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At least 595 records · Page 33
All sourcesNASA NTRSDOE OSTI
DOE OSTI2015

Development of Human Factors Awareness for Criticality Safety Specialists at Westinghouse Nuclear Fuels - 14223

Although human factors assessment typically involves specialist expertise, it is considered that enhanced local knowledge of this area for criticality safety specialists supports the incorporation of human factors consideration into tasks such as safety assessment, design and hazard reviews, development of operational and engineered criticality controls, training, incident investigation and emergency response. At the Westinghouse Springfields Fuel Manufacturing Site in the United Kingdom, specialist human factor support has been engaged to identify key competencies and training plans for criticality safety specialists. In addition, discussions have been held with the UK's Office for Nuclear Regulation (ONR) to outline the proposal and to discuss the approach. Following completion of an internationally recognised human factors training course the learning is now being applied by criticality safety specialists. Recent examples of learning applied include: 1) Review of past events and incidents to support the consideration of operator/equipment interfaces, leading to improved designs and processes. 2) Identification of critical tasks and the level of human factor assessment that is likely to be required. To support this, guidance has been produced by the criticality section for staff and contractors performing criticality safety assessments. 3) Assessment of the 'aims and operability' of engineered and procedural controls derived as part of the criticality safety assessment process. This involves participation of plant management and operators. 4) Consideration of human factors in emergency response activities such as infrequent tasks and tasks being undertaken under time pressures etc. This has been examined in recent emergency exercises and in the development of a recent criticality exercise scenario. 5) Criticality training has been reviewed with Plant Management, focussing on the methods utilised to deliver training (e.g. classroom based, computer training, on plant walk-downs); the aims and scope of training and how understanding is validated. 6) The link between criticality safety assessment and how the operations are / will be conducted has been reviewed as part of formal and informal criticality meetings and inspections. A key aspect of this is the criticality specialist's interaction with both plant management and operational staff. The development of human factors awareness into the criticality safety specialist's competency framework continues to be developed at Westinghouse but real benefits to criticality safety are already being demonstrated by this approach. (author)

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗
DOE OSTI2024

Estimating the Contributions to Human Error Probability from the Convolution of the Distribution of Time Available and Time Required

As part of their duties, Human Reliability Analysis must often evaluate if crews in nuclear power plants (NPPs) can complete tasks associated with a human-failure event within time limits. For example, the time required in NPP scenarios is determined by systematic and structured walkthroughs, feasibility studies, recorded times from training exercises, and interviews with experienced operators and experts. Typically, a point estimate is derived for the estimate (mean, maximum, or 95th percentile of time required). Using point-estimate values can mask the risk associated with variability among crews, plant conditions and set-up, environmental conditions, and other impact factors under which these actions are executed. While point estimates for time required and time available have served the industry well, without considering the uncertainty they could lead to biased understanding about the risk. The Integrated Human Event Analysis System - General Methodology (IDHEAS-G) model (developed by the US Nuclear Regulatory Commission, NRC) for human error probability calculates human error probability by summing two probabilities: insufficient time and cognitive error. As such, the model takes a more holistic approach by considering the full distributions for time required and time available to calculate the human error probability because the time available to complete the task is insufficient. In this study, we expand on the work of the NRC and discuss methods for estimating these time considerations. For example, for the time required, the impact of Performance Influencing Factors (PIFs) on the distribution was divided into impacts that are aleatory in nature, such as crew-to-crew variability, and those that are epistemic (i.e., the PIFs). Starting with the factors that introduce aleatory uncertainty, a first-order distribution was developed from a large set of time required (i.e., NPP task completion times) data for the range of operator actions that occur in the NPP control room under simulated accident conditions. The first-order distribution can then be adjusted to account for epistemic uncertainty using research associated with the impact of applicable PIFs on the time required. We also develop guidance for analysts to address the probability distributions for the time available. The guidance we developed on how to estimate time required and time available distributions is based on the identification of pertinent research and data, data analyses, and expert knowledge elicitation.

human error probability, human performance, time e↗
NASA NTRS1996

The human power amplifier technology at the University of California, Berkeley

A human's ability to perform physical tasks is limited by physical strength, not by intelligence. We define "extenders" as a class of robot manipulators worn by humans to augment human mechanical strength, while the wearer's intellect remains the central control system for manipulating the extender. Our research objective is to determine the ground rules for the design and control of robotic systems worn by humans through the design, construction, and control of several prototype experimental direct-drive/non-direct-drive multi-degree-of-freedom hydraulic/electric extenders. The design of extenders is different from the design of conventional robots because the extender interfaces with the human on a physical level. Two sets of force sensors measure the forces imposed on the extender by the human and by the environment (i.e., the load). The extender's compliances in response to such contact forces were designed by selecting appropriate force compensators. This paper gives a summary of some of the selected research efforts related to Extender Technology, carried out during 1980s. The references, at the end of this article, give detailed description of the research efforts.

NASA Discipline Space Human Factors↗
DOE OSTI2024

Human–mouse comparison of the multistage nature of radiation carcinogenesis in a mathematical model

Abstract Mouse models are vital for assessing risk from environmental carcinogens, including ionizing radiation, yet the interspecies difference in the dose response precludes direct application of experimental evidence to humans. Herein, we take a mathematical approach to delineate the mechanism underlying the human–mouse difference in radiation‐related cancer risk. We used a multistage carcinogenesis model assuming a mutational action of radiation to analyze previous data on cancer mortality in the Japanese atomic bomb survivors and in lifespan mouse experiments. Theoretically, the model predicted that exposure will chronologically shift the age‐related increase in cancer risk forward by a period corresponding to the time in which the spontaneous mutational process generates the same mutational burden as that the exposure generates. This model appropriately fitted both human and mouse data and suggested a linear dose response for the time shift. The effect per dose decreased with increasing age at exposure similarly between humans and mice on a per‐lifespan basis (0.72‐ and 0.71‐fold, respectively, for every tenth lifetime). The time shift per dose was larger by two orders of magnitude in humans (7.8 and 0.046 years per Gy for humans and mice, respectively, when exposed at ~35% of their lifetime). The difference was mostly explained by the two orders of magnitude difference in spontaneous somatic mutation rates between the species plus the species‐independent radiation‐induced mutation rate. Thus, the findings delineate the mechanism underlying the interspecies difference in radiation‐associated cancer mortality and may lead to the use of experimental evidence for risk prediction in humans.

Oncology↗
DOE OSTI2021

High-Grade Vulvar, Vaginal, and Anal Precancers Among U.S. Adolescents and Young Adults After Human Papillomavirus Vaccine Introduction

Since human papillomavirus vaccine introduction, incidence rates of cervical precancers have decreased; however, the vaccine's impact on noncervical anogenital precancers has not been shown. These precancers are identified opportunistically and are not collected routinely by most cancer registries. This study examined the incidence rates of high-grade (intraepithelial lesions grade 3) vulvar, vaginal, and anal precancers among persons aged 15–39 years using 2000–2017 data from select cancer registries covering 27.8% of the U.S. population that required reporting of these precancers. Trends in incidence rates were evaluated with Joinpoint regression. Analyses were conducted in 2020. High-grade vulvar precancer rates declined by 21.0% per year after human papillomavirus vaccine introduction among females aged 15–19 years. In addition, high-grade vaginal precancer rates declined by 19.1% per year among females aged 15–29 years after human papillomavirus vaccine introduction. Compared with that in the prevaccine period when high-grade anal precancer rates were increasing, anal precancer rates after human papillomavirus vaccine introduction were stable among females aged 15–29 years and among males aged 30–39 years. Among males aged 15–29 years, the rates increased over the entire period but less so after human papillomavirus vaccine introduction. In conclusion, opportunistically-detected high-grade vulvar and vaginal precancers among females aged 15–29 years decreased and anal precancers stabilized in years after the introduction of the human papillomavirus vaccine, which is suggestive of the impact of the vaccine on noncervical human papillomavirus cancers.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Klotho down-regulates Egr-1 by inhibiting TGF-β1/Smad3 signaling in high glucose treated human mesangial cells

Diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease worldwide and is associated with glomerular mesangial cell (MC) proliferation and excessive extracellular matrix (ECM) production. Klotho can attenuate renal fibrosis in part by inhibiting TGF-β1/Smad3 signaling in DKD. Early growth response factor 1 (Egr-1) has been shown to play a key role in renal fibrosis in part by facilitating the formation of a positive feedback loop involving TGF-β1. However, whether Klotho down-regulates Egr-1 by inhibiting TGF-β1/Smad3 signaling in DKD is unclear. In the present study, we assessed human MCs that were incubated under high-glucose conditions to mimic diabetes. Then, we transfected the cells with Klotho plasmid or siRNA to overexpress or knock down Klotho gene and protein expression. Klotho, Egr-1, fibronectin (FN), collagen type I (Col I), Smad3 and phosphorylated Smad3 (p-Smad3) gene and protein expression levels were determined by RT-qPCR and western blotting respectively. High glucose time-dependently down-regulated Klotho mRNA and protein expression in cultured human MCs. pcDNA3.1-Klotho transfection-mediated Klotho overexpression down-regulated Egr-1, FN and Col I expression and the p-Smad3/Smad3 ratio in human MCs. Conversely, siRNA-mediated Klotho silencing up-regulated Egr-1, FN, and Col I expression and the p-Smad3/Smad3 ratio. Moreover, the effects of si-Klotho on Egr-1 expression were abolished by the TGF-β1 inhibitor SB-431542. Klotho overexpression can prevent mesangial ECM production in high-glucose-treated human MCs, an effect that has been partially attributed to Egr-1 down-regulation facilitated by TGF-β1/Smad3 signaling inhibition. - Highlights: • High glucose time-dependently down-regulated Klotho mRNA and protein expression in cultured human MCs. • Klotho overexpression down-regulated Egr-1 and prevented mesangial ECM production in high-glucose-treated human MCs. • Klotho down-regulated Egr-1 by inhibiting TGF-β1/Smad3 signaling in high-glucose-treated human MCs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Conditionally reprogrammed human normal bronchial epithelial cells express comparable levels of cytochromes p450 and are sensitive to BaP induction

Highlights: • Conditionally reprogrammed human normal bronchial epithelial cells can be propagated for a long term in vitro. • Conditionally reprogrammed human normal bronchial epithelial cells maintain normal karyotype and differentiation potential. • Conditionally reprogrammed human normal bronchial epithelial cells express comparable levels of Cytochromes p450 enzymes. • Conditionally reprogrammed human normal bronchial epithelial cells are sensitive to BaP induction. Cytochromes p450 (CYPs) metabolize thousands of endogenous and exogenous chemicals, including toxic compounds and drugs. The primary cells have relative short life span and are not able to sustain levels of metabolic enzymes CYPs expression and activity long enough in vitro. The immortalized cell lines are also not ideal for toxicity testing because of their low levels of CYPs expression. In this study, we established human normal bronchial epithelial cells using conditional reprogramming (CR) technique from three human donors (named as CR-HNBE1-3). These CR cells can proliferate continuously in defined culture system over 50 PDs within 2 months. The CR-HNBE cells exhibited the normal diploid karyotype, normal response to DNA damage and normal differentiation potential under the matrigel 3D culture condition. The CR-HNBE cells express the basal epithelial marker cytokeratin 14 (CK14) and epithelial secretory marker Mucin 5AC. Most importantly, CR-HNBE cells express comparable levels of CYP1B1 and CYP2E1 as those in lung tissue. These CR cells also express comparable mRNA of CYP1A1/CYP1A2, CYP2B6/CYP2C9/CYP2D6 and CYP3A4/CYP3A5 compared to the lung tissue. The basal activity of CYP1A1/CYP1B1 in these CR cells was 3–6 folds higher than that of 16HBE cells (an immortalized cell line widely used in toxicology field). Our data also demonstrated that Benzo(a)pyrene (BaP) induced up to 100 folds of mRNA expression of CYP1A1 or CYP1A2 in CR-HNBE cells. The activity of CYP1A1/CYP1B1 was induced by BaP up to 7–8 folds in CR-HNBE cells, while the activity of CYP1A1/CYP1B1 was induced maximum 2.5 folds in 16HBE cells. Taken together, CR-HNBE cells express comparable levels of CYPs and are sensitive to BaP induction, and will serve a sensitive, physiological and valuable in vitro toxicity testing model. This is the first report that normal human airway cells can be propagated for a long time and maintain comparable levels of CYPs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The heterozygous R155C VCP mutation: Toxic in humans! Harmless in mice?

Highlights: • Mutations of the human VCP gene cause several neurodegenerative diseases. • R155C VCP knock-in mice display multiple abnormalities but no typical VCP diseases. • Mutant VCP mRNA levels were markedly increased in man, but decreased in mice. • R155C VCP mRNA species in man and mice have different biological half lifes. Heterozygous missense mutations in the human VCP gene cause inclusion body myopathy associated with Paget disease of bone and fronto-temporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS). The exact molecular mechanisms by which VCP mutations cause disease manifestation in different tissues are incompletely understood. In the present study, we report the comprehensive analysis of a newly generated R155C VCP knock-in mouse model, which expresses the ortholog of the second most frequently occurring human pathogenic VCP mutation. Heterozygous R155C VCP knock-in mice showed decreased plasma lactate, serum albumin and total protein concentrations, platelet numbers, and liver to body weight ratios, and increased oxygen consumption and CD8+/Ly6C + T-cell fractions, but none of the typical human IBMPFD or ALS pathologies. Breeding of heterozygous mice did not yield in the generation of homozygous R155C VCP knock-in animals. Immunoblotting showed identical total VCP protein levels in human IBMPFD and murine R155C VCP knock-in tissues as compared to wild-type controls. However, while in human IBMPFD skeletal muscle tissue 70% of the total VCP mRNA was derived from the mutant allele, in R155C VCP knock-in mice only 5% and 7% mutant mRNA were detected in skeletal muscle and brain tissue, respectively. The lack of any obvious IBMPFD or ALS pathology could thus be a consequence of the very low expression of mutant VCP. We conclude that the increased and decreased fractions of the R155C mutant VCP mRNA in man and mice, respectively, are due to missense mutation-induced, divergent alterations in the biological half-life of the human and murine mutant mRNAs. Furthermore, our work suggests that therapy approaches lowering the expression of the mutant VCP mRNA below a critical threshold may ameliorate the intrinsic disease pathology.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Assessing corporate project impacts in changeable contexts: A human rights perspective

Project-level impact assessment was originally conceived as a snapshot taken in advance of project implementation, contrasting current conditions with a likely future scenario involving a variety of predicted impacts. Current best practice guidance has encouraged a shift towards longitudinal assessments from the pre-project stage through the implementation and operating phases. Experience and study show, however, that assessment of infrastructure-intensive projects rarely endures past the project's construction phase. Negative consequences for environmental, social and health outcomes have been documented. Such consequences clarify the pressing need for longitudinal assessment in each of these domains, with human rights impact assessment (HRIA) as an umbrella over, and critical augmentation of, environmental, social and health assessments. Project impacts on human rights are more closely linked to political, economic and other factors beyond immediate effects of a company's policy and action throughout the project lifecycle. Delineating these processes requires an adequate framework, with strategies for collecting longitudinal data, protocols that provide core information for impact assessment and guidance for adaptive mitigation strategies as project-related effects change over time. This article presents general principles for the design and implementation of sustained, longitudinal HRIA, based on experience assessing and responding to human rights impact in a uranium mining project in Malawi. The case study demonstrates the value of longitudinal assessment both for limiting corporate risk and improving human welfare. - Graphical abstract: Assessing changes in human rights condition as affected by both project and context, over time. - Highlights: • Corporate capital projects affect human rights in myriad ways. • Ongoing, longitudinal impact assessment techniques are needed. • We present an approach for conducting longitudinal human rights impact assessment. • Our methodology allows distinguishing corporate impacts from contextual changes. • Promptly observing context changes and impacts enables companies to react nimbly.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2017

Updated indicators of Swedish national human toxicity and ecotoxicity footprints using USEtox 2.01

In a recent paper, Sörme et al. (Environ. Impact Assess. Rev., 56, 2016), took a first step towards an indicator of a national chemical footprint, and applied it to Sweden. Using USEtox 1.01, they calculated national impact potentials for human toxicity and ecotoxicity. The results showed that zinc dominated impacts, both for human toxicity and ecotoxicity. We calculated updated indicators of the Swedish national human toxicity and ecotoxicity footprint using USEtox 2.01. We also compared impact potentials based on USEtox with the mass of chemical emissions. The two model versions produced relatively consistent results. Zinc is still a major contributor to the human toxicity and ecotoxicity impact potentials when characterized with USEtox 2.01. The mass-based indicator pinpoints somewhat different substances than the impact-based indicators. - Highlights: • USEtox 1.01 and 2.01 are relatively consistent in identifying the substances with largest impact potentials. • Metals were identified as a priority group of substances for both human toxicity and ecotoxicity. • Zinc is a major contributor to the human toxicity impact potential, in both model versions. • Zinc’s dominance concerning human toxicity sharply contrasts results from other studies: this is somewhat of a paradox. • Using the mass of chemical emissions as a simplified indicator pinpoints somewhat different substances.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

The human skin as a sub-THz receiver – Does 5G pose a danger to it or not?

Highlights: • The sweat duct is regarded as a helical antenna in the sub-THz band, reflectance depends on perspiration. • We outline the background for non-thermal effects based on the structure of sweat ducts. • We have introduced a realistic skin EM model and found the expected SAR for the 5G standard. In the interaction of microwave radiation and human beings, the skin is traditionally considered as just an absorbing sponge stratum filled with water. In previous works, we showed that this view is flawed when we demonstrated that the coiled portion of the sweat duct in upper skin layer is regarded as a helical antenna in the sub-THz band. Experimentally we showed that the reflectance of the human skin in the sub-THz region depends on the intensity of perspiration, i.e. sweat duct's conductivity, and correlates with levels of human stress (physical, mental and emotional). Later on, we detected circular dichroism in the reflectance from the skin, a signature of the axial mode of a helical antenna. The full ramifications of what these findings represent in the human condition are still unclear. We also revealed correlation of electrocardiography (ECG) parameters to the sub-THz reflection coefficient of human skin. In a recent work, we developed a unique simulation tool of human skin, taking into account the skin multi-layer structure together with the helical segment of the sweat duct embedded in it. The presence of the sweat duct led to a high specific absorption rate (SAR) of the skin in extremely high frequency band. In this paper, we summarize the physical evidence for this phenomenon and consider its implication for the future exploitation of the electromagnetic spectrum by wireless communication. Starting from July 2016 the US Federal Communications Commission (FCC) has adopted new rules for wireless broadband operations above 24 GHz (5 G). This trend of exploitation is predicted to expand to higher frequencies in the sub-THz region. One must consider the implications of human immersion in the electromagnetic noise, caused by devices working at the very same frequencies as those, to which the sweat duct (as a helical antenna) is most attuned. We are raising a warning flag against the unrestricted use of sub-THz technologies for communication, before the possible consequences for public health are explored.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2022

A framework to implement human reliability analysis during early design stages of advanced reactors

Nuclear power plants require human actions throughout their lifecycle from design, construction, operation, and decommissioning. However, for advanced reactors (e.g., Generation IV), the reliance on human intervention in safety-related actions is expected to be reduced or completely replaced by automated actions. The Probabilistic Risk Assessment (PRA) Standard for Advanced Non-LWR Nuclear Power Plants requires that the impacts of all operator actions are captured and incorporated in the risk of the modeled plant. Moreover, the Modernization of Technical Requirements for Licensing Advanced Reactors requires human reliability analysis (HRA) to be included throughout all design and PRA development stages. However, due to the lack of details during the early design stages, HRA is often postponed until the design is mature enough. Conducting HRA in later design stages, though it may be adequate in capturing pre-, at-, and post-initiators comes short of informing the design itself in the iterative design lifecycle. Hence, this paper presents a framework to include HRA during the design's early stages, pre-conceptual or conceptual. The proposed framework provides a process for the removal of operator actions that do not contribute to the risk and the identification of all key operator actions that are critical to the safety of the design. The results of this framework are then used to inform the design of those safety-related operator actions to update the design further. Then, using information from the updated design, this framework can be reapplied to investigate the impact of the design update on human reliability. The PRA model of the X-energy's pre-conceptual Xe-100 high-temperature gas-cooled pebble-bed reactor (HTGR-PB) design is used to demonstrate the approach. In the pre-conceptual Xe-100 PRA model, also called Phase 0 PRA model, human actions were considered an integral part of analyzing the plant response to different initiating events. Hence, in this paper, all possible human actions in the Xe-100 PRA model are identified, analyzed, and removed to emulate a design relying only on the available automated control systems. The preliminary results of this assessment show how safe the Xe-100 design is even without crediting any human actions. The results also list necessary sequences in which operator actions are critical to the risk profile of the design.

22 GENERAL STUDIES OF NUCLEAR REACTORS↗
DOE OSTI2017

Single-walled carbon nanotubes (SWCNTs) inhibit heat shock protein 90 (HSP90) signaling in human lung fibroblasts and keratinocytes

Single-walled carbon nanotubes (SWCNTs) are carbon-based nanomaterials that possess immense industrial potential. Despite accumulating evidence that exposure to SWCNTs might be toxic to humans, our understanding of the mechanisms for cellular toxicity of SWCNTs remain limited. Here, we demonstrated that acute exposure of short (1–3 μm) and regular-length (5–30 μm) pristine, carboxylated or hydroxylated SWCNTs inhibited cell proliferation in human somatic and human stem cells in a cell type-dependent manner. The toxicity of regular-length pristine SWCNT was most evidenced in NP69 > CYT00086 > MCF-10A > MRC-5 > HaCaT > HEK-293 T > HepG2. In contrast, the short pristine SWCNTs were relatively less toxic in most of the cells being tested, except for NP69 which is more sensitive to short pristine SWCNTs as compared to regular-length pristine SWCNTs. Interestingly, carboxylation and hydroxylation of regular-length SWCNTs, but not the short SWCNTs, significantly reduced the cytotoxicity. Exposure of SWCNTs also induced caspase 3 and 9 activities, mitochondrial membrane depolarization, and significant apoptosis and necrosis in MRC-5 embryonic lung fibroblasts. In contrast, SWCNTs inhibited the proliferation of HaCaT human keratinocytes without inducing cell death. Further analyses by gene expression profiling and Connectivity Map analysis showed that SWCNTs induced a gene expression signature characteristic of heat shock protein 90 (HSP90) inhibition in MRC-5 cells, suggesting that SWCNTs may inhibit the HSP90 signaling pathway. Indeed, exposure of MRC-5 cells to SWCNTs results in a dose-dependent decrease in HSP90 client proteins (AKT, CDK4 and BCL2) and a concomitant increase in HSP70 expression. In addition, SWCNTs also significantly inhibited HSP90-dependent protein refolding. Finally, we showed that ectopic expression of HSP90, but not HSP40 or HSP70, completely abrogated the cytotoxic effects of SWCNTs, suggesting that SWCNT-induced cellular toxicity is HSP90 dependent. In summary, our findings suggest that the toxic effects of SWCNTs are mediated through inhibition of HSP90 in human lung fibroblasts and keratinocytes. - Highlights: • SWCNTs inhibited cell proliferation in human somatic and human stem cells. • SWCNTs induced cytotoxicity and growth inhibition in MRC-5 and HaCat cells respectively. • SWCNTs induced a gene signature characteristic of HSP90 inhibition. • SWCNT-induced toxicity in MRC-5 and HaCat is HSP90-dependent.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Modelling human myoblasts survival upon xenotransplantation into immunodeficient mouse muscle

Cell transplantation has been challenged in several clinical indications of genetic or acquired muscular diseases, but therapeutic success were mitigated. To understand and improve the yields of tissue regeneration, we aimed at modelling the fate of CD56-positive human myoblasts after transplantation. Using immunodeficient severe combined immunodeficiency (SCID) mice as recipients, we assessed the survival, integration and satellite cell niche occupancy of human myoblasts by a triple immunohistochemical labelling of laminin, dystrophin and human lamin A/C. The counts were integrated into a classical mathematical decline equation. After injection, human cells were essentially located in the endomysium, then they disappeared progressively from D0 to D28. The final number of integrated human nuclei was grossly determined at D2 after injection, suggesting that no more efficient fusion between donor myoblasts and host fibers occurs after the resolution of the local damages created by needle insertion. Almost 1% of implanted human cells occupied a satellite-like cell niche. Our mathematical model validated by histological counting provided a reliable quantitative estimate of human myoblast survival and/or incorporation into SCID muscle fibers. Informations brought by histological labelling and this mathematical model are complementary.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Human enhancement

Abstract Genetic engineering opens new possibilities for biomedical enhancement requiring ethical, societal and practical considerations to evaluate its implications for human biology, human evolution and our natural environment. In this Commentary, we consider human enhancement, and in particular, we explore genetic enhancement in an evolutionary context. In summarizing key open questions, we highlight the importance of acknowledging multiple effects (pleiotropy) and complex epigenetic interactions among genotype, phenotype and ecology, and the need to consider the unit of impact not only to the human body but also to human populations and their natural environment (systems biology). We also propose that a practicable distinction between ‘therapy’ and ‘enhancement’ may need to be drawn and effectively implemented in future regulations. Overall, we suggest that it is essential for ethical, philosophical and policy discussions on human enhancement to consider the empirical evidence provided by evolutionary biology, developmental biology and other disciplines. Lay Summary: This Commentary explores genetic enhancement in an evolutionary context. We highlight the multiple effects associated with germline heritable genetic intervention, the need to consider the unit of impact to human populations and their natural environment, and propose that a practicable distinction between ‘therapy’ and ‘enhancement’ is needed.

Almeida, Mara↗
DOE OSTI2024

HumoNet: A Framework for Realistic Modeling and Simulation of Human Mobility Network

Understanding, analyzing, and predicting human mobility and dynamics are valuable to solving pressing problems, developing effective plans, and prescribing timely remedies. As a computational approach, realistic human mobility simulations allow us to understand, analyze, and predict complex systems, including human societies. Accurate simulations rely on (1) the model that captures interactions and behaviors of myriad entities in our society and (2) the mapping of model instances to real-world entities. Taking this into account, this paper introduces the Human Mobility Network simulation framework (HumoNet), an integrated patterns of life (POL) simulation framework that leverages real-world data layers including transportation networks, points of interest, populations, popularity, and human trajectories. HumoNet is a data informed model in which agents are equipped with activities, locomotion, and planning capabilities. To simulate realistic kinematic maneuvers of individuals in transportation networks, HumoNet harnesses a microscopic traffic simulator that provides interaction among vehicles and traffic objects. In this paper, we describe the framework, outline our methodologies, and discuss the data processing and challenges of each data layer. Through experiments, we demonstrate that our simulations capture key features of human mobility by comparing them to the literature and real data using standard measures of human mobility (i.e., the radius of gyration, number of locations visited, level of exploration) and metrics scoring (i.e., Jensen-Shannon divergence). We envision that the synthetic data produced by HumoNet will serve as a benchmark for analyzing epidemics, deploying EV charging networks, and validating AI/ML tasks such as location prediction.

Kim, Joon-Seok↗
DOE OSTI2023

A Multi-Objective Bayesian Optimized Human Assessed Multi-Target Generated Spectral Recommender System for Rapid Pareto Discoveries of Material Properties

Optimization for different tasks like material characterization, synthesis, and functional properties for desired applications over multi-dimensional control parameter and function spaces need a rapid strategic search through active learning. However, in all cases prior to optimization, the target material properties are assumed known and fixed, which mostly deviates from real-world scenarios in material synthesis. This can be critical for running expensive experiments on new materials, when the experimental results are fuzzy for any scientific outcomes due to improper target setting, ultimately wasting time and cost. The failure rate and cost are even higher over exploring on multi-target space, where we want to learn the pareto among multiple properties, to jointly optimize during material synthesis for desired applications. To address the challenge, here we introduce the human-operator attempt flexibility in the active learning based automated experiment framework, with generating multiple human assessed targets through a voting-based recommender system during real-time microscope measurements over the large material image space, sequentially learn/update multiple desired targets through a weighting system, and adaptively search in multiple material properties functional space for non-dominated pareto discoveries to maximize the custom structural similarity based acquisition function. We term this a multi-objective Bayesian optimized human assessed multi-target generated spectral recommender systems (MOBO-HAM-SRS). The approach has been demonstrated to peizoresponse force spectroscopy of a ferroelectric thin film, exploring with different kernels and acquisition functions. This work shows an advancement towards human-AI collaborated automated experiments, steering optimization trajectories through human overpowering AI at the early stage when uncertainty is high and AI overpowering human at the later stage with rapid exploration towards optimal goal, following human-assessed multiple targets properties.

Biswas, Arpan↗
DOE OSTI2018

Antibody-Mediated Killing of Carbapenem-Resistant ST258 Klebsiella pneumoniae by Human Neutrophils

ABSTRACT Carbapenem-resistant Klebsiella pneumoniae is a problem worldwide. A carbapenem-resistant K. pneumoniae lineage classified as multilocus sequence type 258 (ST258) is prominent in the health care setting in many regions of the world, including the United States. ST258 strains can be resistant to virtually all clinically useful antibiotics; treatment of infections caused by these organisms is difficult, and mortality is high. As a step toward promoting development of new therapeutics for ST258 infections, we tested the ability of rabbit antibodies specific for ST258 capsule polysaccharide to enhance human serum bactericidal activity and promote phagocytosis and killing of these bacteria by human neutrophils. We first demonstrated that an isogenic wzy deletion strain is significantly more susceptible to killing by human heparinized blood, serum, and neutrophils than a wild-type ST258 strain. Consistent with the importance of capsule as an immune evasion molecule, rabbit immune serum and purified IgG specific for ST258 capsule polysaccharide type 2 (CPS2) enhanced killing by human blood and serum in vitro . Moreover, antibodies specific for CPS2 promoted phagocytosis and killing of ST258 by human neutrophils. Collectively, our findings suggest that ST258 CPS2 is a viable target for immunoprophylactics and/or therapeutics. IMPORTANCE Infections caused by carbapenem-resistant K. pneumoniae are difficult to treat, and mortality is high. New prophylactic approaches and/or therapeutic measures are needed to prevent or treat infections caused by these multidrug-resistant bacteria. A strain of carbapenem-resistant K. pneumoniae , classified by multilocus sequence typing as ST258, is present in many regions of the world and is the most prominent carbapenem-resistant K. pneumoniae lineage in the United States. Here we show that rabbit antibodies specific for capsule polysaccharide of ST258 significantly enhance human serum bactericidal activity and promote phagocytosis and killing of this pathogen by human neutrophils. These studies have provided strong support for the idea that development of an immunotherapy (vaccine) for carbapenem-resistant K. pneumoniae infections is feasible and has merit.

59 BASIC BIOLOGICAL SCIENCES↗