Risk-Driven Design Processes: Balancing Efficiency with Resilience in Product Design

Current design methods and approaches focus on increasing the efficiency of the product design system by, for example, eliminating waste and focusing on value creation. However, continuing failures in the development of complex, large scale products and systems point towards weaknesses in the existing approaches. We argue that product development organizations are hindered by the many uncertainties that are inherent in the process. Common management heuristics ignore uncertainty and thus overly simplify the decision making process. Creating transparency regarding uncertainties and the associated risks (i.e. effect of uncertainties on design objectives) is not seen as an explicit priority. Consequently organizations are unable to balance risk and return in their development choices. Product development processes do not emphasize reduction of risks, particularly those risks that are apparent early in the process. In addition, the resilience of the PD system, i.e. its ability to deliver on-target results under uncertainty, is not deliberately designed to match the level of residual uncertainty. This chapter introduces the notion of Risk-Driven Design and its four principles of 1. Creating transparency regarding design risks; 2. Risk-driven decision making; 3. Minimizing uncertainty; and 4. Creating resilience.Massachusetts Institute of Technology. Lean Advancement InitiativeCenter for Clean Water and Clean Energy at MIT and KFUP

Hypercoagulability progresses to hypocoagulability during evolution of acetaminophen-induced acute liver injury in pigs

Increases in prothrombin time (PT) and international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF), yet a wide heterogeneity in clotting abnormalities exists. This study defines evolution of coagulopathy in 10 pigs with acetaminophen (APAP)-induced ALI compared to 3 Controls. APAP administration began at 0 h and continued to ‘ALF’, defined as INR >3. In APAP pigs, INR was 1.05 ± 0.02 at 0 h, 2.15 ± 0.43 at 16 h and > 3 at 18 ± 1 h. At 12 h thromboelastography (TEG) demonstrated increased clot formation rate, associated with portal vein platelet aggregates and reductions in protein C, protein S, antithrombin and A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats–13 (ADAMTS-13) to 60%, 24%, 47% and 32% normal respectively. At 18 ± 1 h, INR > 3 was associated with: hypocoagulable TEG profile with heparin-like effect; falls in thrombin generation, Factor V and Factor VIII to 52%, 19% and 17% normal respectively; further decline in anticoagulants; thrombocytopenia; neutrophilia and endotoxemia. Multivariate analysis, found that ADAMTS-13 was an independent predictor of a hypercoagulable TEG profile and platelet count, endotoxin, Protein C and fibrinogen were independent predictors of a hypocoagulable TEG profile. INR remained normal in Controls. Dynamic changes in coagulation occur with progression of ALI: a pro-thrombotic state progresses to hypocoagulability

Gas and dust in a z=2.8 obscured quasar

We present new detections of the CO(5-4), CO(7-6), [CI](1-0) and [CI](2-1) molecular and atomic line transitions towards the unlensed, obscured quasar AMS12 (z=2.7672), observed with the IRAM PdBI. This is the first unlensed, high redshift source to have both [CI] transitions detected. Continuum measurements between 70 $\mu$m and 3 mm are used to constrain the FIR SED, and we find a best fit FIR luminosity of log[Lfir/Lsol] = 13.5+/-0.1, dust temperature T_d = 88+/-8 K and emissivity index {\beta} = 0.6+/-0.1. The highly-excited molecular gas probed by CO(3-2), (5-4) and (7-6), is modelled with large velocity gradient (LVG) models. The gas kinetic temperature T_g, density n(H2), and the characteristic size r0, are determined using the dust temperature from the FIR SED as a prior for the gas temperature. The best fitting parameters are T_g = 90+/-8 K, n(H2) = 10^(3.9+/-0.1) cm^(-3) and r0 = 0.8+/-0.04 kpc. The ratio of the [CI] lines gives a [CI] excitation temperature of 43+/-10 K, indicating the [CI] and the high-excitation CO are not in thermal equilibrium. The [CI] excitation temperature is below that of T_d and T_g of the high-excitation CO, perhaps because [CI] lies at a larger radius where there may also be a large reservoir of CO at a cooler temperature, perhaps detectable through the CO(1-0). Using the [CI](1-0) line we can estimate the strength of the CO(1-0) line and hence the gas mass. This suggests that a significant fraction (~30%) of the molecular gas is missed from the high-excitation line analysis. The Eddington limited black hole mass is found from the bolometric luminosity to be Mbh >~ 1.5x10^9 Msol. Along with the stellar mass of 3x10^11 Msol, these give a black hole - bulge mass ratio of Mbh/Mbulge >~ 0.005. This is in agreement with studies on the evolution of the Mbh/Mbulge relationship at high redshifts, which find a departure from the local value ~0.002.Comment: Accepted by MNRAS, 17 pages, 9 figure

Dissipative dynamics of vortex lines in superfluid 4^{4}He

We propose a Hamiltonian model that describes the interaction between a vortex line in superfluid $^{4}$He and the gas of elementary excitations. An equation of irreversible motion for the density operator of the vortex, regarded as a macroscopic quantum particle with a finite mass, is derived in the frame of Generalized Master Equations. This enables us to cast the effect of the coupling as a drag force with one reactive and one dissipative component, in agreement with the assumption of the phenomenological theories of vortex mutual friction in the two fluid model.Comment: 16 pages, no figures, to be published in PR

L,L-Diaminopimelate Aminotransferase from Chlamydomonas reinhardtii: A Target for Algaecide Development

In some bacterial species and photosynthetic cohorts, including algae, the enzyme l,l-diaminopimelate aminotransferase (DapL) (E.C. 2.6.1.83) is involved in the anabolism of the essential amino acid L-lysine. DapL catalyzes the conversion of tetrahydrodipicolinate (THDPA) to l,l-diaminopimelate (l,l-DAP), in one step bypassing the DapD, DapC and DapE enzymatic reactions present in the acyl DAP pathways. Here we present an in vivo and in vitro characterization of the DapL ortholog from the alga Chlamydomonas reinhardtii (Cr-DapL). The in vivo analysis illustrated that the enzyme is able to functionally complement the E. coli dap auxotrophs and was essential for plant development in Arabidopsis. In vitro, the enzyme was able to inter-convert THDPA and l,l-DAP, showing strong substrate specificity. Cr-DapL was dimeric in both solution and when crystallized. The structure of Cr-DapL was solved in its apo form, showing an overall architecture of a α/β protein with each monomer in the dimer adopting a pyridoxal phosphate-dependent transferase-like fold in a V-shaped conformation. The active site comprises residues from both monomers in the dimer and shows some rearrangement when compared to the apo-DapL structure from Arabidopsis. Since animals do not possess the enzymatic machinery necessary for the de novo synthesis of the amino acid l-lysine, enzymes involved in this pathway are attractive targets for the development of antibiotics, herbicides and algaecides

Human embryonic stem cells from aneuploid blastocysts identified by pre-implantation genetic screening

Human embryonic stem cells are derived from the inner cell mass of pre-implantation embryos. The cells have unlimited proliferation potential and capacity to differentiate into the cells of the three germ layers. Human embryonic stem cells are used to study human embryogenesis and disease modeling and may in the future serve as cells for cell therapy and drug screening. Human embryonic stem cells are usually isolated from surplus normal frozen embryos and were suggested to be isolated from diseased embryos detected by pre-implantation genetic diagnosis. Here we report the isolation of 12 human embryonic stem cell lines and their thorough characterization. The lines were derived from embryos detected to have aneuploidy by pre-implantation genetic screening. Karyotype analysis of these cell lines showed that they are euploid, having 46 chromosomes. Our interpretation is that the euploid cells originated from mosaic embryos, and in vitro selection favored the euploid cells. The undifferentiated cells exhibited long-term proliferation and expressed markers typical for embryonic stem cells such as OCT4, NANOG, and TRA-1-60. The cells manifested pluripotent differentiation both in vivo and in vitro. To further characterize the different lines, we have analyzed their ethnic origin and the family relatedness among them. The above results led us to conclude that the aneuploid mosaic embryos that are destined to be discarded can serve as source for normal euploid human embryonic stem cell lines. These lines represent various ethnic groups; more lines are needed to represent all populations

Spinor condensates and light scattering from Bose-Einstein condensates

These notes discuss two aspects of the physics of atomic Bose-Einstein condensates: optical properties and spinor condensates. The first topic includes light scattering experiments which probe the excitations of a condensate in both the free-particle and phonon regime. At higher light intensity, a new form of superradiance and phase-coherent matter wave amplification were observed. We also discuss properties of spinor condensates and describe studies of ground--state spin domain structures and dynamical studies which revealed metastable excited states and quantum tunneling.Comment: 58 pages, 33 figures, to appear in Proceedings of Les Houches 1999 Summer School, Session LXXI

The dynamics and star-forming potential of the massive Galactic centre cloud G0.253+0.016

Context: The massive infrared dark cloud G0.253+0.016 projected ~45 pc from the Galactic centre contains ~105 M⊙ of dense gas whilst being mostly devoid of observed star-formation tracers. Aims: Our goals are therefore to scrutinise the physical properties, dynamics and structure of this cloud with reference to its star-forming potential. Methods: We have carried out a concerted SMA and IRAM 30 m study of this enigmatic cloud in dust continuum, CO isotopologues, several shock tracing molecules, as well as H2CO to trace the gas temperature. In addition, we include ancillary far-IR and sub-mm Herschel and SCUBA data in our analysis. Results: We detect and characterise a total of 36 dust cores within G0.253+0.016 at 1.3 mm and 1.37 mm, with masses between 25 and approximately 250 M⊙, and find that the kinetic temperature of the gas traced by H2CO ratios is >320 K on size-scales of ~0.15 pc. Analysis of the position–velocity diagrams of our observed lines shows broad linewidths and strong shock emission in the south of the cloud, indicating that G0.253+0.016 is colliding with another cloud at vLSR ~ 70 km s-1. We confirm via an analysis of the observed dynamics in the Central Molecular Zone that it is an elongated structure, orientated with Sgr B2 closer to the Sun than Sgr A*, however our results suggest that the actual geometry may be more complex than an elliptical ring. We find that the column density probability distribution function of G0.253+0.016 derived from SMA and SCUBA dust continuum emission is log-normal with no discernible power-law tail, consistent with little star formation, and that its width can be explained in the framework of theory predicting the density structure of clouds created by supersonic, magnetised turbulence. We also present the Δ-variance spectrum of this region, a proxy for the density power spectrum of the cloud, and show it is consistent with that expected for clouds with no current star formation. Finally, we show that even after determining a scaled column density threshold for star formation by incorporating the effects of the increased turbulence in the cloud, we would still expect ten stars with masses >15 M⊙ to form in G0.253+0.016. If these cannot be accounted for by new radio continuum observations, then further physical aspects may be important, such as the background column density level, which would turn an absolute column density threshold for star formation into a critical over-density. Conclusions: We conclude that G0.253+0.016 contains high-temperatures and wide-spread shocks, displaying evidence of interaction with a nearby cloud which we identify at vLSR ~ 70 km s-1. Our analysis of the structure of the cloud can be well-explained by theory of magnetised turbulence, and is consistent with little or no current star formation. Using G0.253+0.016 as a test-bed of the conditions required for star formation in a different physical environment to that of nearby clouds, we also conclude that there is not one column density threshold for star formation, but instead this value is dependant on the local physical conditions

Respiratory epithelial cells require Toll-like receptor 4 for induction of Human β-defensin 2 by Lipopolysaccharide

BACKGROUND: The respiratory epithelium is a major portal of entry for pathogens and employs innate defense mechanisms to prevent colonization and infection. Induced expression of human β-defensin 2 (HBD2) represents a direct response by the epithelium to potential infection. Here we provide evidence for the critical role of Toll-like receptor 4 (TLR4) in lipopolysaccharide (LPS)-induced HBD2 expression by human A549 epithelial cells. METHODS: Using RTPCR, fluorescence microscopy, ELISA and luciferase reporter gene assays we quantified interleukin-8, TLR4 and HBD2 expression in unstimulated or agonist-treated A549 and/or HEK293 cells. We also assessed the effect of over expressing wild type and/or mutant TLR4, MyD88 and/or Mal transgenes on LPS-induced HBD2 expression in these cells. RESULTS: We demonstrate that A549 cells express TLR4 on their surface and respond directly to Pseudomonas LPS with increased HBD2 gene and protein expression. These effects are blocked by a TLR4 neutralizing antibody or functionally inactive TLR4, MyD88 and/or Mal transgenes. We further implicate TLR4 in LPS-induced HBD2 production by demonstrating HBD2 expression in LPS non-responsive HEK293 cells transfected with a TLR4 expression plasmid. CONCLUSION: This data defines an additional role for TLR4 in the host defense in the lung