Dandruff is a common scalp condition, which frequently causes psychological distress in those affected. Dandruff is considered to be caused by an interplay of several factors. However, the pathogenesis of dandruff remains under‐investigated, especially with respect to the contribution of the hair follicle. As the hair follicle exhibits unique immune‐modulatory properties, including the creation of an immunoinhibitory, immune‐privileged milieu, we propose a novel hypothesis taking into account the role of the hair follicle. We hypothesize that the changes and imbalance (...) of yeast and bacterial species, along with increasing proinflammatory sebum by‐products, leads to the activation of immune response and inflammation. Hair follicle keratinocytes may then detect these changes in scalp microbiota resulting in the recruitment of leukocytes to the inflammation site. These changes in the scalp skin immune‐microenvironment may impact hair follicle immune privilege status, which opens new avenues into exploring the role of the hair follicle in dandruff pathogenesis. Also see the video abstract here: https://youtu.be/mEZEznCYtNs. (shrink)

We suggest a new view of secretory and membrane protein folding that emphasizes the role of pathways of biogenesis in generating functional and conformational heterogeneity. In this view, heterogeneity results from action of accessory factors either directly binding specific sequences of the nascent chain, or indirectly, changing the environment in which a particular domain is synthesized. Entrained by signaling pathways, these variables create a combinatorial set of necessary‐but‐not‐sufficient conditions that enhance synthesis and folding of particular alternate, functional, conformational forms. (...) We therefore propose that protein conformation is productively regulated by the cell during translocation across the endoplasmic reticulum (ER), a concept that may account for currently poorly understood aspects of physiological function, natural selection, and disease pathogenesis. BioEssays 24:741–748, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Converging data from different disciplines are showing the role of classical conditioning processes in the elaboration of human and animal behavior to be larger than previously supposed. Restricted views of classically conditioned responses as merely secretory, reflexive, or emotional are giving way to a broader conception that includes problem-solving, and other rule-governed behavior thought to be the exclusive province of either operant conditiońing or cognitive psychology. These new views have been accompanied by changes in the way conditioning is (...) conducted and evaluated. Data from a number of seemingly unrelated phenomena such as relapse to drug abuse by postaddicts, the placebo effect, and the immune response appear to involve classical conditioning processes. Classical conditioning, moreover, has been found to occur in simpler and simpler organisms and recently even demonstrated in brain slices and in utero. This target article will integrate the several research areas that have used the classical conditioning process as an explanatory model; it will challenge teleological interpretations of the classically conditioned CR and offer some basic principles for testing conditioning in diverse areas. (shrink)

Electron microscopic examination of the non‐granulated cells of the adenohypophysis of several species has evidenced a unity of structure amongst vertebrates. Efforts to correlate structure and function have been made, but they have often been hampered by the scarcity or absence of direct experimental methods for the investigation of their function. Yet often the evidence in favor of a given role has been circumstantial, relying on coincidences between changes in the secretory activity of the gland and changes (...) in the ultrastructure of the non‐granulated cells or in colloid production. At the present time, the prevailing hypothesis is that, in addition to a possible role in mechanical support within the gland, the non‐granulated cells seem to be important with respect to the secretory process of the endocrine cells and/or to the metabolism of the adenohypophysis. (shrink)

A Paramecium cell has a stereotypically patterned surface, with regularly arranged cilia, dense‐core secretory vesicles and subplasmalemmal calcium stores. Less strikingly, there is also a patterning of molecules; for instance, some ion channels are restricted to certain regions of the cell surface. This design may explain very effective and selective responses, such as that to Ca2+ upon stimulation. It enables the cell to respond to a Ca2+ signal precisely secretion (exocytosis) or by changing its ciliary activity. These responses depend (...) on the location and/or type of signal, even though these two target structures co‐exist side‐by‐side, and normally only limited overlap occurs between the different functions. Furthermore, the patterning of exocytotic sites and the possibility of synchronous exocytosis induction in the sub‐second time range have considerably facilitated analyses, and thus led to new concepts of exocytotic membrane fusion. It has been possible to dissect complicated events like overlapping Ca2+ fluxes produced from external sources and from internal stores. Since molecular genetic approaches have become available for Paramecium, many different gene products have been identified only some of which are known from “higher” eukaryotes. Although a variety of basic cellular functions are briefly addressed to demonstrate the uniqueness of this unicellular organism, this article focuses on exocytosis regulation. BioEssays 24:649–658, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Citrate, an organic trivalent anion, is a major substrate for generation of energy in most cells. It is produced in mitochondria and used either in the Krebs' cycle or released into cytoplasm through a specific mitochondrial carriers. Citrate can also be taken up from blood through different plasma membrane transporters. In the cytoplasm, citrate can be used ultimately for fatty acid synthesis, which is increased in cancer cells. Here, we review the ways in which citrate can be transported and discuss (...) the changes in transport and metabolism that occur in cancer cells. The primary focus is on the prostate gland, which is known to produce and release large amounts of citrate during its normal secretory function. The significant changes that occur in citrate‐related metabolism and transport in prostate cancer are the second focus. This review strives to relate these mechanisms to molecular biology on the one hand and to clinical applications on the other. (shrink)

Developing cells acquire mature fates in part by selective (i.e. qualitatively different) expression of a few cell‐specific genes. However, all cells share the same basic repertoire of molecular and subcellular building blocks. Therefore, cells must also specialize according to quantitative differences in cell‐specific distributions of those common molecular resources. Here we propose the novel hypothesis that evolutionarily‐conserved transcription factors called scaling factors (SFs) regulate quantitative differences among mature cell types. SFs: (1) are induced during late stages of cell maturation; (2) (...) are dedicated to specific subcellular domains; and, thus, (3) allow cells to emphasize specific subcellular features. We identify candidate SFs and discuss one in detail: MIST1 (BHLHA15, vertebrates)/DIMM (CG8667, Drosophila); professional secretory cells use this SF to scale up regulated secretion. Because cells use SFs to develop their mature properties and also to adapt them to ever‐changing environmental conditions, SF aberrations likely contribute to diseases of adult onset. (shrink)

BackgroundThis research explores how the COVID-19 pandemic has changed the ways doctors make end-of-life decisions, particularly around Do Not Attempt Cardio-Pulmonary Resuscitation (DNACPR), treatment escalation and doctors’ views on the legalisation of euthanasia and physician-assisted suicide.MethodsThe research was conducted between May and August 2021, during which COVID-19 hospital cases were relatively low and pressures on NHS resources were near normal levels. Data were collected via online survey sent to doctors of all levels and specialties, who have worked in the NHS (...) during the pandemic.Results231 participants completed the survey. The research found that over half of participants reported making more patients DNACPR than prepandemic, and this was due, at least in part, to an increased focus on factors including patient age, Clinical Frailty Scores and resource limitations. In addition, a sizeable minority of participants reported that they now had a higher threshold for escalating patients to ITU and a lower threshold for palliating patients, with many attributing these changes to formative experiences gained during the pandemic. Finally, our study found that there has not been a statistically significant change in the views of clinicians on the legalisation of euthanasia or physician-assisted suicide since the start of the pandemic.ConclusionThe COVID-19 pandemic appears to have altered several aspects of end-of-life decision making, and many of these changes have remained even as COVID-19 hospital cases have declined. (shrink)

Reorganization of cell organelle‐deprived host red blood cells by the apicomplexan malaria parasite Plasmodium falciparum enables their cytoadherence to endothelial cells that line the microvasculature. This increases the time red blood cells infected with mature developmental stages remain within selected organs such as the brain to avoid the spleen passage, which can lead to severe complications and cumulate in patient death. The Maurer's clefts are a novel secretory organelle of parasite origin established by the parasite in the cytoplasm of (...) the host red blood cell in order to facilitate the establishment of cytoadherence by conducting the trafficking of immunovariant adhesins to the host cell surface. Another important function of the organelle is the sorting of other proteins the parasite traffics into its host cell. Although the organelle is of high importance for the pathology of malaria, additional putative functions, structure, and genesis remain shrouded in mystery more than a century after its discovery. In this review, we highlight our current knowledge about the Maurer's clefts and other novel secretory organelles established within the host cell cytoplasm by human‐pathogenic malaria parasites and other parasites that reside within human red blood cells. (shrink)

Biological objects are often constructive dynamic systems whose structures evolve as a consequence of their internal dynamics, which in turn is affected by the overall structure. As very few tools are presently adapted to tackle constructive dynamic systems, they constitute fascinating challenges for modeling/simulation. In cell biology, the secretory process in eukaryotic cells corresponds to this type of system, as it appears to autonomously generate new structures as a result of its molecular dynamics. Here I briefly review the only (...) documented case of a membrane-bounded intracellular compartment whose very existence strictly depends on its continued functioning. Indeed, the Golgi apparatus of the yeast Saccharomyces cerevisiae appears at steady-state as a continuously renewed set of transitory membrane-bounded structures that self-mature, rather than as a permanent entity. On the basis of this case and of recent advances in related molecular studies, a detailed model is proposed, that encompasses the birth of a yeast Golgi element and bridges its molecular and morphogenetic aspects. This model is extended to briefly outline three evolutionary inventions, from S. cerevisiae to another yeast, Pichia pastoris, on to plant, and on to animal cells: stacking, stabilizing and aggregating the primary Golgi elements. (shrink)

This book discusses political change in the view of Confucian thought. This study focuses on the Book of Change, which is one of the nine basic books of Confucius School, and has dominated oriental thought in this field for more than three thousand years.

Historians often feel that standard philosophical doctrines about the nature and development of science are not adequate for representing the real history of science. However, when philosophers of science fail to make sense of certain historical events, it is also possible that there is something wrong with the standard historical descriptions of those events, precluding any sensible explanation. If so, philosophical failure can be useful as a guide for improving historiography, and this constitutes a significant mode of productive interaction between (...) the history and the philosophy of science. I illustrate this methodological claim through the case of the Chemical Revolution. I argue that no standard philosophical theory of scientific method can explain why European chemists made a sudden and nearly unanimous switch of allegiance from the phlogiston theory to Lavoisier's theory. A careful re-examination of the history reveals that the shift was neither so quick nor so unanimous as imagined even by many historians. In closing I offer brief reflections on how best to explain the general drift toward Lavoisier's theory that did take place. (shrink)

Most familiar approaches to social conflict moot reasonable ways of dealing with conflict, ways that aim to serve values such as legitimacy, justice, morality, fairness, fidelity to individual preferences, and so on. In this paper, I explore an alternative approach to social conflict that contrasts with the leading approaches of Rawlsians, perfectionists, and social choice theorists. The proposed approach takes intrinsic features of the conflict—what I call a conflict's evaluative ‘structure’—as grounds for a rational way of responding to that conflict. (...) Like conflict within a single person, social conflict can have a distinctive evaluative structure that supports certain rational responses over others. I suggest that one common structure in both intra- and interpersonal cases of conflict supports the rational response of ‘self-governance’. Self-governance in the case of social conflict involves a society's deliberating over the question, ‘What kind of society should we be?’ In liberal democracies, this rational response is also a reasonable one. (shrink)

Many of the experiments that produced the empirical basis of quantum mechanics relied on classical assumptions that contradicted quantum mechanics. Historically this did not cause practical problems, as classical mechanics was used mostly when it did not happen to diverge too much from quantum mechanics in the quantitative sense. That fortunate circumstances, however, did not alleviate the conceptual problems involved in understanding the classical experimental reasoning in quantum-mechanical terms. In general, this type of difficulty can be expected when a coherent (...) scientific tradition undergoes a theoretical upheaval. The problem may be circumvented through the use of phenomenological theory in experimentation during the period of theoretical instability. (shrink)

Why do some epistemic objects persist despite undergoing serious changes, while others go extinct in similar situations? Scientists have often been careless in deciding which epistemic objects to retain and which ones to eliminate; historians and philosophers of science have been on the whole much too unreflective in accepting the scientists’ decisions in this regard. Through a re-examination of the history of oxygen and phlogiston, I will illustrate the benefits to be gained from challenging and disturbing the commonly accepted (...) continuities and discontinuities in the lives of epistemic objects. I will also outline two key consequences of such re-thinking. First, a fresh view on the (dis)continuities in key epistemic objects is apt to lead to informative revisions in recognized periods and trends in the history of science. Second, recognizing sources of continuity leads to a sympathetic view on extinct objects, which in turn problematizes the common monistic tendency in science and philosophy; this epistemological reorientation allows room for more pluralism in scientific practice itself. (shrink)

The target article provides an intermediate account of culture and freedom that is conceived to be curvilinear by treating economic development not as an adaptive outcome in response to climate but as a cause of culture parallel to climate. We argue that the extent of environmental variability, including climatic variability, affects cultural adaptation.

Through a detailed examination of the basis of the idea of communication - with its semantic core of "commonality" or the transcendence of difference - Chang argues against the tendency of theorists to value understanding over misunderstanding, clarity over ambiguity, order over disorder. To this end the author revisits the thought of Derrida and considers deconstruction in general. Specifically, he uses the critique of the phenomenological tradition emerging from poststructuralism to clarify the commitments and assumptions inherent in models of communication. (...) A seminal work, Deconstructing Communication will serve as the guiding framework for a constructive debate about the future direction of communication theory. Situated at the intersection of current debates regarding meaning and representation, Deconstructing Communication casts doubt on the seeming innocence of the activity of communication. Using poststructuralist literary theory and philosophy, Briankle G. Chang argues that modern theories fail to provide an adequate explanation for how communication is possible. (shrink)

We argue why interpretability should have primacy alongside empiricism for several reasons: first, if machine learning models are beginning to render some of the high-risk healthcare decisions instead of clinicians, these models pose a novel medicolegal and ethical frontier that is incompletely addressed by current methods of appraising medical interventions like pharmacological therapies; second, a number of judicial precedents underpinning medical liability and negligence are compromised when ‘autonomous’ ML recommendations are considered to be en par with human instruction in specific (...) contexts; third, explainable algorithms may be more amenable to the ascertainment and minimisation of biases, with repercussions for racial equity as well as scientific reproducibility and generalisability. We conclude with some reasons for the ineludible importance of interpretability, such as the establishment of trust, in overcoming perhaps the most difficult challenge ML will face in a high-stakes environment like healthcare: professional and public acceptance. (shrink)

The role of the state has occupied centre stage in the development of economics as an independent discipline and is one of the most contentious issues addressed by contemporary economists and political economists. The immediate post-war years saw a swing in economic theory towards interventionism, motivated by the urgent need for reconstruction in advanced capitalist countries, the establishment of socialism in parts of Asia and Eastern Europe, and the liberation of many developing nations from colonialism. After a quarter of a (...) century of interventionist policies, a vigourous backlash against state intervention began with the discrediting of welfare statism in advanced capitalist countries, grew through the spread of liberalisation programmes among developing nations during the 1980s, and culminated in the dismantling of socialist central planning since 1989. In this volume, ten distinguished contributors examine patterns of interventionism and anit-interventionism in a wide variety of historical, political and institutional contexts and within different theoretical traditions. Their primary focus is on the internal factors which shape the role of the state and determine its effectiveness in promoting economic change. They explain the growing disenchantment with the Neo-Liberal, anti-interventionist programme--even in Eastern Europe and the former USSR, where the initial optimism in the efficacy of the free market is fading fast. The overall conclusion of the empirical and theoretical analysis is that the simplistic notion of politics fundamental to Neo-Liberal arguments makes them at best misleading and at worst deceitful. Although one can talk of certain general principles, there is no hard and fast rule to determine the optimal degree and the desirable areas of state intervention, which can only be determined in the concrete historical, institutional, and geographical context. The challenge is to form a new synthesis in which the valid insights of Neo-Liberalism are stripped of their ideological baggage and intergrated into a wider and more objective intellectual framework. (shrink)

This book presents the concept of “complementary science” which contributes to scientific knowledge through historical and philosophical investigations. It emphasizes the fact that many simple items of knowledge that we take for granted were actually spectacular achievements obtained only after a great deal of innovative thinking, painstaking experiments, bold conjectures, and serious controversies. Each chapter in the book consists of two parts: a narrative part that states the philosophical puzzle and gives a problem-centred narrative on the historical attempts to solve (...) the puzzle; and the analysis part which provides in-depth analyses of certain scientific, historical, and philosophical aspects of the story. (shrink)

In this article, we propose that giving in cash and non-cash differ in their relation with the giving firm’s future corporate financial performance and only cash giving is associated with future CFP. Using a novel dataset from ASSET4 that differentiates corporate giving over a sample period of 2002–2012, we examine three competing hypotheses: agency cost hypothesis that cash giving reflects agency cost and destroys value for shareholders, investment hypothesis that cash giving is an investment by management that aims for better (...) future return, and information hypothesis that cash giving has informational value to shareholders as cash is a critical resource at a firm and giving is a decision by managers who are insiders. We find that indeed, only cash giving is positively associated with future CFP and firm value, measured by Fama–French five-factor abnormal risk-adjusted stock returns, future return on assets, and Tobin’s Q. In addition, we find that the positive association exists only between excess, i.e., unexpected, but not expected cash giving and future CFP. Our empirical findings support the information hypothesis, but neither the agency hypothesis nor the investment hypothesis, and are robust to a number of endogeneity tests, including orthogonalized cash giving, instrumental variable regression using geography-based instruments, and propensity score matching. Furthermore, we show that the positive association between future CFP and unexpected cash giving is only pronounced at firms with good governance and relatively higher sales growth where agency problems are less likely, and at firms with no alternative mechanisms to demonstrate the strength of cash flow. Additionally, we do not find evidence that suggests in-kind giving to possess any informational value. (shrink)

What, normatively speaking, are the grounds of rational choice? This paper defends ‘comparativism’, the view that a comparative fact grounds rational choice. It examines three of the most serious challenges to comparativism: 1) that sometimes what grounds rational choice is an exclusionary-type relation among alternatives; 2) that an absolute fact such as that it’s your duty or conforms to the Categorial Imperative grounds rational choice; and 3) that rational choice between incomparables is possible, and in particular, all that is needed (...) for the possibility of rational choice is that one alternative is not worse than the others. Each challenge is questioned. If comparativism is correct, then no matter what normative theory you favor, your answer to the question, ‘What makes my choice rational?’ must be comparative in form. In this way, comparativism provides a framework for normative theorizing. (shrink)

This paper argues for the existence of a fourth positive generic value relation that can hold between two items beyond ‘better than’, ‘worse than’, and ‘equally good’: namely ‘on a par’.

ABSTRACT Early modern alchemy studied both matter and life, much like today's life sciences. What material life is and how it comes about intrigued alchemists. Many found the answer by assuming a vital principle that served as the source and cause of life. Recent literature has presented important cases in which vitalist formulations incorporated corpuscular or mechanical elements that were characteristic of the New Science and other cases in which vitalist thinking influenced important figures of the Scientific Revolution. Not merely (...) speculative, vitalist ideas also motivated chymical practice. The unity of life science and material science that is found in many formulations of Renaissance alchemy disintegrated in Georg Ernst Stahl's version of post-Cartesian vitalism. (shrink)

CONTINUOUS MODEL THEORY CHAPTER I TOPOLOGICAL PRELIMINARIES. Notation Throughout the monograph our mathematical notation does not differ drastically from ...

I propose a reformulation of realism, as the pursuit of ontological plausibility in our systems of knowledge. This is dubbed plausibility realism, for convenience of reference. Plausibility realism is non-empiricist, in the sense that it uses ontological plausibility as an independent criterion from empirical adequacy in evaluating systems of knowledge. Ontological plausibility is conceived as a precondition for intelligibility, nor for Truth; therefore, the function of plausibilty realism is to facilitate the kind of understanding that is not reducible to mere (...) description or prediction. Difficulties in making objective judgements of ontological plausibility can be ameliorated if we adhere to the most basic ontological principles. The workings of plausibility realism are illustrated through a detailed discussion of how one ontological principle, which I call the principle of single value, can be employed with great effect. Throughout the paper the discussion draws on concrete examples from the history of science. (shrink)

The theory of Yin and Yang and the Five Movements is based on the concept of cyclical time. This ancient cosmological model postulates that when expansive energy reaches its apex, mutual life-saving relations prevail over mutually conflictual societal relations, and that this cycle repeats. This cosmic change model was first presented in ancient Korea and China, by Hado-Nakseo, via numerological configurations and symbols. The Hado diagram was drawn by a Korean thinker, Bok-hui (?-BC3413), also known as Great Empeor Fuzi or (...) Fu-hsi in Chinese mythology. Confucius once recognized him as the father of I Ching (Book of Changes). The Eastern cosmology was further developed by King Wen and the Duke of Zhou and compiled by Confucius (BC551?-BC 479) during the Spring and Autumn Period and the Warring States Period. Nakseo diagram was first discovered by the famous King Wu of China, who founded the Xia dynasty. In contrast to the harmonious mathematical matrix of Hado, Nakseo symbolizes the conflictual and dynamic expansion of the universe. In the Nakseo world, masculine energy is structurally greater than feminine energy, continuously breeding disequilibrium and conflict. The Yin and Yang model suggests that everything in the universe exists as a combination of opposing dynamics. At any given time, one of the two dynamics grows while the other declines. When Yang energy is at its peak, Yin energy is at its nadir; then, a reversal occurs; and envetually the whole cycle repeats. It would thus be logical to express that when conflictual energy has reached its apex harmonious energy begins to wax. It can be argued that since the state of disequilibrium within the universe represented by Nakseo cannot indefinitely sustain its dynamic of expansion, harmonious international relationships eventually come to pervade the world. This argument represents a unique applicationof the concept of Yin and Yang logic to international arms race and arms control. This cyclical dynamics can explain the long-term process of arms build-up followed by eventually by nuclear standoff and subsequent nuclear arms control regimes as NPT, CTBT, MTCR, SALT, START, PSI and etc. One can boldly claim that Yin and Yang logic offers a clue to creating a theory of structural peace by discovering a constructivist element in the model. The esoteric matrixes of ancient Korea and China thus provide humanity with an new vision for nuclear disarmament and a sustainable peace. (shrink)