bluuebunny/crossref_metadata_2025 huggingface dataset:
The Generation of Hyperbaric Oxygen Tensions in Fish
Authors: Pelster Bernd
Published: December 2017

Surprising inventiveness in the molecular interactions in fish hemoglobins that express the Root effect (decreased oxygen-carrying capacity at low pH) and in metabolic adaptations in swim bladder gas gland cells and retinal tissues causes local acidification of blood and generates hyperbaric oxygen tensions that drive oxygen into the swim bladder (regulating buoyancy) and ensures the oxygen supply to the avascularized retinae.
Muscle Fatigue: Lactic Acid or Inorganic Phosphate the Major Cause?
Authors: Westerblad Håkan , Allen David G. , Lännergren Jan
Published: December 2017

Intracellular acidosis due mainly to lactic acid accumulation has been regarded as the most important cause of skeletal muscle fatigue. Recent studies on mammalian muscle, however, show little direct effect of acidosis on muscle function at physiological temperatures. Instead, inorganic phosphate, which increases during fatigue due to breakdown of creatine phosphate, appears to be a major cause of muscle fatigue.
Thrombopoietin: The Novel Hepatic Hormone
Authors: Wolber Eva-Maria , Jelkmann Wolfgang
Published: December 2017

The glycoprotein thrombopoietin (TPO) is the major stimulator of megakaryopoiesis and platelet production. Hepatocytes express TPO mRNA at a constant rate. The plasma TPO level is inversely correlated to the mass of megakaryocytes and platelets, which degrade the hormone following its binding to specific membrane receptors.
The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)
Authors: Santos Robson Augusto Souza , Sampaio Walkyria Oliveira , Alzamora Andreia C. , Motta-Santos Daisy , Alenina Natalia , Bader Michael , Campagnole-Santos Maria Jose
Published: December 2017

The renin-angiotensin system (RAS) is a key player in the control of the cardiovascular system and hydroelectrolyte balance, with an influence on organs and functions throughout the body. The classical view of this system saw it as a sequence of many enzymatic steps that culminate in the production of a single biologically active metabolite, the octapeptide angiotensin (ANG) II, by the angiotensin converting enzyme (ACE). The past two decades have revealed new functions for some of the intermediate products, beyond their roles as substrates along the classical route. They may be processed in alternative ways by enzymes such as the ACE homolog ACE2. One effect is to establish a second axis through ACE2/ANG-(1–7)/MAS, whose end point is the metabolite ANG-(1–7). ACE2 and other enzymes can form ANG-(1–7) directly or indirectly from either the decapeptide ANG I or from ANG II. In many cases, this second axis appears to counteract or modulate the effects of the classical axis. ANG-(1–7) itself acts on the receptor MAS to influence a range of mechanisms in the heart, kidney, brain, and other tissues. This review highlights the current knowledge about the roles of ANG-(1–7) in physiology and disease, with particular emphasis on the brain.
Deglutition: Pharyngeal Stage
Authors: Bosma James F.
Published: December 2017

James F. Bosma, “Deglutition: Pharyngeal Stage”

Page 289: line 32, should read: “… and respiration share the pharynx as a common portal, without a separate spout …”
Blood Volume
Authors: Gregersen Magnus I. , Rawson Ruth A.
Published: December 2017

M. I. Gregersen and Ruth A. Rawson, “Blood Volume”

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Page 327, line 28, should read: “Percentage fat = 1OO − (% water/0.73)”

Page 327, line 33, should read: “Fat-free body weight = A + 0.563 (A − E)”

Page 327, line 34, should read: “...where A = antipyrine space and E = 0.7 x thiocyanate space.”
Dimensional analysis and theory of biological similarity
Authors: Gunther B.
Published: December 2017

From this review we conclude the following: 1) The body weight of an organism is an adequate reference index for the correlation of morphological and physiological characteristics. In comparative physiology, body weight can be recommended as a unifying frame of reference, particularly if the ponderal scale includes several decades, in order to apply logarithmic scales for the variables involved. (See article). 2) The statistical analysis of the experimental data can be represented conveniently by means of the logarithmic equivalent of Huxley's allometric equation (y = a-Wb), which is the most simple and at the same time the most versatile mathematical expression for intra- or interspecies comparisons. The exponents (b) for the allometric equations can be predicted for all biological variables definable in terms of the MLT system of physics (M = mass, L = length, T = time) or of a four-dimensional system MLTt where t = temperature. 3) By means of dimensional analysis and the theory of biological similarity a range of similarity criteria can be established: a) mechanical or dynamic similarity, b) kinematic or biological similarity; and c) hydrodynamic or transport similarity. Most functions obey the so-called biological (kinematic) similarity, particularly when the concept of operational time is introduced into Lambert-Teissier's original theory. 4) A satisfactory correlation (r = 0.99) for 80 empirical allometric exponents (b) describing morphological and physiological characteristics of living beings was found. These results are discussed in relation to Rosen's optimality principles in biology. 5) Organisms should be considered as mixed regimes. This means that no single similarity criterion can predict the allometric exponent (b) of all functions that dimensionally belong to MLT or MLTt systems, despite the fact that in the great majority of cases kinematic similarity will satisfactorily predict the reduced exponent (b). Nevertheless, in some instances mechanical (dynamic) similarity must be applied, and in other circumstances hydrodynamic (transport) similarity. 6) Cellular or molecular levels are not in the domain of the present theory, since neither cell dimensions nor molecular processes (viz., blood viscosity, diffusion capacity) can be predicted by biological similarity criteria.
Control of acetylcholine receptors in skeletal muscle
Authors: Fambrough D. M.
Published: December 2017

An ACh receptor is the molecular entity that, in its native habitat, possesses the binding sites for ACh and all the other components required to generate the ion channels mediating the ACh response. Narrower definitions of an ACh receptor (as the binding site for ACh or the polypeptide chain that is folded to form the binding site) could lead to semantic arguments about receptor structure. Experimentally, ACh receptors are defined by their total function (when electrophysiological tests are used) or by ligand binding. There is no evidence that the ligand-binding portions of ACh receptors ever exist in vivo without the associated channel-forming mechanism and vice versa. Most data are consistent with the idea that detergent-solubilized glycoproteins retaining the ACh binding sites of the receptor also include the channel-forming components, although it appears that the mechanism is prone to denaturation or proteolytic damage. Studies of receptor-rich membranes and of solubilized receptor glycoprotein have not yet yielded a totally satisfactory image of receptor structure. Most evidence favors an ACh receptor composed of three or four different types of glycosylated polypeptide chains organized into a unit of aggregate molecular weight about 300,000--400,000 daltons. Plasma membranes are dynamic structures in two different ways. First, their constituent molecules are in rapid thermal motion and, when these molecules are not tethered to extramembranous structures or mired in large aggregates, they fairly rapidly change their position in the plane of the lipid bilayer. Second, all membrane components are continually being synthesized and degraded. Acetylcholine receptors participate in both aspects of this dynamism. In this review it is proposed that the number and the distribution of ACh receptors in skeletal muscle are controlled by modulation of receptor metabolism and modulation of associations between receptor molecules or between receptors and other, as yet unidentified, elements in neuromuscular junctions and at extrajunctional sites where receptors are clustered. The arrangements of receptors in skeletal muscle and the total number of receptors in skeletal muscle may be regulated by separate mechanisms. Clusters of ACh receptors apparently can form spontaneously in extrajunctional areas of denervated muscles and in tissue-cultured embryonic muscle. Such clusters may be positionally stable and the receptor molecules in them may be highly restricted in mobility. Nevertheless, these receptors have average lifetimes on the order of 20 h, just like the nonclustered, mobile extrajunctional receptors. Receptor clusters also form at sites of innervation. In the chick embryo the junctional receptor molecules remain short-lived. The metabolism of ACh receptors is highly regulated. The biosynthesis of receptors commences during myogenesis at about the time myogenic cells become competent to fuse. Later, biosynthesis is dramatically repressed by muscle activity and possibly by other factors...
Hepatic bile flow
Authors: Strange R. C.
Published: December 2017

The hepatocyte is a polar cell that can remove a variety of molecules from blood and excrete them into bile. This review is primarily concerned with the mechanism of transport of the principal anions--the bile salts--across the sinusoidal membrane, their passage through the cell, and excretion across the canalicular membrane. Clearly much of this process is poorly understood, but the study of the membrane stages should be facilitated by the ability to prepare purified sinusoidal and canalicular membrane vesicles. For example, the relative importance of albumin-binding sites as well as the putative bile salt receptor proteins can be better assessed. It seems likely that although the interaction of bile salts with receptor proteins is important, it is an initial event that puts the bile salt in the correct place for uptake to occur. The driving force for uptake is the Na+ gradient created across the basolateral membrane by the activity of the Na+-K+-ATPase. Within the cell, various modes of transport have been suggested. Several authors emphasize the importance of protein binding of bile salts, either because of their presumed ability to maintain the concentration of these anions in the hepatocyte below their critical micellar concentration or because of their putative role in transport. It is important to understand these aspects of the role of cytosolic proteins for several reasons. Knowledge of the true concentration of free bile salt within the cell should allow estimation of whether the electrochemical gradient is sufficient for bile salts to accumulate in bile without the need for active transport of molecules from the cell into the canaliculus. The compartmental model described by Strange et al. (153) offers one theoretical way of determining the concentration of free bile salt, although the problems inherent in studying amphipath binding to the membranes of subcellular organelles (31) require that the model be reevaluated by the hygroscopic-desorption method. The second role suggested for the cytosolic bile salt-binding proteins is as transport proteins. As discussed in section VI, I think it is unlikely that the proteins identified so far act in this way, and it is more likely that movement occurs by diffusion in free solution. It is also important to determine the possible involvement of subcellular organelles such as Golgi bodies. Little is known of their role in the transport of bile salts or indeed where bile salt micelles are formed.(ABSTRACT TRUNCATED AT 400 WORDS)
Translation of sensory signals into commands for control of saccadic eye movements: role of primate superior colliculus
Authors: Sparks D. L.
Published: December 2017

Afferent signals that guide orienting movements converge in the deeper layers of the SC in a wide variety of animals. The sensory cells are arranged topographically according to their receptive-field locations and, thereby, form maps of sensory space. Maps of visual, somatosensory, and/or auditory space have been obtained in the iguana, mouse, hamster, barn owl, chinchilla, cat, and monkey. The deeper layers of the SC also contain neurons involved in the generation of movements of the eyes, head, vibrissae, and pinnae. Thus the SC, a site containing multiple sensory maps and perhaps multiple motor maps, has been selected by many investigators as a structure for investigating the problem of sensorimotor integration. In the mammalian nervous system, emphasized in this review, much remains to be learned about the structure, organization, and function of the SC. While anatomical studies continue to add to the knowledge of the sources of afferent projections, their pattern of laminar termination, and the source and destination of efferent projections, relatively little is known about the intrinsic organization of the colliculus, especially the deeper layers. Recently, electrophysiological studies have moved from an emphasis on the sensory and motor properties of collicular neurons to an examination of the maps of auditory and somatosensory space and the correspondence of these maps. In the future, major efforts aimed at identifying the functional properties of cells that project to the SC from diverse brain regions as well as the functional properties that project to the various structures receiving input from the colliculus are needed. A combination of anatomical and electrophysiological methods is required to describe the signal transforms that occur between the SC and motor areas (such as the paramedian pontine reticular formation) closer to the final common pathway. Conceptual and empirical work is needed to develop and test models of how the dynamic visual and auditory maps found in the primate SC are generated. In general, new and/or improved models of the role of the SC in sensorimotor integration are needed as guides for future research. A point of view emphasized here is that it may be fruitful to examine the function of the SC from a motor perspective. The nature of the motor command imposes constraints on the configuration of signals that can initiate movements and thereby determines the required transformation of sensory signals.
Characteristics and regulatory mechanisms of the amiloride-blockable Na+ channel
Authors: Garty H. , Benos D. J.
Published: December 2017

Studies of active Na+ transport across intact amphibian skin and bladder epithelia and, more recently, epithelial cells in culture have served as prototypes for understanding transport function in other experimentally less accessible epithelia such as renal tubules, lung, and sweat glands. Epithelia of diverse phylogenetic origin contain amiloride-blockable Na+ channels that are undoubtedly involved in the regulation of transepithelial Na+ transport and electrolyte homeostasis. With the advent of the techniques of tissue culture, patch clamp, isotope flux measurements in native vesicles and liposomes, and planar lipid bilayer reconstitution, it has now become possible for the first time to explore the functional operation and regulation of this widespread and important transport protein at the molecular level. Epithelial transport physiology has now reached a point where investigators can embark on studies concerning the cellular and molecular biology of epithelial Na+ channels. In our opinion, concentrated experimental efforts should be directed in three general areas. First, detailed kinetic information concerning the molecular mechanisms of Na+ movement through this channel is required. For example, it is necessary to elucidate the nature (i.e., site and location) of channel block by amiloride and structurally related compounds, the structural determinants of its ion selectivity, the voltage dependence of amiloride and ion blockage, and the minimal number of polypeptide subunits required for channel activity. The second area of study concerns the nature of the regulation of this ion channel. What are the mechanisms of channel regulation and, specifically, how does cAMP and aldosterone activate or recruit these Na+ channels? Does regulation occur at the level of channel synthesis, through posttranslational modifications, or via noncovalent interactions with small molecules or peptides? Third, we feel that the isolation and purification of the Na+ channel is important because it will eventually enable investigators to establish the molecular details of ion movement through individual channels, i.e., structural correlates of ion selectivity, binding and blockade by amiloride, and ion flow. The isolation of the Na+ channel will allow the development of molecular probes of the channel protein. These probes will be useful for immunocytochemical localization studies and, ultimately, will lead to sequencing and site-directed mutagenesis studies. Also, questions concerning the homology between Na+ channels found in different tissues and organisms as well as between the different modes of amiloride-sensitive transporters can be addressed.
Relaxation and diastole of the heart
Authors: Brutsaert D. L. , Sys S. U.
Published: December 2017

In the present review, we adopted the viewpoint of the physiologist looking at the global function of the heart, during relaxation and diastole, as an integrated muscle-pump system. We first focused our attention on properties of relaxation and diastole at the subcellular (SR, contractile proteins), cellular, and multicellular scales of cardiac muscle and then at the scale of the ventricle and intact global heart. At each lower scale we derived properties from experimental facts and examined the extent to which these properties could be extrapolated conceptually to the higher scale. From this muscle-pump approach, we learned that a general and fundamental property of relaxation of the heart as a muscle-pump system is load dependence, i.e., the mutually independent behavior of the time patterns of slow force decline and pressure fall and of rapid lengthening and rapid filling. Load dependence is found at all hierarchic scales, irrespective of whether it is examined under strictly isotonic-isometric or isometric-isotonic or auxotonic loading conditions and despite often substantial nonuniformity. Relaxation is governed by the interaction of the loading conditions and the two major determinants of the inactivation process, i.e., Ca2+ reuptake by the SR and the properties of the contractile proteins. Load dependence is the mere mechanical expression of the unequal contribution, during the two phases of relaxation, of these three interacting determinants of relaxation (load, SR, and contractile proteins). During force decline in isolated muscle and pressure fall in the ventricle, the properties of the contractile proteins predominate over load and SR; during muscle lengthening and rapid ventricular filling, load and SR become more important. As the relative importance of the phenomena above is different during pressure fall in comparison to rapid filling, it is not surprising that directional changes in pressure fall may not predict those in filling. We also saw that the overall time pattern of pressure fall in contrast to rapid filling may sometimes be markedly altered, e.g., with simultaneous increases in peak-dP/dt, indicating more rapid early pressure relaxation, and prolonged time constant tau, indicating slower late pressure relaxation, or vice versa. From this muscle-pump approach, it should also be remembered that optimal efficiency of the heart limits the extent to which nonuniformity may exist. At all hierarchic scales, variations in the degree of nonuniformity, however small, constitute an important physiological modulator of performance throughout systole and diastole.(ABSTRACT TRUNCATED AT 400 WORDS)
Pressure-flow relations in coronary circulation
Authors: Hoffman J. I. , Spaan J. A.
Published: December 2017

The blood vessels that run on the surface of the heart and through its muscle are compliant tubes that can be affected by the pressures external to them in at least two ways. If the pressure outside these vessels is higher than the pressure at their downstream ends, the vessels may collapse and become Starling resistors or vascular waterfalls. If this happens, the flow through these vessels depends on their resistance and the pressure drop from their inflow to the pressure around them and is independent of the actual downstream pressure. In the first part of this review, the physics of collapsible tubes is described, and the possible occurrences of vascular waterfalls in the body is evaluated. There is good evidence that waterfall behavior is seen in collateral coronary arteries and in extramural coronary veins, but the evidence that intramural coronary vessels act like vascular waterfalls is inconclusive. There is no doubt that in systole there are high tissue pressures around the intramyocardial vessels, particularly in the subendocardial muscle of the left ventricle. The exact nature and values of the forces that act at the surface of the small intramural vessels, however, are still not known. We are not certain whether radial (compressive) or circumferential and longitudinal (tensile) stresses are the major causes of vascular compression; the role of collagen struts in modifying the reaction of vessel walls to external pressures is unknown but possibly important; direct examination of small subepicardial vessels has failed to show vascular collapse. One of the arguments in favor of intramyocardial vascular waterfalls has been that during a long diastole the flow in the left coronary artery decreases and reaches zero when coronary arterial pressure is still high: it can be as much as 50 mmHg in the autoregulating left coronary arterial bed and approximately 15-20 mmHg even when the vessels have been maximally dilated. These high zero flow pressures, especially during maximal vasodilatation, have been regarded as indicating a high back pressure to flow that is due to waterfall behavior of vessels that are exposed to tissue pressures.(ABSTRACT TRUNCATED AT 400 WORDS)
Developmental mechanisms underlying pathology of arteries
Authors: Schwartz S. M. , Heimark R. L. , Majesky M. W.
Published: December 2017

This review tries to provide a general, and very speculative, view of growth control mechanisms that may be common to the development of blood vessels and to pathological processes including cell proliferation. From a developmental point of view, vascular growth is most likely to include local autocrine or paracrine mechanisms that permit the two cells of the vessel wall to grow, organize into the characteristic tubular and layered structures of the vessel wall, and eventually achieve a return to quiescence. The "real" mechanisms controlling growth in vivo are difficult to ascertain from studies in culture. For example, a large list of angiogenesis molecules must be able to generate endothelial replication, but in culture many of these molecules are inhibitory for each endothelial replication. Similarly, in culture, we have a long list of smooth muscle mitogens, but none of these have as of yet been proven to control smooth muscle growth in vivo. Endothelial growth control has been attributed to the presence of membrane molecules able to inhibit endothelial replication and to the actions of soluble growth factors and their receptors. Unfortunately for the former hypothesis we still lack specific molecules with the properties of contact inhibition of replication. The data discussed here, however, suggest that modulation of expression or function of cell-cell adhesive molecules could be critical both to morphogenic changes and to mitogenesis by release of cells from cell-cell contact. Moreover, our data and data from other laboratories suggest that angiogenic factors, including the HBGFs and TGF-beta, may function in angiogenesis by altering cell-cell and cell-cell substrate interactions rather than via a primary effect on cell replication. This view of angiogenesis is consistent with the absence of a mitogenic effect of some angiogenic factors. Although endothelial cell replication is obviously necessary to angiogenesis, the lack of mitogenic effect of some factors suggests a need for a more general explanation of the actions of angiogenic factors. Endothelial injury may be interrelated with smooth muscle growth. The simplest possibility is that a failure of the endothelial cell barrier function, due either to denudation or an increase in adhesivity for leukocytes, would permit access of platelets or leukocytes to the vessel wall. These extrinsic cells, in turn, would stimulate smooth muscle cell replication by release of growth factors. The second possibility is that the endothelial cell may itself release growth factors into the vessel wall.(ABSTRACT TRUNCATED AT 400 WORDS)
Microlymphatics and lymph flow
Authors: Schmid-Schonbein G. W.
Published: December 2017

A careful review of several different organs shows that with the information available today the beginnings of the microlymphatics in the tissue consist of endothelialized tubes only. Lymphatic smooth muscle within the collecting lymphatics appears further downstream, in some organs only outside the parenchyma. This particular anatomic picture has been observed in many different mammalian organs and in humans. The nonmuscular, so-called initial, lymphatics are the site of interstitial fluid absorption that requires only small and transient pressure gradients from the interstitium into the initial lymphatics. A fundamental question concerns the mechanism that causes expansion and compression of the initial lymphatics. I presented several realistic proposals based on information currently on hand relevant to the tissue surrounding the initial lymphatics. To achieve a continuous lymphatic output, periodic (time variant) tissue stresses need to be applied. They include arterial pressure pulsations; arteriolar vasomotion; intestinal smooth muscle contractions and motilities; skeletal muscle contraction; skin tension; and external compression, such as during walking, running, or massage, respiration, bronchiole constriction, periodic tension in tendon, contraction and relaxation of the diaphragm, tension in the pleural space during respiration, and contractions of the heart. The nonmuscular initial lymphatic system drains into a set of contractile collecting lymphatics, which by way of intrinsic smooth muscle propel lymph fluid. The exact transition between noncontractile and contractile lymphatics has been established only in a limited number of organs and requires further exploration. Retrograde flow of lymph fluid is prevented by valves. There are the usual macroscopic bileaflet valves in the initial and collecting lymphatics and also microscopic lymphatic endothelial valves on the wall of the initial lymphatics. The latter appear to prevent convective reflow into the interstitium during lymphatic compression. Many of the lymph pump mechanisms have been proposed in the past, and most authors agree that these mechanisms influence lymph flow. However, the decisive experiments have not been carried out to establish to what degree these mechanisms are sufficient to explain lymph flow rates in vivo. Because individual organs have different extrinsic pumps at the level of the initial lymphatics, future experiments need to be designed such that each pump mechanism is examined individually so as to make it possible to evaluate the additive effect on the resultant whole organ lymph flow.(ABSTRACT TRUNCATED AT 400 WORDS)
Renal medullary organic osmolytes
Authors: Garcia-Perez A. , Burg M. B.
Published: December 2017

Sorbitol, inositol, GPC, and betaine are the predominant organic osmolytes in renal medullary cells. They protect the cells from harmful effects of the high interstitial NaCl and urea concentrations that occur normally in the renal medulla with operation of the urinary concentrating mechanism. Their levels correlate with extracellular NaCl concentration and, in the case of GPC, also with urea. Sorbitol is synthesized from glucose in a reaction catalyzed by aldose reductase. Inositol and betaine are transported into the cell. Glycerophosphorylcholine synthesis is dependent on choline. The transcription of aldose reductase and the transport of betaine and inositol are regulated, dependent on the degree of hypertonicity. Normal organic osmolyte regulation contributes to the survival and growth of medullary cells in their hyperosmolal environment, and defective regulation can damage them.
Calcium signaling in cell volume regulation
Authors: McCarty N. A. , O'Neil R. G.
Published: December 2017

It is evident from the present analysis that although a role for Ca2+ in controlling hypertonic cell volume regulation and RVI mechanisms has not been shown, Ca2+ plays a central role in activating and controlling hypotonic cell volume regulation and RVD mechanisms in most cells. However, this Ca2+ dependency is highly variable among cell types and tissues. Cells can be grouped into three general categories based on the relative dependency of RVD on Ca2+: 1) cells that are highly dependent on extracellular Ca2+ and the activation of Ca2+ influx, supposedly reflecting activation of Ca2+ channels, such as observed for the renal PST cells and osteosarcoma cells; 2) cells that are not dependent on extracellular Ca2+ and Ca2+ influx but that require at least a certain basal intracellular Ca2+ level or transient release of Ca2+ from internal stores, such as observed for the Ehrlich ascites tumor cells and medullary thick ascending limb cells; and 3) cells that display little if any Ca2+ dependency, such as the lymphocytes. There is initial evidence that this variable dependency of RVD on Ca2+ may reflect, in large part, a variable Ca2+ threshold of RVD processes, although this notion has not been fully investigated. The site and mechanism of Ca2+ dependency of RVD are poorly understood. Initial studies pointed to a possible direct control of K+ and/or Cl- channels by Ca2+ to modulate KCl efflux and, hence, RVD. This view appears to be too simplistic, however, as it is increasingly evident that the ion channels involved in RVD may not be directly Ca2+ dependent and that some other regulatory process controlling the channels, perhaps a phosphorylation step, may be the Ca(2+)-dependent event. Given the added complexity of the time-dependent variability of the action of Ca2+, i.e., the Ca2+ window, coupled with the variability of the RVD mechanisms among cell and tissue types, it is likely that the RVD mechanism is a highly complex process involving events and biochemical pathways throughout the cell rather than events simply localized to the inner face of the plasma membrane. It remains for future studies to determine the exact biochemical events that underly the RVD mechanism and its control, and the Ca2+ dependency of each step, before a full understanding will be attained of the role of Ca2+ in modulating RVD.
Interstitial-lymphatic mechanisms in the control of extracellular fluid volume
Authors: Aukland K. , Reed R. K.
Published: December 2017

While the study of the physiochemical composition and structure of the interstitium on a molecular level is a large and important field in itself, the present review centered mainly on the functional consequences for the control of extracellular fluid volume. As pointed out in section I, a biological monitoring system for the total extracellular volume seems very unlikely because a major part of that volume is made up of multiple, separate, and functionally heterogeneous interstitial compartments. Even less likely is a selective volume control of each of these compartments by the nervous system. Instead, as shown by many studies cited in this review, a local autoregulation of interstitial volume is provided by automatic adjustment of the transcapillary Starling forces and lymph flow. Local vascular control of capillary pressure and surface area, of special importance in orthostasis, has been discussed in several recent reviews and was mentioned only briefly in this article. The gel-like consistency of the interstitium is attributed to glycosaminoglycans, in soft connective tissues mainly hyaluronan. However, the concept of a gel phase and a free fluid phase now seems to be replaced by the quantitatively more well-defined distribution spaces for glycosaminoglycans and plasma protein, apparently in osmotic equilibrium with each other. The protein-excluded space, determined mainly by the content of glycosaminoglycans and collagen, has been measured in vivo in many tissues, and the effect of exclusion on the oncotic buffering has been clarified. The effect of protein charge on its excluded volume and on interstitial hydraulic conductivity has been studied only in lungs and is only partly clarified. Of unknown functional importance is also the recent finding of a free interstitial hyaluronan pool with relatively rapid removal by lymph. The postulated preferential channels from capillaries to lymphatics have received little direct support. Thus the variation of plasma-to-lymph passage times for proteins may probably be ascribed to heterogeneity with respect to path length, linear velocity, and distribution volumes. Techniques for measuring interstitial fluid pressure have been refined and reevaluated, approaching some concensus on slightly negative control pressures in soft connective tissues (0 to -4 mmHg), zero, or slightly positive pressure in other tissues. Interstitial pressure-volume curves have been recorded in several tissues, and progress has been made in clarifying the dependency of interstitial compliance on glycosaminoglycan-osmotic pressure, collagen, and microfibrils.(ABSTRACT TRUNCATED AT 400 WORDS)
Chaos and physiology: deterministic chaos in excitable cell assemblies
Authors: Elbert T. , Ray W. J. , Kowalik Z. J. , Skinner J. E. , Graf K. E. , Birbaumer N.
Published: December 2017

In this review we examined the emerging science of deterministic chaos (nonlinear systems theory) and its application to selected physiological systems. Although many of the popular images of fractals represent fascination and beauty that by analogy corresponds to nature as we see it, the question remains as to its ultimate meaning for physiological processes. It was our intent to help clarify this somewhat popular, somewhat obscure area of nonlinear dynamics in the context of an ever-changing procedural base. We examined not only the basic concepts of chaos, but also its applications ranging from observations in single cells to the complexity of the EEG. We have not suggested that nonlinear dynamics will answer all of our questions; however, we did attempt to illustrate ways in which this approach may help us to answer new questions and to rearticulate old ones. Chaos is revolutionary in that the overall approach requires us to adopt a different frame of reference which, at times, may move us away from previous concerns and methods of data analysis. In sections I-IV, we summarized the nonlinear dynamics approach and described its application to physiology and neural systems. First, we presented a general overview of the application of nonlinear dynamical techniques to neural systems. We discussed the manner in which even apparently simple deterministic systems can behave in an unpredictable manner. Second, we described the principles of nonlinear dynamical systems including the derived analytical techniques. We now see a variety of procedures for delineating whether frenetic chaotic behavior results from a nonlinear dynamical system with a few degrees of freedom, or whether it is caused by an infinite number of variables, i.e., noise. Third, we approached the applications of nonlinear procedures to the cardiovascular systems and to the neurosciences. In terms of time series, we described initial studies which applied the now "traditional" measures of dimensionality (e.g., based on the algorithm by Grassberger and Procaccia) and information change (e.g., Lyapunov exponents). Examples include our own work and that of Pritchard et al., demonstrating that the dynamics of neural mass activity reflect psychopathological states. Today, however, the trend has expanded to include the use of surrogate data and statistical null hypotheses testing to examine whether a given time series can be considered different from that of white or colored noise (cf. Ref. 262). One of the most important potential applications is that of quantifying changes in nonlinear dynamics to predict future states of the system.(ABSTRACT TRUNCATED AT 400 WORDS)
Transport of macromolecules across microvascular walls: the two-pore theory
Authors: Rippe B. , Haraldsson B.
Published: December 2017

In this review we summarized the evidence favoring the concept that the major plasma proteins are passively transported across vascular walls through water-filled pathways by means of convection and diffusion. With regard to solute transport, a majority of microvascular walls seems to show a bimodal size selectivity. This implies the presence of a high frequency of functional small pores, restricting proteins, and an extremely low number of non-size-selective pathways, permitting the passage of macromolecules from blood to tissue, here denoted large pores. We discussed the general behavior of such a heteroporous system. A major consequence of two-pore heteroporosity is that large-solute transport must mainly occur due to convection through large pores at low filtration rates, that is, at normal or even zero lymph flows. Indeed, convection must be the predominating transport mode for most solutes across large pores when the net filtration rate is zero. Under these (transient) conditions, the convective leak of macromolecules across large pores will be counterbalanced by absorption of essentially protein-free fluid through protein-restrictive pores. In a heteroporous membrane, proteins can thus be transported by solvent drag across vascular walls in the absence of a net convection. Normally the steady-state transcapillary fluid flow (lymph flow) is about equally partitioned among small and large pores, which makes lymph essentially a "half and half" mixture of protein-free ultrafiltrate and plasma. With increasing fluid flows, however, the plasma filtrate will be progressively diluted, eventually reaching a protein concentration largely in proportion to the fractional hydraulic conductance accounted for by the large pores (alpha L). Under these high lymph flow conditions, not only the large-pore transport but also the small-pore transport (of smaller macromolecules) will become convective. At low lymph flows, however, the small-pore transport of smaller macromolecules is usually mostly diffusive. An important implication of capillary heteroporosity is that single-pore formalism is inadequate for correctly evaluating the capillary sieving characteristics. With the use of homoporous transport formalism, the "lumped" macromolecular PS and sigma will therefore vary as a function of transcapillary fluid flow (Jv). However, it is approximately correct to use single-pore formalism for conditions when Jv is very high during steady state. Thus, if minimal sieving coefficients can be measured for macromolecules, then these values will accurately reflect (1 - sigma).(ABSTRACT TRUNCATED AT 400 WORDS)
Cellular mechanisms of muscle fatigue
Authors: Fitts R. H.
Published: December 2017

Fatigue, defined as the failure to maintain the required or expected power output, is a complex problem, since multiple factors are clearly involved, with the relative importance of each dependent on the fiber type composition of the contracting muscles(s), and the intensity, type, and duration of the contractile activity. The primary sites of fatigue appear to be within the muscle cell itself and for the most part do not involve the central nervous system or the neuromuscular junction. The major hypotheses of fatigue center on disturbances in the surface membrane, E-C coupling, or metabolic events. The cell sites most frequently linked to the etiology of skeletal muscle fatigue are shown in Figure 1. Skeletal muscles are composed of at least four distinct fiber types (3 fast twitch and 1 slow twitch), with the slow type I and fast type IIa fibers containing the highest mitochondrial content and fatigue resistance. Despite fiber type differences in the degree of fatigability, the contractile properties undergo characteristic changes with the development of fatigue that can be observed in whole muscles, single motor units, and single fibers. The Po declines, and the contraction and relaxation times are prolonged. Additionally, there is a decrease in the peak rate of tension development and decline and a reduced Vo. Changes in Vo are more resistant to fatigue than Po and are not observed until Po has declined by at least 10% of its initial prefatigued value. However, the reduced peak power by which fatigue is defined results from both a reduction in Vo and Po. In the absence of muscle fiber damage, the prolonged relaxation time associated with fatigue causes the force-frequency curve to shift to the left, such that peak tensions are obtained at lower frequencies of stimulation. In a mechanism not clearly understood, the central nervous system senses this condition and reduces the alpha-motor nerve activation frequency as fatigue develops. In some cases, selective LFF develops that displaces the force-frequency curve to the right. Although not proven, it appears likely that this condition is associated with and likely caused by muscle injury, such that the SR releases less Ca2+ at low frequencies of activation. Alternatively, LFF could result from a reduced membrane excitability, such that the sarcolemma action potential frequency is considerably less than the stimulation frequency.(ABSTRACT TRUNCATED AT 400 WORDS)
Regulation of differentiation of vascular smooth muscle cells
Authors: Owens G. K.
Published: December 2017

The vascular smooth muscle cell (SMC) in mature animals is a highly specialized cell whose principal function is contraction. The fully differentiated or mature SMC proliferates at an extremely low rate and is a cell almost completely geared for contraction. It expresses a unique repertoire of contractile proteins, ion channels, and signaling molecules that are required for its contractile function and that when taken in aggregate clearly distinguish it from any other cell type. During vasculogenesis, however, the SMC's principal function is proliferation and production of matrix components of the blood vessel wall. Moreover, even in mature animals, the SMC retains remarkable plasticity, such that it can undergo relatively rapid and reversible changes in its phenotype in response to changes in local environmental cues normally required for maintenance of its differentiated state. A key to understanding SMC differentiation is to identify the key environmental signals and factors that induce or maintain the differentiated state of the SMC and to determine the molecular mechanisms that control the coordinate expression of genes encoding for proteins that are necessary for the contractile function of the SMC. The purpose of this review is to summarize our current knowledge of the regulation of SMC differentiation, with a particular emphasis on consideration of how this process is controlled during normal vascular development and how these control processes might be altered in vascular diseases such as atherosclerosis, which are characterized by marked alterations in the differentiated state of the SMC.
Defining the roles of parathyroid hormone-related protein in normal physiology
Authors: Philbrick W. M. , Wysolmerski J. J. , Galbraith S. , Holt E. , Orloff J. J. , Yang K. H. , Vasavada R. C. , Weir E. C. , Broadus A. E. , Stewart A. F.
Published: December 2017

Parathyroid hormone-related protein (PTHrP) was discovered as a result of a search for the circulating factor secreted by cancers which causes the common paraneoplastic syndrome humoral hypercalcemia of malignancy. Since the identification of the peptide in 1982 and the cloning of the cDNA in 1987, it has become clear that PTHrP is a prohormone that is posttranslationally cleaved by prohormone convertases to yield a complex family of peptides, each of which is believed to have its own receptor. It is also clear that the PTHrP gene is expressed not only in cancers but also in the vast majority of normal tissues during adult and/or fetal life. In contrast to the situation in humoral hypercalcemia of malignancy in which PTHrP plays the role of a classical "endocrine" hormone, under normal circumstances PTHrP plays predominantly paracrine and/or autocrine roles. These apparent physiological functions are also complex and appear to include 1) regulation of smooth muscle (vascular, intestinal, uterine, bladder) tone, 2) regulation of transepithelial (renal, placental, oviduct, mammary gland) calcium transport, and 3) regulation of tissue and organ development, differentiation, and proliferation. In this review, the discovery of PTHrP, the structure of its gene and its cDNAs, and the posttranslational processing of the initial translation products are briefly reviewed. Attention is then focused on a detailed organ system-oriented review of the normal physiological functions of PTHrP.
Molecular mechanisms of iron uptake in eukaryotes
Authors: de Silva D. M. , Askwith C. C. , Kaplan J.
Published: December 2017

Iron serves essential functions in both prokaryotes and eukaryotes, and cells have highly specialized mechanisms for acquiring and handling this metal. The primary mechanism by which the concentration of iron in biologic systems is controlled is through the regulation of iron uptake. Although the role of transferrin in mammalian iron homeostasis has been well characterized, the study of genetic disorders of iron metabolism has revealed other, transferrin-independent, mechanisms by which cells can acquire iron. In an attempt to understand how eukaryotic systems take up this essential element, investigators have begun studying the simple eukaryote Saccharomyces cerevisiae. Several genes have been identified and cloned that act in concert to allow iron acquisition from the environment. Some of these genes appear to have functional homologues in human systems. This review focuses on the recent developments in understanding eukaryotic iron uptake with an emphasis on the genetic and molecular characterization of these systems in both cultured mammalian cells and S. cerevisiae. An unexpected connection between iron and copper homeostasis has been revealed by recent genetic studies, which confirm biologic observations made several decades ago.
Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction
Authors: Ronnov-Jessen L. , Petersen O. W. , Bissell M. J.
Published: December 2017

Reciprocal interactions between epithelium and mesenchyme mediate crucial aspects of embryonic development and direct the coordinated organogenesis, correct spatial orientation, and the timely expression of functional activity consistent with physiological demands. The mesenchymal equivalent in the adult organism is the stroma, i.e., the loose connective tissue that is separated from the epithelial compartment by an intact basement membrane. In carcinomas, the cellular organization is dramatically changed, and the stroma is extensively modified. The basement membrane is penetrated in a process of degradation and/or decreased synthesis, and direct contact between tumor cells and the surrounding stroma coincides with neovascularization, inflammatory cell influx, and extensive remodeling of extracellular matrix. In this review, we highlight our current knowledge of tumor cell stromal interactions in the mammary gland with particular emphasis on cellular origins and functional phenotypes. We focus both on normal mammary gland and breast tumors and on culture systems developed to dissect individual aspects of cell-cell and cell-extracellular matrix interactions.