Calcium and potassium channels. Medical search. Frequent questions

Discovery of Novel Activators of Large-Conductance Calcium-Activated Potassium Channels for the Treatment of Cerebellar Ataxia. (harvard.edu)
Case Report on: Very Early Afterdepolarizations in HiPSC-Cardiomyocytes-An Artifact by Big Conductance Calcium Activated Potassium Current (Ibk,Ca). Cells. (harvard.edu)
Small (SK) and intermediate (IK) conductance calcium-activated potassium channels are candidate ion channels for the regulation of excitability in nociceptive neurones. (dundee.ac.uk)
Small-conductance calcium- activated potassium (SK) channels regulate action potential firing and shape calcium influx through feedback regulation in mature neurons. (units.it)
Large conductance calcium-activated potassium (BK) channels participate in many important Roflumilast physiological functions in excitable cells such as neurons cardiac and clean muscles whereas the knowledge of BK channels in bone cells and osteoblasts remains elusive. (cancer-pictures.org)
Analysis of Single Nucleotide Polymorphisms (SNPs) of the small-conductance calcium activated potassium channel (SK3) gene as genetic modifier of the cardiac phenotype in myotonic dystrophy type 1 patients. (cdc.gov)

The calcium binding domain may be contained in the α subunit sequence, as in KCa1, or may be through an additional calcium binding protein such as calmodulin. (wikipedia.org)
The alpha subunit is a tetramer which forms the pore, the voltage sensor, and the calcium sensing region. (wikipedia.org)
This subunit of the channel is made up of seven trans-membrane units, and a large intracellular region. (wikipedia.org)
The beta subunit of the channel is thought to be a regulatory subunit of the channel. (wikipedia.org)
Additionally, this study shows how the postnatal ontogenetic patterns lead to the adult expression map for each SK channel subunit and how their coexpression in the same regions or neurons varies throughout development. (units.it)
We interrogated the predicted targets of these differentially expressed microRNA families in MPM cell lines, and identified KCa1.1, a calcium-activated potassium channel subunit alpha 1 encoded by the KCNMA1 gene, as a target of miR-17-5p. (bairdinstitute.org.au)
Drosophila Slowpoke (dSlo) calcium-dependent potassium channels bind directly to the catalytic subunit of cAMP-dependent protein kinase (PKAc). (elsevierpure.com)
Here I investigate the effects of subunit composition on toxin blocking affinity, using three members of the Shaker subfamily of potassium channel α-subunits (Kv1.1, Kv1.2 and Kv1.4), which are known to form heteromultimers in vivo, in the Xenopus oocyte expression system. (aspetjournals.org)
The single subunit model, in which a single toxin-sensitive subunit renders the channel toxin sensitive, best described all of the data for the two dendrotoxins and the block of tityustoxin-Kα for a mixed population of channels composed of Kv1.1 and Kv1.2 subunits. (aspetjournals.org)
The data suggest that subunit composition of potassium channels can have a large effect on toxin block and that different toxins yield strikingly diverse results with the same pair of subunits, even when they are nearly identical in blocking affinity for the toxin-sensitive subunit. (aspetjournals.org)

The estimated reversal potential for the calcium-evoked response was about -80 mV and its amplitude depended on the extracellular concentration of potassium but not on the chloride concentration. (ox.ac.uk)
It turns out that cave-dwelling swifts (who fly about in near-total darkness) have their balance organs filled with a liquid which is saturated with potassium chloride, and considerably denser than water whilst being not much more viscous. (halfbakery.com)
This means that ions like sodium, potassium, calcium, and chloride cannot cross membranes to any significant degree by simple diffusion, and must instead be transported by specialized proteins (which we'll discuss later). (khanacademy.org)
Apart from calcium channels, voltage-gated sodium, potassium, and chloride channels were also shown to be activated by pulsed electromagnetic frequencies. (news-medical.net)
sults: sodium 133 mmol/L, potassium membrane regulator gene ( CFTR ) on He was readmitted 5 more times 3.4 mmol/L, chloride 100 mmol/L and chromosome 7. (who.int)
This hyperaldosteronism will potassium chloride supplementation. (who.int)
After being lost to follow-up for number of mutations affecting the in the sweat and the urine, resulting in several years, he was seen again at the chloride channel, the commonest being hypokalaemia [ 3,8-14 ]. (who.int)

Then in 1970, Meech was the first to observe that intracellular calcium could trigger potassium currents. (wikipedia.org)
This family of ion channels is, for the most part, activated by intracellular Ca2+ and contains 8 members in the human genome. (wikipedia.org)
However, some of these channels (the KCa4 and KCa5 channels) are responsive instead to other intracellular ligands, such as Na+, Cl−, and pH. (wikipedia.org)
In any muscle cell, increased intracellular calcium causes contraction. (wikipedia.org)
In smooth muscle cells the elevated levels of intracellular calcium cause the opening of BK channels which in turn allow potassium ions to flow out of the cell. (wikipedia.org)
Potassium channels whose activation is dependent on intracellular calcium concentrations. (harvard.edu)
Calcium injected ionophoretically into an egg from an intracellular micro-electrode caused a reduction of the membrane resistance. (ox.ac.uk)
The presence of the artifact lowers the resting potential and resistance of the cell so that intracellular calcium injection causes a hyperpolarization. (ox.ac.uk)
Changes in intracellular calcium not only modify glial physiology, but they also seem to be involved in complex intercellular communication networks (for review, see Finkbeiner, 1993 ). (jneurosci.org)
The composition is almost exactly the same as the intracellular fluid, with a slight boost so that potassium influx can occur at relevant rates. (halfbakery.com)
TASK-1 channels are sensitive to a wide array of physiological and pharmacological mediators that affect their activity such as unsaturated fatty acids, extracellular pH, hypoxia, anaesthetics and intracellular signalling pathways. (ersjournals.com)

Ion channels, which allow potassium and sodium ions to flow in and out of cells, are crucial in neuronal 'firing' in the central nervous system and for brain and heart function. (medicalxpress.com)

influx via the Gardos channel (IK(Ca)) in human erythrocytes. (lu.se)
Early electrical activity and calcium influx regulate crucial aspects of neuronal development. (units.it)
amazing, I didn't know about cellular potassium INflux, normally sodium is the overwhealmingly dominant extracellular ion. (halfbakery.com)
This neurotoxicity appears also to be mediated by Zn 2+ influx, in large part through voltage-gated Ca 2+ channels and also through NMDA receptor-gated channels ( Koh and Choi, 1994 ) and Ca 2+ -permeable AMPA/kainate receptor-gated channels ( Yin and Weiss, 1995 ). (jneurosci.org)

Effects of calcium-activated potassium channel modulators on afterhyperpolarizing potentials in identified motor and mechanosensory neurons of the medicinal leech. (harvard.edu)
LR ingestion increased excitability (threshold for evoking action potentials) and number of action potentials per depolarizing pulse, decreased calcium-dependent potassium channel (IK(Ca)) opening and decreased the slow afterhyperpolarization (sAHP) in sensory AH neurons, similar to the IK(Ca) antagonists Tram-34 and clotrimazole. (nih.gov)
To allow studies on the contribution of SK channels to different phases of development of single neurons and networks, we have performed a detailed in situ hybridization mapping study, providing comprehensive distribution profiles of all three SK subunits (SK1, SK2, and SK3) in the rat CNS during embryonic and postnatal development. (units.it)
In hypothalamic neurons, modulators such as neuropeptide Y (NPY) and adenosine depress glutamatergic transmission by either a pertussis toxin (PTx)-sensitive G-protein-coupled pathway or by inhibition of voltage-activated calcium channels (VACCs). (jneurosci.org)
The kainate-induced increase was highly sensitive to Gd 3+ or Na + removal in most neurons but insensitive in a minority subpopulation ("cobalt-positive cells"), suggesting that a fourth route of neuronal Zn 2+ entry is through the Ca 2+ -permeable channels gated by certain subtypes of AMPA or kainate receptors. (jneurosci.org)
However, in order to switch ion flow on and off with high enough frequencies to meet the demands of neurons, heart muscle cells and other cell types, some ion channels need an additional, on-the-fly mechanism to stop ion flow-even when the stimulus is still present and the channel structure is in principle in the "open" state. (medicalxpress.com)
Its "MthK" channel is known to be structurally similar to the mammalian "BK" potassium channel that is crucial for the proper function of neurons and many other cell types -yet MthK has key simplifications that make it easier to image. (medicalxpress.com)

Kv7 family channels mediate a voltage-dependent outward flux of potassium ions, which contributes to the establishment of negative membrane potentials in many cell types. (aspetjournals.org)

The NMDA-induced increase was only partly sensitive to Gd 3+ or to removal of extracellular Na + , consistent with a third route of entry directly through NMDA receptor-gated channels. (jneurosci.org)

Apamin-sensitive calcium-activated potassium currents in rabbit ventricles with chronic myocardial infarction. (harvard.edu)
Cerebellar ataxia by enhanced Ca(V)2.1 currents is alleviated by Ca2+-dependent K+-channel activators in Cacna1a(S218L) mutant mice. (harvard.edu)
A lot of work has focused particularly on the role of potassium currents in shaping responsiveness and firing of MNs [ 3 , 5 ]. (biomedcentral.com)
McLarnon JG: Potassium currents in motoneurones. (biomedcentral.com)
McKiernan EC: The role of specific voltage-activated and calcium-activated potassium currents in shaping motor neuron firing output during rhythmic motor activity. (biomedcentral.com)

This gene encodes a member of the potassium channel, voltage-gated, shab-related subfamily. (nih.gov)

The study, published March 18, 2020, in Nature , confirms a long-standing hypothesis about ion channels, and represents a key advance in the understanding of the basic biological processes at work in most cells . (medicalxpress.com)
Ball-and-chain inactivation in a calcium-gated potassium channel, Nature (2020). (medicalxpress.com)

In humans they are divided into three subtypes: large conductance or BK channels, which have very high conductance which range from 100 to 300 pS, intermediate conductance or IK channels, with intermediate conductance ranging from 25 to 100 pS, and small conductance or SK channels with small conductances from 2-25 pS. (wikipedia.org)
Subtypes of BK Channels KCa1.1 (BK, Slo1, Maxi-K, KCNMA1) Beta subunits: β1, β2, β3, β4 Intermediate conductance channels seem to be the least studied of all of the channels. (wikipedia.org)

Proinflammatory mediators as modulators of decidual calcium channel expression and function. (nottingham.ac.uk)

Activators of endogenous PKA that stimulate dSlo phosphorylation, but do not produce detectable PKAc binding to dSlo, do not modulate channel function. (elsevierpure.com)
Furthermore, the catalytically inactive PKAc mutant does bind to dSlo but does not modulate channel activity. (elsevierpure.com)
However, understanding and then targeting this ball-and-chain structure that we were able to image could allow us to therapeutically modulate potassium channels with much more specificity. (medicalxpress.com)

This finding has sparked further exploration surrounding these channels and researchers have found that IK channels regulate the cell cycle in cancer cells, B and T lymphocytes, and stem cells. (wikipedia.org)
These functions, observed in the adult nervous system, make them ideal candidates to regulate activity- and calcium-dependent processes in neurodevelopment. (units.it)
Proteins produced by other genes involved in the condition form or help regulate ion channels that transport calcium or potassium into or out of heart muscle cells. (medlineplus.gov)
These channels use a "ball-and-chain" mechanism to help regulate their ion flow, according to a new study led by Weill Cornell Medicine scientists. (medicalxpress.com)
These channels regulate nerve excitability. (medscape.com)

Structurally they are thought to be very similar to BK channels with the main differences being conductance, and the methods of modulation. (wikipedia.org)
These results are consistent with the hypothesis that both binding of active PKAc to dSlo and phosphorylation of dSlo or some other protein are necessary for channel modulation. (elsevierpure.com)
We studied modulation of glutamate-evoked calcium rises in primary astrocyte cultures using fura-2 ratiometric digital calcium imaging. (jneurosci.org)
The inhibition could be mimicked by the L-type calcium channel blocker nimodipine (1 μ m ) as well as by protein kinase C (PKC) activators phorbol 12,13-dibutyrate (10 μ m ) and phorbol 12-myristate 13-acetate (500 n m ), and blocked by the PKC inactivator (±)-1-(5-isoquinolinesulfonyl)-2-methylpiperazine (200 μ m ), suggesting a mechanism involving PKC modulation of L-type calcium channels. (jneurosci.org)
Recent studies show that modulation of TASK-1 channels, either directly or indirectly by targeting their regulatory mechanisms, has the potential to control pulmonary arterial tone in humans. (ersjournals.com)

This gene provides instructions for making a sodium channel, which normally transports positively charged sodium atoms (ions) into heart muscle cells. (medlineplus.gov)
Mutations in the SCN5A gene alter the structure or function of the channel, which reduces the flow of sodium ions into cells. (medlineplus.gov)

Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). (nih.gov)

Levosimendan is a unique potassium ATP channel activator and calcium sensitizer that affects the heart and vascular system through multiple mechanisms of action. (biospace.com)

We demonstrate here that coexpression of PKAc with dSlo in mammalian cells results in a dramatic decrease of dSlo channel activity. (elsevierpure.com)

These findings may improve our understanding of the roles of these channels in smooth muscle physiology and disease, particularly in conditions where Kv7.4 and Kv7.5 are differentially expressed. (aspetjournals.org)

They found that the mutations create an abnormality within vital structures of heart cells known as the ATP-sensitive potassium channel. (sciencedaily.com)
Different classes of potassium channels in human cells are very similar in their channel structures. (medicalxpress.com)

IK channels have shown a strong connection to calcification in vasculature, as inhibition of the channel causes a decrease in vascular calcification. (wikipedia.org)
We expressed chimeric channels composed of different components of the Kv7.4 and Kv7.5 α -subunits in vascular smooth muscle cells to determine which components are essential for enhancement or inhibition of channel activity. (aspetjournals.org)

Kv7 channels are encoded by KCNQ genes (1 through 5). (aspetjournals.org)
Some of the additional genes involved in Brugada syndrome provide instructions for making proteins that ensure the correct location or function of sodium channels in heart muscle cells. (medlineplus.gov)

The KCa channel α subunits have six or seven transmembrane segments, similar to the KV channels but occasionally with an additional N-terminal transmembrane helix. (wikipedia.org)
The excitatory beta subunits affect the alpha subunits in such a way that the channel seldom inactivates. (wikipedia.org)
However, to date little is known about the onset of expression and regions expressing SK channel subunits in the embryonic and postnatal development of the central nervous system (CNS). (units.it)
The three SK channel subunits display different developmental expression gradients in distinct CNS regions, with time points of expression and up- or downregulation that can be associated with a range of diverse developmental events. (units.it)
The ability of voltage-gated potassium channel α-subunits to form heteromultimers has complicated efforts to use toxins to characterize potassium channels in native cells. (aspetjournals.org)
The present studies identify distinct functional domains that confer differential sensitivities of Kv7.4 and Kv7.5 to stimulatory and inhibitory signaling and reveal structural features of the channel subunits that determine their biophysical properties. (aspetjournals.org)
functional channels form as homo- or hetero-tetramers of α -subunits ( Delmas and Brown, 2005 ). (aspetjournals.org)

The linker between the S5 and S6 region serves to form the pore of the channel. (wikipedia.org)
The pictures revealed that even when the MthK channel is in the calcium-activated, "open" state, the pathway through which ions flow was plugged by a flexible element that sticks into the pore of the channel structure. (medicalxpress.com)

The blocking affinity of two dendrotoxins (DTX-I and δ-DTX) and a scorpion toxin (tityustoxin-Kα) on the resulting mixed population of channels was measured to evaluate three models of toxin block. (aspetjournals.org)

These findings indicate that BK channels are involved in the relaxation of smooth muscle cells. (wikipedia.org)
Hence, potassium-selective channels were studied in freshly dispersed porcine coronary artery smooth muscle cells using the inside-out variant of the patch-clamp technique. (bgu.ac.il)
Silberberg, SD & van Breemen, C 1990, ' An ATP, calcium and voltage sensitive potassium channel in porcine coronary artery smooth muscle cells ', Biochemical and Biophysical Research Communications , vol. 172, no. 2, pp. 517-522. (bgu.ac.il)
The type III mGluR agonist l -2-amino-4-phosphonobutyrate consistently inhibited 5HT-evoked calcium rises, whereas in a smaller number of cells quisqualate and L-CCG-I showed both inhibitory and additive effects. (jneurosci.org)
A proper level of potassium enables the cells to restore electrical balance following each heartbeat, and limits the entrance of calcium into the cells. (sciencedaily.com)
Smooth muscle cells express Kv7.4 and Kv7.5 voltage-dependent potassium channels, which have each been implicated as regulators of smooth muscle contractility, though they display different sensitivities to signaling via cAMP/protein kinase A (PKA) and protein kinase C (PKC). (aspetjournals.org)
Subsequent studies showed activation of calcium channels in response to pulsed electromagnetic frequencies in plants, animals, and human cells. (news-medical.net)

Oxcarbazepine and its active metabolite 10-monohydroxy derivative (MHD) work by blocking the voltage-sensitive sodium channels, stabilizing the nerve cell membranes and reducing their excitability. (medicinenet.com)
As with sodium channels, proper flow of ions through calcium and potassium channels in the heart muscle helps maintain a regular heartbeat. (medlineplus.gov)

Oxcarbazepine also enhances potassium conductance and modulates the activity of calcium channels. (medicinenet.com)

Nobody knew exactly how this process actually looks and works-does the "ball" block the opening of the channel, or actually go in and plug the pore, or alternatively, alter the conformation of the channel indirectly? (medicalxpress.com)

Many types of ion channels, including those necessary for neuronal signaling and the beating of the heart, will physically open, allowing a flow of ions in or out of the cell, when a certain stimulus is applied. (medicalxpress.com)

Calcium-activated potassium channels are potassium channels gated by calcium, or that are structurally or phylogenetically related to calcium gated channels. (wikipedia.org)

The syndrome is caused by changes in the structure and function of certain cardiac ion channels and reduced expression of Connexin 43 (Cx43) in the Right Ventricle (RV), predominantly in the Right Ventricular Outflow Tract (VSVD), causing electromechanical abnormalities. (bvsalud.org)

They were first discovered in 1958 by Gardos who saw that calcium levels inside of a cell could affect the permeability of potassium through that cell membrane. (wikipedia.org)

Enteric neuron excitability and ion channel activity were measured using patch clamp recordings. (nih.gov)
The prominence of Kv7 channels as regulators of electrical excitability may be ascribed to their unique properties, such as a very negative threshold of activation (negative to −50 mV), absence of time-dependent inactivation, and high sensitivity to signal transduction pathways that influence their probability of opening, either positively or negatively ( Delmas and Brown, 2005 ). (aspetjournals.org)

By channel we mean a pathway leading throughout the protein structure, without any interruption by an internal cavity, with both sides open to the surrounding solvent. (plos.org)

Calcium is needed for the heart's contractions. (sciencedaily.com)

Covers selective permeability of membranes, diffusion, and facilitated diffusion (including channels and carrier proteins). (khanacademy.org)

A role for two-pore potassium (K2P) channels in endometrial epithelial function Journal of Cellular and Molecular Medicine. (nottingham.ac.uk)

We conclude that membrane potassium channels open in response to a rise in the cytosolic concentration of calcium ions. (ox.ac.uk)

We also present preliminary data consisting of electrophysiological recordings from larval Drosophila showing that the changes in motor output predicted by the model are indeed observed when genetic manipulations of Slo channel density (RNA interference constructs) are targeted to MNs [ 7 ]. (biomedcentral.com)
Early repolarization syndrome is a genetic disorder of cardiomyocyte ion channel function (channelopathy). (msdmanuals.com)

Their early expression in embryonic development suggests an involvement of SK channels in the regulation of developmental processes. (units.it)
It appears, therefore, that this channel shares properties with both the ATP-sensitive and the calcium-regulated potassium channels, raising the possibility that it plays a central role in the regulation of coronary blood flow. (bgu.ac.il)
Calcium plays a key role as a second messenger system in astrocytes, both in regulation of many subcellular processes and in long distance intercellular signaling. (jneurosci.org)
3. Uptake of calcium and its regulation. (elte.hu)
SIGNIFICANCE STATEMENT Kv7.4 and Kv7.5 channels are known signal transduction intermediates and drug targets for regulation of smooth muscle tone. (aspetjournals.org)

Below is a list of the 8 known human calcium-activated potassium channel grouped according to sequence homology of transmembrane hydrophobic cores: Though not implied in the name, but implied by the structure these channels can also be activated by voltage. (wikipedia.org)
Ion channel characterization in the human fetoplacental unit. (nottingham.ac.uk)
Potassium (K + ) channels constitute the largest group of ion channels in the human genome. (ersjournals.com)
One of the first studies to elucidate how the pulsed electromagnetic frequencies could affect human health showed that low-intensity pulsed electromagnetic frequencies could be blocked using drugs that block voltage-gated calcium channels. (news-medical.net)
Multiple calcium (Ca2+) and potassium (K+) channel isoforms have been identified in human testes and spermatozoa. (cdc.gov)
Ion channel polymorphisms may cause differential sensitivities to Cd2+ and Pb2+, explaining in part prospective blinded studies showing high Cd2+ in varicocele-related human infertility and high Pb2+ in unexplained infertility. (cdc.gov)

Ion channel abnormalities have been linked to a long list of disorders including epilepsies, heart arrhythmias, schizophrenia and diabetes. (medicalxpress.com)

This causes further hyperpolarization and closing of voltage gated calcium channels, relaxation can then occur. (wikipedia.org)

There is increasing interest in the roles played by potassium channels of smooth muscle in protecting against ischemic and anoxic insults. (bgu.ac.il)

We have used unique peptide-directed antisera to describe the immunocytochemical distribution of the known isoforms of these ion channels in dorsal root ganglia (DRG) and spinal cord of the rat. (dundee.ac.uk)
Reverse transcriptase-polymerase chain reaction assays for Ca2+ and K+ channel isoforms may identify susceptibility subgroups with lower resistance to environmental exposures. (cdc.gov)

Mutations in K + channel sequences can lead to a variety of clinical disorders exemplifying their physiological importance [ 3 ]. (ersjournals.com)

Tunnels and channels facilitate the transport of small molecules, ions and water solvent in a large variety of proteins. (plos.org)
Herein we present a new version of CAVER enabling automatic analysis of tunnels and channels in large ensembles of protein conformations. (plos.org)
HN - 2008 MH - Superior Sagittal Sinus UI - D054063 MN - A07.231.908.224.667 MS - The long large endothelium-lined venous channel on the top outer surface of the brain. (bvsalud.org)
HN - 2008 MH - Transverse Sinuses UI - D054064 MN - A07.231.908.224.833 MS - The two large endothelium-lined venous channels that begin at the internal occipital protuberance at the back and lower part of the CRANIUM and travels laterally and forward ending in the internal jugular vein (JUGULAR VEINS). (bvsalud.org)

In humans, seven different voltage-gated ion channels are known to be activated by exposure to pulsed electromagnetic frequency. (news-medical.net)

The direct imaging of the ball-and-chain mechanism, using electron-microscopy techniques, can also provide a new angle to design drugs that target it to improve ion channel function. (medicalxpress.com)

This member is a delayed rectifier potassium channel and its activity is modulated by some other family members. (nih.gov)
these changes in PIP 2 affinity have corresponding effects on channel activity. (aspetjournals.org)

In healthy people, the potassium channel synchronizes the proper balance of potassium and calcium flow in the heart. (sciencedaily.com)
The scientists confirmed the function of this plug mechanism by showing that when the 'ball-and-chain' was deleted genetically, the flow of potassium ions through the calcium-activated MthK channel was no longer regulated. (medicalxpress.com)

Anatomy25

Organisms15

Diseases7

Chemicals and Drugs157

Analytical, Diagnostic and Therapeutic Techniques and Equipment9

Phenomena and Processes37

Disciplines and Occupations3

Technology, Industry, Agriculture1

Information Science3

Conductance calcium-activated potassium6

Subunit10

Chloride7

Intracellular11

Ions to flow1

Influx4

Neurons7

Membrane Potentials1

Extracellular1

Currents5

Subfamily1

20202

Intermediate conductance2

Modulators1

Modulate3

Regulate5

Modulation5

Gene2

Shaker1

Activator1

Mammalian1

Physiology1

STRUCTURES2

Inhibition2

Genes2

Subunits7

Pore of the channel2

SCORPION TOXIN1

Cells7

Sodium channels2

Enhances1

Indirectly1

Neuronal1

Structurally1

Cardiac1

Gardos1

Excitability2

Pathway1

Heart's1

Membranes1

Cellular1

Cytosolic1

Genetic2

Regulation5

Human6

Abnormalities1

Hyperpolarization1

Roles1

Isoforms2

Mutations1

Large4

Humans1

Drugs1

Activity2

Flow2