bluuebunny/crossref_metadata_2025 huggingface dataset:
Degeneration and regeneration of axons in the lesioned spinal cord
Authors: Schwab M. E. , Bartholdi D.
Published: December 2017

For many decades, the inability of lesioned central neurons to regrow was accepted almost as a "law of nature", and on the clinical level, spinal cord and brain lesions were seen as being irreversible. Today we are starting to understand the mechanisms of neuronal regeneration in the central nervous system and its presence in the periphery. There is now a rapid expansion in this field of neuroscience. Developmental neurobiology has produced tools and concepts that start to show their impact on regeneration research. This is particularly true for the availability of antibodies and factors and for the rapidly growing cellular and molecular understanding of crucial aspects of neurite growth, guidance, target finding, and synapse stabilization. New cell biological concepts on the mechanisms of neuron survival and death and on the interaction of inflammatory cells with the central nervous system also find their way into the field of spinal cord and brain lesions and have, indeed, led already to new therapeutic approaches. This review briefly summarizes the current knowledge on the mechanisms involved in degeneration and tissue loss and in axonal regeneration subsequent to spinal cord lesions, particularly in mammals and humans.
Malignant hyperthermia: excitation-contraction coupling, Ca2+ release channel, and cell Ca2+ regulation defects
Authors: Mickelson J. R. , Louis C. F.
Published: December 2017

Malignant hyperthermia (MH) is a disorder of skeletal muscle in which certain anesthetic agents trigger a sustained elevation in myoplasmic Ca2+ concentration that activates metabolic and contractile activity. This review focuses on the biochemical and physiological alterations in the skeletal muscle of MH-susceptible (MHS) pigs and humans that appear responsible for this inherited disorder. In porcine MH, these studies identified the skeletal muscle sarcoplasmic reticulum Ca2+ release channel gene (RYR1) as the site of the defect. A mutation in this protein results in altered excitation-contraction coupling and secondary changes in porcine muscle structure and function. Although RYR1 mutations have been reported in many MHS human families, there is also significant genetic heterogeneity, and much less is known as to the underlying mechanism responsible for altered human myoplasmic Ca2+ regulation. The effects of caffeine and anesthetic agents on MHS and normal muscle are also discussed to better understand the basis for the in vitro clinical test for this disorder and mechanisms responsible for the initiation and maintenance of MH episodes in susceptible individuals. Finally, we examine the possiblity of a defect in Ca2+ regulation in tissues other than skeletal muscle. Current understanding of the molecular basis of MH elegantly illustrates the successful integration of knowledge obtained from all fields of biological and clinical science.
Principles of rhythmic motor pattern generation
Authors: Marder E. , Calabrese R. L.
Published: December 2017

Rhythmic movements are produced by central pattern-generating networks whose output is shaped by sensory and neuromodulatory inputs to allow the animal to adapt its movements to changing needs. This review discusses cellular, circuit, and computational analyses of the mechanisms underlying the generation of rhythmic movements in both invertebrate and vertebrate nervous systems. Attention is paid to exploring the mechanisms by which synaptic and cellular processes interact to play specific roles in shaping motor patterns and, consequently, movement.
Gastric endocrine cells: gene expression, processing, and targeting of active products
Authors: Dockray G. J. , Varro A. , Dimaline R.
Published: December 2017

Endocrine cells of the gastric epithelium secrete biologically active peptides and small messenger molecules such as histamine, serotonin, and gamma-aminobutyric acid. The secretory products may act locally (paracrine or autocrine effects) or at distant targets after delivery in the circulation (hormonal effects). the contents of the gastric lumen control both secretion of gastric endocrine cells and the expression of genes involved in the synthesis of their active secretory products; in some cases, gene regulation may occur over periods as short as that required for digestion of a single meal. The conversion of inactive peptide precursors to their active forms takes place during transit along the secretory pathway and is only completed after sequestration in secretory granules. the processing of the gastrin precursor provides a useful model for studying prohormone processing. Generation of the well-known amidated gastrins requires prohormone cleavage and COOH-terminal amidation; the products stimulate acid secretion and mucosal growth. However, recent work indicates that biosynthetic intermediates that do not stimulate acid secretion may nevertheless act at a novel receptor to stimulate growth, so that control of prohormone processing determines which of two alternative types of biologically active peptide is released by gastrin cells. Gastric endocrine cells also have the capacity to accumulate small messenger molecules in secretory vesicles, via proton exchangers. Recent work indicates physiological regulation of the expression of genes encoding cytosolic enzymes such as histidine decarboxylase, which converts histidine to histamine, and of secretory granule transporters such as vesicular monoamine transporter type 2, which concentrates amines in secretory vesicles. Together these findings suggest that modulation of regulatory peptide and amine biosynthesis in gastric endocrine cells constitutes a primary response of the stomach to the arrival of a meal.
Growth, differentiation, and survival: multiple physiological functions for insulin-like growth factors
Authors: Stewart C. E. , Rotwein P.
Published: December 2017

The insulin-like growth factors (IGFs), IGF-I and IGF-II, comprise a conserved pair of secreted proteins with diverse effects on growth, development, and metabolism. Insulin-like growth factor action is initiated upon binding to cell-surface receptors and is modulated through interactions with secreted IGF binding proteins (IGFBPs). The last decade has seen an explosion of new information about the physiological roles of the IGFs. In this review, we critically examine this information from biochemical, cell biological, and molecular genetic perspectives. We discuss the structures and functions of the two IGF receptors, outline the actions of the six IGFBPs, and summarize and interpret recent studies highlighting essential roles for components of the IGF system in the growth and development of the embryo and fetus, in tissue differentiation, in cell survival and proliferation, and in cancer. These results are discussed in the context of new opportunities for understanding the mechanisms of IGF action in multiple biological processes.
Physiological properties of the normal lens
Authors: Mathias R. T. , Rae J. L. , Baldo G. J.
Published: December 2017

The lens is an avascular organ suspended between the aqueous and vitreous humors of the eye. The cellular structure is symmetric about an axis passing through its anterior and posterior poles but asymmetric about a plane passing through its equator. Because of its asymmetric structure, the lens has historically been assumed to perform transport between the aqueous and vitreous humors. Indeed, when anterior and posterior surfaces were isolated in an Ussing chamber, a translens current was measured. However, in the eye, the two surfaces are not isolated. The vibrating probe technique showed the current densities at the surface of a free-standing lens were surprisingly large, about an order of magnitude greater than measured in an Ussing chamber, and were not directed across the lens. Rather, they were inward in the region of either anterior or posterior pole and outward at the equator. This circulating current is the most dramatic physiological property of a normal lens. We believe it is essential to maintain clarity; hence, this review focuses on factors likely to drive and direct it. We review properties and spatial distribution of lens Na+/K+ pumps, ion channels, and gap junctions. Based on these data, we propose a model in which the difference in electromotive potential of surface versus interior cell membranes drives the current, whereas the distribution of gap junctions directs the current in the observed pattern. Although this model is clearly too simple, it appears to quantitatively predict observed currents. However, the model also predicts fluid will move in the same pattern as ionic current. We therefore speculate that the physiological role of the current is to create an internal circulatory system for the avascular lens.
Placental transfer of inorganic ions and water
Authors: Stulc J.
Published: December 2017

There are great interspecies differences in placental structure as well as in permeability properties of the placenta. In all species, however, the placenta behaves like a low-permeability barrier containing specific mechanisms of transcellular transport for minerals and other substrates for fetal growth and metabolism. The minerals that are contained in plasma in low concentrations and that are mainly intracellular or sequestered in bones (K+, Mg2+, Ca2+, phosphate) are transported to the fetus actively. The transfer of the main extracellular ions, Na+ and Cl-, exhibit great interspecies differences. In the sheep, the transfer rates of Na+ and Cl- to the fetus are consistent with passive transfer mechanisms. In the rat, Na+ is transported to the fetus actively and the transfer of Cl- is facilitated by a carrier and/or a channel. Transfer of minerals to the fetus is controlled by a variety of mechanisms ranging from very simple ones depending on intrinsic properties of the transport systems to complex mechanisms of hormonal control. Water is presumed to move across the placenta passively. The transfer may be facilitated by the 28-kDa water channel-forming integral protein (CHIP28), which is expressed in the trophoblast syncytium.
Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives
Authors: Mattson M. P.
Published: December 2017

beta-Amyloid precursor protein (beta-APP), the source of the fibrillogenic amyloid beta-peptide (A beta) that accumulates in the brain of victims of Alzheimer's disease, is a multifunctional protein that is widely expressed in the nervous system. beta-Amyloid precursor protein is axonally transported and accumulates in presynaptic terminals and growth cones. A secreted form of beta-APP (sAPP alpha) is released from neurons in response to electrical activity and may function in modulation of neuronal excitability, synaptic plasticity, neurite outgrowth, synaptogenesis, and cell survival. A signaling pathway involving guanosine 3',5'-cyclic monophosphate is activated by sAPP alpha and modulates the activities of potassium channels, N-methyl-D-aspartate receptors, and the transcription factor NF kappa B. Additional functions of beta-APP may include modulation of cell adhesion and regulation of proliferation of nonneuronal cells. Alternative enzymatic processing of beta-APP liberates A beta, which has a propensity to form amyloid fibrils; A beta can damage and kill neurons and increase their vulnerability to excitotoxicity. The mechanism involves generation of oxyradicals and impairment of membrane transport systems (e.g., ion-motive ATPases and glutamate and glucose transporters). Genetic mutations or age-related metabolic changes may promote neuronal degeneration in Alzheimer's disease by increasing production of A beta and/or decreasing levels of neuroprotective sAPP alpha.
Dopamine Receptors: From Structure to Function
Authors: MISSALE CRISTINA , NASH S. RUSSEL , ROBINSON SUSAN W. , JABER MOHAMED , CARON MARC G.
Published: December 2017

Missale, Cristina, S. Russel Nash, Susan W. Robinson, Mohamed Jaber, and Marc G. Caron. Dopamine Receptors: From Structure to Function. Physiol. Rev. 78: 189–225, 1998. — The diverse physiological actions of dopamine are mediated by at least five distinct G protein-coupled receptor subtypes. Two D1-like receptor subtypes (D1and D5) couple to the G protein Gsand activate adenylyl cyclase. The other receptor subtypes belong to the D2-like subfamily (D2, D3, and D4) and are prototypic of G protein-coupled receptors that inhibit adenylyl cyclase and activate K+channels. The genes for the D1and D5receptors are intronless, but pseudogenes of the D5exist. The D2and D3receptors vary in certain tissues and species as a result of alternative splicing, and the human D4receptor gene exhibits extensive polymorphic variation. In the central nervous system, dopamine receptors are widely expressed because they are involved in the control of locomotion, cognition, emotion, and affect as well as neuroendocrine secretion. In the periphery, dopamine receptors are present more prominently in kidney, vasculature, and pituitary, where they affect mainly sodium homeostasis, vascular tone, and hormone secretion. Numerous genetic linkage analysis studies have failed so far to reveal unequivocal evidence for the involvement of one of these receptors in the etiology of various central nervous system disorders. However, targeted deletion of several of these dopamine receptor genes in mice should provide valuable information about their physiological functions.
Cytosolic Free Calcium and the Cytoskeleton in the Control of Leukocyte Chemotaxis
Authors: PETTIT ELIZABETH J. , FAY† FREDRIC S.
Published: December 2017

Pettit, Elizabeth J., and Frederic S. Fay. Cytosolic Free Calcium and the Cytoskeleton in the Control of Leukocyte Chemotaxis. Physiol. Rev. 78: 949–967, 1998. — In response to a chemotactic gradient, leukocytes extravasate and chemotax toward the site of pathogen invasion. Although fundamental in the control of many leukocyte functions, the role of cytosolic free Ca2+in chemotaxis is unclear and has been the subject of debate. Before becoming motile, the cell assumes a polarized morphology, as a result of modulation of the cytoskeleton by G protein and kinase activation. This morphology may be reinforced during chemotaxis by the intracellular redistribution of Ca2+stores, cytoskeletal constituents, and chemoattractant receptors. Restricted subcellular distributions of signaling molecules, such as Ca2+, Ca2+/calmodulin, diacylglycerol, and protein kinase C, may also play a role in some types of leukocyte. Chemotaxis is an essential function of most cells at some stage during their development, and a deeper understanding of the molecular signaling and structural components involved will enable rational design of therapeutic strategies in a wide variety of diseases.
Biosynthesis and Degradation of CFTR
Authors: KOPITO RON R.
Published: December 2017

Kopito, Ron R. Biosynthesis and Degradation of CFTR. Physiol. Rev. 79, Suppl.: S167–S173, 1999. — Many of the mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that cause cystic fibrosis interfere with the folding and biosynthetic processing of nascent CFTR molecules in the endoplasmic reticulum. Mutations in the cytoplasmic nucleotide binding domains, including the common allele ΔF508, decrease the efficiency of CFTR folding, reduce the probability of its dissociation from molecular chaperones, and largely prevent its maturation through the secretory pathway to the plasma membrane. These mutant CFTR molecules are rapidly degraded by cytoplasmic proteasomes by a process that requires covalent modification by multiubiquitination. The effects of temperature and chemical chaperones on the intracellular processing of mutant CFTR molecules suggest that strategies aimed at increasing the folding yield of this protein in vivo may eventually lead to the development of novel therapies for cystic fibrosis.
Vacuolar and Plasma Membrane Proton-Adenosinetriphosphatases
Authors: Nelson Nathan , Harvey William R.
Published: December 2017

The vacuolar H+-ATPase (V-ATPase) is one of the most fundamental enzymes in nature. It functions in almost every eukaryotic cell and energizes a wide variety of organelles and membranes. V-ATPases have similar structure and mechanism of action with F-ATPase and several of their subunits evolved from common ancestors. In eukaryotic cells, F-ATPases are confined to the semi-autonomous organelles, chloroplasts, and mitochondria, which contain their own genes that encode some of the F-ATPase subunits. In contrast to F-ATPases, whose primary function in eukaryotic cells is to form ATP at the expense of the proton-motive force (pmf), V-ATPases function exclusively as ATP-dependent proton pumps. The pmf generated by V-ATPases in organelles and membranes of eukaryotic cells is utilized as a driving force for numerous secondary transport processes. The mechanistic and structural relations between the two enzymes prompted us to suggest similar functional units in V-ATPase as was proposed to F-ATPase and to assign some of the V-ATPase subunit to one of four parts of a mechanochemical machine: a catalytic unit, a shaft, a hook, and a proton turbine. It was the yeast genetics that allowed the identification of special properties of individual subunits and the discovery of factors that are involved in the enzyme biogenesis and assembly. The V-ATPases play a major role as energizers of animal plasma membranes, especially apical plasma membranes of epithelial cells. This role was first recognized in plasma membranes of lepidopteran midgut and vertebrate kidney. The list of animals with plasma membranes that are energized by V-ATPases now includes members of most, if not all, animal phyla. This includes the classical Na+absorption by frog skin, male fertility through acidification of the sperm acrosome and the male reproductive tract, bone resorption by mammalian osteoclasts, and regulation of eye pressure. V-ATPase may function in Na+uptake by trout gills and energizes water secretion by contractile vacuoles in Dictyostelium. V-ATPase was first detected in organelles connected with the vacuolar system. It is the main if not the only primary energy source for numerous transport systems in these organelles. The driving force for the accumulation of neurotransmitters into synaptic vesicles is pmf generated by V-ATPase. The acidification of lysosomes, which are required for the proper function of most of their enzymes, is provided by V-ATPase. The enzyme is also vital for the proper function of endosomes and the Golgi apparatus. In contrast to yeast vacuoles that maintain an internal pH of ∼5.5, it is believed that the vacuoles of lemon fruit may have a pH as low as 2. Similarly, some brown and red alga maintain internal pH as low as 0.1 in their vacuoles. One of the outstanding questions in the field is how such a conserved enzyme as the V-ATPase can fulfill such diverse functions.
Mechanism of Action and In Vivo Role of Platelet-Derived Growth Factor
Authors: Heldin Carl-Henrik , Westermark Bengt
Published: December 2017

Platelet-derived growth factor (PDGF) is a major mitogen for connective tissue cells and certain other cell types. It is a dimeric molecule consisting of disulfide-bonded, structurally similar A- and B-polypeptide chains, which combine to homo- and heterodimers. The PDGF isoforms exert their cellular effects by binding to and activating two structurally related protein tyrosine kinase receptors, denoted the α-receptor and the β-receptor. Activation of PDGF receptors leads to stimulation of cell growth, but also to changes in cell shape and motility; PDGF induces reorganization of the actin filament system and stimulates chemotaxis, i.e., a directed cell movement toward a gradient of PDGF. In vivo, PDGF has important roles during the embryonic development as well as during wound healing. Moreover, overactivity of PDGF has been implicated in several pathological conditions. The sis oncogene of simian sarcoma virus (SSV) is related to the B-chain of PDGF, and SSV transformation involves autocrine stimulation by a PDGF-like molecule. Similarly, overproduction of PDGF may be involved in autocrine and paracrine growth stimulation of human tumors. Overactivity of PDGF has, in addition, been implicated in nonmalignant conditions characterized by an increased cell proliferation, such as atherosclerosis and fibrotic conditions. This review discusses structural and functional properties of PDGF and PDGF receptors, the mechanism whereby PDGF exerts its cellular effects, and the role of PDGF in normal and diseased tissues.
Mammalian Distal Tubule: Physiology, Pathophysiology, and Molecular Anatomy
Authors: Reilly Robert F. , Ellison David H.
Published: December 2017

The distal tubule of the mammalian kidney, defined as the region between the macula densa and the collecting duct, is morphologically and functionally heterogeneous. This heterogeneity has stymied attempts to define functional properties of individual cell types and has led to controversy concerning mechanisms and regulation of ion transport. Recently, molecular techniques have been used to identify and localize ion transport pathways along the distal tubule and to identify human diseases that result from abnormal distal tubule function. Results of these studies have clarified the roles of individual distal cell types. They suggest that the basic molecular architecture of the distal nephron is surprisingly similar in mammalian species investigated to date. The results have also reemphasized the role played by the distal tubule in regulating urinary potassium excretion. They have clarified how both peptide and steroid hormones, including aldosterone and estrogen, regulate ion transport by distal convoluted tubule cells. Furthermore, they highlight the central role that the distal tubule plays in systemic calcium homeostasis. Disorders of distal nephron function, such as Gitelman's syndrome, nephrolithiasis, and adaptation to diuretic drug administration, emphasize the importance of this relatively short nephron segment to human physiology. This review integrates molecular and functional results to provide a contemporary picture of distal tubule function in mammals.
Molecular Analysis of the Sodium/Iodide Symporter: Impact on Thyroid and Extrathyroid Pathophysiology
Authors: De la Vieja Antonio , Dohan Orsolya , Levy Orlie , Carrasco Nancy
Published: December 2017

The Na+/I−symporter (NIS) is an intrinsic membrane protein that mediates the active transport of iodide into the thyroid and other tissues, such as salivary glands, gastric mucosa, and lactating mammary gland. NIS plays key roles in thyroid pathophysiology as the route by which iodide reaches the gland for thyroid hormone biosynthesis and as a means for diagnostic scintigraphic imaging and for radioiodide therapy in hyperthyroidism and thyroid cancer. The molecular characterization of NIS started with the 1996 isolation of a cDNA encoding rat NIS and has since continued at a rapid pace. Anti-NIS antibodies have been prepared and used to study NIS topology and its secondary structure. The biogenesis and posttranslational modifications of NIS have been examined, a thorough electrophysiological analysis of NIS has been conducted, the cDNA encoding human NIS (hNIS) has been isolated, the genomic organization of hNIS has been elucidated, the regulation of NIS by thyrotropin and I−has been analyzed, the regulation of NIS transcription has been studied, spontaneous NIS mutations have been identified as causes of congenital iodide transport defect resulting in hypothyroidism, the roles of NIS in thyroid cancer and thyroid autoimmune disease have been examined, and the expression and regulation of NIS in extrathyroidal tissues have been investigated. In gene therapy experiments, the rat NIS gene has been transduced into various types of human cells, which then exhibited active iodide transport and became susceptible to destruction with radioiodide. The continued molecular analysis of NIS clearly holds the potential of an even greater impact on a wide spectrum of fields, ranging from structure/function of transport proteins to the diagnosis and treatment of cancer, both in the thyroid and beyond.
Corticotropin Releasing Hormone and Proopiomelanocortin Involvement in the Cutaneous Response to Stress
Authors: Slominski Andrzej , Wortsman Jacobo , Luger Thomas , Paus Ralf , Solomon Samuel
Published: December 2017

The skin is a known target organ for the proopiomelanocortin (POMC)-derived neuropeptides α-melanocyte stimulating hormone (α-MSH), β-endorphin, and ACTH and also a source of these peptides. Skin expression levels of the POMC gene and POMC/corticotropin releasing hormone (CRH) peptides are not static but are determined by such factors as the physiological changes associated with hair cycle (highest in anagen phase), ultraviolet radiation (UVR) exposure, immune cytokine release, or the presence of cutaneous pathology. Among the cytokines, the proinflammatory interleukin-1 produces important upregulation of cutaneous levels of POMC mRNA, POMC peptides, and MSH receptors; UVR also stimulates expression of all the components of the CRH/POMC system including expression of the corresponding receptors. Molecular characterization of the cutaneous POMC gene shows mRNA forms similar to those found in the pituitary, which are expressed together with shorter variants. The receptors for POMC peptides expressed in the skin are functional and include MC1, MC5 and μ-opiate, although most predominant are those of the MC1 class recognizing MSH and ACTH. Receptors for CRH are also present in the skin. Because expression of, for example, the MC1 receptor is stimulated in a similar dose-dependent manner by UVR, cytokines, MSH peptides or melanin precursors, actions of the ligand peptides represent a stochastic (predictable) nonspecific response to environmental/endogenous stresses. The powerful effects of POMC peptides and probably CRH on the skin pigmentary, immune, and adnexal systems are consistent with stress-neutralizing activity addressed at maintaining skin integrity to restrict disruptions of internal homeostasis. Hence, cutaneous expression of the CRH/POMC system is highly organized, encoding mediators and receptors similar to the hypothalamic-pituitary-adrenal (HPA) axis. This CRH/POMC skin system appears to generate a function analogous to the HPA axis, that in the skin is expressed as a highly localized response which neutralizes noxious stimuli and attendant immune reactions.
Membrane Transport in the Malaria-Infected Erythrocyte
Authors: Kirk Kiaran
Published: December 2017

The malaria parasite is a unicellular eukaryotic organism which, during the course of its complex life cycle, invades the red blood cells of its vertebrate host. As it grows and multiplies within its host blood cell, the parasite modifies the membrane permeability and cytosolic composition of the host cell. The intracellular parasite is enclosed within a so-called parasitophorous vacuolar membrane, tubular extensions of which radiate out into the host cell compartment. Like all eukaryote cells, the parasite has at its surface a plasma membrane, as well as having a variety of internal membrane-bound organelles that perform a range of functions. This review focuses on the transport properties of the different membranes of the malaria-infected erythrocyte, as well as on the role played by the various membrane transport systems in the uptake of solutes from the extracellular medium, the disposal of metabolic wastes, and the origin and maintenance of electrochemical ion gradients. Such systems are of considerable interest from the point of view of antimalarial chemotherapy, both as drug targets in their own right and as routes for targeting cytotoxic agents into the intracellular parasite.
Physiological and Molecular Basis of Thyroid Hormone Action
Authors: Yen Paul M.
Published: December 2017

Thyroid hormones (THs) play critical roles in the differentiation, growth, metabolism, and physiological function of virtually all tissues. TH binds to receptors that are ligand-regulatable transcription factors belonging to the nuclear hormone receptor superfamily. Tremendous progress has been made recently in our understanding of the molecular mechanisms that underlie TH action. In this review, we present the major advances in our knowledge of the molecular mechanisms of TH action and their implications for TH action in specific tissues, resistance to thyroid hormone syndrome, and genetically engineered mouse models.
Nuclear Hormone Receptors and Gene Expression
Authors: Aranda Ana , Pascual Angel
Published: December 2017

The nuclear hormone receptor superfamily includes receptors for thyroid and steroid hormones, retinoids and vitamin D, as well as different “orphan” receptors of unknown ligand. Ligands for some of these receptors have been recently identified, showing that products of lipid metabolism such as fatty acids, prostaglandins, or cholesterol derivatives can regulate gene expression by binding to nuclear receptors. Nuclear receptors act as ligand-inducible transcription factors by directly interacting as monomers, homodimers, or heterodimers with the retinoid X receptor with DNA response elements of target genes, as well as by “cross-talking” to other signaling pathways. The effects of nuclear receptors on transcription are mediated through recruitment of coregulators. A subset of receptors binds corepressor factors and actively represses target gene expression in the absence of ligand. Corepressors are found within multicomponent complexes that contain histone deacetylase activity. Deacetylation leads to chromatin compactation and transcriptional repression. Upon ligand binding, the receptors undergo a conformational change that allows the recruitment of multiple coactivator complexes. Some of these proteins are chromatin remodeling factors or possess histone acetylase activity, whereas others may interact directly with the basic transcriptional machinery. Recruitment of coactivator complexes to the target promoter causes chromatin decompactation and transcriptional activation. The characterization of corepressor and coactivator complexes, in concert with the identification of the specific interaction motifs in the receptors, has demonstrated the existence of a general molecular mechanism by which different receptors elicit their transcriptional responses in target genes.
Mechanisms of Estrogen Action
Authors: Nilsson Stefan , Mäkelä Sari , Treuter Eckardt , Tujague Michel , Thomsen Jane , Andersson Göran , Enmark Eva , Pettersson Katarina , Warner Margaret , Gustafsson Jan-Åke
Published: December 2017

Our appreciation of the physiological functions of estrogens and the mechanisms through which estrogens bring about these functions has changed during the past decade. Just as transgenic mice were produced in which estrogen receptors had been inactivated and we thought that we were about to understand the role of estrogen receptors in physiology and pathology, it was found that there was not one but two distinct and functional estrogen receptors, now called ERα and ERβ. Transgenic mice in which each of the receptors or both the receptors are inactive have revealed a much broader role for estrogens in the body than was previously thought. This decade also saw the description of a male patient who had no functional ERα and whose continued bone growth clearly revealed an important function of estrogen in men. The importance of estrogen in both males and females was also demonstrated in the laboratory in transgenic mice in which the aromatase gene was inactivated. Finally, crystal structures of the estrogen receptors with agonists and antagonists have revealed much about how ligand binding influences receptor conformation and how this conformation influences interaction of the receptor with coactivators or corepressors and hence determines cellular response to ligands.
The Hypothalamus and Hypertension
Authors: De Wardener H. E.
Published: December 2017

Most forms of hypertension are associated with a wide variety of functional changes in the hypothalamus. Alterations in the following substances are discussed: catecholamines, acetylcholine, angiotensin II, natriuretic peptides, vasopressin, nitric oxide, serotonin, GABA, ouabain, neuropeptide Y, opioids, bradykinin, thyrotropin-releasing factor, vasoactive intestinal polypeptide, tachykinins, histamine, and corticotropin-releasing factor. Functional changes in these substances occur throughout the hypothalamus but are particularly prominent rostrally; most lead to an increase in sympathetic nervous activity which is responsible for the rise in arterial pressure. A few appear to be depressor compensatory changes. The majority of the hypothalamic changes begin as the pressure rises and are particularly prominent in the young rat; subsequently they tend to fluctuate and overall to diminish with age. It is proposed that, with the possible exception of the Dahl salt-sensitive rat, the hypothalamic changes associated with hypertension are caused by renal and intrathoracic cardiopulmonary afferent stimulation. Renal afferent stimulation occurs as a result of renal ischemia and trauma as in the reduced renal mass rat. It is suggested that afferents from the chest arise, at least in part, from the observed increase in left auricular pressure which, it is submitted, is due to the associated documented impaired ability to excrete sodium. It is proposed, therefore, that the hypothalamic changes in hypertension are a link in an integrated compensatory natriuretic response to the kidney's impaired ability to excrete sodium.
Spinal and Supraspinal Factors in Human Muscle Fatigue
Authors: Gandevia S. C.
Published: December 2017

Muscle fatigue is an exercise-induced reduction in maximal voluntary muscle force. It may arise not only because of peripheral changes at the level of the muscle, but also because the central nervous system fails to drive the motoneurons adequately. Evidence for “central” fatigue and the neural mechanisms underlying it are reviewed, together with its terminology and the methods used to reveal it. Much data suggest that voluntary activation of human motoneurons and muscle fibers is suboptimal and thus maximal voluntary force is commonly less than true maximal force. Hence, maximal voluntary strength can often be below true maximal muscle force. The technique of twitch interpolation has helped to reveal the changes in drive to motoneurons during fatigue. Voluntary activation usually diminishes during maximal voluntary isometric tasks, that is central fatigue develops, and motor unit firing rates decline. Transcranial magnetic stimulation over the motor cortex during fatiguing exercise has revealed focal changes in cortical excitability and inhibitability based on electromyographic (EMG) recordings, and a decline in supraspinal “drive” based on force recordings. Some of the changes in motor cortical behavior can be dissociated from the development of this “supraspinal” fatigue. Central changes also occur at a spinal level due to the altered input from muscle spindle, tendon organ, and group III and IV muscle afferents innervating the fatiguing muscle. Some intrinsic adaptive properties of the motoneurons help to minimize fatigue. A number of other central changes occur during fatigue and affect, for example, proprioception, tremor, and postural control. Human muscle fatigue does not simply reside in the muscle.
A Privacy Protection User Authentication and Key Agreement Scheme Tailored for the Internet of Things Environment: PriAuth
Authors: Chen Yuwen , Martínez José-Fernán , Castillejo Pedro , López Lourdes
Published: December 2017

In a wearable sensor-based deployment, sensors are placed over the patient to monitor their body health parameters. Continuous physiological information monitored by wearable sensors helps doctors have a better diagnostic and a suitable treatment. When doctors want to access the patient’s sensor data remotely via network, the patient will authenticate the identity of the doctor first, and then they will negotiate a key for further communication. Many lightweight schemes have been proposed to enable a mutual authentication and key establishment between the two parties with the help of a gateway node, but most of these schemes cannot enable identity confidentiality. Besides, the shared key is also known by the gateway, which means the patient’s sensor data could be leaked to the gateway. In PriAuth, identities are encrypted to guarantee confidentiality. Additionally, Elliptic Curve Diffie–Hellman (ECDH) key exchange protocol has been adopted to ensure the secrecy of the key, avoiding the gateway access to it. Besides, only hash and XOR computations are adopted because of the computability and power constraints of the wearable sensors. The proposed scheme has been validated by BAN logic and AVISPA, and the results show the scheme has been proven as secure.
Weak and Strong Convergence Theorems for the Multiple-Set Split Equality Common Fixed-Point Problems of Demicontractive Mappings
Authors: Wang Yaqin , Kim Tae-Hwa , Fang Xiaoli
Published: December 2017

We consider mixed parallel and cyclic iterative algorithms in this paper to solve the multiple-set split equality common fixed-point problem which is a generalization of the split equality problem and the split feasibility problem for the demicontractive mappings without prior knowledge of operator norms in real Hilbert spaces. Some weak and strong convergence results are established. The results obtained in this paper generalize and improve the recent ones announced by many others.
State of Charge Estimation for Lithium‐Ion Battery by Using Dual Square Root Cubature Kalman Filter
Authors: Chen Luping , Xu Liangjun , Wang Ruoyu
Published: December 2017

The state of charge (SOC) plays an important role in battery management systems (BMS). However, SOC cannot be measured directly and an accurate state estimation is difficult to obtain due to the nonlinear battery characteristics. In this paper, a method of SOC estimation with parameter updating by using the dual square root cubature Kalman filter (DSRCKF) is proposed. The proposed method has been validated experimentally and the results are compared with dual extended Kalman filter (DEKF) and dual square root unscented Kalman filter (DSRUKF) methods. Experimental results have shown that the proposed method has the most balance performance among them in terms of the SOC estimation accuracy, execution time, and convergence rate.
Developing a Model for Chloride Ions Transport in Cement Concrete under Dynamic Flexural Loading and Dry‐Wet Cycles
Authors: Guan Bo-wen , Wu Jia-yu , Yang Tao , Xu An-hua , Sheng Yan-ping , Chen Hua-xin
Published: December 2017

Chloride ions attack is the main factor leading to the degradation of concrete durability, while the diffusion process would be significantly aggravated under the dynamic flexural loading and dry‐wet cycles. In this paper, the influence coefficients of dynamic flexural loading on chloride/water diffusion coefficients were established, based on the relationship between the dynamic flexural loading and the chloride ions diffusion coefficient of concrete. Based on the model of chloride ions transporting in dry‐wet cycle environment, the transport model of chloride ions in concrete under the dynamic flexural loading and dry‐wet cycles was established. The effects of different factors on the chloride ions transport law in concrete were analyzed through laboratory test. The results showed that the model was in good agreement with the experimental results. The theory and assumptions proposed applied in the model of chloride ions transport in concrete under the dynamic flexural loading and dry‐wet cycles had certain rationality and scientificity.
Synthesis and Bioevaluation of Iodine-131 Directly Labeled Cyclic RGD-PEGylated Gold Nanorods for Tumor-Targeted Imaging
Authors: Zhang Yingying , Zhang Yongxue , Yin Lianglan , Xia Xiaotian , Hu Fan , Liu QingYao , Qin Chunxia , Lan Xiaoli
Published: December 2017

Introduction.Radiolabeled gold nanoparticles play an important role in biomedical application. The aim of this study was to prepare iodine-131 (131I)-labeled gold nanorods (GNRs) conjugated with cyclic RGD and evaluate its biological characteristics for targeted imaging of integrinαvβ3-expressing tumors.Methods.HS-PEG(5000)-COOH molecules were applied to replace CTAB covering the surface of bare GNRs for better biocompatibility, and c(RGDfK) peptides were conjugated onto the carboxyl terminal of GNR-PEG-COOH via EDC/NHS coupling reactions. The nanoconjugate was characterized, and131I was directly tagged on the surface of GNRs via AuI bonds for SPECT/CT imaging. We preliminarily studied the characteristics of the probe and its feasibility for tumor-targeting SPECT/CT imaging.Results.The[131I]GNR-PEG-cRGD probe was prepared in a simple and rapid manner and was stable in both PBS and fetal bovine serum. It targeted selectively and could be taken up by tumor cells mainly via integrinαvβ3-receptor-mediated endocytosis. In vivo imaging, biodistribution, and autoradiography results showed evident tumor uptake in integrinαvβ3-expressing tumors.Conclusions.These promising results showed that this smart nanoprobe can be used for angiogenesis-targeted SPECT/CT imaging. Furthermore, the nanoprobe possesses a remarkable capacity for highly efficient photothermal conversion in the near-infrared region, suggesting its potential as a multifunctional theranostic agent.
Structural Modulation of Gut Microbiota during Alleviation of Suckling Piglets Diarrhoea with Herbal Formula
Authors: Liu Cui , Zhang Chao , Lv Weijie , Chao Limin , Li Zengquan , Shi Dayou , Guo Shining
Published: December 2017

To determine whether the traditional Chinese herbal formula of Shen Ling Baizhu (SLB) could modulate the composition of the gut microbiota and alleviate diarrhoea in suckling piglets, twenty‐four newly born piglets (Large White × Landrace × Duroc) were selected and allocated to 4 groups (control group and experimental groups I, II, and III) randomly. Faecal microbiome composition was assessed by 16S rRNA gene 454‐pyrosequencing. The result indicated that experimental groups I and II exhibited significantly different gut microbiota from the control group. Most notably, the genera Lactobacillus and Bifidobacterium were significantly elevated in experimental group II compared with the control group (P < 0.05). Collinsella and Faecalibacterium were also enhanced in experimental group II compared with the control group (P < 0.05). The results showed that SLB treatment could modulate the gut microbiota composition of suckling piglets, enriching the amount of beneficial bacteria in particular. The observed changes in the gut microbiota could provide the basis for further research on the pharmacological mechanism of the tested Chinese herbal formula.
Electrolyte Composition for Distinguishing Corrosion Mechanisms in Steel Alloy Screening
Authors: Bösing Ingmar , Thöming Jorg , Baune Michael
Published: December 2017

The formation and breakdown of passive layers due to pitting corrosion are a major cause of failure of metal structures. The investigation of passivation and pitting corrosion requires two different electrochemical measurements and is therefore a time consuming process. To reduce time in material characterization and to study the interactions of both mechanisms, here, a combined experiment addressing both phenomena is introduced. In the presented electrolyte the different corrosion mechanisms are distinguished and investigated by cyclic voltammograms and polarization scans. The measurements show a passive area, metastable pit growth, and pitting corrosion as well as repassivation. The pitting corrosion is separated from additional dissolution processes and the standard deviation of the corrosion potential is smaller than in other electrolytes. Both passivation and pitting corrosion can be observed in one measurement without additional corrosion attacks. The deviation between different measurements of the same steel is small; this is helpful for the screening of similar materials.
Facile Preparation of Porous Inorganic SiO2 Nanofibrous Membrane by Electrospinning Method
Authors: Chang Meng-Jie , Cui Wen-Na , Liu Jun
Published: December 2017

We presented a straightforward method to fabricate porous inorganic SiO2 nanofibrous membrane by one-step calcination of electrospun nanofibers, which encapsulated with carbon nanospheres as template for nanopore generation. The structure, morphology, and composition of the as-spun fibers (PVA/SiO2/C) and porous SiO2 were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). The detective results indicated that the carbon nanospheres were uniformly encapsulated inside the PVA/SiO2/C nanofibers. After calcination, PVA polymer was removed and high flexible inorganic nanofibrous membrane composed of amorphous SiO2 was obtained. Simultaneously, carbon nanosphere template was decomposed and uniform nanopores were generated inside the SiO2 nanofibers. This new method is simple and of low cost and hence is suitable to prepare other porous inorganic nanofibers with high surface area for practical application.
Stent and Dual Antiplatelet Therapy Duration Comparisons in the Setting of a Multicenter Randomized Controlled Trial: Can the Operator Experience Affect the Study Results?
Authors: Gargiulo Giuseppe , Heg Dik , Ferrari Fabrizio , Percoco Gianfranco , Campo Gianluca , Tumscitz Carlo , Colombo Federico , Zuffi Andrea , Castriota Fausto , Cremonesi Alberto , Windecker Stephan , Valgimigli Marco
Published: December 2017

Background

Operator experience influences outcomes after percutaneous coronary intervention, but this association in the controlled setting of a randomized, clinical trial is unclear.

Methods and Results

We investigated operator‐related outcomes (30‐day and 2‐year efficacy and safety end points) among patients undergoing percutaneous coronary intervention and randomized to different dual antiplatelet therapy durations and stent types. A total of 2003 patients were analyzed, and 7 operator groups were compared. The majority of preprocedural and postprocedural characteristics were imbalanced. The primary end point of the study, the composite of death, myocardial infarction, or cerebrovascular accidents, did not differ among operators at 30 days or 2 years. There were no significant differences also for all other individual and composite end points analyzed at 30 days and 2 years, except for 2‐year stent thrombosis (
P
=0.048) and bleeding events (
P
=0.022 for Bleeding Academic Research Consortium type 2, 3, or 5). Adjusted comparisons for the main end points showed slight differences among operators at 30 days, but not at 2 years. There was no interaction of operator with dual antiplatelet therapy duration (
P
=0.112) or stent type (
P
=0.300). Results remained entirely consistent when operators were stratified by their experience.

Conclusions

There was a weak signal of heterogeneity across study operators for the 30‐day, but not the 2‐year, main study outcomes. No clear effect of operator or operator experience was observed for the comparative efficacy and safety profile of the randomized stent types or dual antiplatelet therapy duration regimens.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
00611286.