Taking Shots at Private Military Firms: International Law Misses its Mark (Again)

Part I of this Article takes a brief tour through military history on the consistent use of mercenaries through the ages, which Peter Singer illuminates masterfully in Corporate Warriors. Next, a brief overview on the binding nature (or not) of international custom and treaty is explored in Part II and then the codifications of international law are taken up in Part III, beginning with the Hague and Geneva Conventions. Several United Nations (“U.N.”) instruments are analyzed for their efficacy in changing the long-standing customary international law on the use of mercenaries and whether or not each is applicable to PMF contractors. Part IV closes out the Article by discussing alternative bodies of domestic law that provide criminal accountability, including the recent case of Alaa Mohammad Ali, a civilian contractor working in Iraq who was convicted on June 23, 2008 by court martial under the recent changes to the Uniform Code of Military Justice (“UCMJ”)

The thermodynamics of computational copying in biochemical systems

Living cells use readout molecules to record the state of receptor proteins, similar to measurements or copies in typical computational devices. But is this analogy rigorous? Can cells be optimally efficient, and if not, why? We show that, as in computation, a canonical biochemical readout network generates correlations; extracting no work from these correlations sets a lower bound on dissipation. For general input, the biochemical network cannot reach this bound, even with arbitrarily slow reactions or weak thermodynamic driving. It faces an accuracy-dissipation trade-off that is qualitatively distinct from and worse than implied by the bound, and more complex steady-state copy processes cannot perform better. Nonetheless, the cost remains close to the thermodynamic bound unless accuracy is extremely high. Additionally, we show that biomolecular reactions could be used in thermodynamically optimal devices under exogenous manipulation of chemical fuels, suggesting an experimental system for testing computational thermodynamics.Comment: Accepted versio

For T Cell Receptors, Some Breakups Might Not Last Forever

Does the affinity or half-life of peptide-MHC-T cell receptor (TCR) interactions determine T cell activation? In this issue of Immunity, Aleksic et al. (2010) propose a role for the on rate through multiple rebindings to the same TCR

Stochastic and spatiotemporal effects in T-cell signaling

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2011.Cataloged from PDF version of thesis.Includes bibliographical references.T lymphocytes are key orchestrators of the adaptive immune response in higher organisms. This thesis seeks to apply different techniques from engineering and the physical sciences to understand how T cells balance the risks of autoimmunity and infection. (1) What features of proteins do T cells search for that correlate with pathogenicity, distinguishing self from foreign? Two contrasting theories have emerged that attempt to describe T cell ligand potency, one based on the half-life (tv12) of the interaction between T cell receptors (TCR) and peptide-MHC complexes (pMHC), the second on the equilibrium affinity (KD). We study an extensive set of TCR-pMHC interactions in CD4+ T cells which have differential KD and kinetics of binding. The data indicate that ligands with short t1/2 can be highly stimulatory if they have fast on-rates. Simple models suggest these fast-kinetic ligands are stimulatory because the pMHC bind and rebind the same TCR several times. Accounting for rebinding, ligand potency is KD-based when ligands have fast on-rates and t1/2-based when they have slow on-rates, unifying previous theories. (2) How do T cells make optimal responses with the imperfect information they receive through their receptors? Recent experiments suggest that T cells sometimes make stochastic decisions. Biological systems without sensors and genetic diversity, such as some bacteria, make stochastic decisions to diversify responses in uncertain environments, thereby optimizing performance (e.g. growth). T cells, however, can draw on considerable environmental and genetic diversity to diversify their responses. Using T cell biology as a guide, we identify a new role for noise in such systems: it helps systems achieve complex goals with simple signaling machinery. With decision-theoretic techniques, we suggest necessary conditions for noise to be useful in this way. (3) How can biological systems, like T cells, maintain desired responses in the presence of molecular noise, suppressing it or exploiting it as needed? We develop a semianalytical technique to determine how small changes in the rate constants of different reactions or in the concentrations of different species affect the rate at which biological systems escape stable cellular states. A single deterministic simulation yields the sensitivities with respect to all reactions and species in the system. This helps to predict those species or interactions that are most critical for regulating molecular noise, suggesting those most promising as drug targets or most vulnerable to mutation. These projects and others discussed in this thesis recruit techniques from random walks, statistical inference, and large deviation theory to understand problems ranging in scale from individual molecular interactions to the population of T cells acting in concert.by Christopher C. Govern.Ph.D

HIGH TEMPERATURE HEAT EXCHANGERS FOR NUCLEAR APPLICATIONS

ABSTRACT Many nuclear engineering applications, current and future, require heat exchangers operating at high temperatures. The operating conditions and performance requirements of these heat exchangers present special design challenges. This paper considers these challenges with respect to a simple heat exchanger design manufactured of a novel carbon material. Heat transfer and effectiveness calculations are performed for several parametric studies regarding heat exchanger parameters. These results are used to better understand the design challenges of high temperature heat exchangers as well as provide a starting point for future optimization work on more complex heat exchanger designs

Health promoting settings in primary health care - "hälsotorg": an implementation analysis

Background Sweden, like many other western countries, faces increasing rates of lifestyle related diseases and corresponding rise in costs for health care. To meet these challenges, a number of efforts have been introduced at different societal levels. One such effort is "Hälsotorg" (HS). HS is a new health promotion setting that emerged in collaboration between the Swedish County Councils and Apoteket AB, a state-owned pharmacy company. HS's overall aim was to improve population health and facilitate inhabitants' responsibility for self-care. A new National Public Health Policy, introduced in 2008, emphasizes more focus on individual's needs and responsibility as well as strong need for county councils to provide supportive environment for individual-centred health services and increased health literacy among the population. In light of this policy, there is a need to examine existing settings that can provide supportive environment for individuals at community level. The aim of this study was to explore HS's policy implementation at local level and analyse HS's activities, in order to provide a deeper understanding of HS's potential as a health promoting setting. Methods Materials included a survey and key documents related to the development and nature of HS on local and national levels. A policy analysis inspired by Walt and Gilson was used in data analysis. In addition, an analysis using the principles of health promotion in relation to HS policy process and activities was also carried out. Results The analysis illuminated strengths and weaknesses in the policy process, its actors, contextual factors and activities. The health communication approach in the analysed documents contained health promoting intentions but the health promoting approach corresponding to a health promoting setting was neither apparent nor shared among the stakeholders. This influenced the interpretation and implementation of HS negatively. Conclusions The analysis indicates that HS has potential to be a valuable health promotion setting for both population and individuals, given the strong intentions for a health and empowerment building approach that is expressed in the documents. However, for a more sustainable implementation of HS, there is need for an in- depth understanding of the health promotion approach among HS stakeholders

Dysregulated RasGRP1 Responds to Cytokine Receptor Input in T Cell Leukemogenesis

Enhanced signaling by the small guanosine triphosphatase Ras is common in T cell acute lymphoblastic leukemia/lymphoma (T-ALL), but the underlying mechanisms are unclear. We identified the guanine nucleotide exchange factor RasGRP1 (Rasgrp1 in mice) as a Ras activator that contributes to leukemogenesis. We found increased RasGRP1 expression in many pediatric T-ALL patients, which is not observed in rare early T cell precursor T-ALL patients with KRAS and NRAS mutations, such as K-Ras[superscript G12D]. Leukemia screens in wild-type mice, but not in mice expressing the mutant K-Ras[superscript G12D] that encodes a constitutively active Ras, yielded frequent retroviral insertions that led to increased Rasgrp1 expression. Rasgrp1 and oncogenic K-Ras[superscript G12D] promoted T-ALL through distinct mechanisms. In K-Ras[superscript G12D] T-ALLs, enhanced Ras activation had to be uncoupled from cell cycle arrest to promote cell proliferation. In mouse T-ALL cells with increased Rasgrp1 expression, we found that Rasgrp1 contributed to a previously uncharacterized cytokine receptor–activated Ras pathway that stimulated the proliferation of T-ALL cells in vivo, which was accompanied by dynamic patterns of activation of effector kinases downstream of Ras in individual T-ALLs. Reduction of Rasgrp1 abundance reduced cytokine-stimulated Ras signaling and decreased the proliferation of T-ALL in vivo. The position of RasGRP1 downstream of cytokine receptors as well as the different clinical outcomes that we observed as a function of RasGRP1 abundance make RasGRP1 an attractive future stratification marker for T-ALL.National Institutes of Health (U.S.). Pioneer AwardNational Cancer Institute (U.S.). Physical Sciences-Oncology Center (U54CA143874)National Institutes of Health (U.S.). (P01 AI091580

The lag-phase during diauxic growth is a trade-off between fast adaptation and high growth rate

Bi-phasic or diauxic growth is often observed when microbes are grown in a chemically defined medium containing two sugars (for example glucose and lactose). Typically, the two growth stages are separated by an often lengthy phase of arrested growth, the so-called lag-phase. Diauxic growth is usually interpreted as an adaptation to maximise population growth in multi-nutrient environments. However, the lag-phase implies a substantial loss of growth during the switch-over. It therefore remains unexplained why the lag-phase is adaptive. Here we show by means of a stochastic simulation model based on the bacterial PTS system that it is not possible to shorten the lag-phase without incurring a permanent growth-penalty. Mechanistically, this is due to the inherent and well established limitations of biological sensors to operate efficiently at a given resource cost. Hence, there is a trade-off between lost growth during the diauxic switch and the long-term growth potential of the cell. Using simulated evolution we predict that the lag-phase will evolve depending on the distribution of conditions experienced during adaptation. In environments where switching is less frequently required, the lag-phase will evolve to be longer whereas, in frequently changing environments, the lag-phase will evolve to be shorter