The emerging science is a new science originated with the explosion of natural and integrative medicine; it is the science of epigenetics and nutrigenomics which studies, treats, and analyzed how the environment and lifestyle can affect our genes with all the pathological consequences from related mutations, ways, and natural remedies to prevent, to address and treat the related dysfunctions.
This is the main concept of the emerging science and what most of the experts are treating and commenting in their articles, blogs, books, seminars and webinars, summits and conferences, and that bloggers and writers like myself try to report and share with the public.
But we can all feel overwhelmed from a lot of information from all kinds of sources, and we all may know already enough of these new lifestyle protocols and suggestions.
Why I chose the title of “The Emerging Science” for my blog’s site then?
One of my first blogs, titled “The World Summit” was partially describing the essential point of the “Emerging Science” and why I did get involved with that.
The purpose of the functional and integrative medicine is to find the “root cause” of a disease, and we all know this now very well.
“Every disease begins in the gut” and/or “we are what we eat” are other sentences more time repeated from naturopaths.
Hippocrates the “Father of Medicine” was mentioning these sentences and still today are so valid and true.
We now know so well that the food and ways we eat, our lifestyle and environment are the main reasons of our health issues and of the major diseases today.
The health of the microbiome is so important and the wellbeing of our digestive tract even more because- in short and simplified- if this is damaged, or leaky the bacteria and fragments of proteins and molecules, and toxins from the intestine can migrate in other systems causing variety of problems.
So, what can we do to keep our microbiome healthy and so the intestinal wall?
The food obviously is what we introduce more frequently in our body, and this is why we need to make sure first of all to pick healthy, clean and safe food, but also, we must look at our body’s tolerance. As we know there are food to which we might be sensitive or intolerant and these are those we should avoid and that will cause the problems. Or if we refer to the Blood Type Diet of Dr. Peter D’Adamo whose father was testing that a food who is medicine for one can be poison for another in a book titled “One Man’s Food”, and based on experience with his patients, we should eat following the prototypes and protocols of our blood type avoiding foods that can cause agglutinations for the presence of lectins which are substantially toxins.
I am not expert of other diets because I personally follow and refer to the Mediterranean Diet and Blood Type Diet, and which are anti-inflammatory diets with some restrictions.
If there are instead more serious digestive problems, like IBS, SIBO, or yeast infections, or others, those suggested are elimination diets, or microbiome diets, or fodmap diets which are pretty restrictive.
The other way we can alter our microbiome and not simply this is with the introduction of toxins, the doctors talk incessantly about this and the number and type of these are enormous, they come with foods as poison, as lectins that agglutinate cells, with products we use for cleaning, or any other purpose, from the environment, as emissions of gas and chemicals of all types. The alternatives to these are many and mainly coming from natural products or essential oils, while in case of pollution several attempts for reduction of emissions or other type of strategies have been adopted from years and even more lately because of the world’s catastrophic damages on the environment.
When these external attacks on our body and systems reach the limit, we start to react and to get sick also based on the strength of our immune system and that depends on how we nourish and supplement and from how much inflammation there is in our body caused from these external causes. It is all connected, and one can influence another, our internal feedback systems help to alert, and repair the damages till possible, otherwise we must take action.
Here is why prevention is particularly important and must be addressed as soon as possible before these damages can initiate with serious and drastic consequences.
I am not a health coach, but a biologist, and I encourage all of whom are interested in becoming a health coach to look at the options because this is a growing field and with career opportunities at these times.
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Nitric Oxide is the molecule with the chemical formula NO. This is also known as nitrogen monoxide and is a colorless gas. When exposed to air, it reacts with oxygen, to produce much more harmful nitrogen dioxide gas or NO2. Nitric oxide is an intermediate in some chemical reactions. It is produced as a by-product in fossil fuel burning in vehicle engines and machines. This nitric oxide can cause ozone depletion together with nitrogen dioxide. Naturally, nitric oxide is produced in the air when lightening occurs. In this process, atmospheric nitrogen and oxygen are mixed to produce nitric oxide; this is a major step in the nitrogen cycle, the nitrate source for providing nutrition for plants.
Nitric oxide, or NO is also an endogenous mediator of particularly important biochemical processes, such as vasodilation and transmission of nerve impulses.
In our body the synthesis of this compound is performed from a group of enzymes belonging to the nitric oxide synthetase family, NOS, which use arginine as a substrate, an essential amino acid in children and conditionally essential in adults.
Picture by personaltrainer.it
The synthesis of nitric oxide is regulated by varied factors such as the one called “shear stress”, a parameter that measures the force applied by the flow of blood on the walls of the vessels. When blood pressure rises excessively, the body defends itself by synthesizing nitric oxide which, by dilating the walls of the vessels, contributes to the lowering of pressure. In contrast, the inhibition of nitric oxide synthesis determines an increase in peripheral resistance and a consequent increase in blood pressure.
The synthesis of nitric oxide by endothelial walls can be also promoted by molecules like norepinephrine and cytokines.
The half-life of nitric oxide is markedly short, its rapid catabolism involves binding to the eme group of hemoglobin, this process leads to the consequent production of methemoglobin, a non-functioning form, then nitrites and nitrates, NO2 and NO3, which are eliminated by the kidney.
Nitric oxide modulates nerve and neuromuscular transmission by acting as a neurotransmitter in the central nervous system and in the peripheral non-adrenergic and non-cholinergic nerve plexuses of the bronchial tree, bronchodilator- anti-asthmatic effect, and gastro-intestinal tract.
It relaxes not voluntary smooth muscle, exercises vasodilator action on the systemic, coronary, and renal vascular endothelium.
It intervenes directly in the immune system; nitric oxide is produced by some cells of the immune system that use it to defend themselves from the aggressions of antigens. In this case it is utilized its oxidant action and consequent ability to release free radicals capable of destroying the plasma membrane of microbial agents.
Nitric oxide, in addition, appears to stimulate cell proliferation of T and B lymphocytes during the immune response.
In conclusion, nitric oxide has therapeutic potential for reducing blood pressure, strengthening the immune system, preventing angina, stroke, and heart attack, and for the treatment of erectile dysfunction.
The cytotoxic effects of this molecule are mainly due to its strong oxidizing action which express with increase of the production of free radicals, the most dangerous cause of premature aging, degenerative diseases, and some forms of cancer.
The food supplementation sector is progressively expanding with products capable of increasing the endogenous synthesis of nitric oxide. In particular, the focus is on the administration of high doses of the precursor amino acid L-arginine orally. According to supporters of these supplements, regular intake of arginine would be able to increase the synthesis of nitric oxide.
In fact, the synthesis of nitric oxide is a complicated process, which responds to endocrine and mechanical factors. The stimulatory effect of arginine becomes appreciable only in case of increased need or in the presence of deficiencies induced by a diet low in this nutrient.
Recently instead of traditional arginine it has been proposed the integration of a precursor, the amino acid L-citrulline, in the form of citrulline malate with the purpose of increasing in way dose-dependent the quantity of arginine available for the synthesis of oxide nitric.
Nitric Oxide vs Nitrous Oxide
Nitric oxide and nitrous oxide are molecules of nitrogen (N) and oxygen (O2). Both are gases in the atmosphere. Today, they are emitted mostly by anthropogenic activities and affecting the environment in harmful ways.
Nitrous Oxide commonly known as laughing gas is an oxide of nitrogen with the formula N2O. At room temperature, it is a colorless non-inflammable gas. At elevated temperatures, nitrous oxide is a powerful oxidizer like molecular oxygen.
Nitrous oxide has significant medical uses, especially in surgery and dentistry, for its anesthetic and pain reducing effects. Its name as “laughing gas” is due to the euphoric effects following inhalation. It is also used as an oxidizer in rocket propellant, and in motor racing to increase the power output of engines.
Global reporting of N2O sources over the decade indicates that about 40% of the average of emissions originated from human activity and shows that emissions growth mainly come from expanding agriculture and industry sources within emerging economies. For these reasons, nitrous oxide also substantially contributes to global warming.
Additionally for Dr. Ben Lynch, molecular biologist, ND and epigenetics expert, nitrous oxide irreversibly inactivates cobalamin, the active form of vitamin B12, essential for methionine synthase activity in brain; practically inhibits cobalamin to function as a coenzyme in the methylation cycle.
Under his knowledge there have been reported exposures (~30,000) to N2O and neurological diseases among dental professionals manifesting with symptoms as numbing, tingling and muscle weakness; for those heavy exposed complications are even greater.
Still from his statement there are a wide range of people who may exhibit sensitivity to nitrous oxide, among the populations at risks there are: those with oxidative stress cause of glutathione deficiency and cellular membrane damage, inflammation and increase of TNFa factor (a tumoral factor).
Pathogens as candida, viral infections, and H. Pilory, heavy metals load, MTHFR SNPs, low or high homocysteine, methionine deficiency, SAMe, B-vitamins, selenium, glycine, and glutamine deficiency. Exposure to chemicals and post-operative dementia.
Verification of data by PubChem (nih.gov) “Nitric Oxide”
Nitric oxide appears as a colorless gas. Non-combustible but accelerates the burning of combustible material. Vapors heavier than air. It is a nitrogen oxide which is a free radical. It has a role as a neurotransmitter, a signaling molecule, a vasodilator agent, a bronchodilator agent, a radical scavenger, a human metabolite, an Escherichia coli metabolite, and a mouse metabolite.
Nitric oxide or Nitrogen monoxide is a chemical compound with chemical formula NO. This gas is an important signaling molecule in the body of mammals including humans and is an extremely important intermediate in the chemical industry. It is also a toxic airpollutant produced by automobile engines and power plants. Nitric oxide (NO) should not be confused with nitrous oxide (N2O), a general anesthetic, or with nitrogen dioxide (NO2) which is another poisonous air pollutant. Nitric Oxide as a free radical has high reactivity and reacts with NO2 in the air producing even more toxic gas.
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This abstract comprises a simple analysis and description of the virus genome.
Human coronaviruses, or HCoVs consist of HCoV-229E and HCoV-NL63 in the Alphacoronavirus family and HCoV-OC43 and HCoV-HKU1 in the Betacoronavirus family.
Four CoVs, for instance, HKU1, NL63, 229E and OC43, are mainly responsible for mild respiratory disorders in human circulation.
SARS-CoV-2 is a β-coronavirus carrying a single positive RNA strand as genetic material, it has a lipidic envelope that confers an elliptic morphology.
CoVs evolved a relatively complex multiplicationmechanism to facilitate virus reproduction. In their viral life cycle CoVs transmit genomes and subgenomicRNAs only from RNA templates, and do not need a step of DNA. CoVs use exonuclease NSP14, the first known RNA virus-encoded proofreading enzyme that in comparison with other error-prone RNA viruses, could be adapted to handle CoVs‘ large RNA genome.
“Prolonged SARS-CoV-2 RNA shedding, and recurrence of PCR-positive tests have been widely reported in patients after recovery, yet these patients most commonly are non-infectious”. The researchers in this article have investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the human genome and that transcription of the integrated sequences may be responsible for PCR-positive tests.
In support of this hypothesis, they found chimeric transcripts consisting of viral fused to cellularsequences in published data sets of SARS-CoV-2 infected cultured cells and primary cells of patients, consistent with the transcription of viral sequences integrated into the genome.
To experimentally corroborate the possibility of viral retro-integration, they describe evidence that SARS-CoV-2 RNAs can be reverse transcribed in human cells by reverse transcriptase, RT from LINE-1 elements or by HIV-1 RT, and that these DNA sequences can be integrated into the cell genome and subsequently be transcribed.
-This is, of course, referred to an infection with SARS-CoV-2, and not to the genetic material (mRNA) introduced with the vaccine-
In this last article slightly modified and reduced from myself also is commented about the reverse transcription of SARS-CoV-2.
The authors report that: “The researchers explored the occurrence of reverse transcription of the SARS-CoV-2 RNA into the human genome. This would result in positive PCR tests due to the continuing transcription of viral RNAs.
Reverse transcriptaseactivity has been detected within human cells, so as integration of the reverse transcription products.
The endogenous RT is potentially present in the form of human LINE-1 elements, which make up 17% of the human genome. These are autonomous retrotransposon elements that can transpose themselves as well as other elements of the genome back into the DNA of the nucleus for future transcription.
The researchers looked at the published RNA-sequences from SARS-CoV-2 infected cells, their purpose was to find chimeric transcripts, fusing human and viral RNA into the same genome. They found a good number of these in several different cell types, and from cells recovered from the bronchoalveolar lavage fluid obtained from COVID-19 patients.
The proportion of these chimeric sequences was directly correlated with the level of viralRNA in each sample. The greatest proportion was in cells recovered from the bronchoalveolar lavage fluid of severe COVID-19 patients, while there were almost none in blood cells.
Most of the host-viral chimeric protein contained the nucleocapsid sequences, as expected since this is the most abundant viral particles. This would, therefore, be the most likely to be reverse transcribed and then integrated. These findings for the researchers support the occurrence of this event within infected cells.
They conducted then an experiment inducing the overexpression of human LINE-1 elements or HIV-1 RT, in the cell line.
These cells were then infected with SARS-CoV-2. At two days post-infection, they carried out polymerase chain reaction, PCR, tests to detect the viral sequences, using the N-targetingprimer sets used in the commonly used COVID-19 PCR tests.
PCR amplification of the purified cell DNA from infected cells showed the presence of the Nprotein bands. This did not occur in non-transfected or uninfected cells.
They also conducted an in vitro RT experiment, which showed that cell lysates from cells expressing RT of either type could cause reverse transcription of purified viral RNA from infected cells.
Using fluorescent in situ hybridization, FISH, technology, they trapped down the presence and ongoing transcription of the viral N sequences within the cell nucleus with the help of N–targeting fluorescent probes. The N sequences were found in the cytoplasm, as expected of cells infected by SARS-CoV-2.
However, FISH also picked up N RNA signals from the nucleus of cells that overexpressedLINE-1, showing that integrated N sequences in the host genome were being transcribed there.
The integrated sequences are probably sub-genomic and cannot produce live infectiousvirions. This explains the positivity of later PCR tests for viral RNA in clinically recovered patients.
The authors suggest that the site of insertion and regulation by epigenetic factors, besides the existing immune state of the patient, may affect the translation of these sequences and their possible clinical consequences.
In conclusion, the study suggests that many PCR positive results could be due to viraltranscripts from chimeric sequences instead of reflecting the presence of replicating virus in the host. If validated, this will require better tests to be used when assessing the efficacy of COVID-19 therapies in clinical trials, for example, in the future.
It looks like that the earliest reports of a coronavirus infection in animals took place in the late 1920s, when an acute respiratory infection of domesticated chickens emerged in North America. The virus responsible that caused the infection was isolated in 1933 and was then known as infectious bronchitis virus, IBV. New researchers cultivated the virus for the first time in 1937 and the specimen was known as the Beaudette strain. In the late 1940s, two more animal coronaviruses, JHM that causes brain disease in mice, and mouse hepatitis virus, MHV were discovered. At the time it was still not evidence that these three different viruses were related.
Human coronaviruses were discovered in the 1960s using two different methods in the United Kingdom and the United States. Scientists working at the Common Cold Unit of the British Medical Council Research collected a unique common cold virus denominated B814 in 1961. The virus could not be cultivated using standard techniques as those used for rhinoviruses, adenoviruses, and other known common cold viruses.
In 1965, the British scientists successfully cultivated the novel virus by serially passing it through organ culture of human embryonic trachea. The isolated virus when inoculated intranasally into volunteers caused a cold and was inactivated by ether which pointed to the presence of a lipid envelope. Scientists at the University of Chicago isolated a novel cold from medical students in 1962, they isolated and grew the virus in kidney tissue culture, denominating it 229E. The novel virus caused a cold in volunteers and, like B814, was inactivated by ether.
Scientists at St. Thomas Hospital in London, collaborating with those from the Medical Council Research in 1967 compared the structures of IBV, B814 and 229E using electron microscopy. The three viruses were shown to be morphologically related by their general shape and distinctive club-like spikes.
A research group at the National Institute of Health the same year was able to isolate another member of this new group of viruses using organ culture and entitled one of the samples OC43, OC is for organ culture. Like B814, 229E, and IBV, the novel cold virus OC43 had distinctive club-like spikes when observed with the electron microscope.
The IBV-like novel cold viruses were soon shown to be also morphologically related to the mouse hepatitis virus. This new group of viruses were named coronaviruses after their distinctive morphological appearance. Other human coronaviruses have since been identified, including SARS-Covid in 2003, HCoV-NL63 in 2003, HCoV-HKU-1 in 2004, MERS-Co-V in 2013, and SARS-CoV-2 in 2019. There have also been many animal coronaviruses identified since the 1960s.
Coronaviruses belongs to the family of Coronaviridae, subfamily Orthocoronavirinae, order Nidovirales, and realm Riboviria. They are divided into the four genera: Alpha-coronavirus, Beta-coronavirus, Gamma-coronavirus, and Delta-coronavirus. Alfa-coronaviruses and Beta-coronaviruses infect mammals, while Gamma-coronaviruses and Delta-coronaviruses primarily infect birds.
The genus alfa-coronavirus includes the Human coronavirus 229E and Human coronavirusNL63 among other animal coronaviruses
To the beta-coronavirus belong, the Human coronavirus HKU1, and OC43,MERS, SARS-CoV, and SARS-CoV-2 among other animal coronaviruses.
Delta and gamma genus includes only animal coronaviruses, (As of Wikipedia literature).
CDC Classification of Coronaviruses types
Alpha-coronavirus– 229E, Alpha-coronavirus– NL63
Beta-coronavirus– OC43, Beta-coronavirus– HKUI
-These are not to related to the variants of SARS-CoV-2, but to the genera of the coronaviruses family, variants are due to mutations of the same virus and are designed with same Greek alphabetical letters-
The most recent common ancestor of all coronaviruses is estimated to have existed as 8000 BCE, some models place the common ancestor even as far back as 55 million years or more, suggesting long term coevolution with bat and avian species. Bats and birds, as warm-blooded flying vertebrates, are an ideal natural reservoir for the coronavirus gene pool.
It seems that bats were the reservoir for alpha-and beta-coronavirus, and birds the reservoir for gamma and delta-coronaviruses. The large number and global range of bat and avian species that host viruses have facilitated massive evolution and dissemination of coronaviruses.
Many human coronaviruses have their origin in bats. MERS-CoV emerged in humans from bats through the intermediate host of camels. MERS-Cov, although related to several bat coronavirus species, appears to have diverged from these several centuries ago. The most closely related bat coronavirus and SARS-CoV diverged in 1986. The ancestors of SARS-CoV first infected leaf-nose bats of the genus Hipposideridae; subsequently, they spread to horseshoe bats in the species Rhinolophidae, then to Asian Palm civets, and finally to humans.
Unlike other beta-coronaviruses, bovine coronavirus of the species Beta-coronavirus-1 is thought to have originated in rodents and not in bats. In the 1790s, equine coronavirus diverged from the bovine coronavirus after a cross-species jump. Later in the 1890s, human coronavirus OC43 diverged from bovine coronavirus after another cross-species spillover event. It is speculated that the flu pandemic of 1980 may have been caused by this spillover event, and not by the influenza virus, because of the related timing, neurological symptoms, and unknown causative agent of the pandemic.
Besides causing respiratory infections, human coronavirus OC43 is also suspected of playing a role in neurological diseases. In the 1950s, the human coronavirus OC43 began to diverge into its present genotypes. Phylogenetically, mouse hepatitis virus, murine coronavirus, which infects the mouse’s liver and central nervous system is related to human coronavirus OC43 and bovine coronavirus. Human coronavirus HKU1, like the above-mentioned viruses, also has its origins in rodents.
Infection in Humans
Coronaviruses vary significantly in risk factor, they can cause colds with major symptoms, such as fever, and a sore throat from swollen adenoids, they can cause pneumonia, either direct viral pneumonia or secondary bacterial pneumonia, and bronchitis, either direct viral bronchitis or secondary bacterial bronchitis. The human coronavirus discovered in 2003, SARS–CoV, which causes severe acute respiratory syndrome, SARS, has a unique pathogenesis because it causes both upper and lower respiratory tract infection.
Six species of human coronaviruses are known, with one species subdivided into two differentstrains, making seven strains of human coronaviruses in total.
Four human coronaviruses produce symptoms that are generally mild, even though it is argued they might have been more aggressive in the past:
Human coronavirus (HCoV-OC43), β-CoV
Human coronavirus HKU1 (HCoV-HKU1), β-CoV
Human coronavirus 229E (HCoV-229E), α-CoV
Human coronavirus NL63 (HCoV-NL63), α-CoV
Three human coronaviruses produce potentially severe symptoms:
Severe acute respiratory syndrome (SARS-CoV), β-CoV (identified in 2003)
Middle East respiratory syndrome related coronavirus (MERS-CoV), β-CoV (identified in 2012)
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), β-CoV (identified in 2019)
These cause the diseases commonly known as SARS, MERS, and COVID-19 respectively.
Although the common cold is usually caused by rhinoviruses in about 15% of cases the cause is a coronavirus. The human coronaviruses HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63 continually circulate in the human population in adults and children worldwide and produce the generally mild symptoms of the common cold. The four mild coronaviruses have a seasonal incidence occurring in the winter months in temperate climates. There is no preponderance in any season in tropical climates.
Severe Acute Respiratory Syndrome, SARS
In 2003, following the outbreak of severe acute respiratory syndrome, SARS was developing in Asia, and secondary cases elsewhere in the world, the World Health Organization, WHO, released a statement where was tested that a novel coronavirus identified by several laboratories was the causative agent for SARS. The virus was officially named the SARS coronavirus, SARS-CoV.
Middle East Respiratory Syndrome, MERS
In September 2012, a new type of coronavirus was identified and officially called Middle East respiratory syndrome coronavirus, MERS-CoV. The WHO issued a global alert soon after, and update in September 2012 that the virus did not seem to pass easily from person to person. However, in May 2013, a case of human-to-human transmission in France was confirmed by the French Ministry of Social Affairs and Health. In addition, cases of human-to-human transmission were reported by the Ministry of Health in Tunisia. Despite this, it appears the virus had trouble spreading from human to human, as most individuals who are infected do not transmit the virus.
After the Dutch Erasmus Medical Center sequenced the virus, the virus was given a new name, Human Coronavirus—Erasmus Medical Centre, HCoV-EMC. The final name for the virus is Middle East respiratory syndrome coronavirus, MERS-CoV. The only U.S. cases, both survived, were recorded in May 2014.
In May 2015, an outbreak of MERS-CoV occurred in the Republic of Korea, when a man who had traveled to the Middle East, visited four hospitals in the Seoul area to treat his illness. This caused one of the largest outbreaks of MERS-CoV outside the Middle East.
Coronavirus Disease 2019, COVID-19
In December 2019, a pneumonia outbreak was reported in Wuhan, China on December 31, 2019, the outbreak was traced to a novel strain of coronavirus, which was given the name 2019-nCoV by the WHO later renamed SARS-CoV-2 by the International Committee on Taxonomy of Viruses.
The Wuhan strain has been identified as a new strain of β-coronavirus from group 2B with approximately 70% genetic similarity to the SARS-CoV. The virus has a 96% similarity to a bat coronavirus, so it is widely suspected to originate from bats as well, new variants due to mutations have been identified since the begin.
-The 70% of genetic similarity to SARS-CoV, justifies for myself the reason of cross reactivity from previous infections with other types of coronaviruses, like those responsible of common cold, for example, and why some people were infected in more serious and dramatic way while others in a mild way, or not at all, or did not get sick despite of not being vaccinated; all of this to account to the distinction of the population in secretor and non-secretor, blood group influence and methylation status-
Microbiology and Virology were two branches of Biology I was always very interested, and since the pandemic I have been dedicating more time to these discipline
With the raise of cases all over around the world due to new variants, mutations, and other reasons our interest and concerns for the coronaviruses have regrown, and for this reason I have wanted to look to a much deeper way at the microbiology of these viruses. I am not here to talk about all the matter of this pandemic because I am certainly not qualified for this and, honestly, in the middle of not knowing what to believe myself; either way I am not going to talk about remedies and therapies; there is plenty of information out there, the best specialists and scientists are greatly conversing and debating about from both sides, conventional and integrative doctors, those who believe in vaccine and those who not. I have been treating in previous blogs, and many of the natural adjuvants of support and prevention therapies look like to be still valid and the same.
I have watched among others the last of a serial of webinars on Covid-19 hosted by Dr.Michael Murray, one of the naturopaths I trust most in regard of this complicate and complex dilemma we all are living; it seems that he has revalidated the most of his believes and founds with few more updates on the whole situation and results from clinical trials. It can be found on YouTube for whom is interested.
Coronaviruses- as of Wikipedia description, one of my preferred and recurrent sources of information- are a group of RNA viruses responsible of diseases in mammals and birds. In humans and birds, they cause respiratory tract infections diseases that can range from mild to lethal. Mild illnesses in humans include the common cold also caused by other viruses like rhinoviruses, while more lethal varieties can cause SARS, MERS, and COVID-19.
Coronaviruses belong to the family of Coronaviridae and are enveloped viruses with a positive-sense single strandedRNA genome and a nucleocapsid of helical symmetry. The genome size of coronaviruses is one of the largest among RNA viruses and has a 5’ methylated cap and a 3’polyadenylated tail. They have characteristic club-shaped spikes that project from their surface, which under electron microscope appears as an image of the solar corona, from which their name derives.
This class of viruses are large spherical particles with unique surface projections. Their size is highly variable with average diameters of 80 to 120 nm. Extreme sizes are known from 50 to 200 nm in diameter. The total molecular mass is on average 40,000 Dalton. They are enclosed in an envelope surrounded of various protein molecules. The lipid bilayer envelope, membrane proteins, and nucleocapsid protect the virus when it is outside the host cell.
The envelope and membrane protein are the structural proteins that combined with the lipid bilayer to form the viral envelope. Spike proteins are needed for interaction with the host cells. The membrane protein is the main structural protein of the envelope that provides the general shape. This protein is crucial during the assembly, growing, envelope formation, and pathogenesis stages of the virus lifecycle.
The envelope’s proteins are highly variable in different species. They are integral proteins and have two domains, a transmembrane domain and an extramembrane C-terminal domain. They are almost fully α-helical, with a single α-helical transmembrane domain, and form pentameric ionic channels in the lipid bilayer. They are responsible for virion assembly, intracellular operating, and morphogenesis.
The spikes, the most typical feature of coronaviruses, are responsible for the corona- or halo-like surface. A coronavirus particle on average is made of 74 surface spikes. Each spike is about 20 nm long and is composed of a trimer of the spike. The spike, or S protein is in turn composed of two subunits, S1 and S2.
The spike proteins are a class of fusion proteins which mediate the receptor binding and membrane fusion between the virus and host cell. The S1 subunit forms the head of the spike and has the receptor-binding domain. The S2 subunit secures the spike in the viral envelope and on protease activation enables fusion.
The two subunits remain noncovalently linked as they are exposed on the viral surface until they attach to the host cell membrane. In a functionally active state, three S1 are attached to two S2 subunits. The subunit complex is split into individual subunits when the virus binds and fuses with the host cell under the action of proteases like the cathepsin family and transmembrane protease serine 2 of the host cell.
S1 proteins are the most critical components in terms of infection. They are also the mostvariable components as they are responsible for host cell specificity. They possess two majordomains, the N-terminal domain, and the C-terminal domain, both of which serve as the receptor-binding domains. The N-terminal domain recognizes and bind sugars on the surface of the host cell.
A subset of coronaviruses, specifically the members of beta coronavirus subgroup A, also has a shorter spike-like surface protein called hemagglutinin esterase. These proteins appear as tiny surface projections of 5 to 7 nm long implanted between the spikes. They play a role also in the attachment and detachment from the host cell.
Inside the envelope, there is the nucleocapsid, which is formed from multiple copies of the nucleocapsidprotein, which are bound to the positive-sense single-stranded RNA genome in a continuous beads-on- a-string type conformation. Nucleocapsid protein is a phosphoprotein divided into three conserved domains. Most of the protein is made up of domains 1 and 2, which are typically rich in arginine and lysine while domain 3 has a short carboxy terminal end and has a net negative charge due to excess of acidic over basic amino acid residues.
-The chemical composition is what can influence the behavior and function of a molecule, specificity, site of attachment and more, and this is probably one of the characteristics that researchers study to try to find answers and solutions-
Infection begins when the viral spike protein attaches to its complementary host cell receptor. After attachment, a protease of the host cell cuts and activates the receptor-attached spike protein. Depending on the host cell protease available, cleavage and activation allows the virus to enter the host cell by endocytosis or direct fusion of the viral envelope with the host membrane.
-This is where most of the drugs are, eventually, supposed to act to block the entrance of the virus into the cells-
As into the host cell, the virus particle is uncoated, and its genome enters the cell cytoplasm. The coronavirus RNA genome has a 5′ methylated cap and a 3′ polyadenylated tail, which allows it to act like a messenger RNA, or m-RNA and be directly translated by the host cell’s ribosomes. The host ribosomes translate the initial overlapping open reading frame and a same frame of the virus genome into two large overlapping polyproteins.
The larger polyprotein is a result of a -1ribosomal frameshift caused by a slippery sequence (UUUAAAC) and a downstream RNA pseudoknot at the end of open reading frame. The ribosomal frameshift allows for the continuous translation of the overlapping reading frames.
The polyproteins have their own proteases, which split the polyproteins at different specific sites. Product proteins include various replication proteins such as RNA-dependent RNA polymerase, (RdRp), RNA helicase, and exoribonuclease.
Several of the nonstructural proteins come together to form a multi-protein replicase-transcriptase complex. The main replicase-transcriptase protein is the RNA-dependent RNApolymerase which is directly involved in the replication and transcription of RNA from an RNA strand. The other nonstructural proteins in the complex assist in the replication and transcription process. The exoribonuclease nonstructural protein provides extra reliability to replication by delivering a proofreading function which the RNA-dependent RNA polymerase lacks.
One of the main functions of the complex is to replicate the viral genome. RdRp directly mediates the synthesis of negative-sense genomic RNA from the positive-sense genomicRNA. This is followed by the replication of positive-sense genomic RNA from the negative-sense genomic RNA.
The other important function of the complex is to transcribe the viral genome. The replication process is followed by the transcription of these negative-sense subgenomic RNA molecules to their corresponding positive-sense mRNAs. The subgenomic mRNAs form a “nested set” which have a common 5′-head and partially duplicate 3′-end.
-I probably missed to interpret the nature of the coronaviruses transcriptase from the begin because I thought that the RNA-transcriptase were a reverse-transcriptase so as in Retroviruses, and that therefore they were producing DNA from RNA templates, but it does not look to be. In the same time I have read some articles from PubMed that were talking about the possibility of “reverse transcribed” of SARS-CoV-2RNA to explain the why of many positive cases and reinfection. I am going to discuss in a next blog-
The replicase-transcriptase complex is also capable of genetic recombination when at least two viral genomes are present in the same infected cell. RNA recombination appears to be a major driving force in determining genetic variability within a coronavirus species, the capability of a coronavirus species to jump from one host to another and, infrequently, in determining the emergence of novel coronaviruses. The exact mechanism of recombination in coronaviruses is unclear, but likely involves template switching during genome replication.
Assembly and release
The replicated positive-sense genomic RNA becomes the genome of the progeny viruses. The mRNAs are gene transcripts of the last third of the virus genome after the initial overlapping reading frame. These mRNAs are translated by the host’s ribosomes into the structural proteins and many accessory proteins. RNA translation occurs inside the endoplasmicreticulum. The viral structural proteins S, E, and M move along the secretory pathway into the Golgi intermediate compartment. There, the M proteins direct most protein-proteininteractions required for the assembly of viruses following its binding to the nucleocapsid. Progeny viruses are then released from the host cell by exocytosis through secretory vesicles. Once released the viruses can infect other host cells.
Infected carriers can shed viruses into the environment. The interaction of the coronavirus spike protein with its complementary cell receptors is central in determining the tissue tropism, infectivity, and species range of the released virus. Coronaviruses mainly target epithelial cells. They are transmitted from one host to another host, depending on the coronavirus species, by either an aerosol, contaminated objects, or fecal-oral route.
Human coronaviruses infect the epithelial cells of the respiratory tract, while animal coronaviruses generally infect the epithelial cells of the digestive tract. SARS coronavirus, for example, infects the human epithelial cells of the lungs via an aerosol route by binding to the angiotensin-converting enzyme 2, (ACE2) receptors. Transmissible gastroenteritis coronavirus, which is an alfa-coronavirus, infects pigs’ epithelial cells of the digestive tract via a fecal-oral route by binding to the alanine amino-peptidase receptor.