NPC1 plays a central role in cholesterol egress from endolysosomes, a critical step for maintaining intracellular cholesterol homeostasis. Despite recent advances in the field, the full repertoire of molecules and pathways involved in this process remains unknown. Emerging evidence suggests the existence of NPC1‐independent, alternative routes. These may involve vesicular and non‐vesicular mechanisms, as well as release of extracellular vesicles. Understanding the underlying molecular mechanisms that bypass NPC1 function could have important implications for the development of therapies (...) for lysosomal storage disorders. Here we discuss how cholesterol may be exported from lysosomes in which NPC1 function is impaired. (shrink)

Hunger is a psychological state that serves physiological energy homeostasis. I argue that it is a pure underived desire to eat and examine its role in homeostasis. After scene-setting explanations of homeostasis and desire, I argue that hunger is a close phenomenological match with underived desire. Then, I show why desire is an apt instrument for energy homeostasis. Finally, I argue that energy homeostasis is a multi-factorial future-regarding behavioural strategy. Hunger is a special purpose sensory (...) state that serves only to implement the strategy. Thus, it is a sensory desire. I conclude by reflecting on the credibility of this desire. (shrink)

Christopher Boorse’s Biostatistical Theory of Health has been the main contender among naturalistic accounts of health for the last 40 years. Yet, a recent criticism of this theory, presented by Elselijn Kingma, identifies a dilemma resulting from the BST’s conceptual linking of health and statistical typicality. Kingma argues that the BST either cannot accommodate the situation- specificity of many normal functions or cannot account for many situation-specific diseases. In this article, we expand upon with Daniel Hausman’s response to Kingma’s dilemma. (...) We propose that recalling Boorse’s specification that health is an intrinsic property of its bearers and explicating this intrinsic property in relation to the concept of homeostasis can illuminate how proponents of naturalistic accounts of health should deal with the situation- specificity of normal functions. We argue that beyond what Boorse and Hausman have delineated, the situation- specificity of normal function cannot be fully captured in a simple dichotomy between normal and abnormal environment or between relevant and irrelevant situations. By bringing homeostasis to the fore of the analysis of health, we set out a richer picture of what the various situations that affect living organisms’ functional performance can be. Accordingly, we provide a broader classification of these various situations which, we contend, better accounts for the main intuitions that philosophers of medicine have sought to accommodate than previous naturalistic theories of health. (shrink)

Several authors have argued that higher taxa are monophyletic homeostatic property cluster natural kinds. On the traditional definition of monophyly, this will not work: the emergence of taxon-defining homeostatic property clusters would not always correspond to unique speciation events. An alternative conception of monophyly is developed and advocated, which can accommodate the homeostatic property cluster proposal. Recent work in philosophy of science shows that it meets appropriate standards of objectivity and precision.

The first and rate‐limiting step of steroidogenesis is the transfer of cholesterol from the outer mitochondrial membrane to the inner membrane where it is converted to pregnenolone by cytochrome P450 side‐chain cleavage (P450scc). This reaction is modulated in the gonads and adrenals by the steroidogenic acute regulatory protein (StAR), however, the mechanism used by StAR is not understood. The outer and inner mitochondrial membranes are joined at contact sites that are thought to be held in place by protein complexes (...) that bridge the two membranes. While it is generally accepted that proteins are imported into the mitochondrion via contact sites, it is not clear whether cholesterol takes the same conduit to the inner membrane. Strategies to combat diseases caused by interrupted cholesterol transfer will rely on a full understanding of the steroidogenic mechanism. The challenge for the future is to determine whether StAR relies on the molecular architecture that spans the mitochondrial intermembrane space to deliver its cargo. BioEssays 25:252–258, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Antonio Damasio elabora una teoría de la mente humana y de la conducta moral a partir de su hipótesis sobre la evolución de los mecanismos de autorregulación biológicos. En ella, a la capacidad para representar relaciones organismo-mundo se le confiere un importante papel en los cambios organizacionales que emergen de los sistemas con un sistema nervioso central. Concretamente, en nuestro artículo analizamos, en primer lugar, la tesis acerca de la doble homeostasis biológica- mental que caracteriza a los agentes racionales. (...) Desde su perspectiva, la conciencia es producto y manifestación de complejos procesos del procesamiento de representaciones, los cuales favorecen la regulación no consciente. Además, para entender los procesos conscientes también es clave, según Damasio, conocer cómo la evolución de tales mecanismos está asociada con el desarrollo de áreas neuronales próximas al córtex emocional, especialmente, el giro cingulado. Los argumentos que Damasio utiliza para vincular los procesos representacionales con la particular preocupación humana por los sentimientos de los otros es la segunda cuestión que evaluamos. (shrink)

The formal properties of orbits in a plane are explored by elementary topology. The notions developed from first principles include: convex and polygonal orbits; convexity; orientation, winding number and interior; convex and star-shaped regions. It is shown that an orbit that is convex with respect to each of its interior points bounds a convex region. Also, an orbit that is convex with respect to a fixed point bounds a star-shaped region.Biological considerations that directed interest to these patterns are indicated, and (...) the implications of the prospect of higher orders of star-shapedness mentioned. (shrink)

Yan Xin Life Science Technology-Optimized Caloric Restriction (YXLST-CR) is a unique food abstinence, which suppresses appetite and sensation of hunger while maintaining physiological homeostasis. The authors review the first clinical case study on YXLST-CR, or YXLST-bigu, a 15-day, 24-hour observation in 1987 on a 21-year-old female undergoing YXLST-bigu for several months. The participant took no food or water and conducted normal physical activities. The daily records of body weight, temperature, pulse rate, blood pressure, and daily urine test results showed (...) no abnormalities. Homeostasis was maintained during YXLST-CR. The authors also report serum leptin levels in a group of individuals undergoing YXLST-CR and a control group before and after a 24-hour water-only period. The leptin level prior to the observation for the YXLST-CR group was lower than that for the control group and remained unchanged during the observation, suggesting the possibilities of an established metabolic adaptation. (shrink)

Some properties are discussed of regular polygons that may result from angular homeostatic processes in stable orbit. To characterize these homeostatic polygons we need to discuss the winding number, the sidedness (integer, fractional and irrational), multiplicity, envelopes, and density. A regular (i.e., equilateral, equiangular) polygon may be closed in one revolution about its unique center, in multiple revolutions, or not at all. A homeostatic polygon can be generated only if all vertices are included in a single polygon, which occurs if (...) and only if the number of vertices and the number of revolutions required to complete the polygon are relatively prime. For the homeostatic polygon to have a finite number of sides (without repeating itself) the angle subtended by any two successive vertices at the center must be a rational multiple of 2. Biological implications of these properties are illustrated. (shrink)

"Exhalation," a 2008 science fiction short story by Ted Chiang, virtuoso of the genre and the form, begins with a truism, refuted: "It has long been said that air (which others call argon) is the source of life. This is not in fact the case, and I engrave these words to describe how I came to understand the true source of life and, as a corollary, the means by which life will one day end" (37). The narrator's promise is so (...) alluring—knowledge of life's origin, knowledge of its expiration, and knowledge of the relation between the two—that we may be forgiven for overlooking the parenthetical. Argon amounts to less than one percent of the air breathed within Earth's atmosphere. The narrator specifies that "others call... Read More. (shrink)

We propose that sleep is linked to synaptic homeostasis. Specifically, we propose that: (1) Wakefulness is associated with synaptic potentiation in cortical circuits; (2) synaptic potentiation is tied to the homeostatic regulation of slow wave activity; (3) slow wave activity is associated with synaptic downscaling; and (4) synaptic downscaling is tied to several beneficial effects of sleep, including performance enhancement.

The close link between signaling by the developmental regulators of the Hedgehog family and cholesterol biochemistry has been known for some time. The morphogen is covalently attached to cholesterol in a peculiar autocatalytic reaction and embryonal disruption of cholesterol synthesis leads to malformations that mimic Hh signaling defects. Recently, it was furthermore shown that secreted Hh could hitchhike on lipoprotein particles to establish its morphogenic gradient in the developing embryo. Additionally, there is new evidence that the Hh‐receptor (...) Patched transmits the Hh signal by modulating the secretion of an inhibitory sterol molecule from the receiving cells. Here we present some of the most recent discoveries on the Hh–sterol link and discuss their implications from a systems design perspective. We predict that a robust functioning of the Hh pathway will require the involvement of more sterol metabolites, and these should be the subject of future research. BioEssays 29:1085–1094, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Ubiquitin is the most phylogenetically conserved protein known. This 8,500 Da polypeptide can be covalently attached to cellular proteins as a posttranslational modification. In most cases, the addition of multiple ubiquitin adducts to a protein targets it for rapid degradation by a multisubunit protease known as the 26S proteasome. While the ubiquitin/26S proteasome pathway is responsible for the degradation of the bulk of cellular proteins during homeostasis, it may also be responsible for the rapid loss of protein during the (...) programmed death of certain cells, such as skeletal muscle during insect metamorphosis. In addition, alterations in the expression and regulation of ubiquitin may play significant roles in pathological disorders. For example, dramatic increases in ubiquitin and ubiquitin‐protein conjugates are observed in a wide variety of neurodegenerative disorders, including Alzheimer's disease. Patients suffering from the autoimmune disease systemic lupus erythematosus generate antibodies reacting with ubiquitin and ubiquitinated histones. At present, it is not known whether these changes in ubiquitin expression and regulation initiate pathological changes in these diseases or if they are altered as a consequence of these disorders. (shrink)

While purely causal theories of reference have provided a plausible account of the meanings of names and natural kind terms, they cannot handle vacuous theoretical terms. The causal homeostasis theory can but incurs other difficulties. Theories of reference that are intensional and not purely causal tend to be molecularist or holist. Holist theories threaten transtheoretic reference, whereas molecularist theories must supply a principled basis for selecting privileged meaning-determining relations between terms. The causal homeostasis theory is a two-factor molecularist (...) theory, but it fails to provide such a principled basis and collapses into holism. A naturalistic, non-foundationalist holism that deploys strategies of intertheoretic reduction and co-evolutionary pluralism can, however, yield a credible version of transtheoretic reference. (shrink)

The concentration of low‐density lipoprotein (LDL) cholesterol (C) in plasma is a key determinant of cardiovascular disease risk and human genetic studies have long endeavoured to elucidate the pathways that regulate LDL metabolism. Massive genome‐wide association studies (GWASs) of common genetic variation associated with LDL‐C in the population have implicated SORT1 in LDL metabolism. Using experimental paradigms and standards appropriate for understanding the mechanisms by which common variants alter phenotypic expression, three recent publications have presented divergent and even contradictory (...) findings. Interestingly, although these reports each linked SORT1 to LDL metabolism, they did not agree on a mechanism to explain the association. Here, we review recent mechanistic studies of SORT1 – the first gene identified by GWAS as a determinant of plasma LDL‐C to be evaluated mechanistically. (shrink)

The idea that a human being may select at will outcomes of certain quantum events, and that this is free will, has been put forward long ago. But how can such a possibility to control quantum randomness be recombined with the necessity to obey the known statistical distributions of the laws of nature? Antoine Suarez proposes a Quantum Homeostasis Hypothesis (QHH), where this may happen during sleep or dreams. Divine providence may also be placed exactly here without violating the (...) free will of a human being, and in accordance with the necessity to follow the statistical laws of nature. God may instruct one during sleep and dreams. Apart from the Bible, this is attested to by sources in many ancient civilizations. This essay addresses this aspect of QHH in an attempt to answer the question whether data may show that our “acts of will” during dreams differ from such during a fully conscious state of mind. (shrink)