Characterization of zebrafish (Danio rerio) NCX4: a novel NCX with distinct electrophysiological properties

2009 ◽  
Vol 296 (1) ◽  
pp. C173-C181 ◽  
Author(s):  
Caly On ◽  
Christian R. Marshall ◽  
Steve F. Perry ◽  
Hoa Dinh Le ◽  
Vladimir Yurkov ◽  
...  
Keyword(s):  
Danio Rerio ◽  
Splice Variants ◽  
Inhibitory Peptide ◽  
Electrophysiological Properties ◽  
Outward Currents ◽  
Dependent Inactivation ◽  
Wide Range ◽  
Heterologous Expression Systems ◽  
High Degree ◽  
First Time

Members of the Na+/Ca2+ exchanger (NCX) family are important regulators of cytosolic Ca2+ in myriad tissues and are highly conserved across a wide range of species. Three distinct NCX genes and numerous splice variants exist in mammals, many of which have been characterized in a variety of heterologous expression systems. Recently, however, we discovered a fourth NCX gene ( NCX4), which is found exclusively in teleost, amphibian, and reptilian genomes. Zebrafish ( Danio rerio) NCX4a encodes for a protein of 939 amino acids and shows a high degree of identity with known NCXs. Although knockdown of NCX4a activity in zebrafish embryos has been shown to alter left-right patterning, it has not been demonstrated that NCX4a functions as a NCX. In this study, we 1) demonstrated, for the first time, that this gene encodes for a novel NCX; 2) characterized the tissue distribution of zebrafish NCX4a; and 3) evaluated its kinetic and transport properties. While ubiquitously expressed, the highest levels of NCX4a expression occurred in the brain and eyes. NCX4a exhibits modest levels of Na+-dependent inactivation and requires much higher levels of regulatory Ca2+ to activate outward exchange currents. NCX4a also exhibited extremely fast recovery from Na+-dependent inactivation of outward currents, faster than any previously characterized wild-type exchanger. While this result suggests that the Na+-dependent inactive state of NCX4a is far less stable than in other NCX family members, this exchanger was still strongly inhibited by 2 μM exchanger inhibitory peptide. We demonstrated that a new putative member of the NCX gene family, NCX4a, encodes for a NCX with unique functional properties. These data will be useful in understanding the role that NCX4a plays in embryological development as well as in the adult, where it is expressed ubiquitously.

L-Type CaV1.2 Calcium Channels: From In Vitro Findings to In Vivo Function

2014 ◽  
Vol 94 (1) ◽  
pp. 303-326 ◽  
Author(s):  
Franz Hofmann ◽  
Veit Flockerzi ◽  
Sabine Kahl ◽  
Jörg W. Wegener
Keyword(s):  
Calcium Channel ◽  
Splice Variants ◽  
Kinetic Properties ◽  
Expression Systems ◽  
Smooth Muscle Contractility ◽  
Dependent Inactivation ◽  
Heterologous Expression Systems ◽  
Channel Properties

The L-type Cav1.2 calcium channel is present throughout the animal kingdom and is essential for some aspects of CNS function, cardiac and smooth muscle contractility, neuroendocrine regulation, and multiple other processes. The L-type CaV1.2 channel is built by up to four subunits; all subunits exist in various splice variants that potentially affect the biophysical and biological functions of the channel. Many of the CaV1.2 channel properties have been analyzed in heterologous expression systems including regulation of the L-type CaV1.2 channel by Ca2+ itself and protein kinases. However, targeted mutations of the calcium channel genes confirmed only some of these in vitro findings. Substitution of the respective serines by alanine showed that β-adrenergic upregulation of the cardiac CaV1.2 channel did not depend on the phosphorylation of the in vitro specified amino acids. Moreover, well-established in vitro phosphorylation sites of the CaVβ2 subunit of the cardiac L-type CaV1.2 channel were found to be irrelevant for the in vivo regulation of the channel. However, the molecular basis of some kinetic properties, such as Ca2+-dependent inactivation and facilitation, has been approved by in vivo mutagenesis of the CaV1.2α1 gene. This article summarizes recent findings on the in vivo relevance of well-established in vitro results.

Understanding Conformational Entropy in Small Molecules

2020 ◽  
Author(s):  
Lucian Chan ◽  
Garrett Morris ◽  
Geoffrey Hutchison
Keyword(s):  
Small Molecules ◽  
Degrees Of Freedom ◽  
Absolute Error ◽  
Low Energy ◽  
Standard Entropy ◽  
Free Energies ◽  
Conformational Entropy ◽  
Wide Range ◽  
High Degree ◽  
Empirical Corrections

The calculation of the entropy of flexible molecules can be challenging, since the number of possible conformers grows exponentially with molecule size and many low-energy conformers may be thermally accessible. Different methods have been proposed to approximate the contribution of conformational entropy to the molecular standard entropy, including performing thermochemistry calculations with all possible stable conformations, and developing empirical corrections from experimental data. We have performed conformer sampling on over 120,000 small molecules generating some 12 million conformers, to develop models to predict conformational entropy across a wide range of molecules. Using insight into the nature of conformational disorder, our cross-validated physically-motivated statistical model can outperform common machine learning and deep learning methods, with a mean absolute error ≈4.8 J/mol•K, or under 0.4 kcal/mol at 300 K. Beyond predicting molecular entropies and free energies, the model implies a high degree of correlation between torsions in most molecules, often as- sumed to be independent. While individual dihedral rotations may have low energetic barriers, the shape and chemical functionality of most molecules necessarily correlate their torsional degrees of freedom, and hence restrict the number of low-energy conformations immensely. Our simple models capture these correlations, and advance our understanding of small molecule conformational entropy.

Safety assessment of biological raw materials in the system of medicines quality assurance

2020 ◽  
pp. 63-72
Author(s):  
Yu. Olefir ◽  
E. Sakanyan ◽  
I. Osipova ◽  
V. Dobrynin ◽  
M. Smirnova ◽  
...  
Keyword(s):  
Raw Materials ◽  
State Level ◽  
The State ◽  
Spongiform Encephalopathy ◽  
Safety Standards ◽  
Wide Range ◽  
The Russian Federation ◽  
Key Aspects ◽  
First Time ◽  
Medicines Quality

The entry of a wide range of biotechnological products into the pharmaceutical market calls for rein-forcement of the quality, efficacy and safety standards at the state level. The following general monographs have been elaborated for the first time to be included into the State Pharmacopoeia of the Russian Federation, XIV edition: "Viral safety" and "Reduction of the risk of transmitting animal spongiform encephalopathy via medicinal products". These general monographs were elaborated taking into account the requirements of foreign pharmacopoeias and the WHO recommendations. The present paper summarises the key aspects of the monographs.

Genetic Diversity of Basil (Ocimum spp. - Lamiaceae) Based on RAPD Markers and Volatile Oil Constituents

HortScience ◽  
1998 ◽  
Vol 33 (3) ◽  
pp. 492f-493
Author(s):  
Roberto F. Vieira ◽  
James E. Simon ◽  
Peter Goldsbrough ◽  
Antonio Figueira
Keyword(s):  
Genetic Diversity ◽  
Molecular Markers ◽  
Rapd Markers ◽  
Volatile Oil ◽  
Essential Oil Composition ◽  
Oil Composition ◽  
Traditional Medicines ◽  
The Tropics ◽  
High Degree ◽  
First Time

Essential oils extracted from basil (Ocimum spp.) by steam distillation are used to flavor foods, oral products, in fragrances, and in traditional medicines. The genus Ocimum contains around 30 species native to the tropics and subtropics, with some species naturalized and/or cultivated in temperate areas. Interand intraspecific hybridization have created significant confusion in the botanical systematics of this genus. Taxonomy of basil (O. basilicum) is also complicated by the existence of numerous varieties, cultivars, and chemotypes within the species that do not differ significantly in morphology. In this study we are using RAPD markers and volatile oil composition to characterize the genetic diversity among the most economically important Ocimum species. We hypothesize that the genetic similarity revealed by molecular markers will more accurately reflect the morphological and chemical differences in Ocimum than essential oil composition per se. Preliminary research using five Ocimum species, four undetermined species, and eight varieties of O. basilicum (a total of 19 accessions) generated 107 polymorphic fragments amplified with 19 primers. RAPDs are able to discriminate between Ocimum species, but show a high degree of similarity between O. basilicum varieties. The genetic distance between nine species and among 55 accessions within the species O. americanum, O. basilicum, O. campechianum, O. × citriodorum, O. gratissimum, O. kilimandscharium, O. minimum, O. selloi, and O. tenuiflorum will be analyzed by matrix of similarity and compared to the volatile oil profile. This research will for the first time apply molecular markers to characterize the genetic diversity of Ocimum associate with volatile oil constituent.

Innovation in Byzantine Medicine

2020 ◽  
Author(s):  
Petros Bouras-Vallianatos
Keyword(s):  
Human Physiology ◽  
Medical Literature ◽  
Cultural Exchange ◽  
Significant Degree ◽  
Medieval Medicine ◽  
Medieval Latin ◽  
Main Thesis ◽  
Wide Range ◽  
Comprehensive Examination ◽  
First Time

Byzantine medicine is still a little-known and misrepresented field not only in the wider arena of debates on medieval medicine but also among Byzantinists. Byzantine medical literature is often viewed as ‘stagnant’ and mainly preserving ancient ideas; and our knowledge of it continues to be based to a great extent on the comments of earlier authorities, which are often repeated uncritically. This book presents the first comprehensive examination of the medical corpus of, arguably, the most important late Byzantine physician John Zacharias Aktouarios (c.1275–c.1330). The main thesis is that John’s medical works show an astonishing degree of openness to knowledge from outside Byzantium combined with a significant degree of originality, in particular, in the fields of uroscopy, pharmacology, and human physiology. The analysis of John’s edited (On Urines and On Psychic Pneuma) and unedited (Medical Epitome) works is supported for the first time by the consultation of a large number of manuscripts. The study is also informed by evidence from a wide range of medical sources, including previously unpublished ones, and texts from other genres, such as epistolography and merchants’ accounts. The contextualization of John’s works sheds new light on the development of Byzantine medical thought and practice, and enhances our understanding of the late Byzantine social and intellectual landscape. Finally, John’s medical observations are also examined in the light of examples from the medieval Latin and Islamic worlds, placing his medical theories in the wider Mediterranean milieu and highlighting the cultural exchange between Byzantium and its neighbours.

Rebels, Believers, Survivors

2020 ◽  
Author(s):  
Noel Malcolm
Keyword(s):  
Catholic Church ◽  
Religious Conversion ◽  
Late Nineteenth Century ◽  
Napoleonic Wars ◽  
Conversion To Islam ◽  
Wide Range ◽  
History Of ◽  
External Powers ◽  
First Time ◽  
Modern Myth

This book of essays covers a wide range of topics in the history of Albania and Kosovo. Many of the essays illuminate connections between the Albanian lands and external powers and interests, whether political, military, diplomatic or religious. Such topics include the Habsburg invasion of Kosovo in 1689, the manoeuvrings of Britain and France towards the Albanian lands during the Napoleonic Wars, the British interest in those lands in the late nineteenth century, and the Balkan War of 1912. On the religious side, essays examine ‘crypto-Christianity’ in Kosovo during the Ottoman period, the stories of conversion to Islam revealed by Inquisition records, the first theological treatise written in Albanian (1685), and the work of the ‘Apostolic Delegate’ who reformed the Catholic Church in early twentieth-century Albania. Some essays bring to life ordinary individuals hitherto unknown to history: women hauled before the Inquisition, for example, or the author of the first Albanian autobiography. The longest essay, on Ali Pasha, tells for the first time the full story of the role he played in the international politics of the Napoleonic Wars. Some of these studies have been printed before (several in hard-to-find publications, and one only in Albanian), but the greater part of this book appears here for the first time. This is not only a contribution to Albanian and Balkan history it also engages with many broader issues, including religious conversion, methods of enslavement within the Ottoman Empire, and the nature of modern myth-making about national identity.

Recycling and Reuse in the Roman Economy

2020 ◽  
Keyword(s):  
Building Materials ◽  
Computational Modelling ◽  
Late Antique ◽  
Roman Economy ◽  
Wide Range ◽  
The Status ◽  
Recent Developments ◽  
Methodological Approaches ◽  
First Time ◽  
Site Types

The recycling and reuse of materials and objects were extensive in the past, but have rarely been embedded into models of the economy; even more rarely has any attempt been made to assess the scale of these practices. Recent developments, including the use of large datasets, computational modelling, and high-resolution analytical chemistry, are increasingly offering the means to reconstruct recycling and reuse, and even to approach the thorny matter of quantification. Growing scholarly interest in the topic has also led to an increasing recognition of these practices from those employing more traditional methodological approaches, which are sometimes coupled with innovative archaeological theory. Thanks to these efforts, it has been possible for the first time in this volume to draw together archaeological case studies on the recycling and reuse of a wide range of materials, from papyri and textiles, to amphorae, metals and glass, building materials and statuary. Recycling and reuse occur at a range of site types, and often in contexts which cross-cut material categories, or move from one object category to another. The volume focuses principally on the Roman Imperial and late antique world, over a broad geographical span ranging from Britain to North Africa and the East Mediterranean. Last, but not least, the volume is unique in focusing upon these activities as a part of the status quo, and not just as a response to crisis.

Cerebellotrigeminal Dermal Dysplasia (Gómez-López-Hernández Syndrome)

2018 ◽  
Vol 16 (05) ◽  
pp. 362-368 ◽  
Author(s):  
Federica Sullo ◽  
Agata Polizzi ◽  
Stefano Catanzaro ◽  
Selene Mantegna ◽  
Francesco Lacarrubba ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosomal Rearrangements ◽  
Number Of Patients ◽  
Wide Range ◽  
Visual Problems ◽  
Neurodevelopmental Abnormalities ◽  
Clinical Triad ◽  
High Degree ◽  
Motor Handicap

Cerebellotrigeminal dermal (CTD) dysplasia is a rare neurocutaneous disorder characterized by a triad of symptoms: bilateral parieto-occipital alopecia, facial anesthesia in the trigeminal area, and rhombencephalosynapsis (RES), confirmed by cranial magnetic resonance imaging. CTD dysplasia is also known as Gómez-López-Hernández syndrome. So far, only 35 cases have been described with varying symptomatology. The etiology remains unknown. Either spontaneous dominant mutations or de novo chromosomal rearrangements have been proposed as possible explanations. In addition to its clinical triad of RES, parietal alopecia, and trigeminal anesthesia, CTD dysplasia is associated with a wide range of phenotypic and neurodevelopmental abnormalities.Treatment is symptomatic and includes physical rehabilitation, special education, dental care, and ocular protection against self-induced corneal trauma that causes ulcers and, later, corneal opacification. The prognosis is correlated to the mental development, motor handicap, corneal–facial anesthesia, and visual problems. Follow-up on a large number of patients with CTD dysplasia has never been reported and experience is limited to few cases to date. High degree of suspicion in a child presenting with characteristic alopecia and RES has a great importance in diagnosis of this syndrome.

scholarly journals A Virtual Telescope for the Open University Science Foundation Course

1998 ◽  
Vol 162 ◽  
pp. 100-105
Author(s):  
Andrew J. Norton ◽  
Mark H. Jones
Keyword(s):  
Social Science ◽  
Open University ◽  
Distance Teaching ◽  
The Arts ◽  
Wide Range ◽  
University Science ◽  
First Time ◽  
Degree Level ◽  
Selection Of

The Open University is the UK's foremost distance teaching university. For over twenty five years we have been presenting courses to students spanning a wide range of degree level and vocational subjects. Since we have no pre-requisites for entry, a major component of our course profile is a selection of foundation courses comprising one each in the Arts, Social Science, Mathematics, Technology and Science faculties. The Science Faculty's foundation course is currently undergoing a substantial revision. The new course, entitled “S103: Discovering Science”, will be presented to students for the first time in 1998.

scholarly journals Dissecting the Molecular Determinants of GABAA Receptors Current Rundown, a Hallmark of Refractory Human Epilepsy

2021 ◽  
Vol 11 (4) ◽  
pp. 441
Author(s):  
Pierangelo Cifelli ◽  
Silvia Di Angelantonio ◽  
Veronica Alfano ◽  
Alessandra Morano ◽  
Eleonora De Felice ◽  
...  
Keyword(s):  
Gabaa Receptors ◽  
Drug Resistant ◽  
Human Embryonic Kidney Cells ◽  
Inhibitory Function ◽  
Human Epilepsy ◽  
Wide Range ◽  
Molecular Determinants ◽  
The Central Nervous System ◽  
Heterologous Expression Systems ◽  
Important Therapeutic Target

GABAA receptors-(Rs) are fundamental for the maintenance of an efficient inhibitory function in the central nervous system (CNS). Their dysfunction is associated with a wide range of CNS disorders, many of which characterized by seizures and epilepsy. Recently, an increased use-dependent desensitization due to a repetitive GABA stimulation (GABAA current rundown) of GABAARs has been associated with drug-resistant temporal lobe epilepsy (TLE). Here, we aimed to investigate the molecular determinants of GABAA current rundown with two different heterologous expression systems (Xenopus oocytes and human embryonic kidney cells; HEK) which allowed us to manipulate receptor stoichiometry and to study the GABAA current rundown on different GABAAR configurations. To this purpose, we performed electrophysiology experiments using two-electrode voltage clamp in oocytes and confirming part of our results in HEK. We found that different degrees of GABAA current rundown can be associated with the expression of different GABAAR β-subunits reaching the maximum current decrease when functional α1β2 receptors are expressed. Furthermore, the blockade of phosphatases can prevent the current rundown observed in α1β2 GABAARs. Since GABAAR represents one important therapeutic target in the treatment of human epilepsy, our results could open new perspectives on the therapeutic management of drug-resistant patients showing a GABAergic impairment.

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