Whole-cell model simulations for medicine and bioengineering

Whole-cell models predict cell behaviors by modeling all molecular components and their interactions. Recently, we and other developed the first whole-cell model. The model represents the functionality of all 409 characterized genes and 725 metabolites throughout one life cycle of the reduced bacterium Mycoplasma genitalium. This model was validated against a broad range of data and provided insights into many previously unobserved cellular behaviors. Simulating the behavior of a single cell required modest computing resources – 1 core-day of an Intel E5520 CPU, capable of 3.3×1015 double-precision floating-point operations during the computation. Sampling the organism’s behavior required 128 simulations. Nevertheless, we anticipate that exascale computing resources will be required to use more comprehensive and more accurate whole-cell models to personalize medicine and engineer bacteria

Dynamical quenching and annealing in self-organization multiagent models

We study the dynamics of a generalized Minority Game (GMG) and of the Bar Attendance Model (BAM) in which a number of agents self-organize to match an attendance that is fixed externally as a control parameter. We compare the usual dynamics used for the Minority Game with one for the BAM that makes a better use of the available information. We study the asymptotic states reached in both frameworks. We show that states that can be assimilated to either thermodynamic equilibrium or quenched configurations can appear in both models, but with different settings. We discuss the relevance of the parameter $G$ that measures the value of the prize for winning in units of the fine for losing. We also provide an annealing protocol by which the quenched configurations of the GMG can progressively be modified to reach an asymptotic equlibrium state that coincides with the one obtained with the BAM.Comment: around 20 pages, 10 figure

Concert/C: A language for distributed programming

Concert/C is a new language for distributed C programming that extends ANSI C to support distribution and process dynamics. Concert/C provides the ability to create and terminate processes, connect them together, and communicate among them. It supports transparent remote function calls (RPC) and asynchronous messages. Interprocess communications interfaces are typed in Concert/C, and type correctness is checked at compile time wherever possible, otherwise at runtime. All C data types, including complex data structures containing pointers and aliases, can be transmitted in RPCs. Concert/C programs run on a heterogeneous set of machine architectures and operating systems and communicate over multiple RPC and messaging protocols. The current Concert/C implementation runs on AIX 3.2 1, SunOS 4.1, Solaris 2.2 and OS/2 2.1, and communicates over Sun RPC, OSF/DCE and UDP multicast. Several groups inside and outside IBM are actively using Concert/C, and it is available via anonymous ftp from software.watson.ibm.com:/pub/concert.

Biomorpher: interactive evolution for parametric design

Combining graph-based parametric design with metaheuristic solvers has to date focussed solely on performance based criteria and solving clearly defined objectives. In this paper, we outline a new method for combining a parametric modelling environment with an interactive Cluster-Orientated Genetic Algorithm (COGA). In addition to performance criteria, evolutionary design exploration can be guided through choice alone, with user motivation that cannot be easily defined. As well as numeric parameters forming a genotype, the evolution of whole parametric definitions is discussed through the use of genetic programming. Visualisation techniques that enable mixing small populations for interactive evolution with large populations for performance-based optimisation are discussed, with examples from both academia and industry showing a wide range of applications

Short-term effects of amelogenin gene splice products A+4 and A-4 implanted in the exposed rat molar pulp

In order to study the short-time effects of two bioactive low-molecular amelogenins A+4 and A-4, half-moon cavities were prepared in the mesial aspect of the first maxillary molars, and after pulp exposure, agarose beads alone (controls) or beads soaked in A+4 or A-4 (experimental) were implanted into the pulp. After 1, 3 or 7 days, the rats were killed and the teeth studied by immunohistochemistry. Cell proliferation was studied by PCNA labeling, positive at 3 days, but decreasing at day 7 for A+4, whilst constantly high between 3 and 7 days for A-4. The differentiation toward the osteo/odontoblast lineage shown by RP59 labeling was more apparent for A-4 compared with A+4. Osteopontin-positive cells were alike at days 3 and 7 for A-4. In contrast, for A+4, the weak labeling detected at day 3 became stronger at day 7. Dentin sialoprotein (DSP), an in vivo odontoblast marker, was not detectable until day 7 where a few cells became DSP positive after A-4 stimulation, but not for A+4. These results suggest that A +/- 4 promote the proliferation of some pulp cells. Some of them further differentiate into osteoblast-like progenitors, the effects being more precocious for A-4 (day 3) compared with A+4 (day 7). The present data suggest that A +/- 4 promote early recruitment of osteogenic progenitors, and evidence functional differences between A+4 and A-4

Broker Fixed: The Racialized Social Structure and the Subjugation of Indigenous Populations in the Andes

Responding to calls to return racial analysis to indigenous Latin America, this article moves beyond the prejudicial attitudes of dominant groups to specify how native subordination gets perpetuated as a normal outcome of the organization of society. I argue that a naturalized system of indirect rule racially subordinates native populations through creating the position of mestizo “authoritarian intermediary.” Natives must depend on these cultural brokers for their personhood, while maintaining this privileged position requires facilitating indigenous exploitation. Institutional structures combine with cultural practices to generate a vicious cycle in which increased village intermediary success increases native marginalization. This racialized social structure explains my ethnographic findings that indigenous villagers continued to support the same coterie of mestizos despite their regular and sometimes extreme acts of peculation. My findings about the primacy of race suggest new directions for research into indigenous studies, ethnic mobilizations, and the global dimensions of racial domination

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology