Engineering Ethics: Looking Back, Looking Forward

The eight pieces constituting this Meeting Report are summaries of presentations made during a panel session at the 2011 Association for Practical and Professional Ethics (APPE) annual meeting held between March 3rd and 6th in Cincinnati. Lisa Newton organized the session and served as chair. The panel of eight consisted both of pioneers in the field and more recent arrivals. It covered a range of topics from how the field has developed to where it should be going, from identification of issues needing further study to problems of training the next generation of engineers and engineering-ethics scholars.

The intracellular Ig fold: a robust protein scaffold for the engineering of molecular recognition

Protein scaffolds that support molecular recognition have multiple applications in biotechnology. Thus, protein frames with robust structural cores but adaptable surface loops are in continued demand. Recently, notable progress has been made in the characterization of Ig domains of intracellular origin--in particular, modular components of the titin myofilament. These Ig belong to the I(intermediate)-type, are remarkably stable, highly soluble and undemanding to produce in the cytoplasm of Escherichia coli. Using the Z1 domain from titin as representative, we show that the I-Ig fold tolerates the drastic diversification of its CD loop, constituting an effective peptide display system. We examine the stability of CD-loop-grafted Z1-peptide chimeras using differential scanning fluorimetry, Fourier transform infrared spectroscopy and nuclear magnetic resonance and demonstrate that the introduction of bioreactive affinity binders in this position does not compromise the structural integrity of the domain. Further, the binding efficiency of the exogenous peptide sequences in Z1 is analyzed using pull-down assays and isothermal titration calorimetry. We show that an internally grafted, affinity FLAG tag is functional within the context of the fold, interacting with the anti-FLAG M2 antibody in solution and in affinity gel. Together, these data reveal the potential of the intracellular Ig scaffold for targeted functionalization.

Exigencies for engaging undergraduates in rhetorical problem solving : insights from engineering managers and A3 report analyses

Undergraduate education has a historical tradition of preparing students to meet the problem-solving challenges they will encounter in work, civic, and personal contexts. This thesis research was conducted to study the role of rhetoric in engineering problem solving and decision making and to pose pedagogical strategies for preparing undergraduate students for workplace problem solving. Exploratory interviews with engineering managers as well as the heuristic analyses of engineering A3 project planning reports suggest that Aristotelian rhetorical principles are critical to the engineer's success: Engineers must ascertain the rhetorical situation surrounding engineering problems; apply and adapt invention heuristics to conduct inquiry; draw from their investigation to find innovative solutions; and influence decision making by navigating workplace decision-making systems and audiences using rhetorically constructed discourse. To prepare undergraduates for workplace problem solving, university educators are challenged to help undergraduates understand the exigence and realize the kairotic potential inherent in rhetorical problem solving. This thesis offers pedagogical strategies that focus on mentoring learning communities in problem-posing experiences that are situated in many disciplinary, work, and civic contexts. Undergraduates build a flexible rhetorical technê for problem solving as they navigate the nuances of relevant problem-solving systems through the lens of rhetorical practice.

SPATIAL UNDERSTANDING OF MATRIX INVERSION FOR INVERSE FORCE ESTIMATION

A basic approach to study a NVH problem is to break down the system in three basic elements – source, path and receiver. While the receiver (response) and the transfer path can be measured, it is difficult to measure the source (forces) acting on the system. It becomes necessary to predict these forces to know how they influence the responses. This requires inverting the transfer path. Singular Value Decomposition (SVD) method is used to decompose the transfer path matrix into its principle components which is required for the inversion. The usual approach to force prediction requires rejecting the small singular values obtained during SVD by setting a threshold, as these small values dominate the inverse matrix. This assumption of the threshold may be subjected to rejecting important singular values severely affecting force prediction. The new approach discussed in this report looks at the column space of the transfer path matrix which is the basis for the predicted response. The response participation is an indication of how the small singular values influence the force participation. The ability to accurately reconstruct the response vector is important to establish a confidence in force vector prediction. The goal of this report is to suggest a solution that is mathematically feasible, physically meaningful, and numerically more efficient through examples. This understanding adds new insight to the effects of current code and how to apply algorithms and understanding to new codes.

DISTRIBUTED APPROACH FOR SOLVING OPTIMAL POWER FLOW PROBLEMS IN THREE-PHASE UNBALANCED DISTRIBUTION NETWORK

The objective of this report is to study distributed (decentralized) three phase optimal power flow (OPF) problem in unbalanced power distribution networks. A full three phase representation of the distribution networks is considered to account for the highly unbalance state of the distribution networks. All distribution network’s series/shunt components, and load types/combinations had been modeled on commercial version of General Algebraic Modeling System (GAMS), the high-level modeling system for mathematical programming and optimization. The OPF problem has been successfully implemented and solved in a centralized approach and distributed approach, where the objective is to minimize the active power losses in the entire system. The study was implemented on the IEEE-37 Node Test Feeder. A detailed discussion of all problem sides and aspects starting from the basics has been provided in this study. Full simulation results have been provided at the end of the report.

Economic Talc Deposits of Montana and Related Firing Problems

This thesis has to do with a study of the produc­tion of talc in Montana, describing the local geology of each deposit, and a description of the laboratory tests that were made on various grades of Montana talc in an attempt to determine why some grades of talc can be burned in solid forms while others must be ground, mixed with a binder and molded.

Montana Talc; Problems in Physical Properties

General information on talc, including foreign and United States occurrences, origin, and uses is covered. Montana deposits are discussed in greater detail as to location, geology, mineralogy, and mining. Studies of talc by petrographic and x-ray methods and an experiment to determine the porosity are described and discussed.

Estimating the patient's contribution during robot-assisted therapy

Robot-assisted therapy has become increasingly common in neurorehabilitation. Sophisticated controllers have been developed for robots to assist and cooperate with the patient. It is difficult for the patient to judge to what extent the robot contributes to the execution of a movement. Therefore, methods to comprehensively quantify the patient's contribution and provide feedback are of key importance. We developed a method comprehensively to estimate the patient's contribution by combining kinematic measures and the motor assistance applied. Inverse dynamic models of the robot and the passive human arm calculate the required torques to move the robot and the arm and build, together with the recorded motor torque, a metric (in percentage) that represents the patient's contribution to the movement. To evaluate the developed metric, 12 nondisabled subjects and 7 patients with neurological problems simulated instructed movement contributions. The results are compared with a common performance metric. The estimation shows very satisfying results for both groups, even though the arm model used was strongly simplified. Displaying this metric to patients during therapy can potentially motivate them to actively participate in the training.

The cyclotron production and nuclear imaging of bromine-77

In this investigation, bromine-77 was produced with a medical cyclotron and imaged with gamma cameras. Br-77 emits a 240 kev photon with a half life of 56 hours. The C-Br bond is stronger than the C-I bond and bromine is not collected in the thyroid. Bromine can be used to label many organic molecules by methods analogous to radioiodination. The only North American source of Br-77 in the 70's and 80's was Los Alamos National Laboratory, but it discontinued production in 1989. In this method, a p,3n reaction on Br-77 produces Kr-77 which decays with a 1.2 hour half life to Br-77. A cyclotron generated 40 MeV proton beam is incident on a nearly saturated NaBr or LiBr solution contained in a copper or titanium target. A cooling chamber through which helium gas is flowed separates the solution from the cyclotron beam line. Helium gas is also flowed through the solution to extract Kr-77 gas. The mixture flows through a nitrogen trap where Kr-77 freezes and is allowed to decay to Br-77. Eight production runs were performed, three with a copper target and five with a titanium target with yields of 40, 104, 180, 679, 1080, 685, 762 and 118 uCi respectively. Gamma ray spectroscopy has shown the product to be very pure, however corrosion has been a major obstacle, causing the premature retirement of the copper target. Phantom and in-vivo rat nuclear images, and an autoradiograph in a rat are presented. The quality of the nuclear scans is reasonable and the autoradiograph reveals high isotope uptake in the renal parenchyma, a more moderate but uniform uptake in pulmonary and hepatic tissue, and low soft tissue uptake. There is no isotope uptake in the brain or the gastric mucosa. ^

Nuclear power plants and childhood leukaemia: lessons from the past and future directions

In the 1980s, leukaemia clusters were discovered around nuclear fuel reprocessing plants in Sellafield and Dounreay in the United Kingdom. This raised public concern about the risk of childhood leukaemia near nuclear power plants (NPPs). Since then, the topic has been well-studied, but methodological limitations make results difficult to interpret. Our review aims to: (1.) summarise current evidence on the relationship between NPPs and risk of childhood leukaemia, with a focus on the Swiss CANUPIS (Childhood cancer and nuclear power plants in Switzerland) study; (2.) discuss the limitations of previous research; and (3.) suggest directions for future research. There are various reasons that previous studies produced inconclusive results. These include: inadequate study designs and limited statistical power due to the low prevalence of exposure (living near a NPP) and outcome (leukaemia); lack of accurate exposure estimates; limited knowledge of the aetiology of childhood leukaemia, particularly of vulnerable time windows and latent periods; use of residential location at time of diagnosis only and lack of data on address histories; and inability to adjust for potential confounders. We conclude that risk of childhood leukaemia around NPPs should continue to be monitored and that study designs should be improved and standardised. Data should be pooled internationally to increase the statistical power. More research needs to be done on other putative risk factors for childhood cancer such as low-dose ionizing radiation, exposure to certain chemicals and exposure to infections. Studies should be designed to allow examining multiple exposures.

Childhood leukaemia risks: from unexplained findings near nuclear installations to recommendations for future research.

Recent findings related to childhood leukaemia incidence near nuclear installations have raised questions which can be answered neither by current knowledge on radiation risk nor by other established risk factors. In 2012, a workshop was organised on this topic with two objectives: (a) review of results and discussion of methodological limitations of studies near nuclear installations; (b) identification of directions for future research into the causes and pathogenesis of childhood leukaemia. The workshop gathered 42 participants from different disciplines, extending widely outside of the radiation protection field. Regarding the proximity of nuclear installations, the need for continuous surveillance of childhood leukaemia incidence was highlighted, including a better characterisation of the local population. The creation of collaborative working groups was recommended for consistency in methodologies and the possibility of combining data for future analyses. Regarding the causes of childhood leukaemia, major fields of research were discussed (environmental risk factors, genetics, infections, immunity, stem cells, experimental research). The need for multidisciplinary collaboration in developing research activities was underlined, including the prevalence of potential predisposition markers and investigating further the infectious aetiology hypothesis. Animal studies and genetic/epigenetic approaches appear of great interest. Routes for future research were pointed out.

Genetic Engineering of Induced Pluripotent Stem Cells and Reprogramming to Motor Neurons to Elucidate Selective Motor Neuron Death in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease, fatal within 1 to 5 years after onset of symptoms. About 3 out of 100’000 persons are diagnosed with ALS and there is still no cure available [1, 2]. 95% of all cases occur sporadically and the aetiology remains largely unknown [XXXX]. However, up to now 16 genes were identified to play a role in the development of familial ALS. One of these genes is FUS that encodes for the protein fused in sarcoma/translocated in liposarcoma (FUS/TLS). Mutations in this gene are responsible for some cases of sporadic as well as of inherited ALS [3]. FUS belongs to the family of heterogeneous nuclear ribonucleoproteins and is predicted to be involved in several cellular functions like transcription regulation [4], RNA splicing [5, 6], mRNA transport in neurons [7] and microRNA processing [8]. Aberrant accumulation of mutated FUS has been found in the cytoplasm of motor neurons from ALS patients [9]. The mislocalization of FUS is based on a mutation in the nuclear localization signal of FUS [10]. However, it is still unclear if the cytoplasmic localization of FUS leads to a toxic gain of cytoplasmic function and/or a loss of nuclear function that might be crucial in the course of ALS. The goal of this project is to characterize the impact of ALS-associated FUS mutations on in vitro differentiated motor neurons. To this end, we edit the genome of induced pluripotent stem cells (iPSC) using transcription activator-like effector nucleases (TALENs) [11,12] to create three isogenic cell lines, each carrying an ALS-associated FUS mutation (G156E, R244C and P525L). These iPSC’s will then be differentiated to motor neurons according to a recently establishe protocol (Ref Wichterle) and serve to study alterations in the transcriptome, proteome and metabolome upon the expression of ALS-associated FUS. With this approach, we hope to unravel the molecular mechanism leading to FUS-associated ALS and to provide new insight into the emerging connection between misregulation of RNA metabolism and neurodegeneration, a connection that is currently implied in a variety of additional neurological diseases, including spinocerebellar ataxia 2 (SCA-2), spinal muscular atrophy (SMA), fragile X syndrome, and myotonic dystrophy.

Genetic Engineering of Induced Pluripotent Stem Cells and Reprogramming to Motor Neurons to Elucidate Selective Motor Neuron Death in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease, fatal within 1 to 5 years after onset of symptoms. About 3 out of 100’000 persons are diagnosed with ALS and there is still no cure available [1, 2]. 95% of all cases occur sporadically and the aetiology remains largely unknown [3]. However, up to now 16 genes were identified to play a role in the development of familial ALS. One of these genes is FUS that encodes for the protein fused in sarcoma (FUS). Mutations in this gene are responsible for some cases of sporadic as well as of inherited ALS [4]. FUS belongs to the family of heterogeneous nuclear ribonucleoproteins and is predicted to be involved in several cellular functions like transcription regulation, RNA splicing, mRNA transport in neurons and microRNA processing [5] Aberrant accumulation of mutated FUS has been found in the cytoplasm of motor neurons from ALS patients [6]. The mislocalization of FUS is based on a mutation in the nuclear localization signal of FUS [7]. However, it is still unclear if the cytoplasmic localization of FUS leads to a toxic gain of cytoplasmic function and/or a loss of nuclear function that might be crucial in the course of ALS. The goal of this project is to characterize the impact of ALS-associated FUS mutations on in vitro differentiated motor neurons. To this end, we edit the genome of induced pluripotent stem cells (iPSC) using transcription activator-like effector nucleases (TALENs) [8,9] to create three isogenic cell lines, each carrying an ALS-associated FUS mutation (G156E, R244C and P525L). These iPSC’s will then be differentiated to motor neurons according to a recently established protocol [10] and serve to study alterations in the transcriptome, proteome and metabolome upon the expression of ALS-associated FUS. With this approach, we hope to unravel the molecular mechanism leading to FUS-associated ALS and to provide new insight into the emerging connection between misregulation of RNA metabolism and neurodegeneration, a connection that is currently implied in a variety of additional neurological diseases, including spinocerebellar ataxia 2 (SCA-2), spinal muscular atrophy (SMA), fragile X syndrome, and myotonic dystrophy. [1] Cleveland, D.W. et al. (2001) Nat Rev Neurosci 2(11): 806-819 [2] Sathasivam, S. (2010) Singapore Med J 51(5): 367-372 [3] Schymick, J.C. et al. (2007) Hum Mol Genet Vol 16: 233-242 [4] Pratt, A.J. et al. (2012). Degener Neurol Neuromuscul Dis 2012(2): 1-14 [5] Lagier-Tourenne, C. Hum Mol Genet, 2010. 19(R1): p. R46-64 [6] Mochizuki, Y. et al. (2012) J Neurol Sci 323(1-2): 85-92 [7] Dormann, D. et al. (2010) EMBO J 29(16): 2841-2857 [8] Hockemeyer, D. et al. (2011) Nat Biotech 29(8): 731-734 [9] Joung, J.K. and J.D. Sander (2013) Nat Rev Mol Cell Biol 14(1): 49-55 [10]Amoroso, M.W. et al. (2013) J Neurosci 33(2): 574-586.

Measurement of the neutrino-oxygen neutral-current interaction cross section by observing nuclear deexcitation γ rays

We report the first measurement of the neutrino-oxygen neutral-current quasielastic (NCQE) cross section. It is obtained by observing nuclear deexcitation γ rays which follow neutrino-oxygen interactions at the Super-Kamiokande water Cherenkov detector. We use T2K data corresponding to 3.01 × 1020 protons on target. By selecting only events during the T2K beam window and with well-reconstructed vertices in the fiducial volume, the large background rate from natural radioactivity is dramatically reduced. We observe 43 events in the 4–30 MeV reconstructed energy window, compared with an expectation of 51.0, which includes an estimated 16.2 background events. The background is primarily nonquasielastic neutral-current interactions and has only 1.2 events from natural radioactivity. The flux-averaged NCQE cross section we measure is 1.55 × 10−38 cm2 with a 68% confidence interval of ð1.22; 2.20Þ × 10−38 cm2 at a median neutrino energy of 630 MeV, compared with the theoretical prediction of 2.01 × 10−38 cm2.