CD71: Role in permafrost immunity.

Iron, an essential constituent of cell metabolism, is transported intra-cellularly bound to the ubiquitous 76 kDa blood glycoprotein transferrin via the transferrin receptor, CD71. Because of its structure, CD71 facilitates the binding and penetration of a large variety of viruses into the host. Among which the hemorrhagic fever-causing New World mammarena viruses (family of single stranded ambisense segmented RNA Arenaviridae), the single stranded positive sense RNA hepatitis C virus, the single stranded negative sense segmented influenza A virus, the single stranded negative sense RNA rabies virus, the single stranded positive sense SARS-CoV2 and possibly many others. In this process, CD71 is associated with the target of the anti-proliferative antibody-1 (CD81) viral co-receptor. In light of the plethora of novel and ancient viruses and microbes emerging from melting eternal glacier ice and permafrost, it is timely and critical to define and characterize interventions, besides the soluble form of CD71 (sCD71), that can abrogate or minimize this novice non-canonical function of CD71.

Nipah: The looming post-covid pandemic.

First identified as a pathogen in Malaysia and Singapore in 1999, Nipah virus (NiV) caused nearly 300 human cases and over 100 fatalities. It also killed about 1 million pigs. Three years later (2002), it was reported in Pteropus bats in Malaysia, in Cambodia & Thailand, (2005), and as far as Madagascar (2007) and Ghana (2008). India (Kerala) reported its first human NiV-caused fatalities in September 2023. Taken together, these trends emphasize its public health threat. In humans, NiV infection initially leads to fever, headache, body aches and muscle pain, nausea and vomiting. The symptoms rapidly evolve into sore throat, cough and atypical pneumonia leading to severe respiratory distress. The cadre of NiV-induced pathology (Nipah disease, NiD) then includes severe dizziness and drowsiness, progressive alteration in cognition and consciousness, acute encephalitis and seizures. Public health protocols (e.g., mask-wearing, quarantine), essential to contain and control CoViD-19, seem insufficient to contain NiD spread because NiV transmission occurs primarily via direct contacts with body fluids of infected carriers, but presumably not by airborne transmission. As in the case of SARS-C0V2, health care providers (i.e., physicians, dentists, nurses, dental assistants) are greatest risks not only of contracting but of spreading NiV infection. NiV is a high-pathogenicity pathogen, against which, at present, we have no anti-viral medications or preventive vaccine. Taken together, the evidence to date heightens the threat of an upcoming NiD pandemic.

CoViD-19 effects on social-emotional development: impact of early intervention.

Age-appropriate development of social and emotional skills is challenging to a child under standard conditions. The CoVID-19 pandemic has likely influenced the development of social, emotional, and communicative skills. Factors like prolonged lockdowns, restricted peer interactions, and mandatory mask-wearing may have hindered children's ability to learn facial expressions and nonverbal cues. The research evidence discussed in this paper confirms that proposition, and examines in further depth the potential impact of the CoViD-19 pandemic. We also discuss groundwork evidence-based early intervention (EI) practices designed to mitigate the negative effects these unprecedented circumstances may have led to, and how tele-medicine alternatives and Artificial intelligence (AI) can expedite interventional childhood plans. The role of bioinformatics is vital in the compilation and analysis of the vast research in this piece related to CoViD-19, serving as a profound search tool for future research endeavors focused on understanding the long term effects of the pandemic.

The lymphatic system: a pathway for meta-inflammation in permafrost immunity.

The lymphatic system is the anatomical substratum of immunity. Lymphatics collect tissue exudates, which contain cell debris, peptides, micronutrients and pathogens, as well as immune naive and memory effector cells from the body tissues and organs into the lymph. Lined by endothelial cells cemented together by tight junctions to ensure their impermeability, lymphatics contain valves that prevent the backward flow of the lymph as it moves forward toward the right and left venous angles, the anatomical site of confluence with the venous blood. Meta-inflammation increases the permeability of lymphatics, rendering the elderly more susceptible to novel and ancient airborne viruses released by melting glaciers and permafrost. Simple public health protocols (e.g., mask-wearing, quarantine) are essential to minimize colliding epidemics/pandemics, and favor permafrost immunity.

Permafrost viremia and immune tweening.

The immune system, an exquisitely regulated physiological system, utilizes a wide spectrum of soluble factors and multiple cell populations and subpopulations at diverse states of maturation to monitor and protect the organism against foreign organisms. Immune surveillance is ensured by distinguishing self-antigens from self-associated with non-self (e.g., viral) peptides presented by major histocompatibility complexes (MHC). Pathology is often identified as unregulated inflammatory responses (e.g., cytokine storm), or recognizing self as a non-self entity (i.e., auto-immunity). Artificial intelligence (AI), and in particular specific machine learning (ML) paradigms (e.g., Deep Learning [DL]) proffer powerful algorithms to better understand and more accurately predict immune responses, immune regulation and homeostasis, and immune reactivity to challenges (i.e., immune allostasis) by their intrinsic ability to interpret immune parameters, pathways and events by analyzing large amounts of complex data and drawing predictive inferences (i.e., immune tweening). We propose here that DL models play an increasingly significant role in better defining and characterizing immunological surveillance to ancient and novel virus species released by thawing permafrost.

Colliding Pandemics and CoViD-19.

Cases of the respiratory syncytial virus (RSV), monkeypox virus (MPXV), and avian influenza A Virus (IAV) have increased during our current prolonged Corona Virus Disease 2019 (CoViD-19) pandemic. The rise of these viral infectious diseases may be associated or even inter-dependent with acute, latent or recurrent infection with Systemic Acute Respiratory Syndrome Corona virus-2 (SARS-CoV2). The nonsensical neologism 'tripledemic' was tentatively introduced to describe the confluent nature of these trends (epidemic comes from two Greek words: epi=on, about, demos=people; pandemic is also derived from Ancient Greek: pan=all, demos=people; but 'tripledemic' would derive from Latin triplus=three, Greek demos=people, and would at best signify 'three countries, three peoples', but certainly not the current threat of confluence of three, or perhaps more pandemics). Emerging evidence suggests that monkey pox and CoViD-19, among several other viral diseases, produce significant observable manifestations in the oral cavity. From a clinical standpoint, dentists and dental personnel may be among the first health professionals to encounter and diagnose clinical signs of converging infections. From the immune surveillance viewpoint, viral recombination and viral interference among these infectious diseases must be examined to determine the potential threat of these colliding pandemics.

Toward a fractalomic idiotype/anti-idiotypic paradigm.

The CoViD-19 pandemic has demonstrated the need for future developments in anti-viral immunology. We propose that artificial intelligence (AI) and machine learning, and in particular fractal analysis could play a crucial role in that context. Fractals - never-ending repeats of self-similar shapes whose composite tend to resemble the whole - are found in most natural biological structures including immunoglobulin and antigenic epitopes. Increased knowledge of the fractalomic properties of the idiotype/anti-idiotypic paradigm should help develop a novel and improved simplified artificial model of the immune system. Case in point, the regulation and dampening of antibodies as well as the synergetic recognition of an antigen by multiple idiotypes are both immune mechanisms that require further analysis. An enhanced understanding of these complexities could lead to better data analysis for novel vaccines to improve their sensitivity and specificity as well as open other new doors in the field of immunology.

Permafrost Immunity.

Thawing permafrost is a serious and worrisome threat to the environment, because it releases trapped heavy metals and greenhouse gasses. Thawing permafrost is also a health threat because, in addition to releasing these noxious gasses, thawing permafrost may free novel and undiscovered antibiotic-resistant bacteria, viruses, fungi and parasites among a plethora of dormant pathogens. Our immune system is ill-prepared to counter these challenges, and will require significant adaptation, or allostasis, which can be subsumed under the generic term of permafrost immunity. Since most of the most gravely threatening pathogens released by thawing permafrost are likely to penetrate the organism through the oral cavity, permafrost immunity may first be identified in the oral mucosa.

Virus interference in CoViD-19.

Virus interference is one of the oldest concepts in immunology. Recent findings indicate that it may depend on the host's anti-viral cellular immune surveillance processes, as well as on sequence-specific gene silencing mechanism guided by double-stranded RNA. Other biological events, unrelated to some degree at least from immune-dependent IFN or RNA-dependent viral interference may be at play as well. We discuss these biological mechanisms in the context of of the Systemic Acute Respiratory Syndrome Corona virus2 (SARS-CoV2) virus responsible for Corona Virus Disease 2019 (CoViD-19).

Post acute CoViD-19 syndrome (PACS) - Long CoViD.

Patients sero-positive for the Systemic Acute Respiratory Syndrome Corona virus2 (SARS-CoV2) virus develop the Corona Virus Disease 2019 (CoViD-19). CoViD-19 may be asymptomatic in some individuals, proffer mild symptoms in other patients, and can be a serious and even lethal disease in a sub-group of the population. The variables that determine the severity of CoViD-19 have not been fully characterized. What is clear is that the patients who survive CoViD-19 return to a state of sero-negativity for SARS-CoV2 generally within 3-5 weeks. However, several cases of repeated infection have been reported, and a large proportion of CoViD-19-recovered patients manifest multi-system and multi-organ symptomatic pathologies several weeks-to-months after resuming sero-negativity for SARS-CoV2. This new pathological condition, originally termed Long Covid, is now recognized as the Post Acute CoViD-19 Syndrome (PACS). The original principal clusters of signs and symptoms of PACS: likelihood of relapse and reinfection, physical fatigue and cognitive slowdown, may actually be broadened to include immune deregulation, cardiovascular disease and coagulation abnormalities. The development and evaluation of new and improved clinical interventions for PACS are critical and timely.

CoViD-19 Susceptibility.

There have been over five million cases of infection with the second Corona virus to induce SARS (SARS-CoV2) and close to half a million deaths worldwide since the first report of Corona Virus Disease in late December 2019 (CoViD-19). Over two million CoViD-19 patients have recovered. The factors and variables that lead certain CoViD-19 patients to survive this otherwise aggressive and lethal viral infection are intensely researched, as is the development of productive anti-virals and of safe and effective vaccines. Several hypotheses invoke putative mutations of the ss-positive RNA SARS-CoV2 virus to states of stronger or weaker virulence and lethality. Other hypotheses propose that the patient's status of immunity, vitamin D level, Zinc deficiency or other physiological parameters determine how any given patient will effectively weather the viremia and the consequential multi-symptomatic CoViD-19. The initial cause - causa prima - underlying all the symptoms of CoViD-19 is infection of the host human cell by SARS-CoV2. The virus spike (S) protein finds its binding site, ACE2, widely distributed in all cells and tissues that potentially proffer CoViD-19 pathology. S consists of two subunits, S1 and S2, which are cleaved by the widely expressed transmembrane protease serine 2 (TMPRSS2) before the virus fuses to the plasma membrane and infects the cell. Current trends show that variant alleles resulting from single nucleotide polymorphisms (SNPs) of ACE2, and genetic variants of TMPRSS2, with putative distinct affinities for S clip, may determine a complex multi-factorial spectrum of SARS-CoV2 virulence across patients, and predict CoViD-19 susceptibility.

Critical comments on COViD-19 outbreak: succinct advice for dentists and oral healthcare professionals by Cirillo (2020).

This article informs dental professionals of timely and critical recommendations to keep the practice of dentistry safe for the patients, the staff, the hygienists and the dentists. Teaching of these recommendations are being integrated in the clinical curriculum of pre-DDS and pre-DMD professionals, as well as in dental hygiene and dental assisting schools. The paper provides an essential and clearly-written overview of new mandatory procedures and protocols for the practice of dentistry, which will spread world-wide in the near future.

Towards Neuro-CoViD-19.

CoViD-19 is the current pandemic caused by the Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2). Infection by SARS-CoV-2 occurs via the binding of its S protein to the angiotensin-converting enzyme-2 receptor (ACE2-R). S binding to ACE2-R leads to a drop in ACE2, a homolog of angiotensin converting enzyme (ACE). In the central nervous system (CNS), ACE mediates neuroinflammation, neurodegeneration and neurotoxicity responsible for several CNS disorders. ACE2 counteracts the damaging effects of ACE on CNS neurons. SARS-CoV-2 can directly access the CNS via the circulation or via cranial nerve I and the olfactory bulb. Inactivation of ACE2 following binding of SARS-CoV-2 S protein to ACE2-R in situ might blunt ACE2-moderating effects upon ACE CNS neurotoxicity and neurodegeneration. Here, we propose a neurobiological mechanism directly involving SARS-CoV-2 binding to ACE2-R in the etiology of putative Neuro-CoViD-19.

2019-nCoV - Towards a 4th generation vaccine.

The first report of the unusual manifestation of pneumonia-like symptoms in Wuhan City, China was made on 31 December 2019. Within one week, the Chinese authorities reported that they had identified the causative agent as a new member of the Coronavirus family, the same family of that was responsible for MERS and SARS not so many years ago. The new virus was called Novel Coronavirus 2019 (2019-nCoV). Three weeks later, the World Health Organization declared that 2019-nCoV was capable of direct human-to-human transmission, the virus had spread across several countries in three continents, and had infected close to two thousand people, of whom at least 1 in 5 quite severely. The number of fatalities was fast rising. Yet, the World Health Organization officially announced that there is still at present no recommended anti-nCoV vaccine for subject at-risk, nor treatment for patients with suspected or confirmed nCoV, let alone 2019-nCov. It is therefore timely and critical to propose new possible and practical approaches for preventive interventions for subjects at-risk, and for treatment of patients afflicted with 2019-nCov-induced disease (Corona Virus Disease 2019; COVID-19) before the present situation explodes into a worldwide pandemic. One such potential clinical protocol is proposed as a hypothesis.

CoViD-19 Immunopathology and Immunotherapy.

New evidence on the T-cell immuno-pathology in patient's with Corona Virus Disease 2019 (CoViD-19) was reported by Diao et al. in MedRxiv (doi: 10.1101/2020.02.18.20024364) [1]. It reports observations on 522 patients with confirmed CoViD-19 symptomatology, compared to 40 control subjects. In brief, notable T cytopoenia was recorded by flow cytometry in the CD4+ and the CD8+ populations, which were significantly yet inversely correlated with remarkably increased serum levels of the pro-inflammatory cytokines IL-6, IL-10 and TNF-a. Flow cytometry established a progressive increase in the expression of programmed cell death marker-1 (PD-1) and T cell immunoglobulin and mucin domain 3 (Tim-3) as patients (n=14) deteriorated from prodromal to symptomatic CoViD-19 requiring intensive care. Here, we interpret these observations of Diao et al from our current understanding of T cell immunophysiology and immunopathology following an immune challenge in the form of sustained viral infection, as is the case in CoViD-19, with emphasis on exhausted T cells (Tex). Recent clinical trials to rescue Tex show promising outcomes. The relevance of these interventions for the prevention and treatment of CoViD-19 is discussed. Taken together, the data of Diao et al could proffer the first glimpse of immunopathology and possible immunotherapy for patients with CoViD-19.

Metascience in Bioinformation.

Metascience refers to the systematic process that uncovers, builds, evaluates, organizes and disseminates scientific advances. It is the principal tool at the disposal of the society to combat the debilitating effects of "false information" on health related data and its constituents.

Translational research of temporomandibular joint pathology: a preliminary biomarker and fMRI study.

BACKGROUND: The temporomandibular joint (TMJ) is well innervated by braches of the trigeminal nerve. The temporomandibular joint disorders (TMD) can cause neural-inflammation in the peripheral nervous system (PNS) at the site of injury, or compression, and may have systemic effects on the central nervous system (CNS). Neural-inflammation causes elevations in cytokine expression and microglia activation. When the site of injury, or compression is treated, or relieved, neural inflammation is reduced. These changes can be seen and measured with fMRI brain activities. METHODS: For this study, patients with comorbid TMD and systemic/neurologic conditions were compared using clinical diagnostic markers, inflammatory, pain, tissue destruction enzymatic biomarkers, and functional magnetic resonance imaging (fMRI) activity of the brain, with and without a custom-made dental orthotic. RESULTS: Our results showed a correlation between the clinical diagnosis of the pathological TMJ, biomarkers and the fMRI study. There was a marked elevation of biomarkers in samples taken from TMJ of patients who were clinically diagnosed with TMD. The fMRI study of TMD patients showed an abnormal hyper-connected salience network and a diminished blood flow to the anterior frontal lobes when they did not wear their customized dental orthotics. CONCLUSIONS: Our findings highlight the importance of TMJ-CNS connections and use of fMRI as an investigative tool for understanding TMD and its related neurological pathologies.

Evidence-Based Dentistry: Two Decades and Beyond.

BACKGROUND: In 1999, the American Dental Association proffered a definition of the term evidence-based dentistry, which is still very much used to this day. It stated that "… evidence-based dentistry is an approach to oral health care that requires the judicious integration of systematic assessments of clinically relevant scientific evidence, relating to the patient's oral and medical condition and history, with the dentist's clinical expertise and the patient's treatment needs and preferences." Concerted research during the past 2 decades have defined and characterized the protocols that obtain the qualitative and quantitative consensus of the best evidence base. This component of evidence-based dentistry, which is referred to as evidence-based dental research, is brought about as comparative effectiveness research with the research synthesis design. The best evidence base is judiciously used to generate evidence-based clinical practice guidelines, which in turn inform evidence-based dental practice. DISCUSSION: At this juncture, the complexity of the construct of evidence-based dentistry dictates several avenues of current and future inquiry and development. The most urgent and important of these is undoubtedly to craft and validate novel didactic and practical methodologies to teach evidence-based dentistry-both research and practice-to the next generation of dental researchers and clinical dentists and to optimize the integration of evidence-based dentistry in the dental curriculum. Secondarily, but certainly not of lesser importance, is the need to open and expand new research opportunities in subdomains critical to successful evidence-based dental practice, such as stakeholder engagement, teledentistry, patient-centered care, individual patient data analysis, and health literacy of the patients and caregivers. CONCLUSIONS: The course that has led evidence-based dentistry from its infancy in 1999 to a state of relative recognition, if not acceptance across academic and private clinical dentistry in the United States and abroad that the field enjoys today, has been arduous. The concerted efforts by researchers and clinicians were aided considerably by the political environment, which, during the years, proffered funding to the Agency for Healthcare Research and Quality and the Patient-Centered Outcome Research Institute. These have been significant catalysts of the field of comparative effectiveness research and evidence-based research in medicine and dentistry and have fostered and defended the pursuit of evidence-based endeavors in translational health care. The road ahead does not promise to be easier in next 2 decades. In fact, it has become all the murkier and more complicated now as phrases such as science based and evidence based have presently been banned and declared politically incorrect.