifically, that the central excess is not due to late-time enrichment by the central galaxy. Consistent with observations at z~0, we measure a diversity of stellar populations in the central brightest cluster galaxies of these four clusters, with star formation rates spanning a factor of ~500, despite the similarity in cooling time, cooling rate, and central entropy. These data suggest that, while the details vary dramatically from system to system, runaway cooling has been broadly regulated in relaxed clusters over the past 6 Gyr.

79 ASTRONOMY AND ASTROPHYSICS↗