Data analysis : operating crew characteristics and interactions during steam generator tube rupture simulation

Statement of responsibility on title page reads: Y. Huang, N. Siu, D. Lanning ,and J. Carroll"June 1990."Includes bibliographical references (leaf 11)This report provides an analysis of the data collected during a one-month visit to a 2-unit, non-U.S. PWR. The data consist of results from interviews (largely with plant operators and former shift engineers) and from reviews of videotapes covering crew responses to steam generator tube rupture training exercises. The interviews were aimed at indicating perceptions of individual and group skills. The analysis shows that the interview results are fairly consistent, that the time required to perform key actions does not generally correlate very well with the team quality ratings obtained from the interviews, and that the team quality ratings obtained from interviews correlate reasonably with ratings of the team performances (during the exercises) developed using the 7-dimension scale described in PNL-7250.Supported by the Office of Nuclear Regulatory Research, United States Nuclear Regulatory Commission NRC-04-89-35

Systems model for dynamic human error during accident sequences

Statement of responsibility on title page reads: Y. Huang, N. Siu, D. Lanning, J. Carroll, and V. Dang"December 1991."Includes bibliographical references (pages 153-155)Final report: "A systems model for dynamic human error during accident sequences"This report describes a systems-based operating crew model designed to simulate the behavior of an nuclear power plant control room crew during an accident scenario. This model can lead to an improved treatment of potential operator-induced multiple failures, since it deals directly with the causal factors underlying individual and group behavior. It is intended that the model, or more advanced developments of the model, will be used in the human reliability analysis portion of a probabilistic risk assessment study, where careful treatment of multiple, dependent failures is required. The model treats the members of the control room crew as separate, reasoning entities. These entities receive information from the plant and each other, process that information, perform actions that affect the plant, and provide information to the other crew members.The information retrieval, processing, and output activities are affected by the characteristics of the individual operator (e.g., his technical ability) and his relationship (measured in terms of "confidence level") with his fellow operators. Group behavior is modeled as the implicit result of individual operator behavior and the interactions between operators. The model is applied towards the analysis of steam generator tube rupture (SGTR) accidents at a non-U.S. pressurized water reactor, using the SIMSCRIPT 11.5 programming language. Benchmark runs, comparing the model predictions with videotaped observations of the performances of three different crews during SGTR training exercises, are performed to tune a small number of model parameters. The tuned model is then applied in a blind test analysis of a fourth crew. In both the benchmarking and blind test runs, the model performs quite well in predicting the occurrence, ordering, and timing of key events.The model is also employed in a number of sensitivity analyses that demonstrate the robustness of the model (it generates plausible results even when the model parameters are assigned values not representative of observed crews) and the model's usefulness in investigating key issues (e.g., the effect of stress buildup on crew performance). iSupported by the Office of Nuclear Regulatory Research, United States Nuclear Regulatory Commission: NRC-04-89-35

Antioxidant and lipid supplementation improve the development of photoreceptor outer segments in pluripotent stem cell-derived retinal organoids

The generation of retinal organoids from human pluripotent stem cells (hPSC) is now a well-established process that in part recapitulates retinal development. However, hPSC-derived photoreceptors that exhibit well-organized outer segment structures have yet to be observed. To facilitate improved inherited retinal disease modeling, we determined conditions that would support outer segment development in maturing hPSC-derived photoreceptors. We established that the use of antioxidants and BSA-bound fatty acids promotes the formation of membranous outer segment-like structures. Using new protocols for hPSC-derived retinal organoid culture, we demonstrated improved outer segment formation for both rod and cone photoreceptors, including organized stacked discs. Using these enhanced conditions to generate iPSC-derived retinal organoids from patients with X-linked retinitis pigmentosa, we established robust cellular phenotypes that could be ameliorated following adeno-associated viral vector-mediated gene augmentation. These findings should aid both disease modeling and the development of therapeutic approaches for the treatment of photoreceptor disorders

The electric double layer has a life of its own

Using molecular dynamics simulations with recently developed importance sampling methods, we show that the differential capacitance of a model ionic liquid based double-layer capacitor exhibits an anomalous dependence on the applied electrical potential. Such behavior is qualitatively incompatible with standard mean-field theories of the electrical double layer, but is consistent with observations made in experiment. The anomalous response results from structural changes induced in the interfacial region of the ionic liquid as it develops a charge density to screen the charge induced on the electrode surface. These structural changes are strongly influenced by the out-of-plane layering of the electrolyte and are multifaceted, including an abrupt local ordering of the ions adsorbed in the plane of the electrode surface, reorientation of molecular ions, and the spontaneous exchange of ions between different layers of the electrolyte close to the electrode surface. The local ordering exhibits signatures of a first-order phase transition, which would indicate a singular charge-density transition in a macroscopic limit

Dementia and COVID-19 in New Zealand, Chile, and Germany: A Research Agenda for Cross-Country Learning for Resilience in Health Care Systems

The COVID-19 pandemic has revealed existing gaps in policies, systems and services, stressing the need for concerted global action on healthy aging. Similar to the COVID-19 pandemic, dementia is a challenge for health systems on a global scale. Our hypothesis is that translational potential lies in cross-country learning by involving three high-income countries with distinct geo political-cultural-social systems in Latin America (Chile), the South Pacific (New Zealand) and Eu rope (Germany). Our vision is that such cross-country learning will lead to providing adequate, equitable and sustainable care and support for families living with dementia during a pandemic and beyond. We are proposing a vision for research that takes a multi-disciplinary, strength-based approach at the intersection of health care research, disaster research, global health research and dementia research. We present some insights in support of our hypothesis and proposed research agenda. We anticipate that this research has the potential to contribute towards strengthening and transforming health care systems in times of crises and beyond

Phenotypic characterization of breast cancer: the role of CDC42

Purpose: The molecular landscape of breast cancer (BC), especially of the Luminal A subtype, remains to be fully delineated. Transcriptomic data shows that Luminal A tumours are enriched for aberrant expression of genes in the cell division control 42 homolog (CDC42) pathway. This study aims to investigate protein expression of CDC42 in BC and assess its clinicopathological significance. Methods: Expression of CDC42 protein was examined by immunohistochemistry on tissue microarrays in a well characterised cohort of 895 early stage (I-IIIa) primary invasive BCs. Results: CDC42 expression was observed in both the cytoplasm and nucleus of BC cells. High nuclear CDC42 expression demonstrated a significant correlation with ER positive, low-grade tumours and was more common in the lobular histological subtype (all p<0.001). In contrast, cytoplasmic CDC42 showed increased expression in the ductal subtype (p<0.001) and correlated with negative prognostic features such as larger size, higher grade (p<0.05), and higher Ki67 labelling index (p=0.001). Nuclear CDC42 expression was associated with a longer BC specific survival in all cases (p=0.025) and in luminal ER positive tumours (p=0.011). In multivariate analyses including size, grade, lymph node stage and intrinsic subtype, CDC42 was an independent prognostic factor (p=0.032). Conclusion: The results indicate that CDC42 is important molecule in luminal BC, with prognostic significance

Designing Irreversible Inhibitors—Worth the Effort?

This is the peer-reviewed version of the following article: González-Bello, C. (2016). Designing Irreversible Inhibitors-Worth the Effort?. Chemmedchem, 11(1), 22-30, which has been published in final form at https://doi.org/10.1002/cmdc.201500469. This article may be used for non-commercial purposes in accordance with Wiley-VCH Terms and Conditions for Self-ArchivingDespite the unquestionable success of numerous irreversible drugs that are currently in clinical use, such as acetylsalicylic acid (Aspirin) and penicillin, the number of such approved drugs is much lower than that of noncovalent drugs. Over the years, the potential off‐target effects of these types of compounds have been the primary concern that has hampered their development. However, their remarkable advantages over noncovalent drugs and a better analysis of the risks have decreased the widespread skepticism surrounding them. The design of irreversible inhibitors is a challenge, particularly considering that in some cases their efficacy is due to complex and unexpected mechanisms of action. In this review the main advantages of irreversible inhibition are summarized, and the complexity of certain covalent modification mechanisms is highlighted with selected examplesSpanish Ministry of Economy and Competitiveness. Grant Number: SAF2013-42899-R Xunta de Galicia. Grant Number: GRC2013-041 European Regional Development Fund (ERDF)S

Promoting communication skills for information systems students in Australian and Portuguese higher education : action research study

This paper aims to examine the value of communication skills learn- ing process through various assessments in Information Systems (IS) postgrad- uate units in Australia and Portugal. Currently, communication skills are indispensable to students in expanding their social networks and their knowl- edge at university and in the future workplace, since businesses expect their employees to have strong communication and presentation skills. This paper provides empirical evidence based on the anonymous quantitative and qualita- tive data collected during 2 years from 126 postgraduate students, which were collected via formal and informal feedback. Various assessment methods were used in Information Systems units to promote and develop the communication skills; these assessments are: reflective journal, business plan and prototype, discussion forum, presentation, and final examination. A Communication skills model (CSM) was developed based on Action research principles to promote the assessments which will assist IS students to enhance their communication skills. The research outcomes indicated that integrating communication skills in the assessments will allow students to promote their communication skills and boost their self-esteem skills. Furthermore, this paper added a new theoretical and practical contribution to higher-education teaching and learning literature, especially the action research for teachers to promote and develop communica- tion skills among students. Finally, integrating these skills in the units should meet the objectives and aims of the units, Master’s degrees, universities, and businesses’ needs, and satisfy our student’s need

Insulin and GH Signaling in Human Skeletal Muscle In Vivo following Exogenous GH Exposure: Impact of an Oral Glucose Load

GH induces acute insulin resistance in skeletal muscle in vivo, which in rodent models has been attributed to crosstalk between GH and insulin signaling pathways. Our objective was to characterize time course changes in signaling pathways for GH and insulin in human skeletal muscle in vivo following GH exposure in the presence and absence of an oral glucose load.Eight young men were studied in a single-blinded randomized crossover design on 3 occasions: 1) after an intravenous GH bolus 2) after an intravenous GH bolus plus an oral glucose load (OGTT), and 3) after intravenous saline plus OGTT. Muscle biopsies were taken at t = 0, 30, 60, and 120. Blood was sampled at frequent intervals for assessment of GH, insulin, glucose, and free fatty acids (FFA).GH increased AUC(glucose) after an OGTT (p<0.05) without significant changes in serum insulin levels. GH induced phosphorylation of STAT5 independently of the OGTT. Conversely, the OGTT induced acute phosphorylation of the insulin signaling proteins Akt (ser(473) and thr(308)), and AS160.The combination of OGTT and GH suppressed Akt activation, whereas the downstream expression of AS160 was amplified by GH. WE CONCLUDED THE FOLLOWING: 1) A physiological GH bolus activates STAT5 signaling pathways in skeletal muscle irrespective of ambient glucose and insulin levels 2) Insulin resistance induced by GH occurs without a distinct suppression of insulin signaling proteins 3) The accentuation of the glucose-stimulated activation of AS 160 by GH does however indicate a potential crosstalk between insulin and GH.ClinicalTrials.gov NCT00477997

Macrocyclic β-Sheet Peptides That Inhibit the Aggregation of a Tau-Protein-Derived Hexapeptide

This paper describes studies of a series of macrocyclic β-sheet peptides 1 that inhibit the aggregation of a tau-protein-derived peptide. The macrocyclic β-sheet peptides comprise a pentapeptide "upper" strand, two δ-linked ornithine turn units, and a "lower" strand comprising two additional residues and the β-sheet peptidomimetic template "Hao". The tau-derived peptide Ac-VQIVYK-NH(2) (AcPHF6) aggregates in solution through β-sheet interactions to form straight and twisted filaments similar to those formed by tau protein in Alzheimer's neurofibrillary tangles. Macrocycles 1 containing the pentapeptide VQIVY in the "upper" strand delay and suppress the onset of aggregation of the AcPHF6 peptide. Inhibition is particularly pronounced in macrocycles 1a, 1d, and 1f, in which the two residues in the "lower" strand provide a pattern of hydrophobicity and hydrophilicity that matches that of the pentapeptide "upper" strand. Inhibition varies strongly with the concentration of these macrocycles, suggesting that it is cooperative. Macrocycle 1b containing the pentapeptide QIVYK shows little inhibition, suggesting the possibility of a preferred direction of growth of AcPHF6 β-sheets. On the basis of these studies, a model is proposed in which the AcPHF6 amyloid grows as a layered pair of β-sheets and in which growth is blocked by a pair of macrocycles that cap the growing paired hydrogen-bonding edges. This model provides a provocative and appealing target for future inhibitor design