Using Sneed's metatheory an attempt is made to reconstruct Hodgkin and Huxley's theory of excitation of cell membranes. The structure of this theory is uncovered by defining set-theoretical predicates for the partial potential models, potential models, and models of the theory. The function of permeability is said to be the only theoretical function with respect to this theory. The main underlying assumptions of the theory are briefly outlined.

Using Sneed''s metatheory an attempt is made to reconstruct Hodgkin and Huxley''s theory of excitation of cell membranes. The structure of this theory is uncovered by defining set-theoretical predicates for the partial potential models, potential models, and models of the theory. The function of permeability is said to be the only theoretical function with respect to this theory. The main underlying assumptions of the theory are briefly outlined.

Lipid droplets (LDs) are ubiquitous, neutral lipid storage organelles that act as hubs of metabolic processes. LDs are structurally unique with a hydrophobic core that mainly consists of neutral lipids, sterol esters, and triglycerides, enclosed within a phospholipid monolayer. Nascent LD formation begins with the accumulation of neutral lipids in the endoplasmic reticulum (ER) bilayer. The ER membrane proteins such as seipin, LDAF1, FIT, and MCTPs are reported to play an important role in the formation of nascent LDs. As (...) the LDs grow, they unmix from the highly charged ER membrane to form mature LDs. LD biogenesis is an exciting, emerging research area, and herein, we discuss the recent progress in our understanding of the formation of eukaryotic nascent LDs. We focus on the role of ER membrane shaping proteins such as reticulons and reticulon‐like proteins, membrane lipids, and cytoskeleton proteins such as septin in the formation of nascent LDs. (shrink)

A reductionistic, bottom‐up, cellular‐based concept of the origins of sentience and consciousness has been put forward. Because all life is based on cells, any evolutionary theory of the emergence of sentience and consciousness must be grounded in mechanisms that take place in prokaryotes, the simplest unicellular species. It has been posited that subjective awareness is a fundamental property of cellular life. It emerges as an inherent feature of, and contemporaneously with, the very first life‐forms. All other varieties of mentation are (...) the result of evolutionary mechanisms based on this singular event. Therefore, all forms of sentience and consciousness evolve from this original instantiation in prokaryotes. It has also been identified that three cellular structures and mechanisms that likely play critical roles here are excitable membranes, oscillating cytoskeletal polymers, and structurally flexible proteins. Finally, basic biophysical principles are proposed to guide those processes that underly the emergence of supracellular sentience from cellular sentience in multicellular organisms. (shrink)

Ion channels play key roles in the generation and propagation of nerve impulses by mediating ionic fluxes across excitable membranes. Elucidation of the structure and function of these proteins is a major goal in understanding the molecular mechanisms of membrane excitability. Much work has focused on sodium channels, whose activity is of primary importance in producing nerve impulses. Despite the recent cloning and sequencing of a sodium channel structural gene, many unanswered questions remain. To address some of these (...) question genetically, Drosophila mutants with altered sodium channels are being isolated and subjected to multidisciplinary analyses. Ultimately, these can provide novel approaches for understanding the function and regulation of sodium channels at a molecular level. (shrink)

The defining principle of evolutionary biology is that all species, extant and extinct, evolved from ancient prokaryotic cells. Their initial appearance and adaptive evolution are proposed to have been accompanied by a cellular sentience, by feelings, subjectivity or, in a word, 'consciousness'. Prokaryotic cells, such as archaea and bacteria, have natural unitary, valence-marked 'mental' representations. They process and evaluate sensory information in a context-dependent manner. They learn, establish memories, and communicate using biophysical fields acting on excitable membranes. Symbiotic eukaryotic cells, (...) which evolved much later, initiated a compound cellular subjectivity utilizing 'senomic' and 'ephaptic' principles that evolved into the varieties of consciousness seen in multicellular species. This Cellular Basis of Consciousness (CBC) model provides a novel framework within which to approach fundamental issues such as the origins of life and the emergence of mind. (shrink)

Cellular circadian clocks represent ancient anticipatory systems which co‐evolved with the first cells to safeguard their survival. Cyanobacteria represent one of the most ancient cells, having essentially invented photosynthesis together with redox‐based cellular circadian clocks some 2.7 billion years ago. Bioelectricity phenomena, based on redox homeostasis associated electron transfers in membranes and within protein complexes inserted in excitable membranes, play important roles, not only in the cellular circadian clocks and in anesthetics‐sensitive cellular sentience (awareness of environment), but also in the (...) coupling of single cells into tissues and organs of unitary multicellular organisms. This integration of cellular circadian clocks with cellular basis of sentience is an essential feature of the cognitive CBC‐Clock basis of cellular life. (shrink)

During sensory stimulation, visual cortical neurons undergo massive synaptic bombardment. This increases their input conductance, and action potentials mainly result from membrane potential fluctuations. To understand the response properties of neurons operating in this regime, we studied a model neuron with synaptic inputs represented by transient membrane conductance changes. We show that with a simultaneous increase of excitation and inhibition, the firing rate first increases, reaches a maximum, and then decreases at higher input rates. Comodulation of excitation and (...) inhibition, therefore, does not provide a straightforward way of controlling the neuronal firing rate, in contrast to coding mechanisms postulated previously. The synaptically induced conductance increase plays a key role in this effect: it decreases firing rate by shunting membrane potential fluctuations, and increases it by reducing the membrane time constant, allowing for faster membrane potential transients. These findings do not depend on details of the model and, hence, are relevant to cells of other cortical areas as well. (shrink)

Libet discovered that a substantial duration (> 0.5-1.0 s) of direct electrical stimulation of the surface of the somatosensory cortex at threshold currents is required before human subjects can report that a conscious somatosensory experience had occurred. Using a reaction time method we confirm that a similarly long stimulation duration at threshold currents is required for activation of elementary visual experiences (phosphenes) in human subjects following stimulation of the surface of the striate cortex. However, the reaction times for the subject (...) to respond to the cessation of the visual experience after the end of electrical stimulation could be as brief as 225-242 ms. We also carried out extensive studies in cats under a variety of anesthetic conditions using the same electrodes and parameters of stimulation employed in the human studies to study the patterns of neuronal activity beneath the stimulating surface electrode. Whereas sufficiently strong currents can activate neurons within milliseconds, stimulating currents close to threshold activate sustained neural activity only after at least 350-500 ms. When currents are close to threshold, some neurons are inhibited for several hundreds of millisecond before the balance between inhibition and excitation shifts towards excitation. These results suggest that the prolonged latencies, i.e., latencies beyond 200-250 ms, for the emergence of conscious experience following direct cortical stimulation result from a delay in the sustained activation of underlying cortical neurons at threshold currents rather than being due to any unusually long duration in central processing time. Intracellular records from cortical neurological cells during repetitive electrical stimulation of the surface of the feline striate cortex demonstrate that such stimulation induces a profound depolarizing shift in membrane potential that may persist after each stimulus train. Such a depolarization is evidence that extracellular K+ concentrations have increased during electrical stimulation. Such an increase in extracellular K+ progressively increases cortical excitability until the threshold for sustained activation of cortical neurons is reached and then exceeded. Consequently, the long latency for threshold activation of cortical neurons depends upon a dynamically increasing cortical facilatory process that begins hundreds of milliseconds before there is sustained activation of such neurons. In some cases, this facilatory process must overcome an initial stimulus-induced inhibition before neuronal firing commences. (shrink)

Short-term motor practice leads to plasticity in the primary motor cortex. The purpose of this study is to investigate the factors that determine the increase in corticospinal tract excitability after motor practice, with special focus on two factors; “the level of muscle activity” and “the presence/absence of a goal of keeping the activity level constant.” Fifteen healthy subjects performed four types of rapid thumb adduction in separate sessions. In the “comfortable task” and “forceful task”, the subjects adducted their thumb (...) using comfortable and strong forces. In the “comfortable with a goal task” and “forceful with a goal task”, subjects controlled the muscle activity at the same level as in the C and F, respectively, by adjusting the peak electromyographic amplitude within the target ranges. Paired associative stimulation, which combines peripheral nerve stimulation and transcranial magnetic stimulation, with an inter-stimulus interval of 25 ms was also done. Before and after the motor tasks and PAS25, TMS was applied to the M1. None of the four tasks showed any temporary changes in behavior, meaning no learning occurred. Motor-evoked potential amplitude increased only after the FG and it exhibited a positive correlation with the MEP increase after PAS25, suggesting that FG and PAS25 share at least similar plasticity mechanisms in the M1. Resting motor threshold decreased only after FG, suggesting that FG would also be associated with the membrane depolarization of M1 neurons. These results suggest task-dependent plasticity from the synergistic effect of forceful muscle activity and of setting a goal of keeping the activity level constant. (shrink)

Don't tell terrible stories—everyone here has enough of their own. Everyone here has a whole bloody sack of terrible stories, and at the bottom of the sack is a hammer the narrator uses to pound you on the skull the instant you dare not believe your ears. Or to pound you when you do believe. Not long ago I saw a tomboyish girl on Khreshchatyk Street demand money of an elderly woman, threatening to bite her and infect her with syphilis. (...) Don't stroll through Volodymyr Hill Park, don't stroll around the botanical garden, and especially don't stroll on Kontraktova Square. Don't stroll anywhere. Don't go to the pavilion with the Golgotha panorama near St. Alexander's Church. Not even the twelve-meter-tall crucified Christ will save you. Don't go outside when it's dark and people turn into shadows a shade darker than dark. Also don't go where you can be seen from far away. Not to imply that people used to be like a bunch of lilies, but now they stink like a cellar of cabbage.The city, which earlier might have had some fun, is now going crazy. It's like a fish in warm water: it doesn't react to anything, swims slowly like it doesn't care if it swallows a hook or not. The excitement and exaltation pass into oppression, just as our necks have sunk into our shoulders, our shoulders into our lumbars, our lumbars into our nether regions. The holiday turns into a funeral, the parades into explosions, depression into mania. Winter passes into summer, people turn into beasts, the hours into ages, and the ages into hours. It's worth simply walking around the city to see a soldier from an unknown army taking a piss near the opera. Farther on is a row of identical old widows selling ball gowns and candelabra. Then there are the aristocrats and manufacturers who throw so much at the prostitutes that they'll soon be richer than their wives.I returned late through the Kyryliv Wood, not heeding all the warnings that I myself have given here. It really is dangerous—the place is famous for it. There's a madhouse nearby, caves where criminals and the sick can hide out. Also, once upon a time, as they say in fairy tales, the great dragon Zmei Gorynich lived here beside the Puchai River. The stench in these places drives away the most committed misanthropes and even one type of philanthrope—that is, perverts. It sounds dumb, but the stench is cleansing. I don't know where it comes from. After the operating theaters and the rooms with amputees, the stench no longer repelled or attracted me; it just was. And this was a great place to think. As I walked, I considered an incident with our patient.The patient, a respectable individual whose name carries too much weight for me to state it directly, one day began to assault people. He nearly strangled a merchant who he believed asked too much for a beaver coat. He likewise wanted to kill his business partner when he didn't say hello loudly enough. But the worst was, he lost all shame of his own nakedness. At first it was the police who took care of it. When our future patient slipped off his pants and undergarments, he was taken to Kyrylivska, which has had means for dealing with such cases dating back to the day when unhinged Cossacks and composers from Kyiv Mohyla Academy were taken there.During the examination we determined that the patient was experiencing a severe breakdown. His wife added that lately, more than once, he had allowed himself strong words in front of the children and often suffered from ennui. Furthermore, she said, the patient had been undergoing treatment for “the French disease” for some years—which was, obviously, where we needed to start.“Syphilis!” Skorsky spat out the matchstick he was chewing on. He was a specialist on the psychological aspects of diseases related to the venereal. “Tertiary syphilis! When poorly treated, over time ‘the French disease’ can destroy the central nervous system. Hence the patient's chicanery. Such theater!”Skorsky and I had not spoken since the incident at Bilinsky's. Meanwhile, something significant had happened to him. The most boring person on earth, Skorsky had simply caught fire. He said hello and kibitzed. I even heard the doctor got drunk alone in his office, then wandered through the forest. Could he be using narcotic substances?“Cocaine!” was the doctor's second proclamation. It was his favorite treatment for the psychological complications of syphilis. Skorsky himself never took what he called “the universal drug”—good for alcoholism and toothaches, neuroses and morphine dependency—though he had read in an article by a respectable Viennese physician, who used cocaine as a panacea, that it was not addictive. That doctor subsequently recanted, but Skorsky paid no attention. He believed the retraction was made under pressure from pharmacologists who had no incentive to cease production of the medications that cocaine might supplant. Their representatives either paid or threatened the Viennese to repent.As the patient was escorted to his room, he assaulted the orderly, Alevtyna. They tried pulling him off her, but, though he released his fingers from her neck, he buried his teeth in her leg. The poor orderly, who had not until then been attacked by a psychotic, nearly died of fear. Later, panic set in over Skorsky's diagnosis. He told her about the consequences of syphilis: grotesque patterns on one's face due to infection of the skin, mucous membranes, cartilage, and bones. He went on about the devastation to the central nervous system, which they had just observed in real life: “The face starts to look like lace some mangy dogs fought over before rolling in the mud.”Alevtyna, who had not yet regained her faculty of speech, straightened up. Ignoring the slavering male orderlies, she bared her leg to get a better look at the wound. She then ran down the hall and out into the garden, where she fell on the ground to rip up grass and small bunches of daisies. Alevtyna ate them along with the soil in their roots.“Minor hysteria. She needs fifteen milligrams of cocaine.”Skorsky took a snuff box out of his pocket and scooped up some white powder with a toothpick made from a goose feather. He gave the order to close Alevtyna's mouth and one of her nostrils, forcing her to snort the medication.We fretted over her so long that evening fell. I decided to walk down, along the ravine, behind the church.It was unlikely there were any large beasts there, but something was rustling. The pits and mounds, ravines, paths, graves of witches whose living sisters flew in the treetops from time to time, the whispers of the forest spirits, the spirits of the nutcases who died in the hospital, the spirits of the monks from the St. Cyril Monastery, Zmei Gorynich and the bogatyrs who wanted to defeat him. The city would be calmer without this forest. I saw the gaps between the trees and went off in the direction of the tram tracks.As I was coming out of the forest, there was a patch of Amanita muscaria that had been trampled into porridge. A bit farther on, the body of Professor Bilinsky lay killed in the blackberry bushes. The way he was lying it looked as though he had not struggled before death. I quickly examined his body but saw nothing out of the ordinary. There were no wounds, no dirt under the fingernails. Animals had not yet smelled the carrion, but swarms of various insects covered him. Oh, why did I have to find the putrid body?The best thing would be to take the tram to his house to inform his relatives. The doors closed, and I noticed my own calm. This death had not evoked any emotions in me other than a feeling of responsibility, the need to tell the family. But also—some alarm at the thought of who the murderer could be. I knew that it was murder.“Your nose is bleeding.” A woman as round as an onion, carrying two baskets full of strawberries, offered me an ironed and starched handkerchief.“Have I dirtied my shirt?”“No, it's as neat as a pin. It's just your nose that's dirty. Wipe it now before you spray blood on my strawberries.”“No one will see the red on red.”“Ah, but it's salty!”“You know why it's not sweet? We'd drink it like syrup.”“Those with Christ in their heart do not talk that way.”“Are your strawberries expensive?”“Why? What?”“I'm checking to see if you have God in your heart.”“Child, if you knew how I have to work for this berry! I have to weed it a hundred times. In a week, the quitch grass grows as high as a horse. And I water it with water I carry from the stream, it kills my arms... ”“How much are the berries?”“They're not for sale. Anyway, soon money won't mean a thing. Soon all money, all these papers made from the skins of sinners on their satanic presses will be annulled. What matters is how we treat each other.”“So if I try your strawberries for free, my ‘thank you’ will be enough?”“Hands off!” she said and thwacked my fingers.I heard loud laughter behind me—same laughter as from the café near the Continental. There was no one sitting near Alina. (This is what fate looks like, remember.) Without asking, I sat next to her, away from the old lady.“Excuse me, but the night before last didn't you, yes, didn't you intrude on my privacy?” She started right away.“I saw it a little differently. Who was that young man with the mustache who paid me for you?”“Are you checking to see if you can flirt?”The tram stopped. People got on and off.“Are you coming back from the hospital?” she asked. “Don't be shocked. My uncle works there. He's told me all about you.”“An uncle by the name of Skorsky?”(Remember: this is what fate looks like.)“Yes. Skorsky's been strange recently—says things that make me wonder if he hasn't lost his mind. Have you noticed anything?”“I don't know.”“You know perfectly well.”“Where are you going?” I tried to change the subject.“I have to send something to my theater friends in Odesa. By the way, they'll be putting on Oedipus Rex soon in Kyiv—in Ukrainian.”“Greek tragedy in Ukrainian! That's a first.”“Exactly. The troupe is rehearsing now in Odesa. The theater where they will perform this fall is being remodeled.”“Wait. Now I remember where I've seen you before—it was at a performance! Vynnychenko's Black Panther and White Bear, at the Bergonier on Fundukleivska.“The same director is doing the Oedipus. He's my friend.”“He's your friend in what sense?”“Again with that tired subject. By the way, I've been thinking about you.”“And I about you.”“That's good. I was thinking not about you, to be precise, but about that elevator you invited me on.”“Who was that man with you?”“Like a broken record! Even if he had been my fiancé, I'm not bought or inherited. I'm not a brooch or a hundred acres of land, and I'm not a house in Kaniv!... Who was with you when you saw Black Panther?“Ah, so.”“Answer!”“That was my mother. She looks very young. She is coming to Kyiv the day after tomorrow. I can introduce you.”“Oh, this is my stop.”I looked out the window and realized that I had long since passed the stop for Bilinsky's.“Can we see each other again?”“We can. But you have only one chance.”Alina the anarchist wrote something on a scrap of paper and handed it to me.Morning, not morning but a thick porridge (I hate porridge). Dew, thick spit, crushed fruits, urine, all on the sparkling cobblestones. The sun, just barely having made its appearance, is already scorching. The human masses scurry and grumble like poorly digested food inside a stomach.I walked diagonally across St. Sofia's Square, then along the perimeter, then one edge, then again diagonally across. I went underground. The basement café of the Continental Hotel was practically empty. I again asked the server to bring the cloth with the embroidered portrait, but I couldn't remember the musician's last name, only that it ended with -sky. The server said that -sky was currently in the southern cities of Yalta and Odesa. I added that Kurbas, the director, Alina's friend, was also in Odesa, rehearsing Oedipus Rex, and that he'd previously put on Black Panther.I was bored, so I walked along Khreshchatyk and then headed down, calling to mind all the Kyiv churches of Podil: there's Birth of Christ, St. Nicholas on the Shore, Intercession, Pyrohoshcha, Holy Presentation, St. Dymytrii Rostovsky, St. Illia's. And also the Epiphany Brotherhood Monastery, Ascension Convent, and St. Katherine's, all these whipped-cream churches on the waffles of our streets. A few of them reminded me of themselves by appearing suddenly out of nowhere.The smells on Kontraktova Plaza where commerce buzzed were like multicolored light bulbs turning on one after another. Here you could catch the aroma of Balabukha jam, which blended with the next smell, English shoe polish at the Raiskys’ shop. Then the crunchy-smelling cabbage from old women standing in a row like herons and spitting out the shells of sunflower seeds. Farther on, the stench of a good-sized rat that crawled under Mrs. Shevchuk's shop where she sells broadcloth. Oh, she can't scream: no, she'll quietly dig that rat out herself so as to not scare off her clients.I bought a paper and two pairs of underwear. I asked two laughing young chambermaids who were secretly puffing in a grape-filled yard for a smoke. I wandered around Podil until evening when I came across a sawmill near the Dnipro that surprisingly smelled pleasantly of mazut fuel oil. The weather was dry, yet in the middle of the road was an enormous puddle, a deep dark black. A forty-year-old woman in a pale pink dress stood near it. The theatricality of it all provoked me to pose her a question,“Ma'am, what should I do?”But she paid me no attention. I shouted,“What should I do?”“What to do, what to do?” she said in Polish. “Jump in the water and swim so far away that you cannot return.”I quickly crossed a section of the forest. The wind brought a mixture of unpleasant air, like a stinky handkerchief held under one's nose. Passing the trees, I saw light in the spaces between them and exited at the hospital.Outside the windows, two orderlies lay in chairs with their heads thrown back. Two others—fools—ran around the yard in different directions, peering out at... something. The lights on the first floor of the hospital were on, and the staff milled about.“You're just in time!” said Ivan, a tall, young orderly.“For what?”“Your patient ran away! We went into his room and he wasn't there.”“What patient?”“The one who bit Alevtyna,” said Danylo, the other orderly, short and middle-aged.“That's Skorsky's patient, not mine.”I had no intention of helping them. This was all history—like my family, Kyiv, and my previous life. I had no intention of thinking about it. I wanted to go to my office, pack up my field surgery kit, and get out. So what? Their psychotic syphilitic ran away—it happened.Of course, that patient could have something to do with Bilinsky's murder. But that was no longer my problem.“What a strange coincidence!” the doctor on duty said. “Comrade doctor, the other one responsible for this patient was just here.”“And where is he now?”“He took off toward the church to look for the patient.”“Didn't the patient escape earlier?”“Don't know.”“How do you not know? You had better call the police, moron, before he kills someone. And get those sleeping orderlies to look for him.”“They can't... ”“Why not? Should I go wake them?”“They're on morphine.”“And you, I can see, have lost your mind. Go, catch your psycho! If it turns out that he killed Bilinsky—and on your watch—you can't imagine what's in store for you.”I adjusted my homburg and set off in the direction of St. Cyril's, that unwelcoming monolithic cube. I glanced around—what if our escaped syphilitic were to jump out of the bushes and bite or strangle me. I looked around because I wasn't sure of my actions, wasn't sure of my choices. Tripping over a clump of clover, I reached the open doors of the church. I couldn't stop myself from going in.The walls and ceiling were covered with frescoes. There was what used to be an angel rolling up the sky on the southern column of the narthex. But also graffiti: people scratched their names on it so as not to be forgotten—their idea of eternity. Prince Volodymyr the Great compared this activity to the desecration of graves. The vandals paid a fine and were beaten with canes. During the raids of Batu Khan, the church was deserted and cracks appeared all over it. Wild martens and feral dogs sought shelter here; insects swarmed under the ceiling with its red mosaics. Birches grew in its midst. Water seeped in the cracks, the water became ice, the ice widened the cracks, more water seeped in the cracks, becoming more ice that further widened the cracks, the wall split and nearly fell over, and then the wall fell over. Yet the angel is still rolling up the sky... When I reached the exit, I heard a rustling behind me. I turned after I stepped outside: in the depths of the church, like a stick in a pot of tar, stood a man with a large bag thrown over his shoulder and a revolver pointed right at me.“Is that you, Doctor?“Don't move!”“What's... Skorsky, what's with you?”“Don't move, I say!”“What are you doing here?”And finally I understood... Skorsky was himself the psycho! (Really, I had known for a while.)“You are the murderer! I knew it! But—why?”“Shut up.”“It was you. You! The stolen cigarettes, the strange behavior, Bilinsky. If I shout, everybody will come running. They've already called the police!”There was heavy breathing behind me. And then a gun rang out.The city is overgrown with new buildings. They encircle everything that was once on the periphery. Kyiv has become an old lady that can no longer restrain herself in the face of pastries. The city climbs farther. It steps over the swamps, turns the old rivers into a series of lakes; the other bodies of water it drives into canals. The grain that falls from the wild wheat is black. When the sun heats it, the grain melts and trickles into the earth. St. Cyril's stands indestructible. No one spackles the small cracks in its walls with either expensive putty or glues, nor with cheap cement and whitewash. One day a small fox appears in the doorway. It runs inside and along the floor of simple gray tiles. The gods watch from the walls, watch and fall into ruin. The fox runs to the iconostasis. Before it is a time-darkened Virgin Mother and Child in oil on sheets of zinc. The fox runs the metal steps that wind up to the second floor. The fox runs past all the vaults, naves, all the frescoes. A buckthorn seed flies in through a broken window. It will be the first. Soon the buckthorn will grow everywhere. A dumb hare will make its nest in the buckthorn bushes and nightingales will settle in the upper branches to sing until the end of the world. The fox runs between the thick rays that penetrate the windows. It catches one of the rays, squints its eyes, and warms itself in the sun.The shot rang out, but I did not fall. I looked around—and on the church threshold was our syphilis patient bearing a rod. His head lay on the rocks by the doorway.“If only he'd been at the stage of nose deformity! Just imagine: a hole instead of a nose plus a hole from the bullet—like an extra pair of eyes!” Skorsky laughed at the corpse.“We need to call the orderlies.”“They heard the shot. They'll run here on their own. You see, Professor Bilinsky believed it would take two or three years to wrap up this patient's case,” Skorsky told me. “But I took care of it much faster!”“Excuse me, but I'm going crazy in this city. I thought that you were Bilinsky's murderer.”“Just so. Why not? I am Bilinsky's murderer.”“Don't tease. You've changed a lot recently, so... ”“Yes, I've started killing people. You might term such a change significant.”“You have the right to irony.”“I am not being ironic.”“Let's call it sarcasm.”“It's the honest-to-God truth.”“And yes, you have the right to mock me.”“Well then, let's be done. To the horses!”“What horses?”“Alina's waiting!”Alina, her uncle Skorsky, a few others I didn't know, and I rode like the wind that ripped off my homburg and carried it back to Kyiv.“There's a fresco in the choir loft at St. Cyril's where Vrubel painted himself and patients from the hospital as the apostles. When I came across it by accident, I really believed they were saints,” Alina said.“I've never been up there. I've only seen the church from below.”“Remember the way back so you can see it sometime.”“The Puchai River used to flow here. You shouldn't trust the landscape,” Skorsky said, reaching for something, perhaps his bag, just when we left the darkness of the trees and saw the endless steppe ahead of us.We rode all night without stopping. Though no one was chasing us. Though we had nowhere to be. We rode like beasts released from a cage. The promises of the horizon turned what we'd left behind into a cage fit for those from whom freedom had been severed, like an anomaly, at birth.The pre-morning sky looked at first like a sack of turnips—filled with something heavy. But with each verst, the sky became lighter. When it was finally light enough to see clearly, we arrived at a knoll at the foot of a stone wall that from a distance had appeared to be a gigantic piece of halva. The exterior ruins of the castle gave no hint of how it was when all was fine here, when people defended themselves successfully from the nomads’ raids. From far off, the wreckage looked like a natural agglomeration of stones—a rocky elevation, no more: a cluster of cliffs. It would rain a few hundred more times, a few hundred more winds from a few hundred directions would blow on this heap, and it would collapse as though nothing had ever been here.A few stalks of wheat grew from one of the rocks. Someone had probably cast a handful of grain here for some birds that forgot to eat it.“Who could this castle belong to?” I asked Skorsky.“I reckon the Swan Princess,” the doctor rejoined, hoping to sound knowledgeable.From behind one of the piles of gray sandstone emerged a young man in a black reptilian coat and a white papakha as lush, bright, and out of place as a dahlia. His name was Artem. The heat was melting our brains, but he was dressed like that, in rooster fashion, which was popular among the otamans. Artem helped Alina dismount her horse and tried to kiss her on the lips, but she offered him a cheek instead.Had she been racing to see this clown?We entered the yard—the ruins had fashioned an internal space that was more or less protected, at least from strangers’ eyes. It turned out that there were even places where it was possible to hide from the rain, and from there the ruins didn't look half bad.In the center of the court was a table, and on it a wooden bucket with pink gladiolas. How romantic! It all looked like it came from outer space. Where on earth, in the middle of the steppe, far from any village or town, did this table, this simple table, come from? And the gladiolas? The steppe hadn't been plowed in so long that any cultivars would have gone wild, degenerated, dried up completely.A campfire crackled nearby—a little preview of what we would soon do to the houses, villages, and cities. Artem the otaman brought over a cezve from the fire and poured the first portion into a small, copper cup for Alina. He also got out a porcelain cup with images of rosy cherubim—but how...?“Who else would like coffee?”Only Skorsky and I responded. The question excited me, even distracted me from the thought of the kiss I had recently witnessed and the Kyiv I had recently left.“It's obvious who the professors here are; cultured people drink coffee. Are you both doctors?”“Uh-huh.”“For wolves of the steppe, like us, doctors are gold, even more precious than gold. Actually, a Hippocrates like you should eat more, because those in your profession will soon be worth your weight in gold. Work on your figures, both of you.”“Who will take pity on the horses that have to carry us?”“We'll find the horses. And very large doctors can be transported on machine-gun carts. We'll need to seat the otamans near you. Only a fool would shoot at a doctor.”“I think we'll find quite enough fools here.”“With your beard, Doctor, you look like Tsar Nicholas II. But even so you won't be shot. You might even be canonized!”“We've only just arrived and you're going on about executions,” Skorsky grumbled and checked to make sure that he still had his bag.“Apologies, apologies, pardonnez-moi. But you are not merely a doctor. A venereologist! Skorsky, you're a specialist! A venereologist is the most important person in wartime. The most valuable! You are the botanists of war. You can't imagine what varieties of flowers grow here, and these beds have long awaited a proper gardener. Or even just a man with a scythe!”“Bite your tongue,” Alina said. “I don't need to listen to this.”“Yes, yes, of course. Excuse me, my r—. ” He almost said “rose.”We rested all day. We went down to a surprisingly close river overgrown with lilies. We rowed the boats left by fishermen. I talked to Skorsky. He took his bag everywhere, refusing even to swim so he wouldn't have to part with it. I asked him what he had in it, but he said it wasn't my damned business.Alina rowed with the otaman to the middle of the river. They were having a loud discussion. She was waving her hands. The current carried their boat downstream slowly and smoothly. What a nuisance, that current!I tried to meet with Alina one-on-one, but she was avoiding me. In the morning I was confused, by lunch I was sad, and after lunch I got angry.In the evening, I lay on the hot grass and drank another cup (I have no idea where they got such good coffee), which had no effect at all on my sleep. I watched the Perseids. Every year, the Earth passes through the tail of Comet Swift-Tuttle. People can see the meteor shower and make a wish. I wished. I counted forty-seven falling stars. All forty-seven of my wishes were for the same thing.Around the campfire, they were sitting, talking. I saw how he tickled her face with a piece of grass and she brushed him off in annoyance. Then they were screaming at each other. Later they again spoke kindly, after which they again quarreled. My joy grew after each tiny mistake that Artem made. I wanted him to show the worst he was capable of.They were screaming at each other, but all I could hear was beautiful opera singing. The stars fell to the sound of their screaming. The stars blessed my joy.Then this happened: Alina kicked the fire, scattered burnt kindling, and burned some of the grass. Artem grabbed her by the arm, but she broke away from him and ran off to the horses.“Go then! I guarantee you'll get to Katerynoslav and return with your tail between your legs.”“I'm going to Huliai-Pole! To Father Makhno!”I jumped up and ran after her.“Where do you think you're going?” Artem shouted.Really—where was I going? I was going after her: to Huliai-Pole, to Katerynoslav, to Rome, to Washington, to Istanbul, to Montevideo... “Go to sleep,” he said. “Come morning, this coquette will be here, right as rain. We've already been through this show. Tomorrow she'll be right here next to my boot!”... No, she won't.In some sort of shape we entered some town. There were some buildings that were some colors, some trees, some streets, some roads, and some signs. Posts, flustered birds’ nests, echoes, colors, shapes—each of some kind. A wedding procession was coming toward us. If you want to make orange, you need to add yellow to red, and then bam—it's black. If you want to salt the soup, shake in a little, and then bam—two handfuls. You want to say a kind word, and then bam—a punch in the face. I was rocked around like a watermelon on a boat and threw up my breakfast straight into the horse's fluffy mane. Sanko found this hilarious, but I said I'd pulverize him. So Sanko sped ahead.No one knew anything about Alina. The daytime sky was like a poorly washed bowl. The sun was a squashed, rotten apricot. The night sky looked like the sole of a boot to me. The moon was a dirty cheap copper coin that had gotten stuck to the sole. Everything seemed spoiled to me, irrelevant, unnecessary. Without her, this journey was a waste of time.“You'd better stay away from everyone,” Artem said. “You'll infect us with your pining, and pining is worse than the clap.”The wedding procession was before us. The young couple, still utter children, walked so calmly it was as if they didn't see us. As if we were made of a light breeze—our bodies, clothes, our horses and their iron shoes—of the lightest gasses. As if we were visible only to ourselves and the coal-black dog that barked, panting and gasping.The wedding was headed straight for us. We were in the middle of the road, and so were they. We approached each other slowly, a wave going toward a wave. Some ten meters before their indifferent faces, I noticed the color of the bride's eyes. And the coral-colored tulips that fell on the road before her. Round goose eggs on meaty stems, the flowers were falling and falling before her. The bride's eyes were almond shaped.“Hey there,” Artem shouted at me. “Wake up!”I came to and saw the whole village, everyone there, not realizing my group had turned left onto a side street away from the procession. The tulips disappeared—where'd they get tulips in the fall? I was sitting alone on my horse in the middle of the road, and the entire wedding procession came to a stop. I moved to the side, and the throng marched on, cutting off our escape route. We rode a few more meters and came across the synagogue.“You know what, you're right,” said the otaman.“Who is?”“Oleksii is the only one here who's right.”“About what?”Artem turned his horse and raced back. Everyone stood still while he ran his horse into the crowd and began firing his revolver. People scattered in all directions. Artem trotted, cackling like an imbecile. The horse kicked an old guy in the mouth. The man fell, spitting out his gold teeth. We rode up to the commotion and formed ranks, but none of us wanted to join the otaman.The bride stopped in the middle of the street. On both sides were buildings and trees, as well as dust, sky, and sun. She stood still, beautiful, as if nothing had happened. Then she adjusted her garland and walked calmly on.“Well, should we get some sugar now?” Artem laughed, looking at the bride, and off he went toward the sugar factory.It was then I noticed that all of the houses had shutters—fuchsia, blue, ocher—and that all the shutters were closed.We flew toward the dirty building, whistling and shouting. If there had been aesthetes among the otamans, they would certainly have razed the abomination in this field after seizing it. They would have spread soil on top and sown buckwheat. Long live buckwheat!, that wonderful crop. Like hunting dogs hot on the trail, we raced to our defenseless victim, with the baying of hundreds of hounds behind us. The field shook beneath us. We became an artist's canvas, evolving from Realism to Romanticism, Romanticism to Expressionism, Expressionism to Suprematism. If we had been painted in black and white, we would have been splotches (until the ink ran, annihilating all remaining patches of white).Two men stood near the gate—unarmed and undressed, in nothing but their undershirts and boots. Our fervor, our kinship with the elements, our entirety, were all for naught.“Jesus Christ! What bores!” Artem exclaimed. “How boring you are!”“Maybe boring for us, but fireworks for them,” Sanko said, dismounting his horse.“The fear of death engenders creativity,” our otaman—a distinguished philosopher of the early twentieth century, that demonic breed—prophesied.He went on, “Excuse me, but with all due respect, we are not going to search you. Just show us right away where the money is. Why are there so few of you? Don't say there's not much money. I want piles and piles of money! If you don't show it to us, we'll print our own on your skin. Believe me, we will.”We entered the factory grounds. There were no workers, only an enormous mountain of sugar beets that looked like a pile of coal from a distance and a pile of dead rats from up close.“So, did you have a good year?” Artem asked a man in an undershirt.“Not really—too dry.”“Nah, that's fine. You wouldn't have been able to gather most of the harvest this year anyway. There's a fire burning across all of Ukraine, all of Russia. The whole world!”While Artem tossed thoughts like well-chewed sunflower seeds into the crowd, the two men quietly stepped aside and then ran fast ahead to the factory's main hall. The gigantic door slammed shut. The gate was locked behind us! The windows were smashed! The factory roared from inside like a cumbersome machine starting up. Bullets whirred through every window.“Bastards! It's a trap! Quick, after me!”Still on horseback, Artem bounded over to a vast window, low to the ground, and smashed it mercilessly. He broke the frame and jumped inside on his horse. I and a few others followed. We broke into their lair, threw open the doors, and let the other warriors inside.Iron vats of hot sugar were steaming, pipes were clattering; machinery groaned.“Parasites!” Artem gritted his teeth. “I'll get you. I'll get you red sons of bitches. Painted whores!”At the word “painted,” his horse fell to the ground. Lying prone, Artem continued fighting, but the red soldiers wouldn't let him stand. Fighting nearby, I rode over to assist but did not know where to aim. Artem got up, ran forward, and brought his sword down on the head of the closest soldier, all the way to the middle of his skull, to the bridge of his nose. It was like butchering a pig. Artem thrust the sword into the buttock of another who was fleeing and cut off his leg at the bend in the knee.“I'll cut off every last one of your asses! Cut off your asses!” Artem bellowed.A half hour later, the dead were lying, the captured sitting, and the victors doing anything they pleased.“Skorsky, are there a lot of casualties?” I asked the doctor, whose hour it was. I hoped not, because I was too tired to help him.“Just a few. The dead are already dead, and the wounded are not ours.”Though Skorsky rarely asked my help, and though I'd become an ordinary soldier, the doctor in me was still present in the most unpleasant attribute—knowledge. Others saw an eviscerated man, pieces of dusty flesh smeared with clay, soil, sand, and straw. I saw a perfectly formed kidney hanging perfectly from the rest of its body like a child's mitten from its coat. You could try this death on for size. Wear it like a sanbenito of the Inquisition.Artem counted the money and then lay on the floor alongside the gigantic sugar mountain in the middle of the room. From time to time, the crystals rustled as they fell.“I didn't think you'd be such a fighter!” the otaman said without turning toward me. “I thought you'd be healing us. You'd keep to the rear and we'd hide you like a girl. But here you are, in the vanguard, like a lion!”“I got excited,” I told him, choosing not to react to the “girl” part.“’Cause Alina said there was no sense counting on you to fight.”“Really?”“Does that sting?”“Why would it? I'm a doctor—not everyone is. It requires a brain. Unlike waving a sword.”“Yeah, yeah. I gave her gladiolas. We were lying in the boat near that castle, doing all manner of things, and she told me all about you. How you met.”“You were lying in that boat talking about me?”“It was the day before you left Kyiv. You agreed to go with the anarchists so quickly!”“Were you surprised? Doctors make fast decisions.”“But you probably had great prospects. Your parents are rich, right?”“And who are your parents?”“Probably all your relatives fled abroad—bourgeois. Why did you stay?”“What the hell's your point?”“Alina, by the way, died a while ago. Probably.”“Don't jinx her.”“Listen here,” he said, staring at the ceiling. “And listen good. If you have designs on her—dead or alive—it's best you castrate yourself now.”“After you.”“If I want to kill somebody, you know, I just do it.”At last he looked at me. I was lying on the floor nearby and looking in his direction, sweaty and relaxed, my appearance complemented by my disdain for his opinion, his authority, his stupid hat. His everything.Artem raised his arm above his head, stuck a finger in the sugar mountain, and licked it. We both got up. Had I anticipated this turn of events, I would have readied a gift for him. Artem held his revolver. Under my hand I found a knife the workers used for gathering beets: it was a deliberately sharpened arc they sank into the swollen brassicas. I jumped up and quickly stepped around the sugar mountain.Artem's bullet hit a pane and broke the glass.“Not man enough for hand-to-hand?”The otaman shot again.“You should've challenged me to a duel, you romantic!”Encrusted with white crystals, I charged Artem from the sugar mountain. We fell in, and the sugar stuck in our hair, mustaches, nostrils, armpits.The gang ran in to get us apart, then backed off because it had nothing to do with them. By now the sugar mountain had burst its banks. Of the once perfect pyramid, a deformed mound remained.Wounded, Artem fell on the sugar mound, turning the white red.I stood before the gang sugar-coated and holding a bloody hook. The old otaman was drawing his last breath. Blood trickled from the corner of Artem's mouth and streamed from the left side of his breast.“What's the commotion?” Old Roman had just come in.“Be quiet,” the boys told him. And a good thing they did.“You killed him? You killed the otaman!”“Shut your mouth,” the boys told him.“You... ”I slugged Roman's stinky herring mouth. How did that son of a bitch find pickled herring in a sugar factory? My fist was now bigger and stronger than ever before, a steel anvil that could split nails and shatter memorial plaques. The unfortunate man's jaw twisted like an upper millstone that had gone off track from the lower.“Let's get out of here and go to Makhno's camp,” I gave my first order.We galloped so fast the grass burned beneath us. The birds and bugs had no time to fly out of the way; hooves trampled the burrows of rodents who didn't dare crawl out of their holes for a long time after. We raced like no one had ever raced before.The steppe, that sly fox, pretended to be an innocent fool. The steppe said, “I'm like Adam: I don't even know my own name.” But its grass harbored the tracks of thousands of armies and the heels of Herodotus, the crunch of Trypillia vessels, and the smell of Scythian hemp, Roman coins, clay figures of wolf people, the chevrons of Denikin's army, glass from the Chekists’ ruby stars, traces of uranium from flying saucers. I threatened it: “Steppe, show me your layers, or I will burn you, plow you under, flood you.” But it just replied: “I'm like Adam: I don't yet know my name.”I lost geography as if it were a silver coin. It fell out of my pocket and rolled through the feather grass that blanketed the steppe in white foam. The open space ahead was so endless that the whole world might as well have been steppe. If people ended up here from somewhere else, they would conclude they were on another planet. The coin fell and became an argentum, became one with the ring on the hand of the princess who had one green eye and one blue, with the twisted candlestick at the monastery on the other side of the steppe, with melted ingots. It broke down into simpler elements, simpler and simpler yet. The horse carried me spreading the seeds of northern plants to the south, just as southern riders had once brought flowers and weeds to the north. And then I turned back. Just as I had no geography, I had no time. Every night I fell asleep with the thought that the next day I would again race. Through all spacelessness, all timelessness. I exchanged one horse for another, got on a train, on a boat, traversed forty versts on foot—in rain that brought the river up to the road, in heat that overturned cattle. The earth I walked on became mine. Mine was the water in the lakes and springs, clean water, dirty water, enlightened water, contaminated with oil, stinking of algae, of fish that died in wells, stinking of the memory of atrocities, water as clean as broken bread. The water did not become Alina.I was doing this for her: I got the basturma out from under my saddle, sodden with the horse's sweat, sliced the throat of a rich man whose daughter I had danced with at a ball, climbed into a vat of beet juice and took a sugar bath, carried out the expropriation of the savings banks, wiped the sweat from my face with my shirt—and the cloth turned red; I didn't know from what. If it was someone else's blood, I didn't care; if it was my own, even less.We mostly came across Reds. We scraped them up like old red paint on a door in order to repaint the boards black. Black looked better. Red is tasteless, but black has style. Healthy men died before us of myocardial rupture like bunnies found in the nest. The ones whose hearts were sewn of steel wire envied the deceased. Seizing estates, banks, distilleries, and prisons reminded us of gathering in the harvest. If you're too lazy to pick an apple, you can shake the tree; some of the fruit gets bruised when it falls. We seized buildings like we were shaking apple trees. No one picked the fruits, we just shook: shook under the beds, under the tables, behind the curtains. No, there was no picking. We just shook until the red juice spurted from the apples.Near the Khorol River with Father Makhno and me in charge, we captured sixteen machine guns and four cannons, as well as five hundred prisoners who immediately came over to our side. The villagers voluntarily gave us bread and cheese, chickens and kvas. People joined us. The front of the machine-gun cart said “You can't run,” and “You won't catch us” at the back. We took factory after factory. Millions of karbovantsi, thousands of poods of sugar, weapons. We smashed the telephone exchanges and captured the telegraphs. We made alliances with some and then with others. Lenin, Wrangel, Frunze, the Germans, Chinese, Australians, Kaiser Wilhelm II, Cleopatra, Maria Theresa Walburga Amalia Christina. We ran the steppe. There were a hundred thousand of us. There were three hundred thousand of them. There were three hundred thousand of us. There were a million of them. There were two million of them. We were all of humanity. We were so many that we were none.The nobles’ estates were long ago forsaken. In the people's deepest trunks lay silks and guipure laces that were once perhaps used only to cover a table. Five steps from the barn in the direction of the pear tree, some silver candlesticks are buried; there's a plaster figure of an angel in the chicken coop, covered with shit and feathers.I was reluctant to be going to my home, but I didn't see any way out. Fate intended me to be a different being from the one I was before.Here my grandfathers and great-grandfathers were born. Here the ones who caused my grandfathers and great-grandfathers to flee had stopped. When we were still far off I noticed that someone was in the house. It was our men—Skorsky had brought them here, about twenty in all. I asked Sanko, whom I had walked with side by side more than once, where the doctor was now. All the men answered that he was around somewhere, but I didn't see him that evening.In 1918, the spirit of my great-grandfather Stepan, along with my mother and uncle, had gotten into a britzka and scrambled off to Paris, to Napoleon, against whom my great-grandfather had fought with the Cossacks, to whom the Russians promised to return self-rule. Following him in the cart went the soul of Grandpa Oleh, who lost a finger when he cut down the old linden near the house; his second finger was blown off by a cannonball near Balaklava, and later his entire hand was cut off by some Turk. Next went the spirit of my father, also Stepan, who did not take part in any war but died of measles at the age of forty. They all got the hell out of here. First, they went to Kyiv, led by my mother, Tamara Makarivna, in order to collect Uncle's family and me, their son. And their son, it turns out, has now come back to rob his own home (I didn't drive my war buddies away, did I?). It's a shame that I didn't know where the bathtub was, or whatever they bathed me in when I was small. It would have been good to walk through the ranks of anarchists with that basin and tell them all to spit into it.Remembering every room, I carried Alina upstairs to my mother's bedchamber. There was no longer furniture or pictures, only bare walls. The bed and mattress remained, but that was enough. Mother hated noise, so she set up her room far away from the running in the halls and the creaks on the stairs. I adjusted the mattress; in a gap, looking like a stalk of wheat, there lay a gold bracelet that she lost in the haste and that the thieves could not find in the mayhem. I tucked it into my pocket.The place could still be saved. It was strong, built under the leadership of my grandfather, who knew how to do it right. He built a sawmill, a gristmill, a dress factory (today it's probably been ransacked, maybe even by our own men).Alina had a complete, displaced break in her right fibula. We needed water first. I went downstairs—the guys were dragging out the piano like an old cow to the slaughter.“What are you doing with that?”“Taking it out.”“Why?”“What's it to you? We want to have fun.”“Can you play?”“We're not your bourgeois lily-handed bitches.”They couldn't play, but they were famous at destruction. “Noise is the music of the new time,” one of the smarter among them might have said. “But noise is the opposite of music. Just as a rose is the opposite of your ugly mugs,” I'd have responded if there was anyone to say it to. I could also have said that this was a Bosendorfer grand piano, that it was very valuable—but do the guys not deserve such a luxury?“Why are you so boring? We're relaxing.”“Then let me play a little first.”“Go ahead, but fast. One-two.”So I played. As before. My fingers ran up and down the black and white keys, which weren't simply keys of these, the simplest, colors. These were the keys that remembered my fingers specifically—achieved by that slovenly German Katerina, our governess. She knew a bundle of languages, could play the piano, and was interested in the latest scientific discoveries. But she had not an ounce of sympathy for anyone who couldn't master anything on the first try. More than once she hit my pinkie against the black key that remembered every one of its four thousand touches. She would pound it on the key and shout, “Si bémol! Si bémol,” and later bang my fingers and translate, “B flach! B flach!”I played. I could not expose myself, so the only thing I could do was believe in miracles. What if these coarse men saw value in this bit of furniture so unintelligible to them? And what if they didn't destroy it, this emblem of my childhood, my land, my air, which I could protect in no other way? My air. My water.“Shchedryk, shchedryk, shchedrivochka,” one of them who recognized the tune began to sing along.“Look at you.” They did not expect music from me, who had until recently been drinking blood like water.They said, “Again, again!”A group of curious men gathered around me. They were ordinary farmers, thieves, and recidivists, peasants and workers, everyone except for Skorsky. They needed this music as they needed baths. The music cleansed them from the inside, perhaps. They had not heard anything besides the whistle of a bullet, the neighing of a horse, or the knocking of a chisel and the whirring of a saw, amputating limbs, for a long time.But it could not go on long. I did not close the piano lid, just stood and went to fetch water for Alina, leaving the unfinished song for later. The well was to the north—that is, at the “Head.” My father once promised to give me a compass if I could learn to identify the ends of the earth by means of the sun. And to make it easier to remember, I gave each one of them a name: the east where the day begins was “Right” (my right hand), the west “Left,” the north “Head,” and the south “Feet.” Back when I could still do whatever I wanted all day long, I would wake in the morning and say: I'm going to the Feet. The mound was at the Feet, Left had the river, Right had the forest. It was only to the Head that I rarely went, because a village was located there. When the villagers saw me, they would speak in whispers and avoid the master's son.... I wiped her brow and her burning, sunken cheeks. I lay down next to her to feel the heat of her skin.When the fire in Alina calmed slightly, I went out into our orchard. My father had once been given a gift from Japan—a tulip tree that blossomed with yellow-green flowers. It had to have grown in the time that I was away. It would have been fatal had it been cut down. I again took the stairs down into the drawing room and came across nobody—they had all disappeared in search of food or were hidden away in their burrows. In the middle of the hall, like an opened rib cage, was the piano, irreparably shattered.B Flach! B Flach!Translation © Ali Kinsella 2022. (shrink)

There is a critical need to establish a space to engage in careful deliberation amid exciting, important, necessary, and groundbreaking technological and clinical advances in pediatric medicine. Extracorporeal membrane oxygenation (ECMO) is one such technology that began in pediatric settings nearly 50 years ago. And while not void of medical and ethical examination, both the symbolic progression of medicine that ECMO embodies and its multidimensional challenges to patient care require more than an intellectual exercise. What we illustrate, then, is (...) a person-centered framework that incorporates the philosophy and practice of palliative care and care-based ethical approaches. This person-centered framework is valuable for identifying and understanding challenges central to ECMO, guides collaborative decision-making, and recognizes the value of relationships within and between patients, families, healthcare teams, and others who impact and are impacted by ECMO. Specifically, this person-centered approach enables caregivers to provide compassionate and effective support in critical, and often urgent, situations where conflicts may emerge among healthcare team members, families, and other decision makers. By reflecting on three cases based on actual situations, we apply our person-centered framework and identify those aspects that were utilized in and informed this project. We aim to fill a current gap in the pediatric ECMO literature by presenting a person-centered framework that promotes caregiving relationships among hospitalized critically ill children, families, and the healthcare team and is supported through the philosophy and practice of palliative care and clinical ethics. (shrink)

According to the model presented in this paper, the beginning of life was marked by the coupling of two complementary nucleotide bases: adenine and thymine. The adenine-thymine system received photons from the sun and stored their energy in the form of a chemical high-energy bond between two phosphoric acid molecules, which were before-hand fixed by adenine from the aqueous environment. The energy of the high-energy bond was then delivered in the form of two waves of electronic excitation. These were utilized (...) to synthesize new molecules, starting from the carbonic acid and ammonia molecules, fixed from the aqueous environment by the polar groups of the nucleotide bases. In this way, a nucleotides-histone protosystem was self-synthesized, evolving step by step towards complexity, by means of some internal cybernetic and informational mechanisms. During its evolution, the NHPS synthesized a limiting membrane, produced the organizing elements of the cellular organelles and constructed microtubules and microfilaments. Subsequently, the NHPS evolved to the building of DNA-histone system and formed the cellular nucleus. (shrink)

Endosomes, which comprise a diverse population of membrane vesicles and tubules, sort proteins and lipids to various cellular destinations. The organization and functions of these pleiomorphic cellular organelles have been extensively studied. Matsuo et al.1 now provide new exciting evidence on the role of lysobiphosphatidic acid (LBPA), a resident phospholipid of internal vesicles of the late endosome, in the control of membrane invagination and endosome biogenesis. In vivo, LBPA functions are controlled by the adaptor protein Alix and depend (...) on pH gradients along the endosomal compartments. BioEssays 26:604–607, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

In the present study, we have demonstrated hysteresis phenomena in the excitability of single, enzymatically dissociated guinea pig ventricular myocytes. Membrane potentials were recorded with patch pipettes in the whole-cell current clamp configuration. Repetitive stimulation with depolarizing current pulses of constant cycle length and duration but varying strength led to predictable excitation (1:l) and non-excitation (1:0) patterns depending on current strength. In addition, transition between patterns depended on the direction of current intensity change and stable hysteresis loops were (...) obtained in stimulus:response pattern vs. current intensity plots in 14 cells. Increase of pulse duration and decrease of stimulation rate contributed to a reduction in hysteresis loop areas. Changes in amplitude and shape of the subthreshold responses during the transitions from one stable pattern to the other, suggested that activity led to an increase in membrane resistance, particularly in the voltage domain between resting potential, and threshold. Therefore, we modelled the dynamic behaviour of the single cells as a function of diastolic membrane resistance, using previously published analytical solutions. Numerical iteration of the analytical model equations closely reproduced the experimental hysteresis loops in both qualitative and quantitative ways. In particular, the effect of stimulation frequency on the model was similar to the experimental findings. The overall study suggests that the excitability pattern of guinea pig ventricular myocytes accounts for hysteresis and bistabilities when current intensity is allowed to fluctuate around threshold levels. (shrink)

Neurotrophins (NTs) are {?AUTHOR} a family of structurally related, secreted proteins that regulate the survival, differentiation and maintenance of function of different populations of peripheral and central neurons.1,2 Among these, BDNF (brain‐derived neurotrophic factor) has drawn considerable interest because both its synthesis and secretion are increased by physiological levels of activity, indicating a unique role of this neurotrophin in coupling neuronal activity to structural and functional properties of neuronal circuits. In addition to its classical neurotrophic effects, which are evident within (...) hours or days and which usually result from changes in cellular gene expression, BDNF exerts acute effects on synaptic transmission and is involved in the induction of long‐term potentiation. Many of these rapid effects of BDNF are mediated by its modulation of ion channel properties following TrkB‐mediated activation of intracellular second messenger cascades and protein phosphorylation. However, recent reports have shown that BDNF not only acts as a modulator of ion channels, but can also directly and rapidly gate a Na+ channel, thereby assigning BDNF the properties of a classical excitatory transmitter. Thus, BDNF, in addition its role as a potent neuromodulator, emerges as an excitatory transmitter‐like substance which acutely controls resting membrane potential, neuronal excitability, synaptic transmission and participates in the induction of synaptic plasticity. BioEssays 26:1185–1194, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The identification of additional subunits of the cGMP-gated cation channel suggests exciting questions about their regulatory roles and about structure/functional relationships. How do the different subunits interact? How is the complex assembled into the plasma membrane? Divalent cations have been implicated in the regulation of adaptation. One often overlooked cation is magnesium. Could this ion play a role in phototransduction?

Ca2+ transients in myocardial cells are modulated by cyclic AMP‐dependent phosphorylation of a protein in the sarcoplasmic reticulum. This protein, termed phospholamban, serves to regulate the Ca2+ pump ATPase of this membrane, thus altering the mode of Ca2+ transients and the myocardial contractile response. Elucidating the structure of phospholamban and its intimate interaction with the Ca2+ pump ATPase should provide the basis for understanding, at the molecular level, how the cAMP system contributes to excitation‐contraction coupling in muscle cells.

The emerging field of lipidomics has identified lipids as key players in disease physiology. Their physicochemical diversity allows precise control of cell structure and signaling events through modulation of membrane properties and trafficking of proteins. As such, lipids are important regulators of brain function and have been implicated in neurodegenerative and mood disorders. Importantly, environmental chronic stress has been associated with anxiety and depression and its exposure in rodents has been extensively used as a model to study these diseases. (...) With the accessibility to modern mass‐spectrometry lipidomic platforms, it is now possible to snapshot the extensively interconnected lipid network. Here, we review the fundamentals of lipid biology and outline a framework for the interpretation of lipidomic studies as a new approach to study brain pathophysiology. Thus, lipid profiling provides an exciting avenue for the identification of disease signatures with important implications for diagnosis and treatment of mood disorders. (shrink)

From understanding ageing to the creation of artificial membrane‐bounded ‘organisms’, systems biology and synthetic biology are seen as the latest revolutions in the life sciences. They certainly represent a major change of gear, but paradigm shifts? This is open to debate, to say the least. For scientists they open up exciting ways of studying living systems, of formulating the ‘laws of life’, and the relationship between the origin of life, evolution and artificial biological systems. However, the ethical and societal (...) considerations are probably indistinguishable from those of human genetics and genetically modified organisms. There are some tangible developments just around the corner for society, and as ever, our ability to understand the consequences of, and manage, our own progress lags far behind our technological abilities. Furthermore our educational systems are doing a bad job of preparing the next generation of scientists and non‐scientists. (shrink)

Thy‐1 is a small glycoprotein of 110 amino acids which, folded in the characteristic structure of an immunoglobulin variable domain1, are anchored to the plasma membrane via a glycophosphatidylinositol (GPI) tail(2,3) (Fig. 1). It is a major component of the surface of various cell types, including neurons, at certain stages of their development (4). These qualities doubtlessly appeal to certain cognoscenti, but it is not clear why they would raise Thy‐1 to the status of a favourite molecule. Indeed, few (...) scientists readily admit to having a favourite. We study individual molecules because science is rooted in specific observations; but we do so in order to discover mechanisms of general importance. A molecule's appeal is dependent on its ability to reveal novel aspects of how nature works.Thy‐1 has been unusual in this respect. It was the first lymphocyte surface antigen shown to be restricted to a functional subset of lymphocytes (T cells in the mouse), a finding crucial to the development of cellular immunology(5); it was one of the first cell surface molecules to be sequenced and indicated the importance of immunoglobulin domains and GPI anchors as structural motifs(1–3); it has been pivotal in studies demonstrating that GPI‐anchored molecules are able to signal across the membrane they do not span(6, 7). Thy‐1 has revealed this much, however, with the charm of an adroit stripper: it has always promised glimpses of things more exciting than that displayed. In particular, the function of this molecule has never emerged.Our current work on Thy‐1 in the nervous system is, we believe, finally prizing this last secret into the open. It suggests that Thy‐1 on the neuronal surface interacts with one of the main glial types of adult brain, the astrocyte, to restrict axonal growth(8). There is no current consensus that astrocytes do regulate such growth, and this is the wider question we are addressing from the perspective of Thy‐1. At issue also is how to progress from knowing the nature of a molecule to defining its function. This task has already been achieved with molecules which were harder to characterise than Thy‐1. The problem is a classic Catch 22 situation: Thy‐1 has been readily characterised because it is small and abundant it is ten times more abundant than any other surface glycoprotein on rat thymocytes(9); but since there is so much of it, whatever it does it must do rather badly (or there would be no need to have so much of it!). Defining a function based on low activity or affinity is not trivial.Here I describe two aspects of work on Thy‐1. One is long completed ‐ the research which led to Thy‐1 being isolated and characterised ‐ and included because it demonstrates features which are still applicable to much research using a antibodies today. The other is our ongoing work on the nervous system, which is at that exciting early stage where hypotheses are formed, but the answers are still coming in. (shrink)

To commemorate 40 years since the founding of the Journal of Business Ethics, the editors-in-chief of the journal have invited the editors to provide commentaries on the future of business ethics. This essay comprises a selection of commentaries aimed at creating dialog around the theme Bringing Excitement to Empirical Business Ethics Research (inspired by the title of the commentary by Babalola and van Gils). These editors, considering the diversity of empirical approaches in business ethics, envisage a future in which quantitative (...) business ethics research is more bold and innovative, as well as reflexive about its techniques, and dialog between quantitative and qualitative research nourishes the enrichment of both. In their commentary, Babalola and van Gils argue that leadership research has stagnated with the use of too narrow a range of perspectives and methods and too many overlapping concepts. They propose that novel insights could be achieved by investigating the lived experience of leadership (through interviews, document analysis, archival data); by focusing on topics of concern to society; by employing different personal, philosophical, or cultural perspectives; and by turning the lens on the heroic leader (through “dark-side” and follower studies). Taking a provocative stance, Bal and Garcia-Lorenzo argue that we need radical voices in current times to enable a better understanding of the psychology underlying ethical transformations. Psychology can support business ethics by not shying away from grander ideas, going beyond the margins of “unethical behaviors harming the organization” and expanding the range of lenses used to studying behavior in context. In the arena of finance and business ethics, Guedhami, Liang, and Shailer emphasize novel data sets and innovative methods. Significantly, they stress that an understanding the intersection of finance and ethics is central to business ethics; financial equality and inclusion are persistent socio-economic and political concerns that are not always framed as ethics issues, yet relevant business policies and practices manifest ethical values. Finally, Charles Cho offers his opinion on the blurry line between the “ethical” versus “social” or “critical” aspects of accounting papers. The Journal of Business Ethics provides fertile ground for innovative, even radical, approaches to quantitative methods (see Zyphur and Pierides in J Bus Ethics 143(1):1–16, https://doi.org/10.1007/s10551-017-3549-8, 2017), as part of a broad goal of ethically reflecting on empirical research. (shrink)

With the same intellectual courage with which she addressed issues of gender, Judith Butler turns her attention to speech and conduct in contemporary political life, looking at several efforts to target speech as conduct that has become subject to political debate and regulation. Reviewing hate speech regulations, anti-pornography arguments, and recent controversies about gay self-declaration in the military, Judith Butler asks whether and how language acts in each of these cultural sites.

With the same intellectual courage with which she addressed issues of gender, Judith Butler turns her attention to speech and conduct in contemporary political life, looking at several efforts to target speech as conduct that has become subject to political debate and regulation. Reviewing hate speech regulations, anti-pornography arguments, and recent controversies about gay self-declaration in the military, Judith Butler asks whether and how language acts in each of these cultural sites.

Both RalA and RalB interact with the ubiquitous calcium sensor, calmodulin (CaM). New structural and biophysical characterisation of these interactions strongly suggests that, in the native membrane‐associated state, only RalA can be extracted from the membrane by CaM and this non‐canonical interaction could underpin the divergent signalling roles of these closely related GTPases. The isoform specificity for RalA exhibited by CaM is hypothesised to contribute to the disparate signalling roles of RalA and RalB in mitochondrial dynamics. This would (...) lead to CaM shuttling RalA to the mitochondrial membrane but leaving RalB localisation unperturbed, and in doing so triggering mitochondrial fission pathways rather than mitophagy. (shrink)

Microfilament interactions with the plasma membranes of animal cells appear to vary with cell type and localization. In the erythrocyte, actin oligomers are associated with the membrane via spectrin and ankyrin. The ends of stress fibers in cultured cells, such as fibroblasts, are attached to the plasma membrane at focal adhesion sites and may involve the protein vinculin as a linking protein. In intestinal brush border microvilli a 110,000 dalton protein links the microfilament bundles to sites on the (...) microvillus. A transmembrane complex containing actin stably associated with a cell surface glycoprotein can be isolated from ascites tumor cell microvilli and can be obtained still associated with microfilaments by gentle extraction and gradient centrifugation of the microvilli. These varied interaction mechanisms are believed to be needed to satisfy the different structural and dynamic requirements of the particular systems. (shrink)

Most metazoan organisms have evolved a mildly acidified and calcium diminished sorting hub in the early secretory pathway commonly referred to as the Endoplasmic Reticulum‐Golgi intermediate compartment (ERGIC). These membranous vesicular‐tubular clusters are found tightly juxtaposed to ER subdomains that are competent for the production of COPII‐coated transport carriers. In contrast to many unicellular systems, metazoan COPII carriers largely transit just a few hundred nanometers to the ERGIC, prior to COPI‐dependent transport on to the cis‐Golgi. The mechanisms underlying formation and (...) maintenance of ERGIC membranes are poorly defined. However, recent evidence suggests an important role for Trk‐fused gene (TFG) in regulating the integrity of the ER/ERGIC interface. Moreover, in the absence of cytoskeletal elements to scaffold tracks on which COPII carriers might move, TFG appears to promote anterograde cargo transport by locally tethering COPII carriers adjacent to ERGIC membranes. This action, regulated in part by the intrinsically disordered domain of TFG, provides sufficient time for COPII coat disassembly prior to heterotypic membrane fusion and cargo delivery to the ERGIC. -/- . (shrink)

One of the earliest structural changes observed in cells in response to many extracellular factors is membrane ruffling: the formation of motile cell surface protrusions containing a meshwork of newly polymerized actin filaments. It is becoming clear that actin reorganization is an integral part of early signal transduction pathways, and that many signalling molecules interact with the actin cytoskeleton. The small GTP‐binding protein Rac is a key regulator of membrane ruffling, and proteins that can regulate Rac activity, such (...) as Bcr, are likely to act on this signalling pathway. In addition, several previously characterized signal transducing molecules are implicated in the membrane‐ruffling response, including Ras, the adaptor protein Grb2, phosphatidyl inositol 3‐kinase, phospholipase A2 and phorbol ester‐responsive proteins. Changes in polyphosphoinositide metabolism and intracellular Ca2+ levels may also play a role. A number of actin‐binding and organizing proteins localize to membrane ruffles and are potential targets for these signal transducing molecules. (shrink)

Integral membrane proteins are found in all cellular membranes and fulfil many of the functions that are central to life. A critical step in the biosynthesis of membrane proteins is their insertion into the lipid bilayer. The mechanisms of membrane protein insertion and folding are becoming increasingly better understood, and efficient methods for the ab initio prediction of three‐dimensional protein structure from the primary amino acid sequence may be within reach. Already, the basic tools needed for engineering (...) and de novo design of integral membrane proteins seem to be at hand. (shrink)

It has long been known that the red blood cell contains a membrane skeleton that stabilizes the plasma membrane, determines its shape, and regulates the lateral distribution of the membrane glyco‐proteins to which it is attached. The way in which these functions are regulated in other cells has not been understood. It has now been shown that platelets also contain a membrane skeleton. In contrast to the membrane skeleton of the red blood cell, the platelet (...) membrane skeleton has actin‐binding protein, not spectrin, as a major component. The platelet membrane skeleton regulates the same cellular functions as the red blood cell membrane skeleton. Other cells may contain a membrane skeleton that is critical to their viability and normal functioning. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Excited DeliriumFalsifiability, Causality, and the Importance of AdvocacyArjun Byju, MD (bio) and Phoebe Friesen, PhD (bio)We want to begin by thanking both Kathryn Petrozzo and Paul B. Lieberman for taking the time to read and respond to our article, “Making Up Monsters, Redirecting Blame: An Examination of Excited Delirium,” so thoughtfully. They each offered us an opportunity to consider dimensions of excited delirium that we had not encountered as (...) of yet and encouraged us to think more carefully about them. In our response, we consider each of their commentaries in turn, given that, as a philosopher and a psychiatrist, they each speak to different aspects of our argument.First, we turn to Kathryn Petrozzo’s commentary “Excited Delirium: The Self-Fulfilling Prophecy of Police Brutality.” We are grateful for her generous comments and careful engagement with our arguments. While much of the commentary is supportive of our piece, Petrozzo makes three critical and insightful points that we hope to respond to here.The first point Petrozzo makes is that our assertion that excited delirium is non-falsifiable is not supported. She suggests that those “seeking to exonerate the police/first responders responsible for these deaths, are not accepting this evidence leading them to reject the excited delirium diagnosis, but rather, are crafting an incorrect causal narrative. This is deeply problematic, but it does not necessarily render excited delirium as nonfalsifiable.”Although we are intrigued by this challenge, we would like to hear more about what it would look like to falsify the phenomenon of excited delirium. The way that the causal theories related to it are structured are such that if one causal factor is not present (e.g., drug use), then another causal factor can be located (e.g., mental health), and if that is not found, another may be simply made up (e.g., genetic predisposition), making excited delirium multiply realizable in a seemingly endless fashion. This is precisely what took place in the case of Anthany Dawson, who was initially said to have been experiencing a mental health crisis, but was later said to have died from excited delirium related to a genetic condition never identified before (Hon, 2004; Razack, 2015). [End Page 361]In practice, confirmations of excited delirium are found on the basis of various unrelated factors, such that after a death involving police force, there is almost always the option to reach for excited delirium as an explanation/exoneration. According to proponents, there is no factor that could be present that could rule out the diagnosis of excited delirium as it is currently constructed. Indeed, even in the presence of video evidence showing police officers choking an individual until they stop breathing, these deaths are still attributed to excited delirium. This seems like a clear instance of non-falsifiability.Although Petrozzo might maintain that this is simply “an incorrect causal narrative,” it is a causal narrative that aligns with the current theoretical scaffolding surrounding excited delirium.The second point Petrozzo makes is regarding widespread criticisms of Popper’s demarcation criterion of falsifiability. Indeed, this criterion has been called too inclusive, in that any empirical claim can be called falsifiable in principle—even if it refers to a future apocalypse or a UFO landing. It has also been criticized for being too exclusive, in that it ignores the “remarkable tenacity of scientific theories,” as Lakatos puts it (2009, p. 516). In practice, scientists do not merely abandon a theory if it is not supported by facts; they tend to find other explanations (e.g., the measurement was faulty) rather than accept an instance of falsification.Despite this, we believe it is still worth discussing falsifiability in the context of excited delirium for two reasons. First, while falsifiability may not be successful as a criterion that draws a line between science and pseudoscience, in this case, we argue, it still works well as a signifier of pseudoscience. Recently, many interested in the demarcation question have turned towards pluralism as a way to identify pseudoscientific practices (Pigliucci & Boudry, 2013). And excited delirium offers an excellent example of a phenomenon that bumps up against many of the features that might indicate a pseudoscientific practice... (shrink)

This paper considers two among the several points of intersection in the work of Roberto Esposito and Jacques Derrida. First, and most obviously: in the context of conceptualizing community, and more broadly, Esposito and Derrida have elaborated concepts of immunity and auto-immunity to refer to auto-destructive modes of defense which profoundly threaten what – seemingly – ought to have been safeguarded through their mechanism. The second point of proximity is the use both make of figures of maternity and birth in (...) these conceptualizations. This comparison not only illuminates the differing philosophical commitments of Derrida and Esposito but also offers a means of challenging the fate of sexual difference in the work of Esposito. (shrink)

The synthesis of biological membranes requires the insertion of proteins into a lipid bilayer. The rough endoplasmic reticulum of eukaryotic cells is a principal site of membrane biogenesis. The insertion of proteins into the membrane of the endoplasmic reticulum is mediated by a resident proteinaceous machinery. Over the last five years several different experimental approaches have provided information about the components of the machinery and how it may function.

Two kinds of membrane contacts in the vertebrate lens are described. Fiber gap junctions are domains where small molecules can pass between lens cells. Membrane structures of ball‐and‐socket type interlock adjacent lens fibers and thus contribute to the structural integrity of the lens. Both of these membrane contacts appear crucial for the maintenance of lens transparency.

Tubulin is the ubiquitous protein that makes up the walls of the cytoskeletal elements known as microtubules. These 20 nm diameter cylindrical fibers are the spindle fibers for mitosis, provide the skeletal framework for cellular elongation, constitute the major structural and motile elements of cilia and flagella and probably play a number of other roles in eukaryote cells. In the electron microscope, they are never seen to attach or protrude directly into or on cellular membranes. It was therefore with much (...) skepticism that cell biologists responded to recent claims purporting to show that tubulin is (or can be) a membrane protein. This skepticism comes from a bias based on the generally understood function of cytoskeletal proteins as representing the intracellular ‘bones’ of cells. The traditional thinking was that microtubules may attach to cellular membranes but only via a cross‐linking connecting protein. In recent years, however, an increasing number of workers have come to believe that tubulin can exist as a normal membrane protein possibly independent of its role in microtubule function. (shrink)

Undoubtedly the Penrose-Hameroff Orch OR model may be considered as a good theory for describing information processing mechanisms and holistic phenomena in the human brain, but it doesn’t give us satisfactory explanation of human perception. In this work a new approach explaining our perception is introduced, which is in good agreement with Orch OR model and other mainstream science theories such as string theory, loop quantum gravity and holographic principle. It is shown that human perception cannot be explained in the (...) terms of elementary particles and we should introduce new indivisible holistic objects with geometry based on smooth infinitesimal analysis - elastic membranes. The example of such a membrane is our Universe which is an indivisible whole. It is shown that our perception may be considered as the result of elastic oscillations of two dimensional (2D) elastic membranes with closed topology embedded in our bodies. Only one elastic membrane responsible for its perceptions will correspond to the selected organism, but there may be other membranes, even at the cell level. In other words, reality may be considered as the process of time evolution of holistic energetically very weak macro objects - elastic membranes with the geometry based on smooth infinitesimal analysis. An embedded membrane in this multidimensional world will look different for the external and internal observers: from the outside it will look like a material object with smooth infinitesimal geometry, while from the inside our Universe-like space-time fabric. When interacting with elementary particles and other membranes, a membrane will transform their energy into its elastic energy (a new form of energy) - the energy of stretching of the infinitesimal segments. The theory postulates that these elastic deformations will not be observable from the point of view of the internal observer. Heisenberg’s uncertainty principle will work in this physics only from the point of view of the internal observer. For the external observer each embedded elastic membrane may be stretched and even a very small region will become observable. For example, living organisms play the role of internal observers of the Universe, and at the same time they serve as external observers for 2D membranes embedded into our Universe. We can observe our 2D self-membranes through our perceptions, which are encoded in elastic oscillations of the elastic membrane. According to the theory, elastic membranes occupy energetically favorable positions around microtubules involved into Orch OR. The theory not only gives us a really multidimensional holistic picture of reality, but it also provides us with a new method for understanding such phenomena as perception, self-awareness and will. (shrink)

The myelin basic proteins are a set of peripheral membrane polypeptides which play an essential role in myelination. Their most well‐documented property is the unique ability to ‘seal’ the cytoplasmic aspects of the myelin membrane, but this is probably not the only function for these highly charged molecules. Despite extensive homology, the individual myelin basic proteins (MBPs) exhibit different expression patterns and biochemical properties, and so it is now believed that the various isoforms are not functionally equivalent in (...) myelinating cells. We now think that while the major MBPs are intracellular adhesion molecules, some of the quantitatively less abundant isoforms that are expressed very early in development may have regulatory effects on the myelination program. (shrink)

The liver was used widely in early studies of polarised transport but has been largely overlooked in recent years, mostly because of the development of epithelial cell lines which provide more tractable experimental systems. The majority of membrane proteins and lipids reach the hepatocyte apical membrane by transcytosis and it remains unclear whether there is a direct route for apical targeting, although the pathways present have yet to be fully characterised. The recent development of systems that allow hepatocyte (...) transport processes to be studied in culture and the observation that transcytosis can be significantly stimulated under physiological conditions suggest that hepatocytes have a role to play in future studies of polarised transport. This review discusses the known features of polarised membrane traffic in hepatocytes and contrasts them with the characteristics of vesicular transport in other epithelial cell types. (shrink)

One persistent puzzle in the life sciences is the asymmetric lipid composition of the cellular plasma membrane: while the exoplasmic leaflet is enriched in lipids carrying predominantly saturated fatty acids, the cytoplasmic leaflet hosts preferentially lipids with (poly‐)unsaturated fatty acids. Given the high energy requirements necessary for cells to maintain this asymmetry, the question naturally arises regarding its inherent benefits. In this paper, we propose asymmetry to represent a potential solution for harmonizing two conflicting requirements for the plasma (...) class='Hi'>membrane: first, the need to build a barrier for the uncontrolled influx or efflux of substances; and second, the need to form a fluid and dynamic two‐dimensional substrate for signaling processes. We hence view here the plasma membrane as a composite material, where the exoplasmic leaflet is mainly responsible for the functional integrity of the barrier and the cytoplasmic leaflet for fluidity. We reinforce the validity of the proposed mechanism by presenting quantitative data from the literature, along with multiple examples that bolster our model. (shrink)

The biological membranes of eukaryotic cells harbor sensitive surveillance systems to establish, sense, and maintain characteristic physicochemical properties that ultimately define organelle identity. They are fundamentally important for membrane homeostasis and play active roles in cellular signaling, protein sorting, and the formation of vesicular carriers. Here, we compare the molecular mechanisms of Mga2 and Ire1, two sensors involved in the regulation of fatty acid desaturation and the response to unfolded proteins and lipid bilayer stress in order to identify their (...) commonalities and specializations. We will speculate on the cellular significance of membrane property sensors in other organelles and discuss their putative mechanisms. Based on these findings, we propose membrane property sensors as an emerging class of proteins with wide implications for organelle communication and function. (shrink)

Cell membranes experience frequent stretching and poking: from cytoskeletal elements, from osmotic imbalances, from fusion and budding of vesicles, and from forces from the outside. Are the ensuing changes in membrane tension localized near the site of perturbation, or do these changes propagate rapidly through the membrane to distant parts of the cell, perhaps as a mechanical mechanism of long‐range signaling? Literature statements on the timescale for membrane tension to equilibrate across a cell vary by a factor (...) of ≈106. This study reviews and discusses how apparently contradictory findings on tension propagation in cells can be evaluated in the context of 2D hydrodynamics and poroelasticity. Localization of tension in the cell membrane is likely critical in governing how membrane forces gate ion channels, set the subcellular distribution of vesicle fusion, and regulate the dynamics of cytoskeletal growth. Furthermore, in this study, it is proposed that cells can actively regulate the degree to which membrane tension propagates by modulating the density and arrangement of immobile transmembrane proteins. Also see the video abstract here https://youtu.be/T6K7AIAqqBs. (shrink)

In the context of 1960s research on biological membranes, scientists stumbled upon a curiously coloured material substance, which became called the “purple membrane.” Interactions with the material as well as chemical analyses led to the conclusion that the microbial membrane contained a photoactive molecule similar to rhodopsin, the light receptor of animals’ retinae. Until 1975, the find led to the formation of novel objects in science, and subsequently to the development of a field in the molecular life sciences (...) that comprised biophysics, bioenergetics as well as membrane and structural biology. Furthermore, the purple membrane and bacteriorhodopsin, as the photoactive membrane transport protein was baptized, inspired attempts at hybrid bio-optical engineering throughout the 1980s. A central motif of the research field was the identification of a functional biological structure, such as a membrane, with a reactive material substance that could be easily prepared and manipulated. Building on this premise, early purple membrane research will be taken as a case in point to understand the appearance and transformation of objects in science through work with material substances. Here, the role played by a perceptible material and its spontaneous change of colour, or reactivity, casts a different light on objects and experimental practices in the late twentieth century molecular life sciences. With respect to the impact of chemical working and thinking, the purple membrane and rhodopsins represent an influential domain straddling the life and chemical sciences as well as bio- and material technologies, which has received only little historical and philosophical attention. Re-drawing the boundary between the living and the non-enlivened, these researches explain and model organismic activity through the reactivity of macromolecular structures, and thus palpable material substances. (shrink)

It is common to say that the origin of the membrane potential is attributed to transmembrane ion transport, but it is theoretically possible to explain its generation by the mechanism of ion adsorption. It has been previously suggested that the ion adsorption mechanism even leads to potential formulae identical to the famous Nernst equation or the Goldman-Hodgkin-Katz equation. Our further analysis, presented in this paper, indicates that the potential formula based on the ion adsorption mechanism leads to an equation (...) that is a function of the surface charge density of the material and the surface potential of the material. Furthermore, we have confirmed that the equation holds in all the different experimental systems that we have studied. This equation appears to be a key equation that governs the characteristics of the membrane potential in all systems. (shrink)

We report that upon excitation by a single pulse, a classical harmonic oscillator immersed in the classical electromagnetic zero-point radiation exhibits a discrete harmonic spectrum in agreement with that of its quantum counterpart. This result is interesting in view of the fact that the vacuum field is needed in the classical calculation to obtain the agreement.