Marr and Reductionism

David Marr's three-level method for completely understanding a cognitive system and the importance he attaches to the computational level are so familiar as to scarcely need repeating. Fewer seem to recognize that Marr defends his famous method by criticizing the “reductionistic approach.” This sets up a more interesting relationship between Marr and reductionism than is usually acknowledged. I argue that Marr was correct in his criticism of the reductionists of his time—they were only describing (cellular activity), not explaining (cognitive functions). But a careful metascientific account of reductionistic neuroscience over the past two decades reveals that Marr's criticisms no longer have force. Contemporary neuroscience now explains cognition directly, although in a fashion—causal-mechanistically—quite different than Marr recommended. So while Marr was correct to reject the reductionism of his day and offer an alternative method for genuinely explaining cognition, contemporary cognitive scientists now owe us a new defense of Marr's famous method and the advantages of its explanations over the type now pursued successfully in current reductionist neuroscience. There are familiar reasons for thinking that this debt will not be paid easily.     

Anatomically contoured large femoral heads can reduce iliopsoas impingement: A cadaver verification study

While use of large heads in total hip arthroplasty (THA) continues to grow, concerns have been raised regarding anterior hip pain resulting from impingement of the prosthetic head against soft-tissues like the iliopsoas. To address these concerns, a new anatomically contoured head (ACH) was developed. In this study cadaver tests were utilized to show that iliopsoas impingement/tenting caused by conventional heads is significantly relieved with the more rounded and reduced distal profile of the ACH. Thus, the ACH implant may be able to decrease the risk of soft-tissue impingement with conventional heads, particularly in the smaller hip.     

For better or worse? Investigating the validity of best–worst discrete choice experiments in health

Discrete choice experiments (DCEs) are frequently used in health economics to measure preferences for nonmarket goods. Best–worst discrete choice experiment (BWDCE) has been proposed as a variant of the traditional “pick the best” approach. BWDCE, where participants choose the best and worst options, is argued to generate more precise preference estimates because of the additional information collected. However, the validity of the approach relies on two necessary conditions: (a) best and worst decisions provide similar information about preferences and (b) asking individuals to answer more than one choice question per task does not reduce data quality. Whether these conditions hold in empirical applications remains under researched. This is the first study to compare participants' choices across three experimental conditions: (a) BEST choices only, (b) WORST choices only, and (c) BEST and WORST choices (BWDCE). We find responses to worst choices are noisier. Implied preferences from the best only and worst only choices are qualitatively different, leading to different WTP values. Responses to BWDCE tasks have lower consistency, and respondents are more likely to use simplifying decision heuristics. We urge caution in using BWDCE as an alternative to the traditional “pick the best” DCE.     

Glutathione conjugation of chlorobenzylidene malononitriles in vitro and the biotransformation to mercapturic acids in rats

The glutathione conjugation of 2-chloro-, 3-chloro-, 4-chloro- and 2,6-dichlorobenzylidene malononitrile (chloroBMNs) was investigated in vitro. In incubation mixtures containing rat liver cytosol (9000 g), the decrease in the initial amount of glutathione due to the various chloroBMNs ranged from 40 to 60% and occurred both enzymatically and spontaneously at physiological conditions (37°C, pH7.4). 2,6-DichloroBMN, however, depleted glutathione largely spontaneously (38±3%). The steric hindrance of the two chlorosubstituents probably plays an important role during the glutathione-S-transferase catalyzed reaction.The hydrolysis of the chloroBMNs to the corresponding chlorobenzaldehydes and malononitrile was studied in a mixture of buffer pH 7.4 and ethanol. The rate of hydrolysis of 2,6-dichloroBMN was slower than those of the related chloroBMNs. This means that 2,6-dichloroBMN will be the most stable compound in the presence of water.Only IP administration of 2-chloroBMN (CS) to adult male Wistar rats gave enhancement of urinary thioether excretion. A thioether could be isolated and was identified as the N-acetyl-S-[2-chlorobenzyl]-L-cysteine. The quantity of this benzylmercapturic acid in the urine of rats amounted to 4.4% dose (0.07 mmol/kg, n=12).After IP administration of 2-chloro- and 3-chlorobenzaldehyde to rats benzylmercapturic acid excretion in the urine was found to be 7.6 and 1.1% of the dose, respectively. Administration of the related 4-chloro- and 2,6-dichlorobenzaldehyde, however, resulted in _no urinary mercapturic acid excretion.It is very likely that in rats the initial biotransformation of chloroBMNs is mainly hydrolysis to corresponding chlorobenzaldehydes, leading in the case of 3-chloro-, 4-chloro- and 2,6-dichloroBMN to no mercapturic acid excretion in the urine.Nevertheless, 2,6-dichloroBMN will be the most reactive compound with proteins and therefore the best haptene in comparison with the related chloroBMNs.This work was financially supported by a grant from the Dutch Foundation for Medical Research FUNGO, grant no. 13-28-57     

Cardiac Electrophysiological Experiments in Numero, Part III: Simulation of Arrhythmias and Pacing

This paper is the third and final part of a series of articles reviewing mathematical and computer models of the electrophysiological processes. This section reviews the arrhythmia simulation and discusses models of arrhythmogenic processes, fibrillation and defibrillation, and of heart-pacemaker interaction. The models of arrhythmogenesis are classified into three main sections: models of reentry and vortex reentry, models of myocardial electrotonic interactions, and models of macroreentrant supraventricular tachycardias. This final part of the review discusses the future potential of mathematical and computer models of different cardiac processes.     

Effects of hydroxocobalamin on rat cardiac papillary muscle

Hydroxocobalamin is a rapid and powerful antidote in acute cyanide poisoning. The effects of hydroxocobalamin (0.1, 0.3, and 1 mM) on intrinsic myocardial contractility were studied on isolated rat cardiac papillary muscles (n=10). Whatever the concentration, hydroxocobalamin did not modify the active isometric force and a slight increase in maximum unloaded shortening velocity was noted at 1 mM. Only 0.3 mM significantly impaired contraction-relaxation coupling under low load, suggesting a slight decrease in sarcoplasmic reticulum function. No changes in contraction relaxation coupling under heavy load were noted, suggesting the lack of modification of myofilament calcium sensitivity. These results suggest that hydroxocobalamin does not induce noticeable changes in intrinsic myocardial contractility. An indirect mechanism might be involved in the previously reported decrease in cardiac function at supratherapeutic concentrations of hydroxocobalamin.     

A review of in-situ EBSD experiments

IntroductionIn the firstautomated Electron Backscatter Diffrac-tion(EBSD)[1]or Orientation Imaging Microscopy(OIM)[2]systems,patterns were indexed at a rate ofabout four seconds per pattern.In the past decade,OIMscan speeds have increased to over 300 times fas-ter than the original measurements.During this sametime period,scanning electron microscope(SEM)technology has also seen large improvements enablingthe OIMtechnique to be applied at higher spatial reso-lutions and with more flex…     

The role of computational models of the immune system in designing vaccination strategies

Mathematical and computational models are designed to improve our understanding of biological phenomena, to confirm/reject hypotheses, and to find points of intervention by altering the behavior of the studied systems. Here we describe the role of mathematical/computational models of the immune system. In particular, we analyze some examples of how mathematical modeling can contribute to finding optimal vaccination strategies. Indeed, computational modeling offers an intriguing opportunity from the theoretical point of view, and it will be of interest for clinically oriented investigators who wish to find optimal therapeutic strategies and for pharmaceutical industries that want to produce effective and successful drugs.