Recently it has become clear that trafficking of integrins to late endosomes is key to the regulation of integrin expression and function during cell migration. Here we discuss the molecular machinery that dictates whether integrins are sorted to recycling endosomes or are targeted to late endosomes and lysosomes. Integrins and other receptors that are sorted to late endosomes are not necessarily degraded and, under certain circumstances, can be spared destruction and returned to the cell surface to drive (...) cell migration and invasion. We will discuss how the exchange of adhesion receptors and other key regulators of cell migration between late endosomes/lysosomes and the plasma membrane can promote dynamic turnover of adhesions during cell migration. (shrink)

Endosomes shuttle select cargoes between cellular compartments and, in doing so, maintain intracellular homeostasis and enable interactions with the extracellular space. Directionality of endosomal transport critically impinges on cargo fate, as retrograde (microtubule minus‐end directed) traffic delivers vesicle contents to the lysosome for proteolysis, while the opposing anterograde (plus‐end directed) movement promotes recycling and secretion. Intriguingly, the endoplasmic reticulum (ER) is emerging as a key player in spatiotemporal control of late endosome and lysosome transport, through the establishment of (...) physical contacts with these organelles. Earlier studies have described how minus‐end‐directed motor proteins become discharged from vesicles engaged at such contact sites. Now, Raiborg et al. implicate ER‐mediated interactions, induced by protrudin, in loading plus‐end‐directed motor kinesin‐1 onto endosomes, thereby stimulating their transport toward the cell's periphery. In this review, we recast the prevailing concepts on bidirectional late endosome transport and discuss the emerging paradigm of inter‐compartmental regulation from the ER‐endosome interface viewpoint. (shrink)

Endosomes, which comprise a diverse population of membrane vesicles and tubules, sort proteins and lipids to various cellular destinations. The organization and functions of these pleiomorphic cellular organelles have been extensively studied. Matsuo et al.1 now provide new exciting evidence on the role of lysobiphosphatidic acid (LBPA), a resident phospholipid of internal vesicles of the late endosome, in the control of membrane invagination and endosome biogenesis. In vivo, LBPA functions are controlled by the adaptor protein Alix and (...) depend on pH gradients along the endosomal compartments. BioEssays 26:604–607, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Abnormalities in the ability of cells to properly degrade proteins have been identified in many neurodegenerative diseases. Recent work has implicated synaptojanin 1 (SynJ1) in Alzheimer's disease and Parkinson's disease, although the role of this polyphosphoinositide phosphatase in protein degradation has not been thoroughly described. Here, we dissected in vivo the role of SynJ1 in endolysosomal trafficking in zebrafish cone photoreceptors using a SynJ1‐deficient zebrafish mutant, nrca14. We found that loss of SynJ1 leads to specific accumulation of late endosomes (...) and autophagosomes early in photoreceptor development. An analysis of autophagic flux revealed that autophagosomes accumulate because of a defect in maturation. In addition we found an increase in vesicles that are highly enriched for PI(3)P, but negative for an early endosome marker in nrca14 cones. A mutational analysis of SynJ1 enzymatic domains found that activity of the 5'phosphatase, but not the Sac1 domain, is required to rescue both aberrant late endosomes and autophagosomes. Finally, modulating activity of the PI(4,5)P2 regulator, Arf6, rescued the disrupted trafficking pathways in nrca14 cones. Our study describes a specific role for SynJ1 in autophagosomal and endosomal trafficking and provides evidence that PI(4,5)P2 participates in autophagy in a neuronal cell type. -/- . (shrink)

Molecules are transferred to lysosomes, the major, acid pH, digestive compartment in eukaryotic cells, by a complex series of pathways that converge at a late endosome/prelysosomal compartment. Here, we discuss the relationship between this compartment and the lysosome. We propose that lysosomes are maintained within cells by a repeated series of kiss and run, transient fusion and fission processes with the late endosome/prelysosome compartment. Directionality to these processes may be conferred by pH gradients and retrieval mechanisms. (...) The future challenge in testing this and any other proposed hypothesis for lysosomal biogenesis will be the establishment of molecular mechanisms. (shrink)

Lysosomes are the site of degradation of obsolete intracellular material during autophagy and of extracellular macromolecules following endocytosis and phagocytosis. The membrane of lysosomes and late endosomes is enriched in highly glycosylated transmembrane proteins of largely unknown function. Significant progress has been made in recent years towards elucidating the pathways by which these lysosomal membrane proteins are delivered to late endosomes and lysosomes. While some lysosomal membrane proteins follow the constitutive secretory pathway and reach lysosomes indirectly via the (...) cell surface and endocytosis, others exit the trans‐Golgi network in clathrin‐coated vesicles for direct delivery to endosomes and lysosomes. Sorting from the Golgi or the plasma membrane into the endosomal system is mediated by signals encoded by the short cytosolic domain of these proteins. This review will discuss the role of lysosomal membrane proteins in the biogenesis of the late endosomal and lysosomal membranes, with particular emphasis on the structural features and molecular mechanisms underlying the intracellular trafficking of these proteins. (shrink)

Cells utilize diverse organelles to maintain homeostasis and to respond to extracellular stimuli. Recently, multifaceted aspects of organelle stress caused by various factors have been emerging. The endosome is an essential organelle, functioning as the central hub for membrane trafficking in cooperation with the ubiquitin system. However, knowledge regarding endosomal stress, which refers to organelle stress of the endosome, is currently limited. We recently revealed ubiquitin‐mediated endosomal stress of early endosomes (EEs) and its responsive signaling pathways. These findings (...) shed light on the relevance of ubiquitin‐mediated endosomal stress to physiological and pathological processes. Here, we present a hypothesis that ubiquitin‐mediated endosomal stress may have significant roles in biological contexts and that ubiquitin‐specific protease 8 is a key regulator of ubiquitin clearance from EEs. (shrink)

Drugs targeting a single TK/RTK in the treatment of solid cancers has not had the same success seen in blood cancers. This is, in part, due to acquired resistance in solid cancers arising from a range of mechanisms including the upregulation of compensatory RTK signalling. Rather than attempting to inhibit individual compensatory RTK—requiring knowledge of which RTKs are upregulated in any given tumour—strategies to universally inhibit signalling from multiple RTKs may represent an effective alternative. Endosomal trafficking of RTKs is a (...) common conduit that can regulate signalling from multiple RTKs simultaneously. As such, we posit that targeting endosomal trafficking—in particular, aberrant post‐translational modifications in cancers that contribute to dysregulated endosomal trafficking—could inhibit oncogenic signalling driven by multiple RTKs and pave the way for the development of a novel class of inhibitors that shift the trafficking of RTKs to inhibit tumour growth. (shrink)

Intercellular communication is an essential process in all multicellular organisms. During this process, molecules secreted by one cell will bind to a receptor on the cognate cell leading to the subsequent uptake of the receptor‐ligand complex. Once inside, the cell then determines the fate of the receptor‐ligand complex and any other proteins that were endocytosed together. Approximately 80% of endocytosed material is recycled back to the plasma membrane either directly or indirectly via the Golgi apparatus and the remaining 20% is (...) delivered to the lysosome for degradation. Although most pathways have been identified, we still lack understanding on how specificity in sorting of recycling cargos into different pathways is achieved, and how the cell reaches high accuracy of these processes in the absence of clear sorting signals in the bulk of the client proteins. In this review, we will summarize our current understanding of the mechanism behind recycling cargo sorting and propose a model of differential affinities between cargo and cargo receptors/adaptors with regards to iterative sorting in endosomes. (shrink)

At the turn of the 17th century, in Romanian philosophy the nobility of spirit is seen as a certain but intermediate value, to be cherished while man waits for his divine reward, which is everlasting life, as presented in Divanul [The Divan] by Dimitrie Cantemir. Two hundred and fifty years later, man is regarded as having evolved from the animal forms of life in Mihai Ralea’s systematic presentation Explicarea omului [An Explanation of Man], and the sole meaning of nobility is (...) the revolutionary one, the heroic one, that is the ethical one. From a totally different point of view, during the interwar period, Constantin Micu Stavilă developed a general theory of man and society thus compellingly arguing against the claims of all ideologists of the natural genesis of human spirituality. In this theory the nobility of spirit was said to come from work and creation. By presenting these examples, my intention is to rediscover this spiritual, moral and socio-cultural ideal in order to find its place, role and profile in designing a new view of human nature, for a more decent human world. (shrink)

The Institute of Social Research, from which the Frankfurt School developed, was founded in the early years of the Weimar Republic. It survived the Nazi era in exile, to become an important centre of social theory in the postwar era. Early members of the school, such as Adorno, Horkheimer and Marcuse, developed a form of Marxist theory known as Critical Theory, which became influential in the study of class, politics, culture and ideology. The work of more recent members, and in (...) particular Habermas, has received wide attention throughout Europe and North America. Tom Bottomore's study takes a new and controversial look at the contributions of the Frankfurt School to modern sociology, examining several issues not previously discussed elsewhere. He discusses the neglect of history and political economy by the critical theorists, and considers the relationship of the later Frankfurt School to the radical movements of the 1960s and the present time. His critical analysis makes the school's writers accessible, through an assessment of their work and an exploration of the relationship of Critical Theory to other forms of sociological thought, especially positivism and structuralism. (shrink)

Child analysis has occupied a special place in the history of psychoanalysis because of the challenges it poses to practitioners and the clashes it has provoked among its advocates. Since the early days in Vienna under Sigmund Freud child psychoanalysts have tried to comprehend and make comprehensible to others the psychosomatic troubles of childhood and to adapt clinical and therapeutic approaches to all the stages of development of the baby, the child, the adolescent and the young adult. Claudine and Pierre (...) Geissmann trace the history and development of child analysis over the last century and assess the contributions made by pioneers of the discipline, whose efforts to expand its theoretical foundations led to conflict between schools of thought, most notably to the rift between Anna Freud and Melanie Klein. Now taught and practised widely in Europe, the USA and South America, child and adolescent psychoanalysis is unique in the insight it gives into the psychological aspects of child development, and in the therapeutic benefits it can bring both to the child and its family. (shrink)

In 2015, the United Nations Sustainable Development Goals set an ethical imperative: end extreme poverty and hunger by 2030. Microfranchising can contribute to this critical effort by offering nonprofit organizations and businesses an opportunity to rapidly scale entrepreneurship within Base of the Pyramid markets. However, while abundant literature exists on traditional franchising, we know little about how to leverage microfranchising in resource-scarce contexts to alleviate poverty. To address this gap, we report a longitudinal case study of a microfranchise network aimed (...) at providing timely access to quality, affordable agricultural input, and services for millions of small-scale farmers in Bangladesh. Anchored in the BOP and microfranchise literature and drawing on innovation theory as an analytical lens, we provide a detailed account of how CARE—a global humanitarian and development non-governmental organization—developed and managed the network. We found that context played a strong role and that adaptability therefore was key to successfully recruiting and engaging BOP entrepreneurs and other business partners in the network. Moreover, as members joined the network with past ties and established practices, managing these path dependencies had important implications for network performance. Network sustainability in terms of financial and social impact was also a key theme that required careful consideration throughout network development. We combine these empirical findings with extant literature to discuss contributions to the theory and practice of microfranchising and innovation networking in the BOP context. (shrink)

This twelfth volume of Correspondence contains authoritative and fully annotated texts of all known letters sent both to and from Bentham between July 1824 and June 1828. The 301 letters, most of which have never before been published, have been collected from archives, public and private, in Britain, the United States of America, Switzerland, France, Japan, and elsewhere, as well as from the major collections of Bentham Papers at University College London Library and the British Library.In mid-1824 Bentham was still (...) preoccupied with the Greek struggle for independence against Turkey, though his active involvement waned as he became disenchanted with the behaviour of the deputies sent to London by the Greek National Assembly. His international reputation was reflected in his continuing contact with Simón Bolívar and Bernardino Rivadavia in South America, and with John Quincy Adams, John Neal, Henry Wheaton, and others in the United States, and his forging of new contacts in Guatemala, India, and Egypt. In the autumn of 1825 he visited France, where he stayed with Jean Baptiste Say and La Fayette, and was fêted by the French liberals.Bentham made considerable progress drafting material for his pannomion, or complete code of laws, and in particular for his Constitutional and Procedure Codes, while John Stuart Mill edited the massive Rationale of Judicial Evidence. Bentham became increasingly active in the cause of law reform, and exchanged a series of letters on the subject with Robert Peel, the Home Secretary, and Henry Brougham. He maintained his friendships with John and Sarah Austin, George and Harriet Grote, James and John Stuart Mill, John Bowring, Joseph Hume, Francis Burdett, Francis Place, and Joseph Parkes, re-established contact with the third Marquis of Lansdowne, son of his old friend the first Marquis, and made new acquaintances in James Humphreys, Sutton Sharpe, and Albany Fonblanque. (shrink)

Jeremy Bentham, the philosopher and reformer, was at the height of his fame and influence in the 1820s. The 301 letters in this volume, many of which are previously unpublished, contain correspondence with international leaders such as Simn Bolvar, the 'Liberator', and Bernardino Rivadavia of Buenos Aires, British statesmen such as Robert Peel and Henry Brougham, and leading intellectuals such as John Stuart Mill and Sarah Austin.

ABSTRACT: In this paper I argue that the ‘discovery’ of the problem of causal determinism and freedom of decision in Greek philosophy is the result of a combination and mix-up of Aristotelian and Stoic thought in later antiquity; more precisely, a (mis-)interpretation of Aristotle’s philosophy of deliberate choice and action in the light of Stoic theory of determinism and moral responsibility. The (con-)fusion originates with the beginnings of Aristotle scholarship, at the latest in the early 2nd century AD. It undergoes (...) several developments, absorbing Epictetan, Middle-Platonist, and Peripatetic ideas; and it leads eventually to a concept of freedom of decision and an exposition of the ‘free-will problem’ in Alexander of Aphrodisias’ On Fate and in the Mantissa ascribed to him. (shrink)

A new edition of a classic work compares Plato's dialogues to Aristotle's depiction of them. Reprint.

A prominent feature of late nineteenth-century psychology was its intense preoccupation with precision. Precision was at once an ideal and an argument: the quest for precision helped psychology to establish its status as a mature science, sharing a characteristic concern with the natural sciences. We will analyse how psychologists set out to produce precision in 'mental chronometry', the measurement of the duration of psychological processes. In his Leipzig laboratory, Wundt inaugurated an elaborate research programme on mental chronometry. We will (...) look at the problem of calibration of experimental apparatus and will describe the intricate material, literary, and social technologies involved in the manufacture of precision. First, we shall discuss some of the technical problems involved in the measurement of ever shorter time-spans. Next, the Cattell-Berger experiments will help us to argue against the received view that all the precision went into the hardware, and practically none into the social organization of experimentation. Experimenters made deliberate efforts to bring themselves and their subjects under a regime of control and calibration similar to that which reigned over the experimental machinery. In Leipzig psychology, the particular blend of material and social technology resulted in a specific object of study: the generalized mind. We will then show that the distribution of precision in experimental psychology outside Leipzig demanded a concerted effort of instruments, texts, and people. It will appear that the forceful attempts to produce precision and uniformity had some rather paradoxical consequences. (shrink)

This article reports a follow-up study of Norwegian nursing students entitled ‘The helping motive -an important goal for choosing nursing education’. It presents and discusses a significant ambiguity within the altruistic helping motive of 301 nursing students in the light of classical and modern virtue ethics. A quantitative longitudinal survey design was used to study socialization and building professional identity. The follow-up study began after respondents had completed more than two-and-a-half years of the three-year educational programme. Data were collected using (...) a questionnaire with closed questions, supplemented by 18 semi-structured, in-depth, audiotaped interviews. A motive such as ‘desire for human contact/to help others’ appeared to be highly significant. The research questions employed were: What motivates nursing students at the end of their studies to help other people? What does helping others mean for nursing students? Factor analysis revealed two factors. Factor 1 can be expressed as an altruism factor and factor 2 can be interpreted as an ‘acknowledgement-from-the-patient factor’ that in fact indicates an ambiguity within the helping motive itself. Findings from the interviews also reveal ambiguous helping motives. On one hand the students want to be altruistic and on the other they wish to receive positive feedback from patients when giving help. The findings indicate that this positive feedback is essential to the students in order for them to provide altruistic care. (shrink)

Gordon Baker and I had been colleagues at St John’s for almost ten years when we resolved, in 1976, to undertake the task of writing a commentary on Wittgenstein’s Philosophical Investigations. We had been talking about Wittgenstein since 1969, and when we cooperated in writing a long critical notice on the Philosophical Grammar in 1975, we found that working together was mutually instructive, intellectually stimulating and great fun. We thought that we still had much to say about Wittgenstein’s philosophy, and (...) it seemed to us that misinterpretations of passages in the Investigations were so extensive that it would be worth trying to write a detailed analytical commentary. It is difficult to recapture the excitement of those early days in being among the first to work on the microfilms and, subsequently, on the photocopies of Wittgenstein’s Nachlass. We spent many hundreds of hours poring over the typescripts and the often only semi-legible manuscripts, fascinated and privileged to be able to try to follow the development of the thoughts of a great philosophical genius. We talked endlessly about what we had found in Wittgenstein’s manuscripts and typescripts, and debated how it should be understood. The first fruit of our labours was Wittgenstein – Understanding and Meaning. Its guiding idea was to draw attention to the manner in which Wittgenstein linked the concepts of meaning, understanding and explanation, and so to bypass the connections between meaning, truth and truth-conditions that so fascinated philosophers of the 1970s, and to abandon the red-herring of assertion-conditions and anti-realism. After a hiatus of four years, during which time we wrote a controversial book entitled Frege – Logical Excavations and a polemical book on contemporary philosophy of language – Language, Sense. (shrink)

This essay responds to the characterization Ted Miller offers (in his December 2008 essay in Political Theory) of the kind of nonfoundationalism I have referred to as "weak ontology," and that Gianni Vattimo frequently calls "weak thought." Miller argues that such a position embodies, first, a philosophy of history in which strong ontologies (e.g., religion) are assessed categorically as passé, and, second, are associated essentially with violence. I show that while these characterizations may be appropriate for Vattimo's thought, they are (...) not for weak ontology as I understand it. Finally, I suggest that the former might more usefully be categorized as "antifoundationalism" and the latter as "nonfoundationalism.". (shrink)

In the essay “What is Enlightenment?”, Foucault espouses a novel and emancipatory“philosophical ethos” which challenges individuals to undertake an ongoing, aesthetic project oftotal self-transformation. By advocating a view of the self---and moreaccurately the relationship one has to oneself --as a free creation on the part of thesubject, Foucault seems to be espousing a pluralistic ethical position. However, I argue that whilethis interpretation is not entirely false, it is not altogether accurate either. Quite simply, it is toobroad in scope. Instead, I (...) argue that Foucault’s philosophical ethos is best described as a DeepEthical Pluralist position. Furthermore, I demonstrate that the two most common objectionsto Foucault’s new ethos for the contemporary subject in the secondary literature, namely theregressive and dandyist objections miss their mark precisely because they are successful onlyagainst ethical pluralism but not DEP. (shrink)

In the late nineteenth century, British anthropometrists attempted to normalize the practice of measuring bodies as they sought to collate data about the health and racial makeup of their fellow citizens. As the country’s leading anthropometrists, Francis Galton and Charles Roberts worked to overcome suspicion about their motives and tried to establish the value of recording physical dimensions from their subjects’ perspective. For Galton, the father of the eugenics movement, the attainment of objective self-knowledge figured alongside the ranking of (...) one’s physique and faculties against established norms. The competitive tests at Galton’s anthropometric laboratory were meant to help subjects identify their strengths and weaknesses, ultimately revealing their level of eugenic fitness. Roberts, on the other hand, saw the particular value of anthropometric data in informing economic and social policy, but capitalized on parents’ interest in their children’s growth rates to encourage regular monitoring of their physical development. While both Galton and Roberts hoped that individuals would ultimately furnish experts with their anthropometric data to analyze, they both understood that the public would need to have explained the practical purposes of such studies and to familiarize themselves with their methods. This article argues that while anthropometry did not become a fully domestic practice in this period, it became a more visible one, paving the way for individuals to take an interest in metrical evaluations of their bodies in the coming years. (shrink)

This scarce antiquarian book is a facsimile reprint of the original. Due to its age, it may contain imperfections such as marks, notations, marginalia and flawed pages. Because we believe this work is culturally important, we have made it available as part of our commitment for protecting, preserving, and promoting the world's literature in affordable, high quality, modern editions that are true to the original work.

This essay examines several works that contribute to an understanding of the nature of contemporary Chinese capitalism and its historical development. Core issues include the character of the bureaucracy, which has had a distinctive relationship to capital formation, and the character of the working class. The periodisation of Chinese capitalism and the relation between the pre- and post-reform periods are pressing political and analytical concerns. This essay suggests the advantages of a clearer focus on the dynamics of depoliticisation in understanding (...) the transition. The contemporary left-intelligentsia in China has in large part pinned its hopes on achieving some form of ideological hegemony within theccp, maintaining that it still operates within its revolutionary tradition. This represents a questionable strategic gamble. Acknowledging the important contributions made by Au’s book and other recent characterisations of China’s political economy from the left, this essay suggests that there remains much to be done. (shrink)

In several recent studies we have developed precise statistical methodologies which have demonstrated that the cursus mixtus was the dominant rhythmical system for final clausulae in Latin prose from the third century a.d. to the fifth. The cursus mixtus consisted of four standard metrical forms derived from the richer variety of Cicero's Asiatic tradition – cretic-spondee, dicretic, cretic-tribrach and ditrochee –, which were structured according to three accentual patterns – planus, tardus and velox. The latter are differentiated by the number (...) of unstressed syllables intervening between and following two accented syllables. The planus has two unaccented syllables between two word accents and one after the last accent. The tardus has two between two accents and two after the last accent. The velox has four between two accents and one after the last accent. The four metrical forms are contained within the parameters of the accentual cadences. The planus contains either the cretic-spondee or the ditrochee ; the tardus either the dicretic or the cretic-tribrach ; the velox either the ditrochee or the cretic-spondee (nimium videbatur. Authors who used the cursus mixtus, however, preferred to effect an exact coincidence between the accent and ictus, and as a result evinced primarily the following standard rhythmical forms: planus/cretic-spondee; tardus/dicretic or cretic-tribrach; and velox/ditrochee. So far now we have examined only the rhythmical properties of final clausulae, but it is appropriate also to investigate for rhythm at internal positions within the sentence. (shrink)