Modulation of host epigenome by coronavirus infections and developing treatment modalities for COVID-19 beyond genetics.

The recent Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) outbreak has resulted in coronavirus disease 2019 (COVID-19) pandemic worldwide, affecting millions of lives. Although vaccines are presently made available, and vaccination drive is in progress to immunize a larger population; still the risk of SARS-CoV-2 infection and related mortality is persistent amid threats of the third wave of the ongoing pandemic. In the scenario of unavailability of robust and efficient treatment modalities, it becomes essential to understand the mechanism of action of the virus and deeply study the molecular mechanisms (both at the virus level and the host level) underlying the infection processes. Recent studies have shown that coronaviruses (CoVs) cause-specific epigenetic changes in the host cells to create a conducive microenvironment for replicating, assembling, and spreading. Epigenetic mechanisms can contribute to various aspects of the SARS-CoV-2 multiplication cycle, like expressing cytokine genes, viral receptor ACE2, and implicating different histone modifications. For SARS-CoV-2 infection, viral proteins are physically associated with various host proteins resulting in numerous interactions between epigenetic enzymes (i.e., histone deacetylases, bromodomain-containing proteins). The involvement of epigenetic mechanisms in the virus life cycle and the host immune responses to control infection result in epigenetic factors recognized as emerging prognostic COVID-19 biomarkers and epigenetic modulators as robust therapeutic targets to curb COVID-19. Therefore, this narrative review aimed to summarize and discuss the various epigenetic mechanisms that control gene expression and how these mechanisms are altered in the host cells during coronavirus infection. We also discuss the opportunities to exploit these epigenetic changes as therapeutic targets for SARS-CoV-2 infection. Epigenetic alterations and regulation play a pivotal role at various levels of coronavirus infection: entry, replication/transcription, and the process of maturation of viral proteins. Coronaviruses modulate the host epigenome to escape the host immune mechanisms. Therefore, host epigenetic alterations induced by CoVs can be considered to develop targeted therapies for COVID-19.

Comparative pathology, molecular pathogenicity, immunological features, and genetic characterization of three highly pathogenic human coronaviruses (MERS-CoV, SARS-CoV, and SARS-CoV-2).

The last two decades have witnessed the emergence of three deadly coronaviruses (CoVs) in humans: severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are still no reliable and efficient therapeutics to manage the devastating consequences of these CoVs. Of these, SARS-CoV-2, the cause of the currently ongoing coronavirus disease 2019 (COVID-19) pandemic, has posed great global health concerns. The COVID-19 pandemic has resulted in an unprecedented crisis with devastating socio-economic and health impacts worldwide. This highlights the fact that CoVs continue to evolve and have the genetic flexibility to become highly pathogenic in humans and other mammals. SARS-CoV-2 carries a high genetic homology to the previously identified CoV (SARS-CoV), and the immunological and pathogenic characteristics of SARS-CoV-2, SARS-CoV, and MERS contain key similarities and differences that can guide therapy and management. This review presents salient and updated information on comparative pathology, molecular pathogenicity, immunological features, and genetic characterization of SARS-CoV, MERS-CoV, and SARS-CoV-2; this can help in the design of more effective vaccines and therapeutics for countering these pathogenic CoVs.

Community-acquired Clostridium difficile: epidemiology, ribotype, risk factors, hospital and intensive care unit outcomes, and current and emerging therapies.

BACKGROUND: The epidemiological landscape of Clostridium difficile infection (CDI) has changed over the past 30 years. AIM: To review studies of CDI in the community setting. METHODS: Electronic databases including PubMed, MEDLINE, Embase, Google Scholar, Scopus, ClinicalTrials.gov and Cochrane Databases were searched for human studies performed between 2000 and 2017 that assessed the epidemiology, risk factors, ribotypes, hospital and intensive care unit (ICU) outcomes, and management of community-acquired CDI. In addition, references were searched manually to identify other relevant studies. FINDINGS: In total, 39 articles met the inclusion criteria. The incidence of community-acquired CDI has almost doubled in the past decade. Approximately half of all cases of CDI are attributed to community origin. Individuals who are younger, female, in the presence of infants, frequently use proton pump inhibitors or specific classes of antibiotics, or live near farms and livestock are at higher risk for community-acquired CDI. Additionally, approximately 40% of all community-acquired cases require hospitalization, where severity has been linked to hypervirulent ribotypes 027 and 078 with poor outcomes. Emerging data on treatment paradigms have led to the revision of clinical guidelines and two potential vaccines in phase three clinical trials. However, ribotype-specific responses to current treatment strategies are lacking. CONCLUSION: Community-acquired CDI represents a growing public health threat and burden on healthcare systems. A multi-disciplinary approach will be required to stem the tides.

Asymmetries in hemispheric control of attention in schizophrenia.

Investigators have long suggested that schizophrenia might be related to an impairment in the regulation of attention. In this report, the performance of schizophrenic patients was compared with nonschizophrenic control subjects in their ability to direct visual attention. In the first experiment, patients were distinguished from controls by a slower response to a target in the right visual field than to a target in the left visual field when attention was not first directed to the target location. In the second experiment, patients were distinguished from controls by a stronger bias in favor of symbolic information over language information about spatial direction. In both experiments, the patients demonstrated deficits in attention similar to patients from previous studies who had unilateral lesions of the left hemisphere. The identification of performance abnormalities using tasks that are simple, have dissectable cognitive components, have been related to discrete neural systems, and control for nonspecific variables provide the basis for constructing reasonable hypotheses about the cognitive psychology and functional neuroanatomy of schizophrenia.

Biochemical changes and essential metals concentration in lead-intoxicated rats pre-exposed to ethanol.

The effects of chronic lead exposure on some hematopoietic and hepatic biochemical indices and urine, feces, and tissue essential metal concentration were investigated in rats pre-exposed to different doses of ethanol. Exposure to ethanol (0.5, 1.0, and 2.0 g/kg intraperitoneally, once daily) for 4 weeks produced an inhibition of blood delta-aminolevulinic acid dehydratase (ALAD) activity and a decrease in hepatic glutathione (GSH) concentration. Ethanol ingestion also produced a dose-dependent elevation of hepatic lipid peroxidation. Blood and hepatic calcium and hepatic magnesium contents decreased and urinary Ca and fecal Ca and Mg contents increased significantly following 4-week exposure to ethanol (2 g/kg). Lead administration (10 mg/kg, orally) for 4 weeks in ethanol pre-exposed (2 g/kg) animals produced a more pronounced inhibition of blood ALAD and elevation of urinary delta-aminolevulinic acid (ALA) excretion and hepatic GSH contents. Hepatic GSH contents decreased and hepatic lipid peroxidation increased significantly in rats given lead and pre-exposed to ethanol (2 g/kg). A more pronounced depletion of blood Ca and Mg and hepatic Mg was observed along with significant elevation of urinary Mg and fecal Ca excretion in animals administered lead and pre-exposed to ethanol (2 g/kg). The results suggest that nutritional deficiencies, particularly depletion of body Ca and Mg levels, play an important role in increasing susceptibility to lead intoxication in the rat.

Effects of combined exposure to aluminium and ethanol on aluminium body burden and some neuronal, hepatic and haematopoietic biochemical variables in the rat.

The effects of the daily administration of aluminium (25 mg kg-1, orally), ethanol (10% v/v, in drinking water) or both to adult rats, for 6 weeks, on the amount of aluminium present in the tissues and the functioning of brain biogenic amines, hepatic and serum transaminases and some haematopoietic variables were investigated. Ethanol alone was seen to inhibit the activity of delta-aminolevulinic acid dehydratase (ALAD), while aluminium alone elevated the activity of blood ALAD. However, aluminium and ethanol combined produced a more pronounced inhibition of blood ALAD and hepatic glutamic pyruvic transaminase (GPT) than either aluminium or ethanol alone. Simultaneous exposure to aluminium and ethanol also produced a significant elevation in urinary delta-aminolevulinic acid (ALA) blood zinc protoporphyrin (ZPP), serum glutamic oxaloacetic transaminase (GOT) and brain homovanillic acid (HVA), and a depletion in brain dopamine (DA) and 5-hydroxytryptamine (5-HT) levels, when compared to rats given aluminium alone. The concentration of aluminium in the blood and liver was significantly higher in rats exposed to both aluminium and ethanol than in those exposed to aluminium alone. Thus the consumption of alcohol may increase the rat's susceptibility to certain effects of aluminium.

Preventive and therapeutic role of vitamin E in chronic plumbism.

The ability of vitamin E to prevent or treat experimental lead intoxication was investigated in rats. Lead ingestion (10 mg/kg, lead as lead acetate, orally for 6 weeks) significantly inhibited the activity of blood delta-aminolevulinic acid dehydratase (ALAD), reduced the brain dopamine (DA) contents, enhanced the blood zinc protoporphyrin, and enhanced the urinary excretion of delta-aminolevulinic acid (ALA). Lead exposure also elevated brain norepinephrine, homovanillic acid, and 5-hydroxyindole acetic acid (5-HIAA) levels and concentration of lead in blood and tissue. Simultaneous supplementation of vitamin E along with lead significantly reduced the inhibition of blood ALAD activity, brain DA and 5-HIAA levels, and elevation of urinary ALA excretion. Blood and liver lead concentrations were also significantly reduced by simultaneous supplementation with vitamin E. Postlead exposure treatment with vitamin E was ineffective in reducing the lead-induced effects, except that the inhibition of blood ALAD activity was slightly reduced. The present results suggest that vitamin E given simultaneously with lead is effective in reducing the severity of lead intoxication.

Preventive effect of vitamin E in cadmium intoxication.

The influence of vitamin E on cadmium intoxication was investigated in rats. The exposure to cadmium (1 mg/kg, Cd as CdCl2.2H2O, intraperitoneally for 7 days) decreased the activity of hepatic and renal glutamic oxalacetic and glutamic pyruvic transaminases (GOT, GPT) and alkaline phosphatase (ALP) accompanied by increase in the levels of serum GOT and GPT and urinary protein. Simultaneous administration of vitamin E (5 mg/kg, intramuscularly for 7 days) reduced these Cd induced biochemical alterations. The accumulation of Cd in blood, liver and kidney also decreased significantly upon co-exposure to vitamin E. The antioxidant property of vitamin E seems to be responsible for the observed protection of Cd intoxication.

In heme catabolism C2 and C4 vinyl groups reduction of cobalt protoporphyrin forms cobalt mesoporphyrin and alters the nature of action of the metalloporphyrin in vivo.

Heme is a tetrapyrrolic ring with iron as the central metal atom and acts as a prosthetic group for a number of enzymes, e.g. cytochromes and globins. It also plays an important role in the regulation of transcription, translation, protein translocation and erythroid differentiation. Thus, heme regulation is under strict control in the body. Our studies on the regulatory enzymes of heme anabolism, aminolevulinic acid synthetase (ALA-S), and of catabolism, heme oxygenase (HMOX), in the spleen has revealed that cobalt protoporphyrin acts as an inducer of HMOX. It is revealed that by alteration of side groups at C2 and C4 changes the nature of action of Co-protoporphyrin from an inducer to a strong inhibitor of HMOX activity. All the three analogues Co-protoporphyrin, Co-mesoporphyrin and Co-hematoporphyrin have been shown to induce the ALA-S activity to the similar extent. NADPH-cytochrome c reductase, a microsomal membrane bound enzyme, is required by HMOX for the enzymatic conversion of heme into biliverdin IXc and is also required for NADPH-dependent lipid peroxidation in the microsomes. It has been observed that Co-mesoporphyrin causes an inhibition of HMOX activity and consequently leads to an induced level of microsomal NADPH-dependent lipid peroxidation.

Influence of selenium supplementation during chelation of lead in rats.

The influence of selenium supplementation during chelation therapy to reduce body burden and toxicity of lead was investigated in rats. Selenium had marginal effects on liver, kidney and blood lead decorporation by calcium disodium ethylenediamine tetra acetic acid (CaNa2EDTA) and activation of inhibited delta- aminolevulinic acid dehydratase (ALAD) activity by calcium trisodium diethylenetriamine penta acetic acid (CaNa3DTPA). Selenium supplementation however, had no influence on lead induced inhibition of renal and hepatic transaminases and alkaline phosphatase. The results suggest that selenium supplementation slightly augments lead mobilization by chelating drugs.

Acoustic and semantic interference effects in words and pictures.

Interference effects for pictures and words were investigated using a probe-recall task. Word stimuli showed acoustic interference effects for items at the end of the list and semantic interference effects for items at the beginning of the list, similar to results of Kintsch and Buschke (1969). Picture stimuli showed large semantic interference effects at all list positions with smaller acoustic interference effects. The results were related to latency data on picture-word processing and interpreted in terms of the differential order, probability, and/or speed of access to acoustic and semantic levels of processing. A levels of processing explanation of picture-word retention differences was related to dual coding theory. Both theoretical positions converge on an explanation of picture-word retention differences as a function of the relative capacity for semantic or associative processing.

Short-term retention of pictures and words: evidence for dual coding systems.

The recall of picture and word triads was examined in three experiments that manipulated the type of distraction in a Brown-Peterson short-term retention task. In all three experiments recall of pictures was superior to words under auditory distraction conditions. Visual distraction produced high performance levels with both types of stimuli, whereas combined auditory and visual distraction significantly reduced picture recall without further affecting word recall. The results were interpreted in terms of the dual coding hypothesis and indicated that pictures are encoded into separate visual and acoustic processing systems while words are primarily acoustically encoded.

Short-term retention of pictures and words as a function of type of distraction and length of delay interval.

Picture and word triads were tested in a Brown-Peterson short-term retention task at varying delay intervals (3, 10, or 30 sec) and under acoustic and simultaneous acoustic and visual distraction. Pictures were superior to words at all delay intervals under single acoustic distraction. Dual distraction consistently reduced picture retention while simultaneously facilitating word retention. The results were interpreted in terms of the dual coding hypothesis with modality-specific interference effects in the visual and acoustic processing systems. The differential effects of dual distraction were related to the introduction of visual interference and differential levels of functional acoustic interference across dual and single distraction tasks. The latter was supported by a constant 2/1 ratio in the backward counting rates of the acoustic vs. dual distraction tasks. The results further suggest that retention may not depend on total processing load of the distraction task, per se, but rather that processing load operates within modalities.

Influence of thiamine and ascorbic acid supplementation on the antidotal efficacy of thiol chelators in experimental lead intoxication.

The influence of the administration of thiamine (vitamin B1), ascorbic acid (vitamin C) or their combination on the efficacy of two thiol metal chelators, viz. alpha-mercapto-beta-(2-furyl) acrylic acid (MFA) and 2,3-dimercaptosuccinic acid (DMS), in counteracting lead (Pb) toxicity was investigated in rats. Ascorbic acid or its combination with thiamine enhanced the urinary elimination of Pb, reduced the hepatic and renal burden of Pb, and reversed the Pb-induced inhibition of the activity of blood delta-aminolevulinic acid dehydratase (delta-ALA-D). All these effects were more evident in DMS- than in MFA-treated rats. The combination of MFA and DMS treatments further improved the performance of the animals in enhancing urinary Pb excretion and in reducing Pb hepatic levels.

Differential distraction effects in short-term and long-term retention of pictures and words.

Picture and word triads were followed by single visual and acoustic distraction tasks and by both tasks in sequence. Short-term retention between and within modalities differed as a function of type of distraction. Individual subject-recall probabilities for each single distraction condition failed to predict performance in the sequential dual-distraction conditions, underestimating performance for words and overestimating performance for pictures. A final delayed recall showed a reversal among distraction conditions within each modality, such that the best short-term retention condition (visual distraction) was poorest in long-term retention. However, long-term retentions of pictures was superior to that of words across all distraction conditions and irrespective of level of short-term retention. The results were interpreted in terms of separate acoustic and visual processing systems and the level of individual item processing within each system as a function of the type of interference originally expected.

Transient solutions to a three level maser.

The transient behavior of three-level paramagnetic masers is investigated theoretically. Exact solutions to three-level maser rate equations are developed and their significance discussed. The results indicate the possibility of obtaining enhanced maser action at low saturation by pulsed pumping. A new method for the measurement of spin-lattice relaxation times for a three-level maser is proposed. The method, in addition to certain well-known static measurements, requires the observation of the decay of the signal strength when the pumping field is switched off.

Chelation of lead during co-exposure to ethanol.

Efficacy of calcium disodium EDTA, D-penicillamine (DPA), 2,3 dimercaptosuccinic acid (DMSA), and alpha-mercapto-beta-(2-furyl) acrylic acid (MFA) to reduce the body burden of lead and restore the altered biochemical variables in lead or lead + ethanol administered rats was investigated. The investigation was aimed to suggest suitable prophylaxis of lead intoxication prevalent among workers co-exposed to lead and alcohol ingestion. Administration of lead (10 mg/kg, oral, once daily for 8 weeks) produced a significant inhibition in the activity of blood delta-aminolevulinic acid dehydratase (ALAD), elevation in the blood zinc protoporphyrin (ZPP) and urinary elimination of lead and delta-aminolevulinic acid (ALA). Lead contents of blood, liver, kidney and brain were also significantly higher than the normal control. The above changes were more marked in animals co-exposed to lead + ethanol (20% in drinking water) compared to lead alone. All the chelators were effective in increasing the urinary lead elimination, reducing the above biochemical alterations and lead contents of tissues. The order of effectiveness being DMSA greater than Calcium disodium EDTA greater than DPA greater than MFA. However, the protection was more noticeable in animals treated with lead alone than with lead and ethanol.

Is word recognition automatic? A cognitive-anatomical approach.

What are the implications of anatomical localization of component mental operations for cognitive models? In this paper we use the anatomical localizations of visual and auditory word processing that were previously reported from PET studies (Petersen, Fox, Posner, Mintun & Raichle, 1988. We hypothesize that two operations performed simultaneously by the same or heavily interconnected anatomical areas will produce specific interference. One task is repeating back (shadowing) auditory words as quickly as possible. This task is shown to interfere with shifts of visual attention in the direction of peripheral cues. Both tasks are known to require common attentional operations localized to the medial frontal lobe. The shadowing task does not interfere with operations involving priming of a visual word form. This kind of priming involves areas of the ventral occipital lobe not used during shadowing. Finally, both shadowing and semantic priming involve anterior semantic and intentional areas. Accordingly, they can interfere. The conditions under which they produce interference suggest that the interference involves operations performed by the anterior attention system. These experiments support the idea that words automatically activate visual word forms, but involve shared attentional systems for higher level processes.