Human slow wave sleep: A review and appraisal of recent findings,with implications for sleep functions,and psychiatric illness

Recent findings concerning human slow wave sleep (hSWS-stages 3+4; delta EEG activity) are critically reviewed. Areas covered include the significance of the first hSWS cycle; hSWS in extended sleep; relationship between hSWS, prior wakefulness and sleep loss; hSWS influence on sleep length; problems with hSWS deprivation; influence of the circadian rhythm; individual differences in hSWS, especially, age, gender and constitutional variables such as physical fitness and body composition. Transient increases in hSWS can be produced by increasing both the quality and quantity of prior wakefulness, with an underlying mechanism perhaps relating to the waking level of brain metabolism. Whilst there may also be thermoregulatory influences on hSWS, hypotheses that energy conservation and brain cooling are major roles for hSWS are debatable. hSWS seems to offer some form of cerebral recovery, with the prefrontal cortex being particularly implicated. The hSWS characteristics of certain forms of major psychiatric disorders may well endorse this prefrontal link.     

Hibernation at moderate temperatures: a continuation of slow wave sleep

Summary Golden-mantled ground squirrels (Citellus lateralis) displayed virtually continuous electrophysiological states of sleep when hibernating at moderate ambient temperatures (22°C). Rapid-eye-movement sleep progressively diminished with the fall in body temperature so that at a body temperature of 23°C it was completely absent. At this temperature hibernation was characterized by slow wave sleep isomorphic with slow wave sleep episodes at non-hibernating (euthermic) body temperatures.Supported by National Institute of Health grants GM 23694 awarded to R.J. Berger and GM 23695 awarded to H.C. Heller.     

Glutamate transporter EAAT2: regulation,function, and potential as a therapeutic target for neurological and psychiatric disease

Glutamate is the predominant excitatory neurotransmitter in the central nervous system. Excitatory amino acid transporter 2 (EAAT2) is primarily responsible for clearance of extracellular glutamate to prevent neuronal excitotoxicity and hyperexcitability. EAAT2 plays a critical role in regulation of synaptic activity and plasticity. In addition, EAAT2 has been implicated in the pathogenesis of many central nervous system disorders. In this review, we summarize current understanding of EAAT2, including structure, pharmacology, physiology, and functions, as well as disease relevancy, such as in stroke, Parkinson’s disease, epilepsy, amyotrophic lateral sclerosis, Alzheimer’s disease, major depressive disorder, and addiction. A large number of studies have demonstrated that up-regulation of EAAT2 protein provides significant beneficial effects in many disease models suggesting EAAT2 activation is a promising therapeutic approach. Several EAAT2 activators have been identified. Further understanding of EAAT2 regulatory mechanisms could improve development of drug-like compounds that spatiotemporally regulate EAAT2.     

Realism,functions, and the a priori: Ernst Cassirer's philosophy of science

This paper presents the main ideas of Cassirer's general philosophy of science, focusing on the two aspects of his thought that—in addition to being the most central ideas in his philosophy of science—have received the most attention from contemporary philosophers of science: his theory of the a priori aspects of physical theory, and his relation to scientific realism.     

The bootstrapped artefact: a collectivist account of technological ontology, functions, and normativity

In 2006, this journal addressed the problem of technological artefacts, and through a series of articles aimed at tackling the ‘dual nature of technical artefacts’, posited an understanding of these as constituted by both a structural (physical) and a functional (intentional) component. This attempt to conceptualise artefacts established a series of important questions, concerning such aspects of material technologies as mechanisms, functions, human intentionality, and normativity. However, I believe that in establishing the ‘dual nature’ thesis, the authors within this issue focused too strongly on technological function. By positing function as the analytic axis of the ‘dual nature’ framework, the theorists did not sufficiently problematise what is ultimately a social phenomenon. Here I posit a complementary analytic approach to this problem; namely, I argue that by using the Strong Programme’s performative theory of social institutions, we can better understand the nature of material technologies. Drawing particularly from Martin Kusch’s work, I here argue that by conceptualising artefacts as artificial kinds, we can better examine technological ontology, functions, and normativity. Ultimately, a Strong Programme approach, constructivist and collectivist in nature, offers a useful elaboration upon the important question raised by the ‘dual nature’ theorists.     

Regulation of sodium and body fluid homeostasis during development: implications for the pathogenesis of hypertension.

The spontaneously hypertensive rat (SHR) is an important animal model of human essential hypertension. During the first month of life, increased retention of sodium is present in the SHR which appears to be mediated by the renin-angiotensin system. The present review will discuss the role that increased activity of the renin-angiotensin system plays in sodium/body fluid regulation during early development. It is hypothesized that disordered regulation of sodium/body fluid homeostasis during this stage leads to pathological cardiovascular regulation in adulthood. Through an understanding of the relationship between sodium/body fluid balance in the young and cardiovascular function in the adult insights may be gained into both the pathological state of hypertension and the critical role played by early development in shaping homeostatic mechanisms in adulthood.     

RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease

Receptor for AGE (RAGE) is a member of the immunoglobulin superfamily that engages distinct classes of ligands. The biology of RAGE is driven by the settings in which these ligands accumulate, such as diabetes, inflammation, neurodegenerative disorders and tumors. In this review, we discuss the context of each of these classes of ligands, including advance glycation end-products, amyloid beta peptide and the family of beta sheet fibrils, S100/calgranulins and amphoterin. Implications for the role of these ligands interacting with RAGE in homeostasis and disease will be considered.     

Human spleen: a new and potent source of human interferon for experimental and therapeutic use

Cells of a single human spleen, cultivated in vitro and induced by Sendai virus, produce constantly more than 10(8) units of interferon per spleen. This interferon can be used for therapeutic assays and new basic investigations.     

Plexin structures are coming: opportunities for multilevel investigations of semaphorin guidance receptors, their cell signaling mechanisms, and functions

Plexin transmembrane receptors and their semaphorin ligands, as well as their co-receptors (Neuropilin, Integrin, VEGFR2, ErbB2, and Met kinase) are emerging as key regulatory proteins in a wide variety of developmental, regenerative, but also pathological processes. The diverse arenas of plexin function are surveyed, including roles in the nervous, cardiovascular, bone and skeletal, and immune systems. Such different settings require considerable specificity among the plexin and semaphorin family members which in turn are accompanied by a variety of cell signaling networks. Underlying the latter are the mechanistic details of the interactions and catalytic events at the molecular level. Very recently, dramatic progress has been made in solving the structures of plexins and of their complexes with associated proteins. This molecular level information is now suggesting detailed mechanisms for the function of both the extracellular as well as the intracellular plexin regions. Specifically, several groups have solved structures for extracellular domains for plexin-A2, -B1, and -C1, many in complex with semaphorin ligands. On the intracellular side, the role of small Rho GTPases has been of particular interest. These directly associate with plexin and stimulate a GTPase activating (GAP) function in the plexin catalytic domain to downregulate Ras GTPases. Structures for the Rho GTPase binding domains have been presented for several plexins, some with Rnd1 bound. The entire intracellular domain structure of plexin-A1, -A3, and -B1 have also been solved alone and in complex with Rac1. However, key aspects of the interplay between GTPases and plexins remain far from clear. The structural information is helping the plexin field to focus on key questions at the protein structural, cellular, as well as organism level that collaboratoria of investigations are likely to answer.     

Kitcher''s Compromise: A critical examination of the Compromise Model of scientific closure, and its implications for the relationship between history and philosophy of science

In The Advancement of Science (1993) Philip Kitcher develops what he calls the ‘Compromise Model’ of the closure of scientific debates. The model is designed to acknowledge significant elements from ‘Rationalist’ and ‘Antirationalist’ accounts of science, without succumbing to the one-sidedness of either. As part of an ambitious naturalistic account of scientific progress, Kitcher's model succeeds to the extent that transitions in the history of science satisfy its several conditions. 1 critically evaluate the Compromise Model by identifying its crucial assumptions and by attempting to apply the model to a major transition in the history of biology: the rejection of ‘naive group selectionism’ in the 1960s. I argue that the weaknesses and limitations of Kitcher's model exemplify general problems facing philosophical models of scientific change, and that recognition of these problems supports a more modest vision of the relationship between historical and philosophical accounts of science.     

The effect of five proteins on stem cells used for osteoblast differentiation and proliferation: a current review of the literature

Bone-tissue engineering is a therapeutic target in the field of dental implant and orthopedic surgery. It is therefore essential to find a microenvironment that enhances the growth and differentiation of osteoblasts both from mesenchymal stem cells (MSCs) and those derived from dental pulp. The aim of this review is to determine the relationship among the proteins fibronectin (FN), osteopontin (OPN), tenascin (TN), bone sialoprotein (BSP), and bone morphogenetic protein (BMP2) and their ability to coat different types of biomaterials and surfaces to enhance osteoblast differentiation. Pre-treatment of biomaterials with FN during the initial phase of osteogenic differentiation on all types of surfaces, including slotted titanium and polymers, provides an ideal microenvironment that enhances adhesion, morphology, and proliferation of pluripotent and multipotent cells. Likewise, in the second stage of differentiation, surface coating with BMP2 decreases the diameter and the pore size of the scaffold, causing better adhesion and reduced proliferation of BMP-MSCs. Coating oligomerization surfaces with OPN and BSP promotes cell adhesion, but it is clear that the polymeric coating material BSP alone is insufficient to induce priming of MSCs and functional osteoblastic differentiation in vivo. Finally, TN is involved in mineralization and can accelerate new bone formation in a multicellular environment but has no effect on the initial stage of osteogenesis.     

Studying non-alcoholic fatty liver disease with zebrafish: a confluence of optics, genetics, and physiology

Obesity is a public health crisis. New methods for amelioration of its consequences are required because it is very unlikely that the social and economic factors driving it will be reversed. The pathological accumulation of neutral lipids in the liver (hepatic steatosis) is an obesity-related problem whose molecular underpinnings are unknown and whose effective treatment is lacking. Here I review how zebrafish, a powerful model organism long-used for studying vertebrate developmental programs, is being harnessed to uncover new factors that contribute to normal liver lipid handling. Attention is given to dietary models and individual mutants. I speculate on the possible roles of non-hepatocyte residents of the liver, the adipose tissue, and gut microbiome on the development of hepatic steatosis. The highlighted work and future directions may lead to fresh insights into the pathogenesis and treatment of excess liver lipid states.     

Retinoids, a new class of compounds with prophylactic and therapeutic activities in oncology and dermatology.

A review of recent investigations in the retinoid field is presented. Retinoic acid exerts a prophylactic and a therapeutic effect on chemically induced benign and malignant epithelial tumors in mice. In clinical studies positive therapeutic results have been obtained in patients with preneoplastic and neoplastic epithelial lesions. However, treatment with retinoic acid is limited by serious side effects (hypervitaminosis A syndrome). Therefore, the synthesis of analogs of retinoic acid (retinoids) possessing a more favorable therapeutic ratio has been initiated. Among a large series of synthesized compounds, certain aromatic analogs proved to have a particularly favorable therapeutic ratio. The structure-activity relationship of the most active retinoids is discussed including some biological data concerning prophylaxis and therapy of epithelial tumors. The total synthesis of retinoids according to various building schemes is discussed in detail. Methods for the synthesis of the cyclic end group, of the polyene chain component, and of the full retinoid skeleton are described. Metabolic studies of retinoic acid and of the most active retinoid, as well as the synthesis of some isolated metabolites are outlined. Suggestions concerning the mechanism of action of retinoids are made. Some clinical results on the treatment of acne, psoriasis and precancerous conditions are reported.