Evolutionary change is opportunistic, but its course is strongly constrained in several fundamental ways. These constraints (historical/phylogenetic, functional/adaptive, constructional/morphogenetic) and their dynamic relationships are discussed here and shown to constitute the conceptual framework of Constructional Morphology. Notwithstanding recent published opinions which claim that the discovery of constraints renders Neodarwinian selection theory obsolete, we regard the insights of Constructional Morphology as being entirely consistent with this theory. As is shown here in the case of the Hyracoidea, formal analysis of the constraints (...) which have framed the evolution of various characters extends our understanding of the evolution of a taxon. (shrink)

BACKGROUND: Alzheimer's disease is intimately tied to amyloid-beta peptide. Extraneuronal brain plaques consisting primarily of Abeta aggregates are a hallmark of AD. Intraneuronal Abeta subunits are strongly implicated in disease progression. Protein sequence mutations of the Abeta precursor protein account for a small proportion of AD cases, suggesting that regulation of the associated gene may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or "proximal regulatory element" , at -76/-47, from the (...) +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones. RESULTS: EMSA probed with the PRE showed DNA-protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 , nm23 nucleoside diphosphate kinase/metastatic inhibitory protein , and specificity protein 1 . These sites crossed a known single nucleotide polymorphism . EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis. CONCLUSIONS: We propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also interacts with the integrins. These proteins are connected to vital cellular and neurological functions. In addition, the transcription factor PuF is a known inhibitor of metastasis and regulates cell growth during development. Given that APP is a known cell adhesion protein and ferroxidase, this suggests biochemical links among cell signaling, the cell cycle, iron metabolism in cancer, and AD in the context of overall aging. (shrink)

Major hallmarks of Alzheimer's disease include brain deposition of the amyloid-beta peptide , which is proteolytically cleaved from a large Abeta precursor protein by beta and gamma- secretases. A transmembrane aspartyl protease, beta-APP cleaving enzyme , has been recognized as the beta-secretase. We review the structure and function of the BACE1 protein, and of 4129 bp of the 5'-flanking region sequence of the BACE1 gene and its interaction with various transcription factors involved in cell signaling. The promoter region and 5'-untranslated (...) region contain multiple transcription factor binding sites, such as AP-1, CREB and MEF2. A 91 bp fragment is the shortest region with significant reporter gene activity and constitutes the minimal promoter element for BACE1. The BACE1 promoter contains six unique functional domains and three structural domains of increasing sequence complexity as the "ATG" start codon is approached. Notably, the BACE1 gene promoter contains basal regulatory elements, inducible features and sites for regulation by various important transcription factors. Herein, we also discuss and speculate how the interaction of these transcription factors with the BACE1 promoter can modulate synaptic plasticity, neuronal apoptosis and oxidative stress, which are pertinent to the pathogenesis and progression of AD. (shrink)

Variations in levels of apolipoprotein E have been tied to the risk and progression of Alzheimer's disease . Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter's role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at -491 , -427 , and at -219 upstream from the (...) +1 transcription start site. The -219 and -491 polymorphic variations have significant association with instance of AD, and -491AA has significant risk even when stratified for the APOEepsilon4 allele. We also show significant effects on reporter gene expression in neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The -491 and -219 polymorphisms may have an interactive effect in addition to any independent activity. DNA-protein interactions differ between each polymorphic state. We propose SP1 and GATA as candidates for regulatory control of the -491 and -219 polymorphic sites. This work's significance lies in drawing connection among APOE promoter polymorphisms' associations with AD to functional promoter activity differences and specific changes in DNA-protein interactions in cell culture-based assays. Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEepsilon4 allele status. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Hume Studies Volume XXIII, Number 2, November 1997, pp. 315-335 Reid: Conception, Representation and Innate Ideas ROGER D. GALLIE Section I of this paper begins with a presentation of Thomas Reid's doctrine of the signification of words, of what words signify or represent. That presentation serves to introduce a problem of interpretation, namely, what Reid thinks the connection is between conceiving something and grasping what a term (...) for it signifies. It is pointed out that even if Reid maintains that what a word signifies is conceived by both speaker and hearer when that word is understood, this is a far cry from the position that he takes the stronger view, whether for all or only for some things, that their being conceived involves the understanding of a term or terms. The position that he does indeed take this stronger, although moderate, view is defended in sections II, III and IV. In sections II and III it is argued that, in Reid's view, for an adequate conception of an individual, real or imaginary, a conception of its attributes is needed. In section IV it is argued that the possession of general conceptions (in distinction from their formation), without which conception of attributes is impossible, requires appropriate understanding of general terms. So since for the conception of an individual a conception of its attributes is needed, and since for the conception of attributes appropriate understanding of general terms is required, we arrive at a textually well-founded position: for the conception of most things, in Reid's view, understanding of terms is indispensable. Roger D. Gallie is at the Department of Philosophy, Nottingham University, University Park, Nottingham NG7 2RD UK. email: Roger[email protected] 316 Roger D. Gallie The remainder of the paper considers the following question: to what extent, if any, Reid is committed to acceptance of nativist views on concept possession? To answer, in section V we consider to what extent Reid's moderate position on the possession of conceptions commits him to accepting Jerry Fodor's representational theory of mind (RTM) for propositional attitudes. It is clear that the view that a propositional attitude state such as belief involves some relation between a person and a representation such as a significant word, phrase or sentence of a natural language such as English can fairly be attributed to Reid. But it is also clear that Reid cannot be an adherent of the view that persons have a functional cum computational relation to Fodorean mental representations, so he cannot be an adherent of any nativism ex- plicitly contained in such a view. But it is to be noted that in his Inquiry, Chapter IV, Reid argues by a different route that in order to acquire a language such as English prior mastery of a system of significant signs is required. In section VI Keith Lehrer's argument in criticism of a reductionist interpretation of a position such as Fodor's is presented: that for a sign to signify something to someone presupposes that that person has a conception of what is signified. It is however pointed out that since there is a case for not viewing Fodor's position as reductionist overall Fodor can accept Lehrer's argument. Lehrer's innatist position, which he both claims to follow easily from this critical argument and to be a correct interpretation of Reid, is then presented: that we must presuppose an innate understanding of some signs to account for our learning the meaning of any signs. The objection that Reid too must accept the alleged innatist implications of Lehrer's critical argument in view of the implications of his moderate position on the possession of conceptions is considered and rebutted. In section VIII argue that while Lehrer makes a respectable case for innate principles of formation of conceptions such as that of hardness, something that Reid clearly endorses in his Inquiry, Chapter V, he does not succeed in making a case for there being any innate possession of conceptions. Finally, in section VIII, Reid's mature views in the Intellectual Powers, Essay VI, on how conceptions come to be possessed are expounded, and are fleshed out with some... (shrink)

BackgroundIn the Canadian Alliance for Healthy Hearts and Minds (CAHHM) cohort, participants underwent magnetic resonance imaging (MRI) of the brain, heart, and abdomen, that generated incidental findings (IFs). The approach to managing these unexpected results remain a complex issue. Our objectives were to describe the CAHHM policy for the management of IFs, to understand the impact of disclosing IFs to healthy research participants, and to reflect on the ethical obligations of researchers in future MRI studies.MethodsBetween 2013 and 2019, 8252 participants (...) (mean age 58 ± 9 years, 54% women) were recruited with a follow-up questionnaire administered to 909 participants (40% response rate) at 1-year. The CAHHM policy followed a restricted approach, whereby routine feedback on IFs was not provided. Only IFs of severe structural abnormalities were reported.ResultsSevere structural abnormalities occurred in 8.3% (95% confidence interval 7.7–8.9%) of participants, with the highest proportions found in the brain (4.2%) and abdomen (3.1%). The majority of participants (97%) informed of an IF reported no change in quality of life, with 3% of participants reporting that the knowledge of an IF negatively impacted their quality of life. Furthermore, 50% reported increased stress in learning about an IF, and in 95%, the discovery of an IF did not adversely impact his/her life insurance policy. Most participants (90%) would enrol in the study again and perceived the MRI scan to be beneficial, regardless of whether they were informed of IFs. While the implications of a restricted approach to IF management was perceived to be mostly positive, a degree of diagnostic misconception was present amongst participants, indicating the importance of a more thorough consent process to support participant autonomy.ConclusionThe management of IFs from research MRI scans remain a challenging issue, as participants may experience stress and a reduced quality of life when IFs are disclosed. The restricted approach to IF management in CAHHM demonstrated a fair fulfillment of the overarching ethical principles of respect for autonomy, concern for wellbeing, and justice. The approach outlined in the CAHHM policy may serve as a framework for future research studies.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/nct02220582. (shrink)

If K is a class of semiassociative relation algebras and K contains the relation algebra of all binary relations on a denumerable set, then the word problem for the free algebra over K on one generator is unsolvable. This result implies that the set of sentences which are provable in the formalism Lwx is an undecidable theory. A stronger algebraic result shows that the set of logically valid sentences in Lwx forms a hereditarily undecidable theory in Lwx. These results generalize (...) similar theorems, due to Tarski, concerning relation algebras and the formalism Lx. (shrink)

For ten years, 1971–1981, the Institute onHuman Values in Medicine (IHVM) played a keyrole in the development of Bioethics as afield. We have written this history andanalysis to bring to new generations ofBioethicists information about the developmentof their field within both the humanitiesdisciplines and the health professions. Thepioneers in medical humanities and ethics cametogether with medical professionals in thedecade of the 1960s. By the 1980s Bioethics wasa fully recognized discipline. We show the rolethat IHVM programs played in defining thefield, training (...) faculty and helping schools todevelop programs. We review the beginnings ofthe IHVM in the crucible of social andtechnological change that led to theestablishment of the IHVM's parentorganization, the Society for Health and HumanValues. We then turn to the IHVM programsthrough which Faculty members receivedfellowships to explore new crossovers betweenthe humanities and the health professions. Wehave not only described the Fellows Program asit existed in 1973–1980, but have completed asurvey of the fellows a quarter of a centuryafter they held their fellowships. We describeother IHVM programs designed to facilitate theinitiation and development of new humanitiesprograms, to explore conceptual issues betweenmedicine and five humanities fields, to conductissue driven or educational method conferencesand to advance humanities programs intograduate education through the Directors ofMedical Education. (shrink)

Volume 24, Issue 7, July 2024, Page 6-12.

Monetary intelligence theory asserts that individuals apply their money attitude to frame critical concerns in the context and strategically select certain options to achieve financial goals and ultimate happiness. This study explores the dark side of monetary Intelligence and behavioral economics—dishonesty. Dishonesty, a risky prospect, involves cost–benefit analysis of self-interest. We frame good or bad barrels in the environmental context as a proxy of high or low probability of getting caught for dishonesty, respectively. We theorize: The magnitude and intensity of (...) the relationship between love of money and dishonest prospect may reveal how individuals frame dishonesty in the context of two levels of subjective norm—perceived corporate ethical values at the micro-level and Corruption Perceptions Index at the macro-level, collected from multiple sources. Based on 6382 managers in 31 geopolitical entities across six continents, our cross-level three-way interaction effect illustrates: As expected, managers in good barrels, mixed barrels, and bad barrels display low, medium, and high magnitude of dishonesty, respectively. With high CEV, the intensity is the same across cultures. With low CEV, the intensity of dishonesty is the highest in high CPI entities —the Enron Effect, but the lowest in low CPI entities. CPI has a strong impact on the magnitude of dishonesty, whereas CEV has a strong impact on the intensity of dishonesty. We demonstrate dishonesty in light of monetary values and two frames of social norm, revealing critical implications to the field of behavioral economics and business ethics. (shrink)

In the second edition of this groundbreaking text in non-Western philosophy, sixteen experts introduce some of the great philosophical traditions in the world. The essays unveil exciting, sophisticated philosophical traditions that are too often neglected in the western world. The contributors include the leading scholars in their fields, but they write for students coming to these concepts for the first time. Building on revisions and updates to the original, this new edition also considers three philosophical traditions for the first time—Jewish, (...) Buddhist, and South Pacific philosophy. (shrink)

A good deal of attention has been recently focused on the presumed advertising excesses of the healthcare industry in its promotion techniques to healthcare professionals, whether through offering gratuities such as gifts, honoraria, or travel support2-6 or through deception. Two basic concerns have been expressed: Does the acceptance of gratuities bias the recipient, tainting his or her responsibilities as the patient's agent? Does acceptance of the gratuity by the healthcare professional contribute to the high cost of healthcare products? The California (...) Society of Hospital Pharmacists was recently asked by its members to formulate a policy for an appropriate relationship between the Society and the healthcare industry, addressing these concerns. In formulating its policy, it became clear that the Society depended on healthcare industry support, gathered through journal advertising, fees for booths at its various educational events, and grants for speakers. (shrink)

ObjectivesThe purpose of the current study was to examine whether a self-report measure identifies prenatal substance use and predicts resulting adverse birth outcomes in a large cohort using electronic medical records.MethodsPregnant patients who were admitted between 2014 and 2015 at Christiana Care Health System and delivered singleton birth were included in the analyses. Participant demographic information, pregnancy comorbidities, self-reported substance use, and birth outcomes were retrieved from electronic medical records. Detailed descriptive analyses of prenatal substance use were conducted, and logistic (...) models were evaluated for the associations between substance use and each birth outcome.ResultsThe average maternal age was 30 years, 37% receiving Medicaid. Over 58% were White, 26% were Black, and 13% were Hispanic. Cigarette smoking only showed the highest prevalence among substance u... (shrink)

In lieu of an abstract, here is a brief excerpt of the content:"General Rules" in Hume's Treatise THOMAS K. HEARN, JR. IT COULDBE CONFIDENTLYASSERTED in 1925 that Hume was "no longer a living figure." x Stuart Hampshire records that when he began his philosophy studies in 1933, Hume's conclusions were regarded at Oxford as "extravagances of scepticism which no one could seriously accept." 2 That virtually no Anglo-American philosopher would now share such opinions about Hume testifies not only to (...) the general change in the philosophical climate but, in addition, it reflects a transformation which has occurred in the interpretation of Hume's philosophy. In eitecting this transformation.much credit is due to the work of Norman Kemp Smith. Kemp Smith argued that preoccupation with Hume's empiricist heritage and his scepticism had blinded scholars to the fundamentally constructive intent of his philosophy, and, indeed, that only from the perspective of his positive achievement was it possible to grasp the nature and significance of Humean scepticism. This paper, in keeping with the basic orientation of Kemp Smith, sets out a central feature in the attempt to describe and assess Hume's constructive, nonsceptical point of view: Hume attributes to general rules "a mighty influence on our actions and understanding..." (374).4 This paper examines the Treatise to show that this was not just a casual comment. To discuss the "influence" of general rules requires an examination of their character and the various aspects of "action and understanding " in which such rules function. The thesis to be developed can be stated briefly. In Book I Hume introduces two sorts of general rules which must be distinguished carefully. One type of rule describes a propensity of the imagination to extend the scope This research was supported by a grant from the National Foundation on the Arts and Humanities. x Charles W. Hendcl, Studies in the Philosophy of David Hume (New York, 1963), p. 20. (First published in 1925.) For Professor Hendel's later comments on this statement, see pp. xxi ft. "Hume's Place in Philosophy" in David Hume, ed. D. F. Pears (London, 1963), p. 3. a Proper stress is due here to the phrase "basic orientation." There is much about Kemp Smith's understanding of Hume which is mistaken in my view. 9 The page references in parentheses refer to the Svlby-Bigge edition of A Treatise o/ Human Nature (Oxford, 1888). [4o5] 406 HISTORY OF PHILOSOPHY of judgments formed in one set of circumstances to other resembling but non-identical circumstances. The other type of general rule, the discussion of which largely occupies this paper, functions to correct certain natural propensities which result in erroneous belief or action if permitted to operate unchecked. The same pattern, a natural tendency requiring correction by general rules, is exhibited in all three books of the Treatise, and can be said to represent one of the basic ingredients in Hume's account of human nature and experience. It is somewhat surprising that in a book which patiently discusses almost evcxy theme in the Treatise, Kemp Smith's study contains no discussion at all of rules. This is the more puzzling as Kemp Smith clearly recognized that by reflection the understanding supplies principles which are normative for the interpretation of experience.5 Our aim in this study is to discuss what for Hume these principles are, and, as far as possible, how they fit into the Humean account of human nature. A fuller understanding of the nature and function of such reflective principles is required to spare Kemp Smith's interpretation from a seeming inconsistency. This apparent inconsistency arises because Kemp Smith takes the slavery of reason to the passions as the "key" to his understanding of Hume, but then develops the view that for Hume reason/s a passion, in Hume's words, "a wonderful and unintelligible instinct." (179)6 The inconsistency disappears when it is recognized that Kemp Smith's account of Hume requires a more subtle and complex understanding of the role of reason than that suggested by the emphasis on the "slavery of reason" especially in the early parts of the book. This study represents a way of supplying the broader and more const,ructive understanding of reason which... (shrink)