Endogenous miRNA-Based Innate-Immunity against SARS-CoV-2 Invasion of the Brain.

The severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, possesses an unusually large positive-sense, single-stranded viral RNA (ssvRNA) genome of about ~29,903 nucleotides (nt). In many respects, this ssvRNA resembles a very large, polycistronic messenger RNA (mRNA) possessing a 5'-methyl cap (m7GpppN), a 3'- and 5'-untranslated region (3'-UTR, 5'-UTR), and a poly-adenylated (poly-A+) tail. As such, the SARS-CoV-2 ssvRNA is susceptible to targeting by small non-coding RNA (sncRNA) and/or microRNA (miRNA), as well as neutralization and/or inhibition of its infectivity via the human body's natural complement of about ~2650 miRNA species. Depending on host cell and tissue type, in silico analysis, RNA sequencing, and molecular-genetic investigations indicate that, remarkably, almost every single human miRNA has the potential to interact with the primary sequence of SARS-CoV-2 ssvRNA. Individual human variation in host miRNA abundance, speciation, and complexity among different human populations and additional variability in the cell and tissue distribution of the SARS-CoV-2 angiotensin converting enzyme-2 (ACE2) receptor (ACE2R) appear to further contribute to the molecular-genetic basis for the wide variation in individual host cell and tissue susceptibility to COVID-19 infection. In this paper, we review recently described aspects of the miRNA and ssvRNA ribonucleotide sequence structure in this highly evolved miRNA-ssvRNA recognition and signaling system and, for the first time, report the most abundant miRNAs in the control superior temporal lobe neocortex (STLN), an anatomical area involved in cognition and targeted by both SARS-CoV-2 invasion and Alzheimer's disease (AD). We further evaluate important factors involving the neurotropic nature of SARS-CoV-2 and miRNAs and ACE2R distribution in the STLN that modulate significant functional deficits in the brain and CNS associated with SARS-CoV-2 infection and COVID-19's long-term neurological effects.

SARS-CoV-2 Infectivity and Neurological Targets in the Brain.

The gateway for invasion by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into human host cells is via the angiotensin-converting enzyme 2 (ACE2) transmembrane receptor expressed in multiple immune and nonimmune cell types. SARS-CoV-2, that causes coronavirus disease 2019 (COVID-19; CoV-19) has the unusual capacity to attack many different types of human host cells simultaneously via novel clathrin- and caveolae-independent endocytic pathways, becoming injurious to diverse cells, tissues and organ systems and exploiting any immune weakness in the host. The elicitation of this multipronged attack explains in part the severity and extensive variety of signs and symptoms observed in CoV-19 patients. To further our understanding of the mechanism and pathways of SARS-CoV-2 infection and susceptibility of specific cell- and tissue-types and organ systems to SARS-CoV-2 attack in this communication we analyzed ACE2 expression in 85 human tissues including 21 different brain regions, 7 fetal tissues and 8 controls. Besides strong ACE2 expression in respiratory, digestive, renal-excretory and reproductive cells, high ACE2 expression was also found in the amygdala, cerebral cortex and brainstem. The highest ACE2 expression level was found in the pons and medulla oblongata in the human brainstem, containing the medullary respiratory centers of the brain, and may in part explain the susceptibility of many CoV-19 patients to severe respiratory distress.

Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer's Disease (AD).

Lipopolysaccharides (LPSs) are microbiome-derived glycolipids that are among the most potent pro-inflammatory neurotoxins known. In Homo sapiens, the major sources of LPSs are gastrointestinal (GI)-tract-resident facultative anaerobic Gram-negative bacilli, including Bacteroides fragilis and Escherichia coli. LPSs have been abundantly detected in aged human brain by multiple independent research investigators, and an increased abundance of LPSs around and within Alzheimer's disease (AD)-affected neurons has been found. Microbiome-generated LPSs and other endotoxins cross GI-tract biophysiological barriers into the systemic circulation and across the blood-brain barrier into the brain, a pathological process that increases during aging and in vascular disorders, including 'leaky gut syndrome'. Further evidence indicates that LPSs up-regulate pro-inflammatory transcription factor complex NF-kB (p50/p65) and subsequently a set of NF-kB-sensitive microRNAs, including miRNA-30b, miRNA-34a, miRNA-146a and miRNA-155. These up-regulated miRNAs in turn down-regulate a family of neurodegeneration-associated messenger RNA (mRNA) targets, including the mRNA encoding the neuron-specific neurofilament light (NF-L) chain protein. While NF-L has been reported to be up-regulated in peripheral biofluids in AD and other progressive and lethal pro-inflammatory neurodegenerative disorders, NF-L is significantly down-regulated within neocortical neurons, and this may account for neuronal atrophy, loss of axonal caliber and alterations in neuronal cell shape, modified synaptic architecture and network deficits in neuronal signaling capacity. This paper reviews and reveals the most current findings on the neurotoxic aspects of LPSs and how these pro-inflammatory glycolipids contribute to the biological mechanism of progressive, age-related and ultimately lethal neurodegenerative disorders. This recently discovered gut-microbiota-derived LPS-NF-kB-miRNA-30b-NF-L pathological signaling network: (i) underscores a direct positive pathological link between the LPSs of GI-tract microbes and the inflammatory neuropathology, disordered cytoskeleton, and disrupted synaptic-signaling of the AD brain and stressed human brain cells in primary culture; and (ii) is the first example of a microbiome-derived neurotoxic glycolipid having significant detrimental miRNA-mediated actions on the expression of NF-L, an abundant filamentous protein known to be important in the maintenance of neuronal and synaptic homeostasis.

Alteration of Biomolecular Conformation by Aluminum-Implications for Protein Misfolding Disease.

The natural element aluminum possesses a number of unique biochemical and biophysical properties that make this highly neurotoxic species deleterious towards the structural integrity, conformation, reactivity and stability of several important biomolecules. These include aluminum's (i) small ionic size and highly electrophilic nature, having the highest charge density of any metallic cation with a Z2/r of 18 (ionic charge +3, radius 0.5 nm); (ii) inclination to form extremely stable electrostatic bonds with a tendency towards covalency; (iii) ability to interact irreversibly and/or significantly slow down the exchange-rates of complex aluminum-biomolecular interactions; (iv) extremely dense electropositive charge with one of the highest known affinities for oxygen-donor ligands such as phosphate; (v) presence as the most abundant metal in the Earth's biosphere and general bioavailability in drinking water, food, medicines, consumer products, groundwater and atmospheric dust; and (vi) abundance as one of the most commonly encountered intracellular and extracellular metallotoxins. Despite aluminum's prevalence and abundance in the biosphere it is remarkably well-tolerated by all plant and animal species; no organism is known to utilize aluminum metabolically; however, a biological role for aluminum has been assigned in the compaction of chromatin. In this Communication, several examples are given where aluminum has been shown to irreversibly perturb and/or stabilize the natural conformation of biomolecules known to be important in energy metabolism, gene expression, cellular homeostasis and pathological signaling in neurological disease. Several neurodegenerative disorders that include the tauopathies, Alzheimer's disease and multiple prion disorders involve the altered conformation of naturally occurring cellular proteins. Based on the data currently available we speculate that one way aluminum contributes to neurological disease is to induce the misfolding of naturally occurring proteins into altered pathological configurations that contribute to the neurodegenerative disease process.

microRNA-146a-5p, Neurotropic Viral Infection and Prion Disease (PrD).

The human brain and central nervous system (CNS) harbor a select sub-group of potentially pathogenic microRNAs (miRNAs), including a well-characterized NF-kB-sensitive Homo sapiens microRNA hsa-miRNA-146a-5p (miRNA-146a). miRNA-146a is significantly over-expressed in progressive and often lethal viral- and prion-mediated and related neurological syndromes associated with progressive inflammatory neurodegeneration. These include ~18 different viral-induced encephalopathies for which data are available, at least ~10 known prion diseases (PrD) of animals and humans, Alzheimer's disease (AD) and other sporadic and progressive age-related neurological disorders. Despite the apparent lack of nucleic acids in prions, both DNA- and RNA-containing viruses along with prions significantly induce miRNA-146a in the infected host, but whether this represents part of the host's adaptive immunity, innate-immune response or a mechanism to enable the invading prion or virus a successful infection is not well understood. Current findings suggest an early and highly interactive role for miRNA-146a: (i) as a major small noncoding RNA (sncRNA) regulator of innate-immune responses and inflammatory signaling in cells of the human brain and CNS; (ii) as a critical component of the complement system and immune-related neurological dysfunction; (iii) as an inducible sncRNA of the brain and CNS that lies at a critical intersection of several important neurobiological adaptive immune response processes with highly interactive associations involving complement factor H (CFH), Toll-like receptor pathways, the innate-immunity, cytokine production, apoptosis and neural cell decline; and (iv) as a potential biomarker for viral infection, TSE and AD and other neurological diseases in both animals and humans. In this report, we review the recent data supporting the idea that miRNA-146a may represent a novel and unique sncRNA-based biomarker for inflammatory neurodegeneration in multiple species. This paper further reviews the current state of knowledge regarding the nature and mechanism of miRNA-146a in viral and prion infection of the human brain and CNS with reference to AD wherever possible.

Atropa belladonna Expresses a microRNA (aba-miRNA-9497) Highly Homologous to Homo sapiens miRNA-378 (hsa-miRNA-378); both miRNAs target the 3'-Untranslated Region (3'-UTR) of the mRNA Encoding the Neurologically Relevant, Zinc-Finger Transcription Factor ZNF-691.

Recent advances in ethnobotanical and neurological research indicate that ingested plants from our diet may not only be a source of nutrition but also a source of biologically relevant nucleic-acid-encoded genetic information. A major source of RNA-encoded information from plants has been shown to be derived from small non-coding RNAs (sncRNAs) such as microRNAs (miRNAs) that can transfer information horizontally between plants and humans. In human hosts, the 3'-untranslated region (3'-UTR) of messenger RNAs (mRNAs) is targeted by these miRNAs to effectively down-regulate expression of that mRNA target in the host CNS. In this paper, we provide evidence that the Atropa belladonna aba-miRNA-9497 (miRBase conserved ID: bdi-miRNA-9497) is highly homologous to the CNS-abundant Homo sapiens miRNA-378 (hsa-miRNA-378) and both target the zinc-finger transcription factor ZNF-691 mRNA 3'-UTR to down-regulate ZNF-691 mRNA abundance. We speculate that the potent neurotoxic actions of the multiple tropane alkaloids of Atropa belladonna may be supplemented by the neuroregulatory actions of aba-miRNA-9497 on ZNF-691, and this may be followed by the modulation in the expression of ZNF-691-sensitive genes. This is the first example of a human brain-enriched transcription factor, ZNF-691, targeted and down-regulated by a naturally occurring plant microRNA, with potential to modulate gene expression in the human CNS and thus contribute to the neurotoxicological-and-psychoactive properties of the Atropa belladonna species of the deadly nightshade Solanaceae family.

Vesicular Transport of Encapsulated microRNA between Glial and Neuronal Cells.

Exosomes (EXs) and extracellular microvesicles (EMVs) represent a diverse assortment of plasma membrane-derived nanovesicles, 30-1000 nm in diameter, released by all cell lineages of the central nervous system (CNS). They are examples of a very active and dynamic form of extracellular communication and the conveyance of biological information transfer essential to maintain homeostatic neurological functions and contain complex molecular cargoes representative of the cytoplasm of their cells of origin. These molecular cargoes include various mixtures of proteins, lipids, proteolipids, cytokines, chemokines, carbohydrates, microRNAs (miRNA) and messenger RNAs (mRNA) and other components, including end-stage neurotoxic and pathogenic metabolic products, such as amyloid beta (Aß) peptides. Brain microglia, for example, respond to both acute CNS injuries and degenerative diseases with complex reactions via the induction of a pro-inflammatory phenotype, and secrete EXs and EMVs enriched in selective pathogenic microRNAs (miRNAs) such as miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155, and others that are known to promote neuro-inflammation, induce complement activation, disrupt innate-immune signaling and deregulate the expression of neuron-specific phosphoproteins involved in neurotropism and synaptic signaling. This communication will review our current understanding of the trafficking of miRNA-containing EXs and EMVs from astrocytes and "activated pro-inflammatory" microglia to target neurons in neurodegenerative diseases with an emphasis on Alzheimer's disease wherever possible.

Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and Ca2+ Homeostasis in Hippocampus; Relevance to Neurodegenerative Disorders.

Acute systemic inflammatory response (SIR) triggers an alteration in the transcription of brain genes related to neuroinflammation, oxidative stress and cells death. These changes are also characteristic for Alzheimer's disease (AD) neuropathology. Our aim was to evaluate gene expression patterns in the mouse hippocampus (MH) by using microarray technology 12 and 96 h after SIR evoked by lipopolysaccharide (LPS). The results were compared with microarray analysis of human postmortem hippocampal AD tissues. It was found that 12 h after LPS administration the expression of 231 genes in MH was significantly altered (FC > 2.0); however, after 96 h only the S100a8 gene encoding calgranulin A was activated (FC = 2.9). Gene ontology enrichment analysis demonstrated the alteration of gene expression related mostly to the immune-response including the gene Lcn2 for Lipocalin 2 (FC = 237.8), involved in glia neurotoxicity. The expression of genes coding proteins involved in epigenetic regulation, histone deacetylases (Hdac4,5,8,9,11) and bromo- and extraterminal domain protein Brd3 were downregulated; however, Brd2 was found to be upregulated. Remarkably, the significant increase in expression of Lcn2, S100a8, S100a9 and also Saa3 and Ch25h, was found in AD brains suggesting that early changes of immune-response genes evoked by mild SIR could be crucial in AD pathogenesis.

Plant and Animal microRNAs (miRNAs) and Their Potential for Inter-kingdom Communication.

microRNAs (miRNAs) comprise a class of ~18-25 nucleotide (nt) single-stranded non-coding RNAs (sncRNAs) that are the smallest known carriers of gene-encoded, post-transcriptional regulatory information in both plants and animals. There are many fundamental similarities between plant and animal miRNAs-the miRNAs of both kingdoms play essential roles in development, aging and disease, and the shaping of the transcriptome of many cell types. Both plant and animal miRNAs appear to predominantly exert their genetic and transcriptomic influences by regulating gene expression at the level of messenger RNA (mRNA) stability and/or translational inhibition. Certain miRNA species, such as miRNA-155, miRNA-168, and members of the miRNA-854 family may be expressed in both plants and animals, suggesting a common origin and functional selection of specific miRNAs over vast periods of evolution (for example, Arabidopsis thaliana-Homo sapiens divergence ~1.5 billion years). Although there is emerging evidence for cross-kingdom miRNA communication-that plant-enriched miRNAs may enter the diet and play physiological and/or pathophysiological roles in human health and disease-some research reports repudiate this possibility. This research paper highlights some recent, controversial, and remarkable findings in plant- and animal-based miRNA signaling research with emphasis on the intriguing possibility that dietary miRNAs and/or sncRNAs may have potential to contribute to both intra- and inter-kingdom signaling, and in doing so modulate molecular-genetic mechanisms associated with human health and disease.

Up-regulated Pro-inflammatory MicroRNAs (miRNAs) in Alzheimer's disease (AD) and Age-Related Macular Degeneration (AMD).

Alzheimer's disease (AD) of the brain neocortex and age-related macular degeneration (AMD) of the retina are two complex neurodegenerative disorders, which (i) involve the progressive dysregulation and deterioration of multiple neurobiological signaling pathways, (ii) exhibit the temporal accumulation of pro-inflammatory lesions including the amyloid beta (Aß) peptide-containing senile plaques of AD and the drusen of AMD, and (iii) culminate in an insidious inflammatory neurodegeneration ending, respectively, in neural cell atrophy and death and progressive loss of cognition and central visual function. Recent independent research studies have indicated that AD and AMD share common, pathological signaling defects and disease mechanisms at the molecular genetic level. Using high-integrity total RNA samples pooled from AD brain and AMD retina, microfluidic hybridization miRNA arrays, and bioinformatics, the current study was undertaken to quantify microRNA (miRNA) speciation and complexity common to both AD and AMD. These small non-coding (sncRNAs) are known to post-transcriptionally regulate multiple neurobiological pathways and an abundance of research information has already been generated on the roles of these miRNAs in pathological situations involving inflammatory neuropathology and neural cell decline. Here, for the first time, we report the sequence and abundance of a septet of sncRNAs including miRNA-7, miRNA-9-1, miRNA-23a/miRNA-27a, miRNA-34a, miRNA-125b-1, miRNA-146a, and miRNA-155 that are significantly increased in abundance and common to both AD-affected superior temporal lobe neocortex (Brodmann A22) and the AMD-affected macular region of the retina. Bioinformatics, miRNA-mRNA complementarity, next-gen RNA sequencing, and feature alignment analysis further indicate that these 7 up-regulated miRNAs have the potential to interact with and down-regulate ~ 9460 target messenger RNAs (mRNAs; about 3.5% of the genome) involved in the synchronization of amyloid production and clearance, phagocytosis, innate-immune, pro-inflammatory, and neurotrophic signaling and/or synaptogenesis in diseased tissues.

Chromosome 21-Encoded microRNAs (mRNAs): Impact on Down's Syndrome and Trisomy-21 Linked Disease.

Down's syndrome (DS; also known as trisomy 21; T21) is caused by a triplication of all or part of human chromosome 21 (chr21). DS is the most common genetic cause of intellectual disability attributable to a naturally-occurring imbalance in gene dosage. DS incurs huge medical, healthcare, and socioeconomic costs, and there are as yet no effective treatments for this incapacitating human neurogenetic disorder. There is a remarkably wide variability in the 'phenotypic spectrum' associated with DS; the progression of symptoms and the age of DS onset fluctuate, and there is further variability in the biophysical nature of the chr21 duplication. Besides the cognitive disruptions and dementia in DS patients other serious health problems such as atherosclerosis, altered lipogenesis, Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), autoimmune disease, various cancers including lymphoma, leukemia, glioma and glioblastoma, status epilepticus, congenital heart disease, hypotonia, manic depression, prostate cancer, Usher syndrome, motor disorders, Hirschsprung disease, and various physical anomalies such as early aging occur at elevated frequencies, and all are part of the DS 'phenotypic spectrum.' This communication will review the genetic link between these fore-mentioned diseases and a small group of just five stress-associated microRNAs (miRNAs)-that include let-7c, miRNA-99a, miRNA-125b, miRNA-155, and miRNA-802-encoded and clustered on the long arm of human chr21 and spanning the chr21q21.1-chr21q21.3 region.

Correction to: Mercury exposure, nutritional deficiencies and metabolic disruptions may affect learning in children.

The original version of this article [1] unfortunately contained an error which has since been acknowledged in this Correction article. The URL link in the Reference 19 was broken and it needs to be replaced with the active link given below.

MicroRNA (miRNA)-Mediated Pathogenetic Signaling in Alzheimer's Disease (AD).

Alzheimer's disease (AD) is an expanding health and socioeconomic concern in industrialized societies, and the leading cause of intellectual impairment in our aging population. The cause of AD remains unknown, and there are currently no effective treatments to stop or reverse the progression of this uniquely human and age-related neurological disorder. Elucidation of the AD mechanism and factors that contribute to the initiation, progression, and spreading of this chronic and fatal neurodegeneration will ultimately result in improved and effective diagnostics and therapeutic strategies.microRNAs (miRNAs) comprise a relatively recently discovered category of 20-24 nucleotide non-coding RNAs that function post-transcriptionally in shaping the transcriptome of the cell, and in doing so, contribute to the molecular-genetics and phenotype of human CNS health and disease. To date about 2550 unique mature human miRNAs have been characterized, however only highly selected miRNA populations appear to be enriched in different anatomical compartments within the CNS.This general commentary for the 'Special Issue: 40th Year of Neurochemical Research' will bring into perspective (i) some very recent findings on the extraordinary biophysics and signaling properties of CNS miRNA in AD and aging human brain; (ii) how specific intrinsic biophysical attributes of miRNAs may play defining roles in the establishment, proliferation and spreading of the AD phenotype; and (iii) how miRNAs can serve as prospective therapeutic targets and biomarkers potentially useful in the clinical management of this terminal neurological disease whose incidence in our rapidly aging population is reaching epidemic proportions.

MicroRNA (miRNA) Signaling in the Human CNS in Sporadic Alzheimer's Disease (AD)-Novel and Unique Pathological Features.

Of the approximately ~2.65 × 10³ mature microRNAs (miRNAs) so far identified in Homo sapiens, only a surprisingly small but select subset-about 35-40-are highly abundant in the human central nervous system (CNS). This fact alone underscores the extremely high selection pressure for the human CNS to utilize only specific ribonucleotide sequences contained within these single-stranded non-coding RNAs (ncRNAs) for productive miRNA-mRNA interactions and the down-regulation of gene expression. In this article we will: (i) consolidate some of our still evolving ideas concerning the role of miRNAs in the CNS in normal aging and in health, and in sporadic Alzheimer's disease (AD) and related forms of chronic neurodegeneration; and (ii) highlight certain aspects of the most current work in this research field, with particular emphasis on the findings from our lab of a small pathogenic family of six inducible, pro-inflammatory, NF-κB-regulated miRNAs including miRNA-7, miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155. This group of six CNS-abundant miRNAs significantly up-regulated in sporadic AD are emerging as what appear to be key mechanistic contributors to the sporadic AD process and can explain much of the neuropathology of this common, age-related inflammatory neurodegeneration of the human CNS.

Intracerebral propagation of Alzheimer's disease: strengthening evidence of a herpes simplex virus etiology.

BACKGROUND: A faulty human protein, abnormally phosphorylated tau, was recently publicized to spread "like a virus" from neuron to neuron in Alzheimer's patients' brains. For several decades, we have been amassing arguments showing that herpes simplex virus type 1 (HSV-1), not p-tau, propagates this interneuronal, transsynaptic pathologic cascade. METHODS: We reiterate convincing data from our own (and other) laboratories, reviewing the first anatomic foothold neurofibrillary tangles gain in brainstem and/or entorhinal cortex; the chronic immunosurveillance cellularity of the trigeminal ganglia wherein HSV-1 awakens from latency to reactivate; the inabilities of p-tau protein's physical properties to promote it to jump synapses; the amino acid homology between human p-tau and VP22, a key target for phosphorylation by HSV serine/threonine-protein kinase UL13; and the exosomic secretion of HSV-1-infected cells' L-particles, attesting to the cell-to-cell passage of microRNAs of herpesviruses. RESULTS: The now-maturing construct that reactivated HSV-1 best accounts for the intracerebral propagation of AD changes in the human brain should at last seem highly attractive. This hypothesis might even explain statins' apparent mechanism in some studies for lowering AD incidence. CONCLUSION: Provided that funding agencies will quickly ignite a new realm of investigation, the rejuvenated enthusiasm for testing this optimistic construct holds incalculable potential for rapid, efficacious clinical application, through already available and relatively safe antiviral therapeutics.

MicroRNA (miRNA) Complexity in Alzheimer's Disease (AD).

AD is a complex, progressive, age-related neurodegenerative disorder representing the most common cause of senile dementia and neurological dysfunction in our elderly domestic population. The widely observed heterogeneity of AD is a reflection of the complexity of the AD process itself and the altered molecular-genetic mechanisms operating in the diseased human brain and CNS. One of the key players in this complex regulation of gene expression in human pathological neurobiology are microRNAs (miRNAs) that, through their actions, shape the transcriptome of brain cells that normally associate with very high rates of genetic activity, gene transcription and messenger RNA (mRNA) generation. The analysis of miRNA populations and the characterization of their abundance, speciation and complexity can further provide valuable clues to our molecular-genetic understanding of the AD process, especially in the sporadic forms of this common brain disorder. Current in-depth analyses of high-quality AD and age- and gender-matched control brain tissues are providing pathophysiological miRNA-based signatures of AD that can serve as a basis for expanding our mechanistic understanding of this disorder and the future design of miRNA- and related RNA-based therapeutics. This focused review will consolidate the findings from multiple laboratories as to which are the most abundant miRNA species, both free and exosome-bound in the human brain and CNS, which miRNA species appear to be the most prominently affected by the AD process and review recent developments and advancements in our understanding of the complexity of miRNA signaling in the hippocampal CA1 region of AD-affected brains.

Higher rates of autism and attention deficit/hyperactivity disorder in American children: Are food quality issues impacting epigenetic inheritance?

In the United States, schools offer special education services to children who are diagnosed with a learning or neurodevelopmental disorder and have difficulty meeting their learning goals. Pediatricians may play a key role in helping children access special education services. The number of children ages 6-21 in the United States receiving special education services increased 10.4% from 2006 to 2021. Children receiving special education services under the autism category increased 242% during the same period. The demand for special education services for children under the developmental delay and other health impaired categories increased by 184% and 83% respectively. Although student enrollment in American schools has remained stable since 2006, the percentage distribution of children receiving special education services nearly tripled for the autism category and quadrupled for the developmental delay category by 2021. Allowable heavy metal residues remain persistent in the American food supply due to food ingredient manufacturing processes. Numerous clinical trial data indicate heavy metal exposures and poor diet are the primary epigenetic factors responsible for the autism and attention deficit hyperactivity disorder epidemics. Dietary heavy metal exposures, especially inorganic mercury and lead may impact gene behavior across generations. In 2021, the United States Congress found heavy metal residues problematic in the American food supply but took no legislative action. Mandatory health warning labels on select foods may be the only way to reduce dietary heavy metal exposures and improve child learning across generations.

HSV-1 latent rabbits shed viral DNA into their saliva.

BACKGROUND: Rabbits latent with HSV-1 strain McKrae spontaneously shed infectious virus and viral DNA into their tears and develop recurrent herpetic-specific corneal lesions. The rabbit eye model has been used for many years to assess acute ocular infections and pathogenesis, antiviral efficacy, as well as latency, reactivation, and recurrent eye diseases. This study used real-time PCR to quantify HSV-1 DNA in the saliva and tears of rabbits latent with HSV-1 McKrae. METHODS: New Zealand white rabbits used were latent with HSV-1 strain McKrae and had no ocular or oral pathology. Scarified corneas were topically inoculated with HSV-1. Eye swabs and saliva were taken from post inoculation (PI) days 28 through 49 (22 consecutive days). Saliva samples were taken four times each day from each rabbit and the DNA extracted was pooled for each rabbit for each day; one swab was taken daily from each eye and DNA extracted. Real-time PCR was done on the purified DNA samples for quantification of HSV-1 DNA copy numbers. Data are presented as copy numbers for each individual sample, plus all the copy numbers designated as positive, for comparison between left eye (OS), right eye (OD), and saliva. RESULTS: The saliva and tears were taken from 9 rabbits and from 18 eyes and all tested positive at least once. Saliva was positive for HSV-1 DNA at 43.4% (86/198) and tears were positive at 28.0% (111/396). The saliva positives had 48 episodes and the tears had 75 episodes. The mean copy numbers ± the SEM for HSV-1 DNA in saliva were 3773 ± 2019 and 2294 ± 869 for tears (no statistical difference). CONCLUSION: Rabbits latent with strain McKrae shed HSV-1 DNA into their saliva and tears. HSV-1 DNA shedding into the saliva was similar to humans. This is the first evidence that documents HSV-1 DNA in the saliva of latent rabbits.

Rabbit and mouse models of HSV-1 latency, reactivation, and recurrent eye diseases.

The exact mechanisms of HSV-1 establishment, maintenance, latency, reactivation, and also the courses of recurrent ocular infections remain a mystery. Comprehensive understanding of the HSV-1 disease process could lead to prevention of HSV-1 acute infection, reactivation, and more effective treatments of recurrent ocular disease. Animal models have been used for over sixty years to investigate our concepts and hypotheses of HSV-1 diseases. In this paper we present descriptions and examples of rabbit and mouse eye models of HSV-1 latency, reactivation, and recurrent diseases. We summarize studies in animal models of spontaneous and induced HSV-1 reactivation and recurrent disease. Numerous stimuli that induce reactivation in mice and rabbits are described, as well as factors that inhibit viral reactivation from latency. The key features, advantages, and disadvantages of the mouse and rabbit models in relation to the study of ocular HSV-1 are discussed. This paper is pertinent but not intended to be all inclusive. We will give examples of key papers that have reported novel discoveries related to the review topics.

Amyloid beta (Aß) peptide modulators and other current treatment strategies for Alzheimer's disease (AD).

Introduction: Alzheimer's disease (AD) is a common, progressive neurological disorder whose incidence is reaching epidemic proportions. The prevailing "amyloid cascade hypothesis," which maintains that the aberrant proteolysis of beta-amyloid precursor protein (ßAPP) into neurotoxic amyloid beta (Aß) peptides is central to the etiopathology of AD, continues to dominate pharmacological approaches to the clinical management of this insidious disorder. This review is a compilation and update on current pharmacological strategies designed to down-regulate Aß42 peptide generation in an effort to ameliorate the tragedy of AD. Areas covered: This review utilized online data searches at various open online-access websites including the Alzheimer Association, Alzheimer Research Forum; individual drug company databases; the National Institutes of Health (NIH) Medline; Pharmaprojects database; Scopus; inter-University research communications; and unpublished research data. Expert opinion: Anti-acetylcholinesterase-, chelation-, N-methyl-D-aspartate (NMDA) receptor antagonist-, statin-, Aß immunization-, ß-secretase-, γ-secretase-based, and other strategies to modulate ßAPP processing, have dominated pharmacological approaches directed against AD-type neurodegenerative pathology. Cumulative clinical results of these efforts remain extremely disappointing, and have had little overall impact on the clinical management of AD. While a number of novel approaches are in consideration and development, to date there is still no effective treatment or cure for this expanding healthcare concern.