COVID-19 vulnerabilities are intensified by declining human serum albumin levels.

What is the topic of this review? Human serum albumin (HSA) a common factor in COVID-19 vulnerabilities. What advances does it highlight? Understanding of HSA capacity, and systemic vulnerabilities to COVID-19. Raising HSA in COVID-19 patients may alleviate systemic injury caused by diminished native HSA binding. A change in fluid therapy administration into the portal system of the liver is proposed to safely raise HSA levels. ABSTRACT: The specific nature of the vulnerabilities to COVID-19 are an intrinsic part of COVID-19 infection in many patients. This paper proposes that vulnerabilities to COVID-19 may be intensified by a decrease in human serum albumin (HSA) as a ligand carrier for nutrients. A mechanism for COVID-19 vulnerabilities is evident from consideration of ligand carriers such as HSA as intermediaries. We hypothesise that low levels of pool HSA binding, caused for whatever reason, affect the performance of albumin as a carrier protein reducing the availability of nutrients. Hypoalbuminaemia (low HSA) has been implicated as an indicator of COVID-19 and long-COVID-19. The levels of HSA directly affect the immune system and vulnerabilities to age, diabetes and obesity in COVID-19. Any slight reduction in available HSA has profound effects on ligand concentrations in the small capillaries where damage occurs in COVID-19. The clinical implication is that attempts should be made to return HSA to clinical levels to compensate for the additional ligands caused by infection (SARS-CoV-2 virions, antibodies and cellular breakdown products). Therapeutic albumin is usually given peripherally, and usual preparations are unbound to ligands, but we suggest that a clinical trial of HSA therapy via the hepatic portal vein should be considered.

The role of non-coding RNAs in neuroprotection and angiogenesis following ischemic stroke.

Stroke is the leading cause of death and physical disability worldwide. Non-coding RNAs (ncRNAs) are endogenous molecules that play key roles in the pathophysiology and retrieval processes following ischemic stroke. The potential of ncRNAs, especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in neuroprotection and angiogenesis highlights their potential as targets for therapeutic intervention. In this review, we document the miRNAs and lncRNAs that have been reported to exert regulatory actions in neuroprotective and angiogenic processes through different mechanisms involving their interaction with target coding genes. We believe that exploration of the expression profiles and the possible functions of ncRNAs during the recovery processes will help comprehension of the molecular mechanisms responsible for neuroprotection and angiogenesis, and may also contribute to find biomarkers and targets for future stroke intervention.

Long non-coding RNAs and cell death following ischemic stroke.

Stroke is a major cause of morbidity and mortality worldwide, and extensive efforts have focused on the improvement of therapeutic strategies to reduce cell death following ischemic stroke. Uncovering the cellular and molecular pathophysiological processes in ischemic stroke have been a top priority. Long noncoding RNAs (lncRNAs) are endogenous molecules that play key roles in the pathophysiology of cerebral ischemia, and involved in the neuronal cell death during ischemic stroke. In recent years, a bulk of aberrantly expressed lncRNAs have been screened out in ischemic stroke insulted animals. LncRNAs along with their targets could affect the genetic machinery at molecular levels, and exploring their functions and mechanisms may be a promising option for ischemic stroke treatment. In this review, we summarize the current knowledge for lncRNAs in ischemic stroke, focusing on the role of specific lncRNAs that may underlie cell death to find possible therapeutic targets.

Pathogenic mechanisms following ischemic stroke.

Stroke is the second most common cause of death and the leading cause of disability worldwide. Brain injury following stroke results from a complex series of pathophysiological events including excitotoxicity, oxidative and nitrative stress, inflammation, and apoptosis. Moreover, there is a mechanistic link between brain ischemia, innate and adaptive immune cells, intracranial atherosclerosis, and also the gut microbiota in modifying the cerebral responses to ischemic insult. There are very few treatments for stroke injuries, partly owing to an incomplete understanding of the diverse cellular and molecular changes that occur following ischemic stroke and that are responsible for neuronal death. Experimental discoveries have begun to define the cellular and molecular mechanisms involved in stroke injury, leading to the development of numerous agents that target various injury pathways. In the present article, we review the underlying pathophysiology of ischemic stroke and reveal the intertwined pathways that are promising therapeutic targets.

Neurocomputational mechanisms underlying perception and sentience in the neocortex.

The basis for computation in the brain is the quantum threshold of "soliton," which accompanies the ion changes of the action potential, and the refractory membrane at convergences. Here, we provide a logical explanation from the action potential to a neuronal model of the coding and computation of the retina. We also explain how the visual cortex operates through quantum-phase processing. In the small-world network, parallel frequencies collide into definable patterns of distinct objects. Elsewhere, we have shown how many sensory cells are meanly sampled from a single neuron and that convergences of neurons are common. We also demonstrate, using the threshold and refractory period of a quantum-phase pulse, that action potentials diffract across a neural network due to the annulment of parallel collisions in the phase ternary computation (PTC). Thus, PTC applied to neuron convergences results in a collective mean sampled frequency and is the only mathematical solution within the constraints of the brain neural networks (BNN). In the retina and other sensory areas, we discuss how this information is initially coded and then understood in terms of network abstracts within the lateral geniculate nucleus (LGN) and visual cortex. First, by defining neural patterning within a neural network, and then in terms of contextual networks, we demonstrate that the output of frequencies from the visual cortex contains information amounting to abstract representations of objects in increasing detail. We show that nerve tracts from the LGN provide time synchronization to the neocortex (defined as the location of the combination of connections of the visual cortex, motor cortex, auditory cortex, etc.). The full image is therefore combined in the neocortex with other sensory modalities so that it receives information about the object from the eye and all the abstracts that make up the object. Spatial patterns in the visual cortex are formed from individual patterns illuminating the retina, and memory is encoded by reverberatory loops of computational action potentials (CAPs). We demonstrate that a similar process of PTC may take place in the cochlea and associated ganglia, as well as ascending information from the spinal cord, and that this function should be considered universal where convergences of neurons occur.

Postscript to Invertebrate Welfare: "We Have Met the Enemy and He Is Us".

Through this collection of papers, we have considered in depth the effects that humans have on invertebrate welfare in a variety of contexts [...].

The Use of Isoflurane and Adjunctive Magnesium Chloride Provides Fast, Effective Anaesthetization of Octopus vulgaris.

A wide variety of substances have been used to anaesthetise invertebrates, but many are not anaesthetics and merely incapacitate animals rather than preventing pain. In essence, the role of an ideal general anaesthetic is to act as a muscle relaxant, an analgesic, an anaesthetic, and an amnesic. To achieve all these properties with a single substance is difficult, and various adjuvants usually need to be administered, resulting in a cocktail of drugs. In a clinical setting, the vast majority of patients are unaware of surgery being carried out and have no memory of it, so they can claim to have felt no pain, but this is much more difficult to demonstrate in invertebrates. Here, we show that 1% MgCl2, a muscle relaxant, is a useful adjuvant for the clinical anaesthetic isoflurane on Octopus vulgaris when applied alone in seawater for 10 min before the clinical anaesthetic. After this, full anaesthesia can be achieved in 5 min using 1% isoflurane insufflated into the saline still containing MgCl2. Full recovery takes place rapidly in about 10 to 15 min. The depth of anaesthesia was monitored using changes in respiratory rate, chromatophore pattern, and withdrawal movements of the arms and siphon. This methodology reduces stress on the animal and minimises the quantity of anaesthetic used.

Does the Brain Function as a Quantum Phase Computer Using Phase Ternary Computation?

Here we provide evidence that the fundamental basis of nervous communication is derived from a pressure pulse/soliton capable of computation with sufficient temporal precision to overcome any processing errors. Signalling and computing within the nervous system are complex and different phenomena. Action potentials are plastic and this makes the action potential peak an inappropriate fixed point for neural computation, but the action potential threshold is suitable for this purpose. Furthermore, neural models timed by spiking neurons operate below the rate necessary to overcome processing error. Using retinal processing as our example, we demonstrate that the contemporary theory of nerve conduction based on cable theory is inappropriate to account for the short computational time necessary for the full functioning of the retina and by implication the rest of the brain. Moreover, cable theory cannot be instrumental in the propagation of the action potential because at the activation-threshold there is insufficient charge at the activation site for successive ion channels to be electrostatically opened. Deconstruction of the brain neural network suggests that it is a member of a group of Quantum phase computers of which the Turing machine is the simplest: the brain is another based upon phase ternary computation. However, attempts to use Turing based mechanisms cannot resolve the coding of the retina or the computation of intelligence, as the technology of Turing based computers is fundamentally different. We demonstrate that that coding in the brain neural network is quantum based, where the quanta have a temporal variable and a phase-base variable enabling phase ternary computation as previously demonstrated in the retina.

SARS-CoV-2 Bound Human Serum Albumin and Systemic Septic Shock.

The emergence of the COVID-19 virus and the subsequent pandemic have driven a great deal of research activity. The effects of COVID-19 are caused by the severe respiratory syndrome coronavirus 2 (SARS-CoV-2) and it is the underlying actions of SARs-CoV-2 virions on the endothelial glycocalyx that we consider here. One of the key factors in COVID-19 infection is its almost unique age-related profile, with a doubling in mortality every 10 years after the age of 50. The endothelial glycocalyx layer is essential in maintaining normal fluid homeostasis, but is fragile and prone to pathophysiological damage. It is physiologically significant in capillary microcirculation and in fluid distribution to the tissues. Human serum albumin (HSA), the most abundant protein in plasma, is created in the liver which also maintains its concentration, but this reduces by 10-15% after 50 years of age. HSA transports hormones, free fatty acids and maintains oncotic pressure, but SARS-CoV-2 virions bind competitively to HSA diminishing its normal transport function. Furthermore, hypoalbuminemia is frequently observed in patients with such conditions as diabetes, hypertension, and chronic heart failure, i.e., those most vulnerable to SARS-CoV-2 infection. Hypoalbuminemia, coagulopathy, and vascular disease have been linked in COVID-19 and have been shown to predict outcome independent of age and morbidity. Hypoalbuminemia is also known factor in sepsis and Acute respiratory distress syndrome (ARDS) occurs when fluids build-up in the alveoli and it is associated with sepsis, whose mechanism is systemic, being associated with the fluid and logistic mechanisms of the circulation. Glycocalyx damage is associated with changes plasma protein concentration, particularly HSA and blockage of albumin transport can produce the systemic symptoms seen in SARS-CoV-2 infection and sepsis. We therefore conclude that albumin binding to SARS-CoV-2 virions may inhibit the formation of the endothelial glycocalyx by inhibition of albumin transport binding sites. We postulate that albumin therapy to replace bound albumin might alleviate some of the symptoms leading to sepsis and that clinical trials to test this postulation should be initiated as a matter of urgency.

A Comparative Study of Cell Specific Effects of Systemic and Volatile Anesthetics on Identified Motor Neurons and Interneurons of Lymnaea stagnalis (L.), Both in the Isolated Brain and in Single Cell Culture.

1. A comparative descriptive analysis of systemic (sodium pentobarbital, sodium thiopentone, ketamine) and volatile (halothane, isoflurane, enflurane) general anesthetics revealed important differences in the neuronal responses of identified motor neurons and interneurons in the isolated central nervous system (CNS) and cultured identified neurons in single cell culture of Lymnaea stagnalis (L.). 2. At high enough concentrations all anesthetics eventually caused cessation of spontaneous or evoked action potentials, but volatile anesthetics were much faster acting. Halothane at low concentrations caused excitation, thought to be equivalent to the early excitatory phase of anesthesia. Strong synaptic inputs were not always abolished by pentobarbital. 3. There were cell specific concentration-dependent responses to halothane and pentobarbital in terms of membrane potential, action potential characteristics, the after hyperpolarization and patterned activity. Individual neurons generated specific responses to the applied anesthetics. 4. The inhalation anesthetics, enflurane, and isoflurane, showed little concentration dependence of effect, in contrast to results obtained with halothane. Enflurane was faster acting than halothane and isoflurane was particularly different, producing quiescence in all cells types studied at all concentrations studied. 5. Halothane, enflurane, the barbiturate general anesthetics, pentobarbital, and sodium thiopentone and the dissociative anesthetic ketamine, produced two distinctly different effects which could be correlated with cell type and their location in the isolated brain: either a decline in spontaneous and evoked activity prior to quiescence in interneurons or paroxysmal depolarizing shifts (PDS) in motor neurons, again prior to quiescence, which were reversed when the anesthetic was eliminated from the bath. In the strongly electrically coupled motor neurons, VD1 and RPD2, both types of response were observed, depending on the anesthetic used. Thus, with the exception isoflurane, all the motor neurons subjected to the anesthetic agents studied here were capable of generating PDS in situ, but the interneurons did not do so. 6. The effects of halothane on isolated cultured neurons indicates that PDS can be generated by single identified neurons in the absence of synaptic inputs. Further, many instances of PDS in neurons that do not generate it in situ have been found in cultured neurons. The nature of PDS is discussed.

The Soliton and the Action Potential - Primary Elements Underlying Sentience.

At present the neurological basis of sentience is poorly understood and this problem is exacerbated by only a partial knowledge of how one of the primary elements of sentience, the action potential, actually works. This has consequences for our understanding of how communication within the brain and in artificial brain neural networks (BNNs). Reverse engineering models of brain activity assume processing works like a conventional binary computer and neglects speed of cognition, latencies, error in nerve conduction and the true dynamic structure of neural networks in the brain. Any model of nerve conduction that claims inspiration from nature must include these prerequisite parameters, but current western computer modeling of artificial BNNs assumes that the action potential is binary and binary mathematics has been assumed by force of popular acceptance to mediate computation in the brain. Here we present evidence that the action potential is a temporal compound ternary structure, described as the computational action potential (CAP). The CAP contains the refractory period, an analog third phase capable of phase-ternary computation via colliding action potentials. This would best fit a realistic BNN and provides a plausible mechanism to explain transmission, in preference to Cable Theory. The action potential pulse (APPulse), is made up of the action potential combined with a coupled synchronized soliton pressure pulse in the cell membrane. We describe a model of an ion channel in a membrane where a soliton deforms the channel sufficiently to destroy the electrostatic insulation thereby instigating a mechanical contraction across the membrane by electrostatic forces. Such a contraction has the effect of redistributing the force lengthways thereby increasing the volume of the ion channel in the membrane. Na ions, once attracted to the interior, balance the forces and the channel reforms to its original shape. A refractory period then occurs until the Na ions diffuse from the adjacent interior space. Finally, a computational model of the action potential (the CAP) is proposed with single action potentials significantly including the refractory period as a computational element capable of computation between colliding action potentials.

Sense and Insensibility - An Appraisal of the Effects of Clinical Anesthetics on Gastropod and Cephalopod Molluscs as a Step to Improved Welfare of Cephalopods.

Recent progress in animal welfare legislation stresses the need to treat cephalopod molluscs, such as Octopus vulgaris, humanely, to have regard for their wellbeing and to reduce their pain and suffering resulting from experimental procedures. Thus, appropriate measures for their sedation and analgesia are being introduced. Clinical anesthetics are renowned for their ability to produce unconsciousness in vertebrate species, but their exact mechanisms of action still elude investigators. In vertebrates it can prove difficult to specify the differences of response of particular neuron types given the multiplicity of neurons in the CNS. However, gastropod molluscs such as Aplysia, Lymnaea, or Helix, with their large uniquely identifiable nerve cells, make studies on the cellular, subcellular, network and behavioral actions of anesthetics much more feasible, particularly as identified cells may also be studied in culture, isolated from the rest of the nervous system. To date, the sorts of study outlined above have never been performed on cephalopods in the same way as on gastropods. However, criteria previously applied to gastropods and vertebrates have proved successful in developing a method for humanely anesthetizing Octopus with clinical doses of isoflurane, i.e., changes in respiratory rate, color pattern and withdrawal responses. However, in the long term, further refinements will be needed, including recordings from the CNS of intact animals in the presence of a variety of different anesthetic agents and their adjuvants. Clues as to their likely responsiveness to other appropriate anesthetic agents and muscle relaxants can be gained from background studies on gastropods such as Lymnaea, given their evolutionary history.

The Interplay of MicroRNAs in the Inflammatory Mechanisms Following Ischemic Stroke.

Immunity and inflammation are important parameters of the pathophysiology of stroke, a destructive illness that is the second most common cause of death worldwide. Following ischemic stroke, neuroinflammation plays a critical role in neurodegeneration and brain injury. MicroRNAs (miRNAs) are a class of endogenously expressed, noncoding RNA molecules that function to inhibit mRNA translation. Recent studies demonstrate that miRNAs are key regulators of inflammatory processes contributing to ischemic stroke injuries. Several miRNAs, and their target genes, have been shown to play a critical role in the innate inflammatory responses mediated by immune cells. The capacity of miRNAs to regulate several target genes demonstrates their exceptional importance in neuroinflammatory therapeutics following ischemic stroke. In this review, we focus on the miRNAs associated with ischemic neuroinflammation and describe the potential of miRNAs as biomarkers of neuroinflammation and promising therapeutic agents for modulation of deleterious inflammatory responses following ischemic stroke.

Emerging Roles of microRNAs in Ischemic Stroke: As Possible Therapeutic Agents.

Stroke is one of the leading causes of death and physical disability worldwide. The consequences of stroke injuries are profound and persistent, causing in considerable burden to both the individual patient and society. Current treatments for ischemic stroke injuries have proved inadequate, partly owing to an incomplete understanding of the cellular and molecular changes that occur following ischemic stroke. MicroRNAs (miRNA) are endogenously expressed RNA molecules that function to inhibit mRNA translation and have key roles in the pathophysiological processes contributing to ischemic stroke injuries. Potential therapeutic areas to compensate these pathogenic processes include promoting angiogenesis, neurogenesis and neuroprotection. Several miRNAs, and their target genes, are recognized to be involved in these recoveries and repair mechanisms. The capacity of miRNAs to simultaneously regulate several target genes underlies their unique importance in ischemic stroke therapeutics. In this Review, we focus on the role of miRNAs as potential diagnostic and prognostic biomarkers, as well as promising therapeutic agents in cerebral ischemic stroke.

Vanillic acid attenuates effects of transient bilateral common carotid occlusion and reperfusion in rats.

Cerebral hypoperfusion induced by transient bilateral common carotid arteries occlusion (tBCCAO), is associated with deleterious alterations in several physiological parameters of the animals. This study aims to investigate the effects of vanillic acid (VA) on memory impairment, locomotion and exploratory deficits, as well as histological and hippocampal long-term potentiation (LTP) injuries induced by tBCCAO procedure followed by reperfusion (BCCAO/R) in rats. Adult male Wistar rats (250-300g) were divided randomly into four groups: Sham-Operated group "Sham"; Vehicle+BCCAO/R group "BCCAO/R"; Vehicle+ Vanillic acid group "VA"; VA (100mg/kg) +BCCAO/R group "VA +BCCAO/R". Cerebral hypoperfusion was induced after 14days of pretreatment with VA and/or normal saline. To induce the animal model of hypoperfusion, bilateral common carotid arteries were occluded for 30min, followed by 72h of reperfusion. Subsequently, behavioral, histopathological and electrophysiological parameters were evaluated after BCCAO/R. Data showed that pretreatment of VA markedly improved locomotion in tBCCAO rats compared with the untreated BCCAO/R rats (p<0.05). Moreover, pretreatment of VA significantly ameliorated memory impairment in "VA+BCCAO/R" group compared with the "BCCAO/R" group (P<0.01). The field excitatory postsynaptic potential (fEPSP) amplitude and slope were significantly decreased in "BCCAO/R" group compared with Sham group (P<0.001). Data indicate that fEPSP amplitude and slope were increased in "VA+BCCAO/R" group compared with the "BCCAO/R" group (P<0.001). Furthermore, histopathological observation in VA pretreated tBCCAO rats showing markedly attenuated of cell death (P<0.01) and arrangement of CA1 neurons as compared with the untreated BCCAO/R rats. Our data confirm the protective role of VA against transient cerebral ischemia and reperfusion in rats. Moreover, it proposes that VA has a beneficial role in cerebrovascular insufficiency states.

Dose-dependent effects of the clinical anesthetic isoflurane on Octopus vulgaris: a contribution to cephalopod welfare.

Recent progress in animal welfare legislation relating to invertebrates has provoked interest in methods for the anesthesia of cephalopods, for which different approaches to anesthesia have been tried but in most cases without truly anesthetizing the animals. For example, several workers have used muscle relaxants or hypothermia as forms of "anesthesia." Several inhalational anesthetics are known to act in a dose-dependent manner on the great pond snail Lymnaea stagnalis, a pulmonate mollusk. Here we report, for the first time, on the effects of clinical doses of the well-known inhalational clinical anesthetic isoflurane on the behavioral responses of the common octopus Octopus vulgaris. In each experiment, isoflurane was equilibrated into a well-aerated seawater bath containing a single adult O. vulgaris. Using a web camera, we recorded each animal's response to touch stimuli eliciting withdrawal of the arms and siphon and observed changes in the respiratory rate and the chromatophore pattern over time (before, during, and after application of the anesthetic). We found that different animals of the same size responded with similar behavioral changes as the isoflurane concentration was gradually increased. After gradual application of 2% isoflurane for a maximum of 5 min (at which time all the responses indicated deep anesthesia), the animals recovered within 45-60 min in fresh aerated seawater. Based on previous findings in gastropods, we believe that the process of anesthesia induced by isoflurane is similar to that previously observed in Lymnaea. In this study we showed that isoflurane is a good, reversible anesthetic for O. vulgaris, and we developed a method for its use.

GABA(A)- and AMPA-like receptors modulate the activity of an identified neuron within the central pattern generator of the pond snail Lymnaea stagnalis.

To examine the neurochemistry underlying the firing of the RPeD1 neuron in the respiratory central pattern generator of the pond snail, Lymnaea stagnalis, we examined electrophysiologically and pharmacologically either "active" or "silent" preparations by intracellular recording and pharmacology. GABA inhibited electrical firing by hyperpolarizing RPeD1, while picrotoxin, an antagonist of GABA(A) receptors, excited silent cells and reversed GABA-induced inhibition. Action potential activity was terminated by 1 mM glutamate (Glu) while silent cells were depolarized by the GluR agonists, AMPA, and NMDA. Kainate exerted a complex triphasic effect on membrane potential. However, only bath application of AMPA desensitized the firing. These data indicate that GABA inhibits RPeD1 via activation of GABA(A) receptors, while Glu stimulates the neuron by activating AMPA-sensitive GluRs.