Sex differences in human circadian rhythms: Intrinsic periods and sleep fractions

Summary The period of freerunning circadian rhythms is significantly shorter and the fraction of sleep is significantly larger in human females than in males, as long as the rhythms run internally synchronized. The sex difference in the period could be a property either of the whole circadian system or of only one of the oscillators in a multi-oscillator system. The sex difference in the sleep fraction could be a fixed property of the sleep-wake rhythm or could depend on interactions in the multi-oscillator system. To investigate these questions, a sample of 33 long-term experiments, in which the rhythms ran internally synchronized in one section and internally desynchronized in another section, were analyzed. The periods of rhythms in rectal temperature were different in females and males during internal synchronization, but became identical during internal desynchronization. In contrast, sex differences in sleep-wake periods were more pronounced when the rhythms were desynchronized than when they were internally synchronized. This result provides evidence that the sex difference in periodicity is a property only of the sleep-wake rhythm; the intrinsic periods of temperature rhythms are identical in females and males, whereas those of sleep-wake rhythms are distinctly shorter in females than in males. In the state of internal synchronization, the joint period is a compromise between the intrinsic periods of the rhythms involved, and therefore it shows a small but significant sex difference. Moreover, the transition from internally synchronized to desynchronized rhythms is combined with a highly significant reduction in the sleep fraction, which is considerably greater in females than in males. These results suggest that the occurrence of internal desynchronization strongly affects the sleep-wake rhythm, and that the influence of rhythm disorders is considerably greater in females than in males.     

Dynamic mechanistic explanation: computational modeling of circadian rhythms as an exemplar for cognitive science

We consider computational modeling in two fields: chronobiology and cognitive science. In circadian rhythm models, variables generally correspond to properties of parts and operations of the responsible mechanism. A computational model of this complex mechanism is grounded in empirical discoveries and contributes a more refined understanding of the dynamics of its behavior. In cognitive science, on the other hand, computational modelers typically advance de novo proposals for mechanisms to account for behavior. They offer indirect evidence that a proposed mechanism is adequate to produce particular behavioral data, but typically there is no direct empirical evidence for the hypothesized parts and operations. Models in these two fields differ in the extent of their empirical grounding, but they share the goal of achieving dynamic mechanistic explanation. That is, they augment a proposed mechanistic explanation with a computational model that enables exploration of the mechanism’s dynamics. Using exemplars from circadian rhythm research, we extract six specific contributions provided by computational models. We then examine cognitive science models to determine how well they make the same types of contributions. We suggest that the modeling approach used in circadian research may prove useful in cognitive science as researchers develop procedures for experimentally decomposing cognitive mechanisms into parts and operations and begin to understand their nonlinear interactions.     

In vitro neurogenesis: development and functional implications of iPSC technology

Neurogenesis is the developmental process regulating cell proliferation of neural stem cells, determining their differentiation into glial and neuronal cells, and orchestrating their organization into finely regulated functional networks. Can this complex process be recapitulated in vitro using induced pluripotent stem cell (iPSC) technology? Can neurodevelopmental and neurodegenerative diseases be modeled using iPSCs? What is the potential of iPSC technology in neurobiology? What are the recent advances in the field of neurological diseases? Since the applications of iPSCs in neurobiology are based on the capacity to regulate in vitro differentiation of human iPSCs into different neuronal subtypes and glial cells, and the possibility of obtaining iPSC-derived neurons and glial cells is based on and hindered by our poor understanding of human embryonic development, we reviewed current knowledge on in vitro neural differentiation from a developmental and cellular biology perspective. We highlight the importance to further advance our understanding on the mechanisms controlling in vivo neurogenesis in order to efficiently guide neurogenesis in vitro for cell modeling and therapeutical applications of iPSCs technology.     

Using computational models to discover and understand mechanisms

Areas of biology such as cell and molecular biology have been dominated by research directed at constructing mechanistic explanations that identify parts and operations that when organized appropriately are responsible for the various phenomena they investigate. Increasingly the mechanisms hypothesized involve non-sequential organization of non-linear operations and so exceed the ability of researchers to mentally rehearse their behavior. Accordingly, scientists rely on tools of computational modeling and dynamical systems theory in advancing dynamic mechanistic explanations. Using circadian rhythm research as an exemplar, this paper explores the variety of roles computational modeling is playing. They serve not just to determine whether the mechanism will produce the desired behavior, but in the discovery process of hypothesizing mechanisms and in understanding why proposed mechanisms behave as they do.     

Phase-dependent shift of free-running human circadian rhythms in response to a single bright light pulse

Responsiveness of free-running human circadian rhythms to a single pulse of bright light was examined in a temporal isolation unit. Bright light (5000 lx) of either 3 or 6 h duration, applied during the early subjective day, produced phase-advance shifts in both the sleep-wake cycle and the rhythm of rectal temperature; the light pulse had essentially no effect on the phase of the circadian rhythms, when it was introduced during the late subjective day or the early subjective night. The results indicate that bright light can reset the human circadian pacemaker.     

Internal interactions within the human circadian system: the masking effect

In the realm of human circadian rhythms, the masking effect is defined as the change in the course of deep body temperature induced by changes in the degree of physical activity, or by the alteration between sleep and wake. This effect is particularly obvious during internal desynchronization where the rhythms of deep body temperature, and the sleep-wake sleep cycle - i.e. one of the masking factors - run with different periods. Every sleep onset is accompanied by a rapid drop, and wake onset by a rapid rise in deep body temperature, each one with an overshoot of about 50% of the steady state variations. When rhythms are calculated, with the dominant temperature period as the screening period, exclusively from data obtained during sleep episodes, on the one hand, and from those obtained exclusively during wake, on the other, two average cycles emerge: the 'sleep temperature curve' and the 'wake temperature curve'. Both run in parallel but are separated by the 'masking effect'. As derived from many experiments, the mean masking effect amounts to 0.28 +/- 0.06 degree C. The masking effect also depends to some extent on the phase of the temperature rhythm; it is larger than average around the temperature maximum and during the descending phase of the temperature cycle, where the alertness commonly is highest and the probability to sleep, in general, and the REM sleep propensity, in particular, are smaller than average. This also can be interpreted to indicate that the sleep temperature curve is phase advanced relative to the wake temperature curve; this, on the average, by 0.9 +/- 0.3 h. If the individually determined amount of masking is added to the temperature data obtained during sleep, or subtracted from the temperature data obtained during wake, a temperature curve emerges that can be thought of as being 'purified' of the masking effect. Analyses of this artificial curve allow estimation of that part of the internal interactions uninfluenced by the masking effect. On the average, about half of the amount of interaction between the rhythm of sleep-wake and that of deep body temperature is explained by the masking effect, whereas the other half is 'oscillatory interaction'. Both types of interaction are inherent and inseparable parts of the circadian clock mechanism, as can be deduced from model considerations.     

Phosphoinositides and Charcot-Marie-Tooth disease: New keys to old questions

Recent research into the genetic basis and the molecular disease mechanisms of Charcot-Marie-Tooth disease (CMT), also called hereditary motor and sensory neuropathies, has highlighted phosphoinositides, membrane-tethered phosphorylated metabolites of phosphatidylinositol, as key regulatory molecules in peripheral nerves in health and disease. Enzymes that dephosphorylate the endosomal phosphoinositides phosphatidylinositol-3-phosphate and/or phosphatidylinositol-3,5-biphosphate, and proteins with binding domains for these phosphoinositides, are mutated in subtypes of CMT. A hypothetical picture emerges suggesting that the precise regulation of phosphoinositide levels within neural cells, a process in turn critical for the correct dynamics of proteins binding to phosphoinositides, is a crucial bottleneck for the accurate function of myelinated peripheral nerves in both neurons and Schwann cells. The underlying molecular and cellular mechanisms are largely unknown. Some hypotheses are discussed in this essay.     

Effects of vitamin B12 on plasma melatonin rhythm in humans: Increased light sensitivity phase-advances the circadian clock?

Vitamin B12 (methylcobalamine) was administered orally (3 mg/day) to 9 healthy subjects for 4 weeks. Nocturnal melatonin levels after exposure to bright light (ca. 2500 lx) were determined, as well as the levels of plasma melatonin over 24 h. The timing of sleep was also recorded. Vitamin B12 was given blind to the subjects and crossed over with placebo. We found that the 24-h melatlonin rhythm was significantly phase-advanced (1.1. h) in the vitamin B12 trial as compared with that in the placebo trial. In addition, the 24-h mean of plasma melatonin level was much lower in the vitamin B12 traial than with the placebo. Furthermore, the nocturnal melatonin levels during bright light exposure were significantly lower in the vitamin B12 trial than with the placebo. On the other hand, vitamin B12 did not affect the timing of sleep. These findings raise the possibility that vitamin B12 phase-advances the human circadian rhythm by increasing the light sensitivity of the circadian clock.     

Rhythms of enzymatic activity in maternal and umbilical cord blood

The 24-h activity patterns of variouns enzymes were determined in human serum, red blood cells and white blood cells of maternal and umbilical cord blood. Blood was drawn from the brachial vein of mothers and from the umbilical cord within ten minutes after delivery. Corresponding blood specimens were obtained from 83 spontaneous labors, occurring at different hours over a period of 60 days. For each variable (variable=activity of a specific enzyme in one of the blood components) the results were grouped according to delivery hour, forming a 24-h pattern which was analyzed to elucidate time dependency. Five out of six corresponding maternal and fetal variables were similar with regard to pattern and peak time. The activity rhythms of glyceraldehyde-3-phosphate dehydrogenase and glucose phosphate isomerase in red blood cells of mothers and fetuses possessed a significant bimodal pattern. The activity rhythms of the latter enzyme in white blood cells and sera exhibited a significant 24-h period. Hexosaminidase activity exhibited a distinct 24-h rhythm in maternal white blood cells, but no significant rhythm could be detected in the fetal white blood cells. The activity of hexosaminidase showed, identical 24-h patterns in maternal and cord serum when analyzed by best fit cosine, and no significant time-dependency when analyzed by ANOVA.     

Comparative ultrastructural and cytochemical analysis of the cephalopod systemic heart and its innervation

Summary The present knowledge of the morphology of cephalopod central hearts is presented. The cytological characteristics of the epicardial, myocardial and endothelial tissue layers are reviewed. Myocardial cells are characterized as obliquely striated myocytes with a high level of oxidative metabolism. The voluminous myocardium is intensively penetrated by nerve fibers controlling the myogenic heart rhythm by different chemical transmitter systems. Catecholaminergic fluorophores and acetylcholinesterase activity could be localized by means of histochemical and cytochemical investigations. A glio-interstitial cell system is shown to be present in connection with nerve fibers and also uncombined between heart muscle cells. Its content of large different-sized inclusions is described and their function discussed.     

支持向量机在围岩变形监测中的应用

根据支特向量机优越的非线性拟合性能,建立变形量的时间序列预测模型,滚动预测围岩变形量,提高了预测模型的训练速度和预测推广能力。该方法用于西乡-固戍盾构段围岩变形预测,并与BP神经网络预测进行比较。结果表明这种模型可预测区间较长且具有较高的准确度,能够科学地指导现场施工和监测。     

Robustness of signal transduction pathways

Signal transduction pathways transduce information about the outside of the cell to the nucleus, regulating gene expression and cell fate. To reliably inform the cell about its surroundings, information transfer has to be robust against typical perturbation that a cell experiences. Robustness of several mammalian signaling pathways has been studied recently by quantitative experimentation and using mathematical modeling. Here, we review these studies, and describe the emerging concepts of robustness and the underlying mechanisms.     

Von der Mathematik der nervösen Ordnungsleistung

Summary An exact analysis of the coordination of movements in arthropods and vertebrates leads to the rejection of older explanations in terms of reflex physiology and to a dynamic conception of the process in the central nervous system, which admits of representation by a physical model (as well as of a mathematical formulation). This conception carries with it the implication that locomotion is caused by automatic elements that work in the rhythm of locomotion and are prior to the motor elements.This view stands in close relation to the physiology of the nervous system and to Gestalt psychology.     

What does interdisciplinarity look like in practice: Mapping interdisciplinarity and its limits in the environmental sciences

In this paper we take a close look at current interdisciplinary modeling practices in the environmental sciences, and suggest that closer attention needs to be paid to the nature of scientific practices when investigating and planning interdisciplinarity. While interdisciplinarity is often portrayed as a medium of novel and transformative methodological work, current modeling strategies in the environmental sciences are conservative, avoiding methodological conflict, while confining interdisciplinary interactions to a relatively small set of pre-existing modeling frameworks and strategies (a process we call crystallization). We argue that such practices can be rationalized as responses in part to cognitive constraints which restrict interdisciplinary work. We identify four salient integrative modeling strategies in environmental sciences, and argue that this crystallization, while contradicting somewhat the novel goals many have for interdisciplinarity, makes sense when considered in the light of common disciplinary practices and cognitive constraints. These results provide cause to rethink in more concrete methodological terms what interdisciplinarity amounts to, and what kinds of interdisciplinarity are obtainable in the environmental sciences and elsewhere.     

The emergence of objectivity: Fleck,Foucault, Kuhn and Hacking

The analytical notions of ‘thought style’, ‘paradigm’, ‘episteme’ and ‘style of reasoning’ are some of the most popular frameworks in the history and philosophy of science. Although their proponents, Ludwik Fleck, Thomas Kuhn, Michel Foucault, and Ian Hacking, are all part of the same philosophical tradition that closely connects history and philosophy, the extent to which they share similar assumptions and objectives is still under debate. In the first part of the paper, I shall argue that, despite the fact that these four thinkers disagree on certain assumptions, their frameworks have the same explanatory goal – to understand how objectivity is possible. I shall present this goal as a necessary element of a common project -- that of historicising Kant's a priori. In the second part of the paper, I shall make an instrumental use of the insights of these four thinkers to form a new model for studying objectivity. I shall also propose a layered diagram that allows the differences between the frameworks to be mapped, while acknowledging their similarities. This diagram will show that the frameworks of style of reasoning and episteme illuminate conditions of possibility that lie at a deeper level than those considered by thought styles and paradigms.     

Endothelial nitric oxide synthase: insight into cell-specific gene regulation in the vascular endothelium

The vascular endothelium plays a crucial role in regulating normal blood vessel physiology. The gene products responsible are commonly expressed exclusively, or preferentially, in this cell type. However, despite the importance of regulated gene expression in the vascular endothelium, relatively little is known about the mechanisms that restrict endothelial-specific gene expression to this cell type. While significant progress has been made towards understanding the regulation of endothelial genes through cis/trans paradigms, it has become apparent that additional mechanisms must also be operative. For example, chromatin-based mechanisms, including cell-specific DNA methylation patterns and post-translational histone modifications, have recently been demonstrated to play important roles in the cell-specific expression of endothelial nitric oxide synthase (eNOS). This review investigates the involvement of epigenetic regulatory mechanisms in vascular endothelial cell-specific gene expression using eNOS as a prototypical model, and will address the possible contributions of these pathways to diseases of the vasculature. Received 13 September 2005; received after revision 13 October 2005; accepted 19 October 2005     

Switching among functional states by means of neuromodulators in the lobster stomatogastric ganglion

Summary The lobster stomatogastric ganglion contains the central pattern generators (CPGs) for the pyloric and gastric mill rhythms. All of the neurons and their synaptic connections have been identified for each rhythm and serve as the basis for understanding the mechanisms by which chemical neuromodulators are able to alter the functional state of each CPG. Using examples of different amines and peptides, I show how these substances can be found within specific neurons and how their application to the CPG can alter the motor patterns in specific ways. I also discuss what changes in cellular and synaptic properties occur as a result of bath application and particularly in the case of proctolin, how these changes may have behavioral correlates. The various outputs appear to be the result of a functional rewiring of anatomically defined neural circuits and this may be a widespread mechanism for the production of closely-linked but behaviorally distinct movement patterns.     

Asymmetric cell division of stem and progenitor cells during homeostasis and cancer

Stem and progenitor cells are characterized by their ability to self-renew and produce differentiated progeny. A fine balance between these processes is achieved through controlled asymmetric divisions and is necessary to generate cellular diversity during development and to maintain adult tissue homeostasis. Disruption of this balance may result in premature depletion of the stem/progenitor cell pool, or abnormal growth. In many tissues, including the brain, dysregulated asymmetric divisions are associated with cancer. Whether there is a causal relationship between asymmetric cell division defects and cancer initiation is as yet not known. Here, we review the cellular and molecular mechanisms that regulate asymmetric cell divisions in the neural lineage and discuss the potential connections between this regulatory machinery and cancer.