Modeling of biological doses and mechanical effects on bone transduction

Shear stress, hormones like parathyroid and mineral elements like calcium mediate the amplitude of stimulus signal, which affects the rate of bone remodeling. The current study investigates the theoretical effects of different metabolic doses in stimulus signal level on bone. The model was built considering the osteocyte as the sensing center mediated by coupled mechanical shear stress and some biological factors. The proposed enhanced model was developed based on previously published works dealing with different aspects of bone transduction. It describes the effects of physiological doses variations of calcium, parathyroid hormone, nitric oxide and prostaglandin E2 on the stimulus level sensed by osteocytes in response to applied shear stress generated by interstitial fluid flow. We retained the metabolic factors (parathyroid hormone, nitric oxide and prostaglandin E2) as parameters of bone cell mechanosensitivity because stimulation/inhibition of induced pathways stimulates osteogenic response in vivo. We then tested the model response in terms of stimulus signal variation versus the biological factors doses to external mechanical stimuli. Despite the limitations of the model, it is consistent and has physiological bases. Biological inputs are histologically measurable. This makes the model amenable to experimental verification.     

Studies on the mechanism of follitropin action at the cellular level

With a view toward understanding better the mechanism of action of follitropin, an attempt was made using granulosa cells obtained from intact immature estrogenized rats to study in short-term incubations the effect of highly purified ovine follitropin on the binding of the hormone to the cells and the associated aromatase response. A modified radioimmunoassay procedure has been used to monitor unlabeled physiologically fully active follitropin bound to the cell. A linear relationship between the actual amount of hormone bound to the cells and the estradiol produced in vitro has been established. The amount of ovine follitropin bound that can elicit a half-maximal response in estrogen production was calculated to be 400 pg. The number of follitropin binding sites per cell was 375 and the K_d of binding was 3.03 × 10^?10m. By the addition of ovine follitropin antiserum at different time points of a 4-h incubation period, a continual need for follitropin support for estradiol production has been established.     

A novel mathematical model of bone remodelling cycles for trabecular bone at the cellular level

After an initial phase of growth and development, bone undergoes a continuous cycle of repair, renewal and optimisation by a process called remodelling. This paper describes a novel mathematical model of the trabecular bone remodelling cycle. It is essentially formulated to simulate a remodelling event at a fixed position in the bone, integrating bone removal by osteoclasts and formation by osteoblasts. The model is developed to construct the variation in bone thickness at a particular point during the remodelling event, derived from standard bone histomorphometric analyses. The novelties of the approach are the adoption of a predator-prey model to describe the dynamic interaction between osteoclasts and osteoblasts, using a genetic algorithm-based solution; quantitative reconstruction of the bone remodelling cycle; and the introduction of a feedback mechanism in the bone formation activity to co-regulate bone thickness. The application of the model is first demonstrated by using experimental data recorded for normal (healthy) bone remodelling to predict the temporal variation in the number of osteoblasts and osteoclasts. The simulated histomorphometric data and remodelling cycle characteristics compare well with the specified input data. Sensitivity studies then reveal how variations in the model's parameters affect its output; it is hoped that these parameters can be linked to specific biochemical factors in the future. Two sample pathological conditions, hypothyroidism and primary hyperparathyroidism, are examined to demonstrate how the model could be applied more broadly, and, for the first time, the osteoblast and osteoclast populations are predicted for these conditions. Further data are required to fully validate the model's predictive capacity, but this work shows it has potential, especially in the modelling of pathological conditions and the optimisation of the treatment of those conditions.     

A theoretical study of bone remodelling under PEMF at cellular level

Pulsed electromagnetic field (PEMF) devices have been used clinically to slow down osteoporosis and accelerate the healing of bone fractures for many years. However, the underlying mechanism by which bone remodelling under PEMF is regulated remains poorly understood. In this paper, a mathematical model of bone cell population of bone remodelling under PEMF at cellular level is developed to address this issue for the first time. On the basis of this model and control theory, parametric study of control mechanisms is carried out and a number of possible control mechanisms are identified. These findings will help further the understanding of bone remodelling under PEMF and advance therapies and pharmacological developments in clinical trials.     

A theoretical study of bone remodelling under PEMF at cellular level

Pulsed electromagnetic field (PEMF) devices have been used clinically to slow down osteoporosis and accelerate the healing of bone fractures for many years. However, the underlying mechanism by which bone remodelling under PEMF is regulated remains poorly understood. In this paper, a mathematical model of bone cell population of bone remodelling under PEMF at cellular level is developed to address this issue for the first time. On the basis of this model and control theory, parametric study of control mechanisms is carried out and a number of possible control mechanisms are identified. These findings will help further the understanding of bone remodelling under PEMF and advance therapies and pharmacological developments in clinical trials.     

Studies on mechano-perception in the Characeae: transduction of pressure signals into electrical signals

Mechano-perception by Chara cells was studied with an emphasis on the role of the nodal complex in transducing pressure signals into electrical signals. Three types of experimental material were used: (1) tandem internodal cells connected by a single layer of nodal cells; (2) single internodal cells, from which either apical or basal nodes were removed by ligation and cutting; (3) single internodes from which both nodes had been removed. Exposure to a hypertonic solution (sorbitol or sucrose) induced a depolarization at the node in 1 and 2. Depolarization did not occur at the ligated end of the cell in 2, or at all in 3. Addition of K+ increased the magnitude of the response, whilst it was significantly decreased by the divalent cations, Ca2+ and Mg2+. Electrical resistance decreased at the node during the depolarization, showing that a passive diffusion potential was responsible. I suggest that the change in the trans-nodal hydraulic pressure difference mechanically stretches the plasma membrane, and this induces the electrical depolarization.     

The biology of breast cancer at the cellular level

Two properties seem fundamental to cancer; heterogeneity and progression (Foulds (1975) Academic Press, New York; Heppner et al. (1979) Commentaries on Research in Breast Disease, Vol. 1 (Bulbrook, R. and Taylor, D.J., eds.), pp. 177-191, Plenum Press, New York). Relatively little is understood about the premalignant stages of human breast disease in vivo. When the disease manifests as invasive carcinoma, its behavior exhibits great diversity, sometimes metastasizing rapidly, while in other cases 10-30 years pass before metastases proliferate. Here we review various aspects of breast cancer in vivo and consider how they predict properties of breast cancer found in culture. All of the experiments are consistent with the hypothesis proposed by Nowell (1976) Science 194, 23-28, that a fundamental aspect of malignancy is an increased genetic instability and that many of the cells within tumors are nonviable results of genetic instability. We suggest that most of the viable cells within primary breast carcinomas are diploid and are not yet capable of aspects of metastatic spread. What these cells have attained is an increased propensity for genetic instability which enables them to generate randomly aneuploid but frequently lethal genetic configurations. Occasionally one of these altered genomes is associated with the ability to proliferate at a metastatic site. This hypothesis implies that metastases from various patients may have arisen by divergent pathways and may also be divergent in many other aspects of their physiology, unrelated to malignancy. Such extreme heterogeneity may hamper attempts to understand fundamental aspects of malignancy. Hence we suggest that the less anaplastic and less divergent diploid cells within the primary carcinomas might be an important resource to gain insights into the critical alterations that are responsible for initiating frankly malignant behavior.     

细胞质内信号分子的核转位及其机制

细胞外信号通过受体及细胞内信号转导引起细胞生长,增殖,分化,凋亡等细胞核反应。进入细胞质内的信号分子及其活化产物必须经过细胞核膜上的核孔复合体（ＮＰＣ）,在核定位信号的介导下,由特异性的载体转运入核,该过程涉及小分子的ＧＴＰａｓｅ Ｒａｎ蛋白及多种可溶性因子。本文简要综述细胞质内信号分子通过核膜向细胞核内转运的过程及其调控机制。     

Baroreceptor mechanisms at the cellular level

Nothing is known of transduction mechanisms of baroreceptors in vivo. Not even the site of transduction is known. However, there are mechanotransducer ion channels that provide a useful model system of transduction. In these channels, transduction is accomplished by a strain-dependent increase in the probability of being open. Membrane tension is coupled to the channel by cytoskeletal strands that concentrate the strain energy from a large (approximately equal to 4000 A diameter) area of membrane and thereby provide high sensitivity. The channel is fast and does not inactivate, but viscoelastic coupling to the channel can dramatically alter the transfer function.     

Thyroid hormone action at the cellular level

Thyroid hormones influence numerous physiological and biochemical functions. The expression of the hormonal effects involves several events. The interaction of T3 with nuclear receptors, and the stimulation of mRNA production appears to be a major step. Extranuclear binding of thyroid hormones could account for early responses. Plasma membrane receptors may play a role in the cellular uptake of T3 and the stimulation of amino acids and sugar transport. A direct control of oxidative phosphorylation through binding of T3 to mitochondrial binding sites has been proposed. The role of cytosolic binding proteins remains unclear. The understanding of the mode of action of thyroid hormones requires a better knowledge of the molecular events occurring at the nuclear level, and the relation between the nuclear and extranuclear binding sites in the hormonal expression.     

Cardiac mechanics at the cellular level.

The active mechanical properties of heart muscle are load, length, and time-dependent. The capability for investigating cardiac mechanisms at the cellular level may help to distinguish between those properties of the myocardium which arise from myocardial cells and those which arise from the tissue architecture and extracellular matrix of connective fibers. We present here, for the first time, a general approach for subjecting single heart cells to isometric, isotonic, afterloaded, or physiological loading sequences, while obtaining on-line measures of cell force and length. This approach has been implemented and tested on freshly dissociated, adult frog ventricular myocytes. Examples are presented for each of the four loading sequences.     

The origin of nematode sperm: Progenesis at the cellular level

Analysis of the development and structure of aberrant sperm of nematodes and other metazoans with internal insemination showed that these spermatozoa have several unusual, but shared features: (1) the absence of a flagellum and an axoneme, an unusual arrangement of centrioles; (2) an amoeboid shape and amoeboid motility due to cytoskeleton components; (3) the poor condensation of nuclear chromatin, which may be diffuse, thread-like, and discrete; (4) the absence of a nuclear envelope; (5) multiple unmodified mitochondria; (6) the absence of an acrosome; (7) unique membranous components derived from the Golgi complex; and (8) the large size of spermatozoa due to prominent cytoplasm filled with a great number of components. These shared features of aberrant spermatozoa may be explained by the conservation of a number of features that are characteristic of the primitive undifferentiated cell (the predecessor of all specialized gametes). The primitive cell features of numerous versions of aberrant sperm reflect the arrest of cytoplasm specialization of male gametes at an early stage of development. This pattern of gamete evolution is quite consistent with the conception of progenesis (retention of juvenile characters by precocious, sexually mature morphologically juvenile stage). Thus, the origin of the aberrant sperm of nematodes and many other metazoans may be interpreted as progenesis at the cellular level.