We recently examined gene expression during Xenopus tadpole tail appendage regeneration and found that carbohydrate regulatory genes were dramatically altered during the regeneration process. In this essay, we speculate that these changes in gene expression play an essential role during regeneration by stimulating the anabolic pathways required for the reconstruction of a new appendage. We hypothesize that during regeneration, cells use leptin, slc2a3, proinsulin, g6pd, hif1α expression, receptor tyrosine kinase (RTK) signaling, and the production of reactive oxygen species (ROS) to (...) promote glucose entry into glycolysis and the pentose phosphate pathway (PPP), thus stimulating macromolecular biosynthesis. We suggest that this metabolic shift is integral to the appendage regeneration program and that the Xenopus model is a powerful experimental system to further explore this phenomenon.Also watch the Video Abstract. (shrink)

It is not clear why cancer cells choose to disrupt their circadian clock rhythms, and whether such disruption governs a selective fitness and a survival advantage. In this review, I focus on understanding the impacts of clock gene disruption on a simpler model, such as the unicellular cyanobacterium, in order to explain how cancer cells may alter the circadian rhythm to reprogram their metabolism based on their needs and status. It appears to be that the activation of the oxidative (...) class='Hi'>pentose phosphate pathway (OPPP) and production of NADPH, the preferred molecule for detoxification of reactive oxygen species, is a critical process for night survival in unicellular organisms. The circadian clock acts as a gatekeeper that controls how the organism will utilize its sugar, shifting sugar influx between glycolysis and OPPP. The circadian clock can thus act as a gatekeeper between an anabolic, proliferative mode and a homeostatic, survival mode. (shrink)

We review here some recent data about glucose‐6‐phosphate dehydrogenase (G6PD), the first and key regulatory enzyme of the pentose phosphate pathway. New evidence has been presented to suggest that malaria is a selective agent for G6PD deficiency, which is the most common enzymopathy in man, and that G6PD deficiency, generally considered to be a mild and benign condition, is significantly disadvantageous in certain environmental conditions. At the molecular level, the enzyme structure has recently been elucidated and (...) mechanisms regulating G6PD gene expression have been determined. A G6PD knock‐out mutation introduced in mouse cells makes them exquisitely sensitive to oxidative stress, indicating that this ubiquitous metabolic enzyme has a major role in the defence against oxidative stress, even in eukaryotic nucleated cells, which have several alternative routes for providing the same protection. Because of the high prevalence of G6PD deficiency in many populations, it is expected that these findings will prompt further studies to ascertain the putative role of G6PD deficiency in conditions such as carcinogenesis and ageing. (shrink)

Phagocytosis is an uptake of large particles governed by the actin-based cytoskeleton. Binding of particles to specific cell surface receptors is the first step of phagocytosis. In higher Eucaryota, the receptors able to mediate phagocytosis are expressed almost exclusively in macrophages, neutrophils, and monocytes, conferring immunodefence properties to these cells. Receptor clustering is thought to occur upon particle binding, that in turn generates a phagocytic signal. Several pathways of phagocytic signal transduction have been identified, including the activation of tyrosine kinases (...) and (or) serine/threonine kinase C in pivotal roles. Kinase activation leads to phosphorylation of the receptors and other proteins, recruited at the sites of phagocytosis. Monomeric GTPases of the Rho and ARF families are likely to be engaged downstream of activated receptors. The GTPases, in cooperation with phosphatidylinositol 4-phosphate 5-kinase and phosphatidylinositol 3-kinase lipid modifying enzymes, can modulate locally the assembly of the submembranous actin filament system leading to particle internalization. BioEssays 21:422–431, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

The inositol phosphate metabolism network has been found to be much more complex than previously thought, as more and more inositol phosphates and their metabolizing enzymes have been discovered. Some of the inositol phosphates have been shown to have biological activities, but little is known about their signal transduction mechanisms except for that of inositol 1,4,5‐trisphosphate. The recent discovery, however, of a number of binding proteins for inositol high polyphosphate [inositol 1,3,4,5‐tetrakisphosphate (IP4), inositol 1,3,4,5,6‐pentakisphosphate, or inositol hexakisphosphate] enables us (...) to speculate on the physiological function of these compounds. In this article we focus on two major issues: (1) the roles of inositol high polyphosphates in vesicular trafficking, especially exocytosis, and (2) pleckstrin homology domaincontaining IP4 binding proteins involved in the Ras signaling pathway. (shrink)

Some metabolic pathways are nearly ubiquitous among organisms: the genes encoding the enzymes for such pathways must therefore be ancient and essential. De novo pyrimidine biosynthesis is an example of one such metabolic pathway. In animals a single protein called CADAbbreviations: CAD, trifunctional protein catalyzing the first three steps of de novo pyrimidine biosynthesis in higher eukaryotes; CPS, carbamyl phosphate synthetase domain; CPSase, carbamyl phosphate synthetase activity; ATC, aspartate transcarbamylase domain; ATCase, aspartate transcarbamylase activity; DHO, dihydroorotase domain; (...) DHOase, dihydroorotase activity; GLN, glutaminase subdomain or subunit of carbamyl phosphate synthetase, GL Nase, glutaminase activity; SYN, synthetase subdomain or subunit of carbamyl phosphate synthetase; SYNase, synthetase activity. carries the first three steps of this pathway. The same three enzymes in prokaryotes are associated with separate proteins. The CAD gene appears to have evolved through a process of gene duplication and DNA rearrangement, leading to an in‐frame gene fusion encoding a chimeric protein. A driving force for the creation of eukaryotic genes encoding multienzymatic proteins such as CAD may be the advantage of coordinate expression of enzymes catalyzing steps in a biosynthetic pathway. The analogous structure in bacteria is the operon. Differences in the translational mechanisms of eukaryotes and prokaryotes may have dictated the different strategies used by organisms to evolve coordinately regulated genes. (shrink)

The fructose 6-phosphate (Fru-6P) saturation curve for phosphofructokinase (PFK) from E. coli is sigmoidal in the presence of saturating MgATP levels, while the corresponding curve for B. stearothermophilus PFK is essentially hyperbolic. Sigmoidality can be due to apparent cooperativity arising from the kinetic mechanism of an enzyme. We have determined the kinetic mechanism of B. stearothermophilus PFK (BsPFK). BsPFK was found to obey a non rapid-equilibrium random mechanism similar to the one E. coli PFK (EcPFK) follows. Substrate inhibition by (...) MgATP was observed. We propose that substrates bind to BsPFK through two alternative pathways, one of which is slower. The substrate inhibition arises in part from reaction flux through the slower pathway. Although EcPFK and BsPFK obey similar kinetic mechanisms, they are inhibited differently by MgATP: EcPFK is profoundly inhibited, BsPFK only weakly. The structural basis for this difference could be closure of the active site via a conformational transition that occurs in EcPFK, but not BsPFK. To investigate the importance of this transition for MgATP inhibition of EcPFK, we have constructed a chimeric enzyme (ChiPFK) that contains the "rigid" ATP-binding domain of BsPFK grafted onto the remainder of the EcPFK subunit. Our results indicate that ChiPFK is locked in an "open" structure resembling the activated form of EcPFK. It is insensitive to heterotropic regulation. Nevertheless, ChiPFK exhibits residual cooperativity. Possible explanations for the cooperativity are discussed. The 6F loop is proposed to be important in PFK allosteric behavior. Residues along the loop are largely conserved between BsPFK and EcPFK, except for 161, which is a glutamate in BsPFK, and a glutamine in EcPFK. Using site-directed mutagenesis, Glu 161 of BsPFK has been changed to glutamine and alanine. Similarly, Gin 161 of EcPFK has been changed to glutamate, arginine and alanine. Of the five mutants, one, QA161, was particularly interesting. Though activated normally by GDP, it was completely insensitive to PEP inhibition. This indicates that the hydrogen-bonding ability of residue 161 is critical for PEP inhibition of EcPFK, and that GDP activation and PEP inhibition follow different structural pathways. (shrink)

: All known life requires phosphorus (P) in the form of inorganic phosphate (PO43x or Pi) and phosphate-containing organic molecules. Pi serves as the backbone of the nucleic acids that constitute genetic material and as the major repository of chemical energy for metabolism in polyphosphate bonds. Arsenic (As) lies directly below P on the periodic table and so the two elements share many chemical properties, although their chemistries are sufficiently dissimilar that As cannot directly replace P in modern (...) biochemistry. Arsenic is toxic because As and P are similar enough that organisms attempt this substitution. We hypothesize that ancient biochemical systems, analogous to but distinct from those known today, could have utilized arsenate in the equivalent biological role as phosphate. Organisms utilizing such ‘ weird life ’ biochemical pathways may have supported a ‘ shadow biosphere ’ at the time of the origin and early evolution of life on Earth or on other planets. Such organisms may even persist on Earth today, undetected, in unusual niches. (shrink)

The Earth agglomerates and heats. Convection cells within the planetary interior expedite the cooling process. Volcanoes evolve steam, carbon dioxide, sulfur dioxide and pyrophosphate. An acidulous Hadean ocean condenses from the carbon dioxide atmosphere. Dusts and stratospheric sulfurous smogs absorb a proportion of the Sun’s rays. The cooled ocean leaks into the stressed crust and also convects. High temperature acid springs, coupled to magmatic plumes and spreading centers, emit iron, manganese, zinc, cobalt and nickel ions to the ocean. Away from (...) the spreading centers cooler alkaline spring waters emanate from the ocean floor. These bear hydrogen, formate, ammonia, hydrosulfide and minor methane thiol. The thermal potential begins to be dissipated but the chemical potential is dammed. The exhaling alkaline solutions are frustrated in their further attempt to mix thoroughly with their oceanic source by the spontaneous precipitation of biomorphic barriers of colloidal iron compounds and other minerals. It is here we surmise that organic molecules are synthesized, filtered, concentrated and adsorbed, while acetate and methane—separate products of the precursor to the reductive acetyl-coenzyme-A pathway—are exhaled as waste. Reactions in mineral compartments produce acetate, amino acids, and the components of nucleosides. Short peptides, condensed from the simple amino acids, sequester ‘ready-made’ iron sulfide clusters to form protoferredoxins, and also bind phosphates. Nucleotides are assembled from amino acids, simple phosphates carbon dioxide and ribose phosphate upon nanocrystalline mineral surfaces. The side chains of particular amino acids register to fitting nucleotide triplet clefts. Keyed in, the amino acids are polymerized, through acid–base catalysis, to alpha chains. Peptides, the tenuous outer-most filaments of the nanocrysts, continually peel away from bound RNA. The polymers are concentrated at cooler regions of the mineral compartments through thermophoresis. RNA is reproduced through a convective polymerase chain reaction operating between 40 and 100°C. The coded peptides produce true ferredoxins, the ubiquitous proteins with the longest evolutionary pedigree. They take over the role of catalyst and electron transfer agent from the iron sulfides. Other iron–nickel sulfide clusters, sequestered now by cysteine residues as CO-dehydrogenase and acetyl-coenzyme-A synthase, promote further chemosynthesis and support the hatchery—the electrochemical reactor—from which they sprang. Reactions and interactions fall into step as further pathways are negotiated. This hydrothermal circuitry offers a continuous supply of material and chemical energy, as well as electricity and proticity at a potential appropriate for the onset of life in the dark, a rapidly emerging kinetic structure born to persist, evolve and generate entropy while the sun shines. (shrink)

One of the most dynamic areas of plant molecular biology is the investigation of the actions of three classes of herbicides: s‐triazines (atrazine, simazine), glyphosate, and sulfonylureas (chlorsulfuron, sulfometuron methyl) (Figure 1). The results of this work are expected to provide the first significant applications of plant biotechnology: directly, in the genetic engineering of crop plants resistant to specific herbicides and, indirectly, in providing a molecular basis for the rational design of new herbicides for specific biological targets.s‐Triazines affect photosynthesis by (...) inhibiting the binding of quinones to the chloroplast membrane QB protein. An s‐triazine resistant QB protein isolated from weeds in fields consistently treated with the herbicide has a serine in place of a glycine in this highly conserved protein. Glyphosate inhibits 5‐enolpyruvyl‐shikimate‐3‐phosphate synthase (EPSP synthase), an enzyme in the aromatic amino acid biosynthetic pathway. Mutagenized bacteria produce a resistant EPSP synthase with a substitution of serine for proline. Sulfonylureas inhibit the acetolactate synthase (ALS) of bacteria, yeast, and higher plants; this enzyme catalyzes the first step in the synthesis of branched chain amino acids. Resistant ALS has been found in bacteria, yeast and tobacco with a proline substituted by serine in yeast ALS. These findings provide a strong basis for developing projected plant biotechnology applications. (shrink)

It has long been believed that membrane proteins present in degradative compartments such as endolysosomes or vacuoles would be destined for destruction. Now however, it appears that mechanisms and machinery exist in simple eukaryotes such as yeast and more complex organisms such as mammals that can rescue potentially “doomed” membrane proteins by retrieving them from these “late” compartments and recycling them back to the Golgi complex. In yeast, a sorting nexin dimer containing Snx4p can recognize and retrieve the Atg27p membrane (...) protein while in mammals, the AP5 complex (with SPG11 and SPG15) directs the recycling of Golgi‐localized proteins along with the cation‐independent mannose 6‐phosphate receptor (CIMPR). Although the respective machinery is different, there is much commonality between yeast and mammals regarding the mechanisms of retrieval and the physiological importance of these late recycling pathways. (shrink)

Sterols and the reductant nicotinamide adenine dinucleotide phosphate (NADPH), essential for eukaryotic life, arose because of, and as an adaptation to, rising levels of molecular oxygen (O2). Hence, the NADPH and O2‐intensive process of sterol biosynthesis is inextricably linked to redox status. In mammals, cholesterol biosynthesis is exquisitely regulated post‐translationally by multiple E3 ubiquitin ligases, with membrane associated Really Interesting New Gene (RING) C3HC4 finger 6 (MARCHF6) degrading at least six enzymes in the pathway. Intriguingly, all these MARCHF6‐dependent (...) enzymes require NADPH. Moreover, MARCHF6 is activated by NADPH, although what this means for control of cholesterol synthesis is unclear. Indeed, this presents a paradox for how NADPH regulates this vital pathway, since NADPH is a cofactor in cholesterol biosynthesis and yet, low levels of NADPH should spare cholesterol biosynthesis enzymes targeted by MARCHF6 by reducing its activity. We speculate MARCHF6 helps mammalian cells adapt to oxidative stress (signified by low NADPH levels) by reducing degradation of cholesterogenic enzymes, thereby maintaining synthesis of protective cholesterol. (shrink)

The type II phosphatidylinositol 4-kinases produce the lipid phosphatidylinositol 4-phosphate and participate in a confusing variety of membrane trafficking and signaling roles. This review argues that both historical and contemporary evidence supports the function of the PI4KIIs in numerous trafficking pathways, and that the key to understanding the enzymatic regulation is through membrane interaction and the intrinsic membrane environment. By summarizing new research and examining the trafficking roles of the PI4KIIs in the context of recently solved molecular structures, I (...) highlight how mechanisms of PI4KII function and regulation are providing insights into the development of cancer and in neurological disease. I present an integrated view connecting the cell biology, molecular regulation, and roles in whole animal systems of these increasingly important proteins. The type II phosphatidylinositol 4-kinases are versatile mediators of membrane trafficking, controlling pathways that impact on disease. Recent advances suggest that the membrane lipid environment regulates enzyme activity and that the complexity of trafficking routes can be explained by the ability of these kinases to promote membrane trafficking in different directions. (shrink)

Bacteria have evolved advanced strategies for surviving during nutritional stress, including expression of specialized enzyme systems that allow them to grow on unusual nutrient sources. Inorganic phosphate (Pi) is limiting in most ecosystems, hence organisms have developed a sophisticated, enzymatic machinery known as carbon‐phosphorus (C‐P) lyase, allowing them to extract phosphate from a wide range of phosphonate compounds. These are characterized by a stable covalent bond between carbon and phosphorus making them very hard to break down. Despite the (...) challenges involved in both synthesizing and catabolizing phosphonates, they are widespread in nature. The enzymes required for the bacterial C‐P lyase pathway have been identified and for the most part structurally characterized. Nevertheless, the mechanistic principles governing breakdown of phosphonate compounds remain enigmatic. In this review, an overview of the C‐P lyase pathway is provided and structural aspects of the involved enzyme complexes are discussed with a special emphasis on the role of ATP‐binding cassette (ABC) proteins. (shrink)

In the present paper we formulate the hypothesis that brain glycogen is a critical determinant in the modulation of carbohydrate supply at the cellular level. Specifically, we propose that mobilization of astrocytic glycogen after an increase in AMP levels during enhanced neuronal activity controls the concentration of glucose phosphates in astrocytes. This would result in modulation of glucose phosphorylation by hexokinase and upstream cell glucose uptake. This mechanism would favor glucose channeling to activated neurons, supplementing the already rich neuron‐astrocyte metabolic (...) and functional partnership with important implications for the energy compounds used to sustain neuronal activity. The hypothesis is based on recent modeling evidence suggesting that rapid glycogen breakdown can profoundly alter the short‐term kinetics of glucose delivery to neurons and astrocytes. It is also based on review of the literature relevant to glycogen metabolism during physiological brain activity, with an emphasis on the metabolic pathways identifying both the origin and the fate of this glucose reserve. (shrink)

Recently, we have presented data supporting the notion that PIKfyve not only produces the majority of constitutive phosphatidylinositol 5‐phosphate (PtdIns5P) in mammalian cells but that it does so through direct synthesis from PtdIns. Another group, albeit obtaining similar data, suggests an alternative pathway whereby the low‐abundance PtdIns(3,5)P2 undergoes hydrolysis by unidentified 3‐phosphatases, thereby serving as a precursor for most of PtdIns5P. Here, we review the experimental evidence supporting constitutive synthesis of PtdIns5P from PtdIns by PIKfyve. We further emphasize (...) that the experiments presented in support of the alternative pathway are also compatible with a direct mechanism for PIKfyve‐catalyzed synthesis of PtdIns5P. While agreeing with the authors that constitutive PtdIns5P could theoretically be produced from PtdIns(3,5)P2 by 3‐dephosphorylation, we argue that until direct evidence for such an alternative pathway is obtained, we should adhere to the existing experimental evidence and quantitative considerations, which favor direct PIKfyve‐catalyzed synthesis for most constitutive PtdIns5P. (shrink)

A better understanding of how schistosomes exploit host nutrients, neuro‐endocrine hormones and signalling pathways for growth, development and maturation may provide new insights for improved interventions in the control of schistosomiasis. This paper describes recent advances in the identification and characterisation of schistosome tyrosine kinase and signalling pathways. It discusses the potential intervention value of insulin signalling, which may play an important role in glucose uptake and carbohydrate metabolism in schistosomes, providing the nutrients essential for parasite growth, development and, notably, (...) female fecundity. Significant progress has also been made in the characterisation of other schistosome growth factor receptors, such as transforming growth factor beta receptor and epidermal growth factor receptor, and in our understanding of their roles in the host‐parasite molecular dialogue and parasite development. The use of parasite signal transduction components as novel vaccine or drug targets may prove invaluable in prevention, treatment and control strategies to combat schistosomiasis. (shrink)

Phosphatidylinositol 5‐phosphate (PtdIns5P), the least characterized among the three phosphatidylinositol monophosphates, is emerging as a bioactive lipid involved in the control of several cellular functions. Similar to PtdIns3P, it is present in low amounts in mammalian cells, and can be detected at the plasma membrane and endomembranes as well as in the nucleus. Changes in PtdIns5P levels are observed in mammalian cells following specific stimuli or stresses, and in human diseases. Recently, the contribution of several enzymes such as PIKfyve, (...) myotubularins, and type II PtdInsP‐kinases to PtdIns5P metabolism has gained a strong experimental support. Here, we provide a picture emerging from recent studies showing how this lipid can be generated and act as a regulator of membrane and cytoskeleton dynamics, and as a modulator of gene expression. We briefly summarize the current methods and tools for studying PtdIns5P, and discuss how PtdIns5P can integrate and coordinate different functions in a spatiotemporal manner. (shrink)

Much of the recent philosophical debate on causation and causal explanation in the biological and biomedical sciences has focused on the notion of mechanism. Mechanisms, their nature and epistemic roles have been tackled by a range of so-called neo-mechanistic theories, and widely discussed. Without denying the merits of this approach, our paper aims to show how lately it has failed to give proper credit to processes, which are central to the field, especially of contemporary molecular biology. Processes can be summed (...) up in the notion of ‘pathway’, which is far from being just equivalent to that of ‘mechanism’ and has a profound epistemological and explanatory relevance. It is argued that an adequate consideration of pathways impels some rethinking of scientific explanation in molecular biology, namely its functional and contextual features. A number of examples are given to suggest that the focus of philosophical attention in this disciplinary field should shift from the notion of mechanism to the notion of pathway. (shrink)

Phosphatidylinositol 3‐phosphate (PtdIns3P) is generated on the cytosolic leaflet of cellular membranes, primarily by phosphorylation of phosphatidylinositol by class II and class III phosphatidylinositol 3‐kinases. The bulk of this lipid is found on the limiting and intraluminal membranes of endosomes, but it can also be detected in domains of phagosomes, autophagosome precursors, cytokinetic bridges, the plasma membrane and the nucleus. PtdIns3P controls cellular functions through recruitment of specific protein effectors, many of which contain FYVE or PX domains. Cellular processes (...) known to be controlled by PtdIns3P and its effectors include endosomal fusion, sorting and motility, autophagy, cytokinesis, regulated exocytosis and signal transduction. Here we discuss how Ptdins3P is generated on specific cellular membranes, how its localizations and functions can be studied, and how its effectors serve to control cellular functions.Editor's suggested further reading in BioEssays:Phosphatidylinositol 4,5‐bisphosphate: Targeted production and signalingAbstractHow does SHIP1/2 balance PtdIns(3,4)P2 and does it signal independently of its phosphatase activity?AbstractPhosphatidylinositol‐3,4,5‐trisphosphate: Tool of choice for class I PI 3‐kinasesAbstractPhosphatidylinositol‐4‐phosphate: The Golgi and beyondAbstract. (shrink)

Nowadays, batteries play an important role in a lot of different applications like energy storage, electro-mobility, consumer electronic and so on. All the battery types have a common factor that is their complexity, independently of its nature. Usually, the batteries have an electrochemical nature. Several different test are accomplished to check the batteries performance, and commonly, it is predictable how they work depending of their technology. The present research describes the hybrid intelligent system created to accomplish fault detection over a (...) Lithium Iron Phosphate—LiFePO4 power cell type, commonly used in electro-mobility applications. The approach is based on the cell temperatures behaviour for voltage and current specific values. Taken into account the operating range of a real system based on a LiFePO4 cell, a large set of points of operation have been used to achieve the dataset. The different behaviour zones have been obtained by clustering as a first step. Then, different regression techniques have been used over each cluster. Polynomial regression, artificial neural networks and support vector regression were the combined techniques to develop the hybrid intelligent model proposed. The intelligent system gives very good results over the operating range, detecting all the faults tested during the validation. (shrink)

Pathways in Philosophy is a unique introductory text that features both a historical and a topical approach to the central problems in the field--questions regarding existence, knowledge, and moral and political value. Organized into two parts, "Metaphysics and Epistemology" and "Ethics and Political Philosophy," the text addresses these problems by providing a guided tour through ten classic philosophical readings. Offering detailed critical commentary, Jacquette carefully explains and analyzes seminal works by Plato, Aristotle, Ockham, Descartes, Berkeley, Kant, Mill, Nietzsche, Moore, and (...) Rawls. He applies the "pathways" metaphor to the various intersecting and overlapping lines of thought represented by this selection of authors, drawing surprising connections between their ideas. This approach enables students to appreciate the relationships between what may otherwise appear to be disparate strands of thought in great works of philosophy and in different traditions of philosophical thought. By following the historical and philosophical narrative in each chapter, students learn how to interpret and critically evaluate difficult philosophical writings in their historical contexts--how to identify concepts, questions, definitions, arguments, and major components of philosophical reasoning in a systematic way. Offering a combination of historical coverage and rigorous critical evaluation, Pathways in Philosophy is ideal for courses in introductory philosophy. The text is enhanced by study questions, key terms, and suggested readings at the end of each chapter, as well as a glossary at the end of the book. (shrink)

The persistence of multiple educational pathways into the nursing profession continues to occupy scholars internationally. In the Netherlands, various groups within the Dutch healthcare sector have tried to differentiate nursing practice on the basis of educational backgrounds for over 50 years. Proponents argue that such reforms are needed to retain bachelor‐trained nurses, improve quality of care and strengthen nurses' position in the sector. Opponents have actively resisted reforms because they would mainly benefit bachelor‐trained nurses and neglect practical experience and technical (...) skills. This historical case study aims to provide insight in this apparent stalemate. Our analysis of this debate is informed by literature on institutional work and current debates within the historiography of nursing. This study contributes to a better understanding of this contemporary debate by examining a broader timeframe than is usually studied, and by highlighting nurses' roles in complex processes of change. We argue that, rather than being stuck in their professional development, different groups of nurses have forged their own path forward in their professional development, albeit via different strategies. (shrink)

How can we know? How can we attain justified belief? These traditional questions in epistemology have inspired philosophers for centuries. Now, in this exceptional work, Alvin Goldman, distinguished scholar and leader in the fields of epistemology and mind, approaches such inquiries as legitimate methods or "pathways" to knowledge. He examines the notion of private and public knowledge, arguing for the epistemic legitimacy of private and introspective methods of gaining knowledge, yet acknowledging the equal importance of social and public mechanisms in (...) the quest for truth. Throughout, he addresses this opposition but proposes a rigorous framework that continues to resolve such contradictions, making this exciting text one of the most important contributions to the theory of knowledge in recent years. (shrink)

What are the prospects for a monistic view of biological individuality given the multiple epistemic roles the concept must satisfy? In this paper, I examine the epistemic adequacy of two recent accounts based on the capacity to undergo natural selection. One is from Ellen Clarke, and the other is by Peter Godfrey-Smith. Clarke’s position reflects a strong monism, in that she aims to characterize individuality in purely functional terms and refrains from privileging any specific material properties as important in their (...) own right. I argue that Clarke’s functionalism impairs the epistemic adequacy of her account compared to a middle-ground position taken by Godfrey-Smith. In comparing Clarke and Godfrey-Smith’s account, two pathways emerge to pluralism about biological individuality. The first develops from the contrast between functionalist and materialist approaches, and the second from an underlying temporal structure involved in using evolutionary processes to define individuality. (shrink)

Pathways of Qi is a complete system for enhanced personal well-being. Join Chinese Medicine expert Matthew Sweigart as he shows how to use Awakening Awareness, Five Element Meditations, and gentle Qigong exercises to clear away blockages and open up all aspects of your being to receive the energetic nourishment you need. Explore the channels of energy flow in the body—known in Chinese Medicine as the twelve meridians—and for each one, discover the limb position, yin/yang properties, corresponding elements, key functions and (...) characteristics, affirmations, and more. Pathways of Qi is a simple, hands-on Qigong healing system based on ancient wisdom to heal the body, mind, emotions, and spirit. Experience the graceful physical movements that anchor these teachings inside your body, and continue these gentle practices for the expansion of awareness, connection, and wellness. (shrink)

Initially identified as a key phosphoinositide that controls membrane trafficking at the Golgi complex, phosphatidylinositol‐4‐phosphate (PI4P) has emerged as a key molecule in the regulation of a diverse array of cellular functions. In this review we will discuss selected examples of the findings that in the last few years have significantly increased our awareness of the regulation and roles of PI4P in the Golgi complex and beyond. We will also highlight the role of PI4P in infection and cancer. We (...) believe that, with the increasing number of regulators and effectors of PI4P identified, the time is ripe for a more integrated approach of study. A first step in this direction is the delineation of PI4P‐centered molecular networks that we provide using data from low and high throughput studies in yeast and mammals. (shrink)

This unique volume is a comprehensive,well-illustrated study of the organization of the white matter pathways of the brain. Schmahmann and Pandya have analyzed and synthesized the corticocortical and corticosubcortical connections of the major areas of the cerebral cortex of the rhesus monkey. The result is a detailed understanding of the constituents of the cerebral white matter and the organization of the fiber tracts. The findings from the 36 cases studied are presented on a single template brain, facilitating comparison of the (...) locations of the different fiber pathways. The summary diagrams provide a comprehensive atlas of the cerebral white matter. The text is enriched by close attention to functional aspects of the anatomical observations. The clinical relevance of the pathways is addressed throughout the text and a chapter is devoted to human white matter diseases. The introductory account gives a detailed historical background. Translations of seminal original observations by early investigators are presented, and when these are considered in the light of the authors' new observations, many longstanding conflicts and debates are resolved. This scholarly book is an important addition to systems and cognitive neuroscience that will be of lasting value to neurobiologists, anatomists, neurologists, neurosurgeons, neuroradiologists, psychiatrists, psychologists, and to their students and trainees. (shrink)

This volume investigates alternative epistemological pathways by which knowledge production in Africa can proceed. The contributors, using different intellectual dynamics, explore the existing epistemological dominance of the West—from architecture to gender discourse, from environmental management to democratic governance—and offer distinct and unique arguments that challenge the denigration of the different and differing modes of knowing that the West considered “barbaric” and “primitive.” This volume therefore constitutes a minimal gesture that further contributes to the ongoing discourse on alternative modes of knowing (...) in Africa. (shrink)

The aim of our themed symposium is to explore the limits and possibilities of corporate reputation for enabling corporate accountability. We articulate three perspectives on corporate accountability. The communicative perspective equates accountability with disclosure and stakeholder engagement. The phenomenological perspective focuses on stakeholder expectations and reputation management. The consequential perspective focuses on effects/consequences. We then examine how corporate accountability is understood, how it relates to ideals, mission, and purpose, alternative pathways to corporate accountability, reputational consequences, and the role algorithms play (...) in relationships between corporate reputation and accountability. Using a multitude of organizational contexts, these papers advance our understanding of how corporate reputation can be used as a mechanism for creating greater corporate accountability, and for identifying alternative pathways when corporate reputation fails to do so. (shrink)

The insulin/insulin‐like growth factor‐1 (IGF‐1) signaling (IIS) pathway is a pivotal genetic program regulating cell growth, tissue development, metabolic physiology, and longevity of multicellular organisms. IIS integrates a fine‐tuned cascade of signaling events induced by insulin/IGF‐1, which is precisely controlled by post‐translational modifications. The ubiquitin/proteasome‐system (UPS) influences the functionality of IIS through inducible ubiquitylation pathways that regulate internalization of the insulin/IGF‐1 receptor, the stability of downstream insulin/IGF‐1 signaling targets, and activity of nuclear receptors for control of gene expression. An (...) age‐related decline in UPS activity is often associated with an impairment of IIS, contributing to pathologies such as cancer, diabetes, cardiovascular, and neurodegenerative disorders. Recent findings identified a key role of diverse ubiquitin modifications in insulin signaling decisions, which governs dynamic adaption upon environmental and physiological changes. In this review, we discuss the mutual crosstalk between ubiquitin and insulin signaling pathways in the context of cellular and organismal homeostasis. (shrink)

Philosophy of science has the potential to enhance scientific practice, science policy, and science education; moreover, recent research indicates that many philosophers of science think we ought to increase the broader impacts of our work. Yet, there is little to no empirical data on how we are supposed to have an impact. To address this problem, our research team interviewed 35 philosophers of science regarding the impact of their work in science-related domains. We found that face-to-face engagement with scientists and (...) other stakeholders was one of the most—if not the most—effective pathways to impact. Yet, working with non-philosophers and disseminating research outside philosophical venues is not what philosophers are typically trained or incentivized to do. Thus, there is a troublesome tension between the activities that are likely to lead to broader uptake of one’s work and those that are traditionally encouraged and rewarded in philosophy. We suggest several ways that philosophers of science, either as individuals or as a community, can navigate these tensions. (shrink)

Ongoing inaction on mitigation and adaptation has turned climate justice debates toward non-ideal theory, where the demand for action-guidance is foregrounded. Some theorists have adopted an understanding of the problem of action-guidance toward climate justice as a “pathway problem.” I argue that this theoretical framework’s assumptions, including a reliance on probabilistic feasibility assessments, makes it inappropriate to guide action toward climate justice.

Planar cell polarity (PCP), the alignment of cells within 2D tissue planes, involves a set of core molecular regulators highly conserved between animals and cell types. These include the transmembrane proteins Frizzled (Fz) and VanGogh and the cytoplasmic regulators Dishevelled (Dsh) and Prickle. It is widely accepted that this core forms part of a ‘PCP pathway’ for signal transduction, which can affect cell morphology through activation of an evolutionary ancient regulatory module involving Rho family GTPases and Myosin II, and/or (...) the JNK kinase cascade. We have re‐examined the evidence for interactions between the proposed PCP pathway components, and question the placing of the cell morphology regulators in the same pathway as the PCP core. While Fz and Dsh are clearly involved in both PCP and Rho‐based cell morphology regulation, available evidence cannot currently discriminate whether these processes are linked mechanistically by a shared Fz/Dsh population, or pass by two distinct pathways. (shrink)

Retrograde plastid‐to‐nucleus signaling plays a central role in coordinating nuclear and plastid gene expression. The gun (genomes uncoupled) mutants of Arabidopsis have been used to demonstrate that Mg‐protoporphyrin (Mg‐Proto) acts as a plastid signal to repress the transcription of nuclear photosynthesis genes.1 It is unclear how Mg‐Proto triggers repression, but several components of this pathway have been recently identified. These include the products of GUN4 and GUN5. GUN5 is the ChlH subunit of Mg‐chelatase, which produces Mg‐Proto, and GUN4 is (...) a regulator of ChlH activity.2 GUN4 might also play a role in photoprotection and in the trafficking of Mg‐Proto. BioEssays 25:631–636, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

There is a task-specificity in the visual-tactile interaction for perception: The polymodal posterior parietal cortex is related to the comparison of the shapes coded by different sensory modalities, whereas the lateral occipital complex is the part of the network for multimodal shape identification. These interactions may be mediated by some latent pathways potentiated by sensory deprivation or learning.

Researchers are pursuing various ways to synthesise human male and female gametes, which would be useful for people facing infertility. Some people are unable to conceive children with their partner because one of them is infertile in the sense of having an anatomical or physiological deficit. Other people—in same sex couples—may not be individually infertile but situationally infertile in relation to one another. Segers et al have described a pathway towards synthetic gametes that would rely on embryonic stem cells, (...) rather than somatic cells. This pathway would be advantageous, they say, for same-sex couples even though it would not offer those couples 50%–50% shared genetics in their children but only 50%–25%. It is unclear, however, why this approach should be preferred morally speaking since it represents a falling off from the kind of shared genetics in children that are functionally a gold standard in parents' expectations generally. Despite raising concerns about whether genetic relatedness is necessary or sufficient as a condition of parental interest in children, Segers et al cede the sociocultural importance of that standard. If so, same-sex couples seem entitled to press a case for some measure of research priority that would offer the same level of access to that social good as everyone else. (shrink)

This article considers concrete manifestations of the politogenesis multilinearity and the variation of its forms; it analyzes the main causes that determined the politogenetic pathway of a given society. The respective factors include the polity's size, its ecological and social environment. The politogenesis should be never reduced to the only one evolutionary pathway leading to the statehood. The early state formation was only one of many versions of development of complex late archaic social systems. The author designates various (...) complex non-state political systems as early state analogues. The early state analogue posed a real alternative to the state for a rather long period of time, whereas in many ecologically marginal regions they could compete quite seriously with the state sometimes until recently. Thus, it was only in the final count that the state became the leading form of political organization of complex societies. The very pathways to statehood had a few versions. One may group them into two main types: ‘vertical’ and ‘horizontal’. Within the ‘vertical’ model the state formation took place in a direct way, i.e. directly from small pre-state polities to primitive statehood. Within the ‘horizontal’ model we first ob-serve the formation of early state analogues that were quite com-parable to the state as regards their complexity, whereas later those analogues were transformed into states . (shrink)

A biochemical pathway is a sequence of chemical reactions in a biological organism. Such pathways specify mechanisms that explain how cells carry out their major functions by means of molecules and reactions that produce regular changes. Many diseases can be explained by defects in pathways, and new treatments often involve finding drugs that correct those defects. This paper presents explanation schemas and treatment strategies that characterize how thinking about pathways contributes to biomedical discovery. It discusses the significance of pathways (...) for understanding the nature of diseases, explanations, and theories. (shrink)

This paper builds on John Dewey’s views on interactions to suggest pathways for enriching the study of philosophy. Along with the notions of body-mind and organism-environment transactions, interactions are part of a philosophical project with transformative implications for education as well. The first part of the paper will contextualize Dewey’s discussion of interactions with regard to his philosophy of experience and democratic theory. The second one will propose two criteria with regard to enriching philosophical training in ways that engage the (...) mind and the body - increasing sociocultural awareness and generating integrative learning experiences – and will add a few examples of how the study of philosophy could benefit from applying an interactionist perspective. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Reviewed by:Zen Pathways by Bret W. DavisRika Dunlap (bio)Zen Pathways. By Bret W. Davis. New York: Oxford Unity Press, 2022. Pp. 455. Hardcover $110.00, isbn 978-0-19-757369-3.Bret Davis introduces Zen Pathways as his attempt to write "the book that I wish had been there for me to read more than thirty years ago, when I started down the parallel pathways of Zen and philosophy" (p. xi). Although much ink has (...) been spilled on the tradition that claims to be beyond words and letters, Davis thinks that this book "makes a unique contribution, one that will be welcomed especially by readers who are interested in both the philosophy and practice of Zen" (p. xi). Davis is right: Zen Pathways stands out as an excellent book of Zen for both philosophers and practitioners as well as for students who are interested in Mahāyāna Buddhism or modern Japanese philosophy of the Kyoto School. The scope of the book is quite comprehensive with twenty-four chapters that seamlessly flow to cover the fundamental teachings of Zen and the philosophical issues therein. While Davis does not divide these chapters with headings, some chapters can be group together under certain themes; the overview of Zen (chapters 1–2), practice of meditation (chapters 3–4), overview of Buddhism, especially Mahāyāna, from the perspective of Zen (chapters 5–7, 10), no self and enlightenment (chapters 8–9, 11), comparative analyses with Christianity (chapters 8–9, 12–16, 23), notable topics in Zen, such as language, art, no-mind, and nature (chapters 17–20), Zen and modern Japanese philosophy (chapters 21), different schools of Zen (chapters 22), and the oxherding pictures as the path of Zen (chapters 24). Readers can focus on one specific theme or read the whole book to get a good grasp of Zen Buddhist philosophy.One of the strengths of Zen Pathways is that it offers clear explanations and rigorous philosophical analyses of Zen teachings without becoming either a purely scholarly inquiry or an anti-intellectual apology for the impossibility of explaining enlightenment. In Chapter 1, "What Really Is Zen?", Davis explains the foundation of Zen in a nutshell: "Zen is neither a matter of subjective opinion nor a matter of objective doctrine; it is a matter of universal truths manifesting in ways and words appropriate to particular times and places" (p. 15). This characterization clarifies two important aspects of enlightenment in Zen Buddhism: there are universal truths or insights that practitioners are after, and once they learn them, they need to live by these insights and actualize [End Page 1] these truths in their own particular ways. Davis endeavors to balance these two aspects through the rigorous yet engaging ways in which he develops these chapters, offering clear philosophical explanations of teachings and kōans while supplying stories and examples from his own experiences of Zen practice. Thus, this book is not just on Zen but of Zen, negotiating these aspects to strike what he calls "the appropriate middle way between the unwholesome and unhelpful extremes of being 'stingy with the Buddha Dharma,' on the one hand, and spreading 'the stench of Zen' by flaunting [his] personal experience, on the other" (p. xix). Given that the intended primary audience is teachers and students in college courses on Asian and comparative philosophy and religion, this book, with the academic rigor of a scholar and the personal touch of a practitioner, is an outstanding resource to learn and teach these universal truths of Zen.The details of these truths are spelled out in chapters 5–11 in particular, as Davis offers philosophical explanations of Zen Buddhist teachings, such as the Four Noble Truths, Middle Way, anātman, nonduality of self and other, panentheism, and enlightenment as realizing one's true self or kenshō. Before plunging into these technical notions, Davis makes it clear that all of these are ultimately about self, that Zen is about realizing one's true self to discover within "an opening to the outside, an opening that in fact frees us from the rigid and absolute distinctions we are accustomed to making between inside and outside, self and other, and... (shrink)

The mutations that cause many forms of inherited retinal degenerations have been identified, yet the mechanisms by which these mutations lead to death of photoreceptor cells of the retina are not completely understood. Investigations of the pathways from mutation to retinal degeneration have focused on spontaneous and engineered animal models of disease. Based on the studies performed to date, four major categories of degeneration mechanism can be identified. These include disruption of photoreceptor outer segment morphogenesis, metabolic overload, dysfunction of retinal (...) pigment epithelial cells, and chronic activation of phototransduction. Future investigations will likely identify additional mechanisms of photoreceptor damage. This review will summarize what has been learned from studying animal models of non-syndromic inherited retinal degenerations. BioEssays 23:605–618, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Although we are beginning to understand the neuronal and biochemical nature of sleep regulation, questions remain about how sleep is homeostatically regulated. Beyond its importance in basic physiology, understanding sleep may also shed light on psychiatric and neurodevelopmental disorders. Recent genetic studies in mammals revealed several non-secretory proteins that determine sleep duration. Interestingly, genes identified in these studies are closely related to psychiatric and neurodevelopmental disorders, suggesting that the sleep-wake cycle shares some common mechanisms with these disorders. Here we review (...) recent sleep studies, including reverse and forward genetic studies, from the perspectives of sleep duration and homeostasis. We then introduce a recent hypothesis for mammalian sleep in which the fast and slow Ca2+-dependent hyperpolarization pathways are pivotal in generating the SWS firing pattern and regulating sleep homeostasis, respectively. Finally, we propose that these intracellular pathways are potential therapeutic targets for achieving depolarization/hyperpolarization balance in psychiatric and neurodevelopmental disorders. How animals implement sleep homeostasis is a great mystery. Here, we review recent studies with highlighting the hypothesis that the slow Ca2+-dependent hyperpolarization pathway regulates sleep homeostasis via modifying the fast pathway; the activity of CaMKIIα/β increases during wakefulness, which triggers sleep by phosphorylating the components in the fast pathway. (shrink)

Testimony and witnessing require sentiency, not humanity. Sentiency is distinguished here as the capacity to experience energetic coalescing between elements/entities/presences and to derive a response from such encounters. Taking as its focal point the kincentric ecology and lifeworld of Yanyuwa Country in the south-west Gulf of Carpentaria, northern Australia, this paper strives to expand the conceptual roots for a discussion of testimony and witnessing through the principle of “unflattening.” Unflattening is a commitment of orientation, one that counteracts the type of (...) narrow, rigid thinking that is flatness, a condition in which humans are often unable to see past the boundaries of current frames of mind, the limits of our existence, our ontology, epistemic and moral habit (Sousanis, Unflattening (Harvard UP, 2015)). In a settler colonial context such as Australia, these are conditions which reflect a dominant epistemic tradition of the West, which relies upon certain ontological habits, reflective of a capitalist, modern, neo-liberal and individualistic tendency. But this is not the only Law and way of knowing that exists across the great landmass of Australia, mapped as it is by the languages and Laws of diverse Indigenous language groups. In Yanyuwa Country, communication between multifarious agents is common, ranging from those between humans, deceased kin who reside as “old people” in Country, Ancestral Beings which have become the embodiment of Country, non-human animals, elements, objects and places. Each and all are capable of communicating; be it as expressions of recognition of one another, revelation of emotional states, health or disorder, responsivity to the presence of others, Law and local empiricism. Drawing on my ethnographic encounters with Yanyuwa families, I aim, throughout this paper, to unflatten on three fronts: first, expand the relational scope of potential communicative pathways to take in sentient presence as a catalyst for relationality (carried forth by responsiveness to and between presences), second, examine the multidimensional nature of testimony and third, expand our vision of the enactment of witnessing – to consider who, what and when. I consider Indigenous, specifically Yanyuwa, relational ontologies as they bond and unify the human and non-human across a field of sentiency and communicative intention, shifting the focus or primal orientation to either side of and all around the human. (shrink)

Combining classical and contemporary readings with original essays, Pathways to Philosophy offers an imaginative introduction to the art of philosophical reflection and wonderment. The collection reflects the inherent multidisciplinary nature of the field - revealing and exploring the connections between philosophy, science, and literature. All material is carefully chosen, edited, and coordinated to ensure its accessibility to readers of all levels. The result is a presentation that is engaging, provocative, and fun. There are four main sections divided into twelve chapters (...) held together by a common thread: analysis and exploration of concepts and dimensions of the Self. The readings cover Eastern as well as Western traditions, and include selections by both women and men. In the process, it provides coverage of a number of topics which, though important, are often omitted from introductory texts. (shrink)

Acknowledged in 2016 by UNESCO as an Intangible Cultural Heritage of Humanity, yoga today can be said to impact three primary sets of stakeholders: global practitioners and professional instructors of studio-based postural yoga; academic scholars investigating yoga’s historical, textual, and cultural life; and traditional culture bearers within established guru lineages in South Asia and the diaspora. These groups are not mutually exclusive, exhaustive, or homogeneous, but there are often significant cleavages between them—particularly in the production and dissemination of authoritative knowledge (...) about yoga’s premodern “roots.” This essay investigates how practitioners of studio-based postural yoga are currently able to access new scholarship on premodern yoga traditions, and the extent to which specialized Sanskrit language training may offer practitioners a pathway for more active participation in this knowledge mobilization process. We suggest that a kinesthetic approach, in which Sanskrit pedagogy is juxtaposed with physical yoga practice in the studio, might further enhance this process, leading to a more equitable engagement between scholars, studio-based practitioners, and traditional culture bearers of yoga. (shrink)

This review shows that there is now a solid scientific evidence base for the “expert” evaluation of disputed confession cases in judicial proceedings. Real-life cases have driven the science by stimulating research into “coercive” police questioning techniques, psychological vulnerabilities to false confession, and the development and validation of psychometric tests of interrogative suggestibility and compliance. Mandatory electronic recording of police interviews has helped with identifying the situational and personal “risk factors” involved in false confessions and how these interact. It is (...) the combination of a detailed evaluation and analysis of real-life cases, experimental work, and community (and prison/police station) studies that have greatly advanced the science over the past 40 years. In this review, the story of the development of the science during this “golden era” is told through the three established error pathways to false confessions and wrongful convictions: misclassification, coercion, and contamination. A case study of a major miscarriage of justice is used to highlight the key issues at each stage of the error pathways and it shows the continued resistance of the judiciary to admit mistakes and learn from them. Science is a powerful platform from which to educate the police and the judiciary. (shrink)

An evolutionary theory of socialization suggests that children from father-absent families will mature earlier, and form less-stable pair bonds, compared with those from father-present families. Using a sample of about 1,000 persons the recent study focuses on elements of father-absent children’s behavior that could be better explained by a Darwinian approach than by rival social science theories. As a result of their enhanced interest in male competition, father-absent boys were found to engage in rule-breaking behavior more intensively than father-present boys. (...) Compared with father-present children, adolescents from widowed households (both boys and girls) showed a higher intensity of various kinds of noncompliant behavior, which can be linked to their earlier maturation. School attendance, age at marriage, and marital success proved to be influenced by the children’s early family experiences, governed by adapted evolutionary strategies. Father-absent daughters conceived more children than those whose fathers were present during their childhood. As evolutionary theory predicts, reproductive behavior of individuals from divorced households differed from that of individuals who grew up in widowed households. Finally, the strong correlation found between spontaneous abortion/stillbirths and family arrangement indicates that father absence has certain direct impacts on the neurohormonal processes of child development. (shrink)