The properties of Msh2-Msh6 ATP binding mutants suggest a signal amplification mechanism in DNA mismatch repair.

DNA mismatch repair (MMR) corrects mispaired DNA bases and small insertion/deletion loops generated by DNA replication errors. After binding a mispair, the eukaryotic mispair recognition complex Msh2-Msh6 binds ATP in both of its nucleotide-binding sites, which induces a conformational change resulting in the formation of an Msh2-Msh6 sliding clamp that releases from the mispair and slides freely along the DNA. However, the roles that Msh2-Msh6 sliding clamps play in MMR remain poorly understood. Here, using Saccharomyces cerevisiae, we created Msh2 and Msh6 Walker A nucleotide-binding site mutants that have defects in ATP binding in one or both nucleotide-binding sites of the Msh2-Msh6 heterodimer. We found that these mutations cause a complete MMR defect in vivo The mutant Msh2-Msh6 complexes exhibited normal mispair recognition and were proficient at recruiting the MMR endonuclease Mlh1-Pms1 to mispaired DNA. At physiological (2.5 mm) ATP concentration, the mutant complexes displayed modest partial defects in supporting MMR in reconstituted Mlh1-Pms1-independent and Mlh1-Pms1-dependent MMR reactions in vitro and in activation of the Mlh1-Pms1 endonuclease and showed a more severe defect at low (0.1 mm) ATP concentration. In contrast, five of the mutants were completely defective and one was mostly defective for sliding clamp formation at high and low ATP concentrations. These findings suggest that mispair-dependent sliding clamp formation triggers binding of additional Msh2-Msh6 complexes and that further recruitment of additional downstream MMR proteins is required for signal amplification of mispair binding during MMR

Age-distribution estimation for karst groundwater: Issues of parameterization and complexity in inverse modeling by convolution

Convolution modeling is useful for investigating the temporal distribution of groundwater age based on environmental tracers. The framework of a quasi-transient convolution model that is applicable to two-domain flow in karst aquifers is presented. The model was designed to provide an acceptable level of statistical confidence in parameter estimates when only chlorofluorocarbon (CFC) and tritium (3H) data are available. We show how inverse modeling and uncertainty assessment can be used to constrain model parameterization to a level warranted by available data while allowing major aspects of the flow system to be examined. As an example, the model was applied to water from a pumped well open to the Madison aquifer in central USA with input functions of CFC-11, CFC-12, CFC-113, and 3H, and was calibrated to several samples collected during a 16-year period. A bimodal age distribution was modeled to represent quick and slow flow less than 50 years old. The effects of pumping and hydraulic head on the relative volumetric fractions of these domains were found to be influential factors for transient flow. Quick flow and slow flow were estimated to be distributed mainly within the age ranges of 0–2 and 26–41 years, respectively. The fraction of long-term flow (\u3e50 years) was estimated but was not dateable. The different tracers had different degrees of influence on parameter estimation and uncertainty assessments, where 3H was the most critical, and CFC-113 was least influential

Age-distribution estimation for karst groundwater: Issues of parameterization and complexity in inverse modeling by convolution

Convolution modeling is useful for investigating the temporal distribution of groundwater age based on environmental tracers. The framework of a quasi-transient convolution model that is applicable to two-domain flow in karst aquifers is presented. The model was designed to provide an acceptable level of statistical confidence in parameter estimates when only chlorofluorocarbon (CFC) and tritium (3H) data are available. We show how inverse modeling and uncertainty assessment can be used to constrain model parameterization to a level warranted by available data while allowing major aspects of the flow system to be examined. As an example, the model was applied to water from a pumped well open to the Madison aquifer in central USA with input functions of CFC-11, CFC-12, CFC-113, and 3H, and was calibrated to several samples collected during a 16-year period. A bimodal age distribution was modeled to represent quick and slow flow less than 50 years old. The effects of pumping and hydraulic head on the relative volumetric fractions of these domains were found to be influential factors for transient flow. Quick flow and slow flow were estimated to be distributed mainly within the age ranges of 0–2 and 26–41 years, respectively. The fraction of long-term flow (\u3e50 years) was estimated but was not dateable. The different tracers had different degrees of influence on parameter estimation and uncertainty assessments, where 3H was the most critical, and CFC-113 was least influential

Teleological Essentialism

Placeholder essentialism is the view that there is a causal essence that holds category members together, though we may not know what the essence is. Sometimes the placeholder can be filled in by scientific essences, such as when we acquire scientific knowledge that the atomic weight of gold is 79. We challenge the view that placeholders are elaborated by scientific essences. On our view, if placeholders are elaborated, they are elaborated Aristotelian essences, a telos. Utilizing the same kinds of experiments used by traditional essentialists—involving superficial change (study 1), transformation of insides (study 2), acquired traits (study 3) and inferences about offspring (study 4)—we find support for the view that essences are elaborated by a telos. And we find evidence (study 5) that teleological essences may generate category judgments

Calibration and Validation of a Finite ELement Model of THor-K Anthropomorphic Test Device for Aerospace Safety Applications

The THOR anthropomorphic test device (ATD) has been developed and continuously improved by the National Highway Traffic Safety Administration to provide automotive manufacturers an advanced tool that can be used to assess the injury risk of vehicle occupants in crash tests. Recently, a series of modifications were completed to improve the biofidelity of THOR ATD [1]. The updated THOR Modification Kit (THOR-K) ATD was employed at Wright-Patterson Air Base in 22 impact tests in three configurations: vertical, lateral, and spinal [2]. Although a computational finite element (FE) model of the THOR had been previously developed [3], updates to the model were needed to incorporate the recent changes in the modification kit. The main goal of this study was to develop and validate a FE model of the THOR-K ATD. The CAD drawings of the THOR-K ATD were reviewed and FE models were developed for the updated parts. For example, the head-skin geometry was found to change significantly, so its model was re-meshed (Fig. 1a). A protocol was developed to calibrate each component identified as key to the kinematic and kinetic response of the THOR-K head/neck ATD FE model (Fig. 1b). The available ATD tests were divided in two groups: a) calibration tests where the unknown material parameters of deformable parts (e.g., head skin, pelvis foam) were optimized to match the data and b) validation tests where the model response was only compared with test data by calculating their score using CORrelation and Analysis (CORA) rating system. Finally, the whole ATD model was validated under horizontal-, vertical-, and lateral-loading conditions against data recorded in the Wright Patterson tests [2]. Overall, the final THOR-K ATD model developed in this study is shown to respond similarly to the ATD in all validation tests. This good performance indicates that the optimization performed during calibration by using the CORA score as objective function is not test specific. Therefore confidence is provided in the ATD model for uses in predicting response in test conditions not performed in this study such those observed in the spacecraft landing. Comparison studies with ATD and human models may also be performed to contribute to future changes in THOR ATD design in an effort to improve its biofidelity, which has been traditionally based on post-mortem human subject testing and designer experience

Mind and body, form and content: how not to do petitio principii analysis

Few theoretical insights have emerged from the extensive literature discussions of petitio principii argument. In particular, the pattern of petitio analysis has largely been one of movement between the two sides of a dichotomy, that of form and content. In this paper, I trace the basis of this dichotomy to a dualist conception of mind and world. I argue for the rejection of the form/content dichotomy on the ground that its dualist presuppositions generate a reductionist analysis of certain concepts which are central to the analysis of petitio argument. I contend, for example, that no syntactic relation can assimilate within its analysis the essentially holistic nature of a notion like justification. In this regard, I expound a form of dialectical criticism which has been frequently employed in the philosophical arguments of Hilary Putnam. Here the focus of analysis is upon the way in which the proponent of a position proceeds to explain or argue for his/her own particular theses. My conclusion points to the use of such dialectic within future analyses of petitio principii

Theories of Reference: What Was the Question?

The new theory of reference has won popularity. However, a number of noted philosophers have also attempted to reply to the critical arguments of Kripke and others, and aimed to vindicate the description theory of reference. Such responses are often based on ingenious novel kinds of descriptions, such as rigidified descriptions, causal descriptions, and metalinguistic descriptions. This prolonged debate raises the doubt whether different parties really have any shared understanding of what the central question of the philosophical theory of reference is: what is the main question to which descriptivism and the causal-historical theory have presented competing answers. One aim of the paper is to clarify this issue. The most influential objections to the new theory of reference are critically reviewed. Special attention is also paid to certain important later advances in the new theory of reference, due to Devitt and others

Emotions and actions associated with altruistic helping and punishment

Evolutionary altruism (defined in terms of fitness effects) exists in the context of punishment in addition to helping. We examine the proximate psychological mechanisms that motivate altruistic helping and punishment, including the effects of genetic relatedness, potential for future interactions, and individual differences in propensity to help and punish. A cheater who is a genetic relative provokes a stronger emotional reaction than a cheater who is a stranger, but the behavioral response is modulated to avoid making the transgression public in the case of cheating relatives. Numerous behavioral differences are not accompanied by emotional differences, suggesting that other psychological mechanisms dictate the specific response to emotion-provoking events. Paradoxically, there is a positive correlation between temptation to cheat and propensity to punish others for cheating, leading to a concept of ?selfish punishment? that has been substantiated by a computer simulation model. This study demonstrates that fictional scenarios can provide an important methodological tool for studying the psychological basis of helping and punishment

From sensorimotor dependencies to perceptual practices: making enactivism social

Proponents of enactivism should be interested in exploring what notion of action best captures the type of action-perception link that the view proposes, such that it covers all the aspects in which our doings constitute and are constituted by our perceiving. This article proposes and defends the thesis that the notion of sensorimotor dependencies is insufficient to account for the reality of human perception, and that the central enactive notion should be that of perceptual practices. Sensorimotor enactivism is insufficient because it has no traction on socially dependent perceptions, which are essential to the role and significance of perception in our lives. Since the social dimension is a central desideratum in a theory of human perception, enactivism needs a notion that accounts for such an aspect. This article sketches the main features of the Wittgenstein-inspired notion of perceptual practices as the central notion to understand perception. Perception, I claim, is properly understood as woven into a type of social practices that includes food, dance, dress, music, etc. More specifically, perceptual practices are the enactment of culturally structured, normatively rich techniques of commerce of meaningful multi- and inter-modal perceptible material. I argue that perceptual practices explain three central features of socially dependent perception: attentional focus, aspects’ saliency, and modal-specific harmony-like relations