Virus-induced host cell metabolic alteration.

Viruses change the host cell metabolism to produce infectious particles and create optimal conditions for replication and reproduction. Numerous host cell pathways have been modified to ensure available biomolecules and sufficient energy. Metabolomics studies conducted over the past decade have revealed that eukaryotic viruses alter the metabolism of their host cells on a large scale. Modifying pathways like glycolysis, fatty acid synthesis and glutaminolysis could provide potential energy for virus multiplication. Thus, almost every virus has a unique metabolic signature and a different relationship between the viral life cycle and the individual metabolic processes. There are enormous research in virus induced metabolic reprogramming of host cells that is being conducted through numerous approaches using different vaccine candidates and antiviral drug substances. This review provides an overview of viral interference to different metabolic pathways and improved monitoring in this area will open up new ways for more effective antiviral therapies and combating virus induced oncogenesis.

Neuromuscular Electrical Stimulation for Venous Thromboembolism Prophylaxis and Its Effects on Somatosensory-Evoked Potentials: A Pretrial Study of a New, U.S. Food and Drug Administration-Approved Device.

BACKGROUND: Neuromuscular electrical stimulation (NMES) has emerged as a viable alternative for venous thromboembolism prophylaxis. Electrical stimulation of the peroneal nerve using NMES may potentially interfere with somatosensory-evoked potential (SSEP) acquisition. This feasibility study evaluates a NMES device and its effect on SSEP acquisition as an initial step in a randomized clinical trial to assess NMES for intraoperative venous thromboembolism prophylaxis. METHODS: Healthy volunteers underwent SSEP testing during NMES in an outpatient setting. Concurrently, SSEP recordings of the posterior tibial nerve with stimulation at each ankle were obtained in 3 conditions: sham, NMES in place but inactive; ipsi, NMES active on leg ipsilateral to SSEP acquisition; and contra, NMES active on the leg contralateral to SSEP acquisition. Nonparametric statistical methods, including repeated measures, were used for data analysis. RESULTS: Stimulation intensities on the left, right, and bilaterally did not differ (P ≥ 0.20). Strong positive correlations were noted between the ipsilateral geko stimulus pulse width and ipsilateral SSEP stimulation intensities (left: rs = 0.866, P = 0.001; right: rs = 0.877, P = 0.001). Women required significantly greater pulse width settings than men (P = 0.01). Finally, visual inspection of waveforms, as used during dynamic IONM, did not show any significant variations of P37 cortical waveforms during NMES. CONCLUSIONS: As a preliminary step to testing NMES intraoperatively for venous thromboembolism prophylaxis, interference with SSEP acquisition was investigated in the outpatient laboratory setting. Within a small sample of healthy volunteers, no significant changes were seen in P37 cortical latencies to suggest interference between the NMES device and SSEP waveforms.

A combinational approach to restore cytokine balance and to inhibit virus growth may promote patient recovery in severe COVID-19 cases.

The COVID-19 pandemic has led to twin public health and economic crises around the world. Not only has it cost hundreds of thousands of lives but also severely impacted livelihoods and placed enormous strain on community healthcare and welfare services. In this review, we explore the events associated with SARS-CoV-2 pathogenesis and host immunopathological reactivity due to the clinical manifestations of this coronavirus infection. We discuss that the metallopeptidase enzyme ADAM17, also known as tumor necrosis factor-α-converting enzyme, TACE, is responsible for shedding of angiotensin-converting enzyme 2 and membrane-bound interleukin (IL)-6 receptor. This leads to elevated pro-inflammatory responses that result in cytokine storm syndrome. We argue that cytokine balance may be restored by recovering an IL-6 trans-signaling neutralizing buffer system through the mediation of recombinant soluble glycoprotein 130 and recombinant ADAM17/TACE prodomain inhibitor. This cytokine restoration, possibly combined with inhibition of SARS-CoV-2 entry as well as replication and coagulopathy, could be introduced as a novel approach to treat patients with severe COVID-19. In cases of co-morbidity, therapies related to the management of associated disease conditions could ameliorate those clinical manifestations.

Regeneration of vestibular horizontal semicircular canal afferents in pigeons.

Spontaneous regeneration of vestibular and auditory receptors and their innervating afferents in birds, reptiles, and amphibians are well known. Here, we produced a complete vestibular receptor loss and epithelial denervation using an ototoxic agent (streptomycin), after which we quantitatively characterized the afferent innervation of the horizontal semicircular canals following completed regeneration. We found that calyx, dimorph, and bouton afferents all regenerate in a manner the recapitulates the epithelial topography of normal birds, but over a slow time course. Similar to previous findings in the vestibular otolith maculae, regeneration occurs according to a three-stage temporal sequence. Bouton afferents regenerate during the first month of regeneration, followed by calyceal-bearing afferents in the second and third months. Calyx afferents were the last to regenerate in the final stage of recovery after 3 mo. We also found that regenerated afferents exhibited terminal morphologies that are significantly smaller, less complex, and innervate fewer receptor cells over smaller epithelial areas than those that develop through normative morphogenesis. These structural fiber changes in afferent innervation correlate to alterations in gaze responses during regeneration, although the exact underlying mechanisms responsible for behavioral changes remain unknown. Plasticity in central vestibular neurons processing motion information seem to be required to explain the observed morphologic and response adaptations observed in regenerating vestibular systems.

Recovery of gaze stability during vestibular regeneration.

Many motion related behaviors, such as gaze stabilization, balance, orientation, and navigation largely depend on a properly functioning vestibular system. After vestibular insult, many of these responses are compromised but can return during the regeneration of vestibular receptors and afferents as is known to occur in birds, reptiles, and amphibians. Here we characterize gaze stability in pigeons to rotational motion during regeneration after complete bilateral vestibular loss via an ototoxic antibiotic. Immediate postlesion effects included severe head oscillations, postural ataxia, and total lack of gaze control. We found that these abnormal behaviors gradually subsided, and gaze stability slowly returned to normal function according to a temporal sequence that lasted several months. We also found that the dynamic recovery of gaze function during regeneration was not homogeneous for all types of motion. Instead high-frequency motion stability was first achieved, followed much later by slow movement stability. In addition, we found that initial gaze stability was established using almost exclusive head-response components with little eye-movement contribution. However, that trend reversed as recovery progressed so that when gaze stability was complete, the eye component had increased and the head response had decreased to levels significantly different from that observed in normal birds. This was true even though the head-fixed VOR response recovered normally. Recovery of gaze stability coincided well with the three stage temporal sequence of morphologic regeneration previously described by our laboratory.

Afferent innervation patterns of the pigeon horizontal crista ampullaris.

The vestibular semicircular canals are responsible for detection of rotational head motion although the precise mechanisms underlying the transduction and encoding of movement information are still under study. In the present investigation, we utilized neural tracers and immunohistochemistry to quantitatively examine the topology and afferent innervation patterns of the horizontal semicircular canal crista (HCC) in pigeons (Columba livia). Two hundred and eighty-six afferents from five horizontal canal organs were identified of which 92 units were sufficiently labeled and isolated to perform anatomical reconstructions. In addition, a three-dimensional contour map of the crista was constructed. Bouton afferents were located only in the peripheral regions of the receptor epithelium. Bouton afferents had the most complex innervation patterns with significantly longer and more numerous branches as well as a higher branch order than any other fiber type. Bouton fibers also contained significantly more bouton terminals than did dimorph afferents. Calyx afferents were located only in the apex and central planar regions. Calyx fibers had the largest axonal diameters yet the smallest fiber lengths and innervation areas, the fewest number of branches, the lowest branch order, and the fewest total number of terminals of all fiber types. Dimorph afferents were located throughout the central crista with afferent terminations that were larger and more complex than calyx fibers but less so than bouton fibers. Overall, the pigeon HCC morphology and innervation shares many common features with those of other animal classes.

Vestibular gaze stabilization: different behavioral strategies for arboreal and terrestrial avians.

In birds, it is thought that head movements play a major role in the reflexive stabilization of gaze and vision. In this study, we investigated the contributions of the eye and head to gaze stabilization during rotations under both head-fixed [vestibuloocular (VOR)] and head-free conditions in two avian species: pigeons and quails. These two species differ both in ocular anatomy (the pigeon has 2 distinct foveal regions), as well as in behavioral repertoires. Pigeons are arboreal, fly extended distances, and can navigate. Quails are primarily engrossed in terrestrial niches and fly only short distances. Unlike the head-fixed VOR gains that were under-compensatory for both species, gaze gains under head-free conditions were completely compensatory at high frequencies. This compensation was achieved primarily with head movements in pigeons, but with combined head and eye-in-head contributions in the quail. In contrast, eye-in-head motion, which was significantly reduced for head-free compared with head-fixed conditions, contributed very little to overall gaze stability in pigeons. These results suggest that disparity between the stabilization strategies employed by these two birds may be attributed to differences in species-specific behavior and anatomy.

Spatial tuning and dynamics of vestibular semicircular canal afferents in rhesus monkeys.

Rotational head motion in vertebrates is detected by the three semicircular canals of the vestibular system whose innervating primary afferent fibers encode movement information in specific head planes. In order to further investigate the nature of vestibular central processing of rotational motion in rhesus monkeys, it was first necessary to quantify afferent information coding in this species. Extracellular recordings were performed to determine the spatial and dynamic properties of semicircular canal afferents to rotational motion in awake rhesus monkeys. We found that the afferents innervating specific semicircular canals had maximum sensitivity vectors that were mutually orthogonal. Similar to other species, afferent response dynamics varied, with regular firing afferents having increased long time constants ( t(1)), decreased cupula velocity time constants ( t(v)), and decreased fractional order dynamic operator values ( s(k)) as compared to irregular firing afferents.

Caspase inhibitors promote vestibular hair cell survival and function after aminoglycoside treatment in vivo.

The sensory hair cells of the inner ear undergo apoptosis after acoustic trauma or aminoglycoside antibiotic treatment, causing permanent auditory and vestibular deficits in humans. Previous studies have demonstrated a role for caspase activation in hair cell death and ototoxic injury that can be reduced by concurrent treatment with caspase inhibitors in vitro. In this study, we examined the protective effects of caspase inhibition on hair cell death in vivo after systemic injections of aminoglycosides. In one series of experiments, chickens were implanted with osmotic pumps that administrated the pan-caspase inhibitor z-Val-Ala-Asp(Ome)-fluoromethylketone (zVAD) into inner ear fluids. One day after the surgery, the animals received a 5 d course of treatment with streptomycin, a vestibulotoxic aminoglycoside. Direct infusion of zVAD into the vestibule significantly increased hair cell survival after streptomycin treatment. A second series of experiments determined whether rescued hair cells could function as sensory receptors. Animals treated with streptomycin displayed vestibular system impairment as measured by a greatly reduced vestibulo-ocular response (VOR). In contrast, animals that received concurrent systemic administration of zVAD with streptomycin had both significantly greater hair cell survival and significantly increased VOR responses, as compared with animals treated with streptomycin alone. These findings suggest that inhibiting the activation of caspases promotes the survival of hair cells and protects against vestibular function deficits after aminoglycoside treatment.