The Science of Conceptual Systems: A Progress Report

In this paper I provide a brief history of the emerging science of conceptual systems, explain some methodologies, their sources of data, and the understandings that they have generated. I also provide suggestions for extending the science-based research in a variety of directions. Essentially, I am opening a conversation that asks how this line of research might be extended to gain new insights—and eventually develop more useful and generally accepted methods for creating and evaluating theory. This effort will support our ability to generate theory that is more effective in practical application as well as accelerating the development of theory to support advances in other sciences.     

Whole-genome analysis informs breast cancer response to aromatase inhibition

To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.     

d-5-Chloro-2-(α-hydroxybenzyl)benzimidazole and 1-Alkyl-5-chloro-2-(α-hydroxybenzyl)benzimidazoles as inhibitors of poliovirus multiplication

Zusammenfassung Died-isomere Verbindung ist verantwortlich für die Poliovirus-hemmende Aktivität vondl-5-Chlor-2-(-oxy-benzyl)-benzimidazol.dl-1-Propyl-5-chlor-unddl-1-Butyl-5-chlor-Derivate sind ausserordentlich wirksam zur Verhinderung der Vermehrung der Typen 1, 2 und 3 des Poliovirus; andere 1-Alkyl-5-chlor-Derivate sind ebenfalls aktiv. Die 1-Alkyl-Grundverbindungen sind jedoch wirksamer als deren gleichartige 1-Alkyl-5-chlor-Derivate.

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The research is supported by the National Fund for Research into Poliomyelitis and other Crippling Diseases.     

New 1,2-disubstituted benzimidazoles with high inhibiting effects on poliovirus Replication

Zusammenfassung 1-Phenyl- und 1--Methylpropyl-2-(-oxy-benzyl)-benzimidazol setzen die Vermehrung des Poliovirus der Arten 1, 2 und 3 in der Gewebekulturzelle stark herab. Die Hemmwirkungen und die Beeinflussung der Toxizitätsverhältnisse der 1-Phenyl-Derivate sind alle grösser, als die der früher untersuchten Benzimidazolene.

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The research is supported by the National Fund for Research into Poliomyelitis and other Crippling Diseases.     

Complete protein sequence and identification of structural domains of human apolipoprotein B

Epidemiological, pathological and genetic studies show a strong positive correlation between elevated plasma concentrations of low-density lipoprotein (LDL) cholesterol and the risk of premature coronary heart disease. Apolipoprotein (apo) B-100 is the sole protein component of LDL and is the ligand responsible for the receptor-mediated uptake and clearance of LDL from the circulation. Apo B-100 is made by the liver and is essential for the assembly of triglyceride-rich very low-density lipoproteins (VLDL) in the cisternae of the endoplasmic reticulum and for their secretion into the plasma. VLDL transports triglyceride to peripheral muscle and adipose tissue, where the triglyceride is hydrolysed by lipoprotein lipase. The resultant particle, relatively enriched in cholesteryl ester, constitutes LDL. LDL delivers cholesterol to peripheral tissues where it is used for membrane and steroid hormone biosynthesis and to the liver, the only organ which can catabolize and excrete cholesterol. Plasma LDL levels are therefore determined by the balance between their rate of production from VLDL and clearance by the hepatic LDL (apo B/E) receptor pathway. Here we report the complete 4,563-amino-acid sequence of apo B-100 precursor (relative molecular mass (Mr) 514,000 (514K] determined from complementary DNA clones. Numerous lipid-binding structures are distributed throughout the extraordinary length of apo B-100 and must underlie its special functions as a nucleus for lipoprotein assembly and maintenance of plasma lipoprotein integrity. A domain enriched in basic amino-acid residues has been identified as important for the cellular uptake of cholesterol by the LDL receptor pathway.     

Single neurons in prefrontal cortex encode abstract rules.

The ability to abstract principles or rules from direct experience allows behaviour to extend beyond specific circumstances to general situations. For example, we learn the 'rules' for restaurant dining from specific experiences and can then apply them in new restaurants. The use of such rules is thought to depend on the prefrontal cortex (PFC) because its damage often results in difficulty in following rules. Here we explore its neural basis by recording from single neurons in the PFC of monkeys trained to use two abstract rules. They were required to indicate whether two successively presented pictures were the same or different depending on which rule was currently in effect. The monkeys performed this task with new pictures, thus showing that they had learned two general principles that could be applied to stimuli that they had not yet experienced. The most prevalent neuronal activity observed in the PFC reflected the coding of these abstract rules.     

The inhibiting actions on poliovirus multiplication of 1-alkyl-2-(α-methoxybenzyl)benzimidazoles

Zusammenfassung 1-Alkyl-2-(-methoxybenzyl)-benzimidazole hemmt die Vermehrung des Poliovirus der Arten 1, 2 und 3, wobei das 1-Propyl-Derivat die grösste Wirkung hat.

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The research is supported by the National Fund for Research into Poliomyelitis and other Crippling Diseases.     

Natural examples of olivine lattice preferred orientation patterns with a flow-normal a-axis maximum

Tectonic plate motion is thought to cause solid-state plastic flow within the underlying upper mantle and accordingly lead to the development of a lattice preferred orientation of the constituent olivine crystals. The mechanical anisotropy that results from such preferred orientation typically produces a direction of maximum seismic wave velocity parallel to the plate motion direction. This has been explained by the existence of an olivine preferred orientation with an 'a-axis' maximum parallel to the induced mantle flow direction. In subduction zones, however, the olivine a axes have been inferred to be arranged roughly perpendicular to plate motion, which has usually been ascribed to localized complex mantle flow patterns. Recent experimental work suggests an alternative explanation: under conditions of high water activity, a 'B-type' olivine preferred orientation may form, with the a-axis maximum perpendicular to the flow direction. Natural examples of such B-type preferred orientation are, however, almost entirely unknown. Here we document widespread B-type olivine preferred orientation patterns from a subduction-type metamorphic belt in southwest Japan and show that these patterns developed in the presence of water. Our discovery implies that mantle flow above subduction zones may be much simpler than has generally been thought.