Obesity becoming New Normal: Reason and Solution

Definition: “Obesity is a complex disease involving an excessive amount of body fat.

Facts: (As per WHO)

·       Worldwide obesity has nearly tripled since 1975.

·     In 2016, more than 1.9 billion adults, 18 years and older, were overweight. Of these over 650 million were obese.

·       39% of adults aged 18 years and over were overweight in 2016, and 13% were obese.

·    Most of the world's population lives in countries where overweight and obese kill more people than underweight.

·       39 million children under the age of 5 were overweight or obese in 2020.

·       Over 340 million children and adolescents aged 5-19 were overweight or obese in 2016.

·       Obesity is preventable. (1)

 How to assess Obesity?

·       Body mass index (BMI) is often used to diagnose obesity.

·       BMI= body weight (kg)/[height (m)] ²

·       BMI should be considered normal within 18.5-24.9.

·       Below this is underweight, and above it is overweight (25-29.9), and beyond it Obesity (1,2)

As per WHO, causes obesity and overweight?

The fundamental cause of obesity and overweight is an energy imbalance between calories consumed and calories expended, [known to every sensible person].

Globally, there has been: [in short- demand vs supply gap]

·       an increased intake of energy-dense foods that are high in fat and sugars; and

·       an increase in physical inactivity due to the increasingly sedentary nature of many forms of work, changing modes of transportation, and increasing urbanization. (1) 

 What WHO won't tell you about simple physiology?

1.      One of the functions of the liver is to modulate the incoming digested nutrients as per body requirements and assure proper storage of surplus biomolecules. (3)

2.     The liver converts the nutrients in our diets into substances that the body can use, stores these substances, and supplies cells with them when needed. (4)

3.   Glycogenesis is the formation of glycogen, stored in the liver and muscle cells of animals, from glucose. (5)

4.     Glycogenesis takes place when blood glucose levels are sufficiently high to allow excess glucose to be stored in liver and muscle cells.

5.     Glycogenolysis is the biochemical pathway in which glycogen breaks down into glucose-1-phosphate and glucose.

6.     During the fasting state, to maintain normal blood glucose levels, the liver plays a central role in producing glucose via glycogenolysis and gluconeogenesis.[6]

7.     In humans, Glycogen is the principal storage form of glucose. During times of need, the body breaks down glycogen to produce glucose.[7]

8.   High glycogen levels enhance glycogen breakdown in isolated contracting skeletal muscle (8)

9.     Muscle glycogen serves mainly as a source of metabolic fuel for your muscles.

10. The body stores 3/4 of your total glycogen in all skeletal muscles so they have a consistent supply of energy, especially during exercise, without dramatically affecting the levels of your blood glucose.

11.   Muscles restore with glycogen when you consume enough carbohydrates. (9)

So, what if the body has sarcopenia and is saturated with glycogen?

The surplus food shall be stored in form of fat in adipose tissues, which is beyond a limit called obesity. Stemina= Glycogen reserve in your body.

To Sum up

·       Lack of optimum muscle mass, which can accommodate surplus digested materials.

·     Increased Gut fermentation by frequent eating habits, besides other reasons, causes the formation of SCFA (Short Chain Fatty Acids), which also develop an alternate route for energy supply.

·       Lack of Physical work in early childhood, especially before attainment of adulthood.

·       Earlier commencement of Puberty is becoming a new trend. [The mean age of puberty in girls in Western populations has been falling for the last 150 years. (10)]

·      High glycogen levels enhance glycogen breakdown in isolated contracting skeletal muscle (11)

·  Gym +Dieting+Treatment: It will only burn the surplus fat that too at a very huge cost to the body. 

The damaging side effects of the thinness pursuit

·       Weight loss programs do not have long-term positive outcomes.

·      This may cause problems, as weight fluctuation is associated with increased mortality and cardiovascular disease.

·       Additionally, chronic restrictive dieting is a significant risk factor for the development of binge behavior and eating disorders.

·       Direct adverse effects of weight loss programs and dangerous weight loss strategies such as laxative use, smoking cigarettes, and very low-calorie diets, pose serious health risks. (12)

Also, your stamina shall be affected.

Muscle mass decreases approximately 3–8% per decade after the age of 30 and this rate of decline is even higher after the age of 60 [12,13]. 

 

Solution:

·       The best option has already gone from your hand and that was to do huge physical work before Puberty.

·       However, maintain the supply chain ratio consistently.

·      Eat what is provided by the nature, and only 2 to 3 times and take a proportionate diet, which will reduce gut fermentation.

·       Apply fasting system shall be helpful.

The Wuhan Virus Is Not a Lab-Made Bioweapon (?)

The most devastating, catastrophic tragedy in the last centuries, which knocked on the door around Dec 2019 (as claimed by Beijing) in Wuhan city of China has infected 152925596 people worldwide and claimed at least 3208694 lives so far. And it keeps on growing like Tsunami. However, there are a sufficient number of significant claims which say that the current number could be reduced significantly if WHO and China could have maintained transparency. The WHO is calling the microbe novel coronavirus 2019-nCoV. 

At a meeting in Geneva on Jan 23, 2020, the organization stopped short of declaring a Public Health Emergency of International Concern, but not declared it as Pandemic till Jan 29, 2020. Nevertheless, the same WHO said, ‘Indian Covid variant’ found in 27 other countries on Apr 28, 2021, which never said Wuhan or Chinese Virus.

What exactly compelled me to write this post is the within 100 days few acclaimed researchers jointly addressed the media and declared the virus as "natural". It was March of 2020, while most researchers are working on strategies to counter the pandemic.

Updates about Variants: 

On May 4th, CCMB study reveals N440K variant of coronavirus 10 times more infectious than others

Explaining about the high spreading characteristics of the Covid-19 virus, Dr. Rakesh Mishra, director of CCMB said that the ability of N440k Spike substitution mutant variant appeared in 50% samples from south India, to generate large amounts of infectious virus articles within a short time period are very high (10x). Dr Mishra added that the main reason for the high rate of infections during the second wave can be attributed to it as the variant is having an edge to produce 10 times more partials as compared to the other mutant (B1.617 and B1.618) (Q).

The N440K variant produced ten times higher infectious viral titers than a prevalent A2a strain, and over 1000 folds higher titers than a much less prevalent A3i strain prototype in Caco2 cells (a preprint of Dixit et al. 2021, Q)

Apr 20^th,  Feb 7^th, 2021 some 13 different mutants are developed by the virus successfully.

The B.1.617 Lineage: The variant first appeared in Oct and is now the most common variant in India

B.1.617 carries more then a dozen mutations but is sometimes called a “double mutant” because of two prominent mutations: E484Q and L452R.

E484Q lies at the same location as E484K, the “Eek” mutation that might help the virus evades some types of antibodies.

L452R is also found in the B.1.429 variant that is widespread in California.

Coronavirus mutations that could 'evade immune response' flagged by Indian scientists: Report (May 01, ‘21): There currently exists no reason to believe these mutations could be dangerous or were expanding.

In Media

·   On Mar 31^st, this year, the WHO released a joint report with Beijing on the origins of the pandemic following a 4-week investigation in China. It concluded, among other things, that the lab leak hypothesis was "extremely unlikely."

·     "I think, there were a lot of people who did put together the fact that you had an outbreak in Wuhan and you have these laboratories in Wuhan fairly immediately," said David Feith, who was an Asia adviser in the Trump administration's State Department when the coronavirus emerged.

·    Jamie Metzl, a senior fellow at the Atlantic Council, "I'm not saying that I am certain that COVID-19 stems from an accidental lab leak, but it would be irresponsible and could only be politically motivated to say that it's not even worth having a full investigation".

·    In Apr 2020, Foreign policy published an article “The coronavirus is the worst intelligence failure in U.S. history”, though it intended to defame the then-White House Administration.

·    Interestingly, the same agency in Jan 2020, had already published which thrown out of the window that “all claims which argue, its lab-made virus are either intentional or useless”

·     “How China is Exploiting the Coronavirus to Weaken Democracies” by By Peter Rough, in Mar 25^th (a former director of research in the office of -U.S. President George W. Bush) Beijing is using the pandemic to drive wedges between members of the European Union and to advance its propaganda war against the United States. As the coronavirus works its way around the globe, it is putting unprecedented strain on public health systems and devastating economies along its path.

·       Conspiracy theories are spreading faster than the coronavirus itself, writes on Jan 29, 2020, Justin Lig, a freelance political journalist based in Ottawa)

o On Sun, the Washington Times - a paper with a distinct ideological bent — published an article on Jan 26^th, 2020, claiming that the virus outbreak could be linked to a military lab in Wuhan.

o  The Wuhan Institute of Virology could have been researching military applications for the coronavirus and may have been the source of the outbreak. The only basis for the claim is a quote from former Israeli intelligence officer Dany Shoham, who has expertise in biological warfare, Lig wrote in his article.

o   He further added that while Shoham never backed up the claim made in the story that the outbreak stemmed from a biological weapon, other outlets nevertheless picked up the idea and ran with it. Lig equipped his claim by using all means to defame Shoham as well as everyone who supported the theory of the Wuhan Virus. Unfortunately, Lig (doctorate in Biochemistry) failed to produce or might not be interested in any technical fact as well, which can disprove what Shoham has claimed.

·   In a stunning revelation, a Chinese virologist, Dr Li-Meng Yan has claimed in an exclusive conversation with 'Loose Women', a British talk shows that the coronavirus was created in a government-controlled laboratory in Wuhan, the original epicenter of the outbreak, and offered scientific evidence to back her claims.

o   Dr Li-Meng, who specialized in virology and immunology at the Hong Kong School of Public Health said that she was assigned to investigate "new pneumonia" in Wuhan, while she discovered a cover-up operation regarding coronavirus during her investigation.

o   As per the claim, she conducted two types of research on new pneumonia in China first between Dec to Jan and the 2^nd one in mid-Jan, before fleeing to the US from Hong Kong.

o   "There was no response from the WHO and my supervisor. Everyone warned me that do not cross the right line and keep silent or else I would be made to disappear," she said.

·     GreatGameIndia, a small ‘conspiracy website’ began publishing reports last week claiming that Canadian researchers had sold this strain of coronavirus to China.

The Toronto Sun columnist Candice Malcolm pumped the theory on her YouTube show, asking: “Why isn’t the mainstream media talking about the origins of this deadly virus? Could it be linked to China’s biological warfare program?”

A group of bioinformaticians at two universities in Delhi published a preprint scientific manuscript on the bioRxiv preprint server on Feb 1^st, 2020 has led many to speculate wildly that 2019-nCoV may have been deliberately engineered using HIV protein sequences.

 

What questions are

Ø   What is viral mutation and Why this virus is mutating faster?

Ø   How most of the mutations are favorable to the individual

Ø   How the mutation leads a complete copy/pest kind of sequences

Ø   Or one nucleotide which changes the entire structure of the protein coat

Ø   Why WHO unprecedently in a faster mode, certified that COVID-19 is the product of natural selection, while most of the world even not reached the complete sequencing.

To understand the series of questions, one has to understand the basics of Covid virology

Basics of the viral genome:

The virus is enveloped, spherical, about 120 nm in diameter. The RNA genome is associated with the N protein to form the helical nucleocapsid for the genus coronavirus. Monopartite, linear ssRNA (+) genome of 27-32kb in size, the largest of all RNA virus genomes. Capped, and polyadenylated. The leader RNA (65-89 bp) at the 5' end of the genome is also present at the end of each sub-genomic RNAs. The lengths range from 27317 nucleotides for HCoV-229E to 31,357 nucleotides for the murine hepatitis virus-A59, establishing the coronavirus genome is the largest known among RNA viruses.

Most of the Mutations are reported in Spike protein, which is responsible to increase the infectivity of the virus.

The basic organization of the coronavirus genome is shared with other members of the Nidovirus order (the torovirus genus, also in the family Coronaviridae, and members of the family Arteriviridae) in that the nonstructural proteins involved in proteolytic processing, genome replication, and subgenomic mRNA synthesis (transcription) (an estimated 14-16 end products for coronaviruses) are encoded within the 5'-proximal two-thirds of the genome on gene 1 and the (mostly) structural proteins are encoded within the 3'-proximal one-third of the genome (8-9 genes for coronaviruses). Genes for the major structural proteins in all coronaviruses occur in the 5' to 3' order as S, E, M, and N. The precise strategy used by coronaviruses for genome replication is not yet known, but many features have been established (Q). The minimum sequence requirements for autonomous replication of an RNA replicon, and the importance of gene order in genome replication.

Enzymatic activities and characteristics of coronavirus nsp protein domains (Q)

Activity	Location and designation	Architecture	Comments
Papain-like proteinase	One or two PLpro domains within nsp3	Finger-palm-thumb	Fingertips contain zinc-binding domain
ADP-ribose 1"-phosphatase	ADRP (or X) domain within nsp3	Three-layered α/β/α	Also found in other plus-strand RNA viruses
3C-like cysteine proteinase	nsp5 (3CLpro or main protease, Mpro)	Twelve antiparallel β-strands	Extra, α-helical, carboxyl-terminal domain III
RNA-dependent RNA polymerase	RdRp domain within nsp12	Finger-palm-thumb (predicted)	RdRp motif VI signature GDD replaced with SDD
5′-to-3′ helicase (associated, NTPase, and RNA 5′-triphosphatase activities)	HEL domain within nsp13	Modeled to Escherichia coli Rep helicase	Adjacent to amino-proximal, binuclear, zinc-binding domain
3′-to-5′ exonuclease	ExoN domain within nsp14	Hexahelical bundle (predicted)	Unable to cleave ribose 2′-O-methylated RNA substrates
Uridylate-specific endoribonuclease	NendoU domain within nsp15	Wing-body-wing (butterfly fold)	Active in hexameric form; RNA bound to the internal cavity
S-adenosylmethionine-dependent 2′-O-methyltransferase	nsp16 (MT)	Methyltransferase fold (predicted)	Activity yet to be determined

 

What is viral mutation and Why this virus is mutating faster?

Mutation is a natural phenomenon in living organisms that cause changes in the body or germplasm. Its chances are directly proportional to the exposure of genetic material of the individual and since it's quite exposed in the case of Viruses, chances are accordingly increased. Nevertheless, in most cases, the mutation is harmful to the individual, while in this case, it seems to reverse. Beneficial mutations occur every 7 - 10 years on average, leading to 1 - 2 generations per year. This requires 100-200 generations per year. 

Rates of spontaneous mutation per genome as measured in the laboratory are remarkably similar within broad groups of organisms but differ strikingly among groups. Mutation rates in RNA viruses, whose genomes contain ca. 104 bases, are roughly 1 per genome per replication for lytic viruses and roughly 0.1 per genome per replication for retroviruses and a retrotransposon. However, the rate of retrovirus mutation per genome per replication in retroelements ranges from 0.04 to 0.22 Spleen necrosis virus to HIV (Drake et. al. 1998). This is also alarming to humankind.

Even with the vaccine and medications against this virus, future outbreaks of similar viruses and pathogens are likely to continue. Therefore, apart from curbing this outbreak, government policies and efforts should be made to formulate thorough measures to prevent future outbreaks of viruses (Q).

How most of the mutations are favorable to the individual

As per new data, though it is observed that SARS-CoV-2 binds to its receptor on the host cells with higher affinities than SARS-CoV, the fatality rate caused by SARS-CoV-2 (3.4%) is significantly less than the reported rate of SARS-CoV (9%–11%, WHO). The reasons behind these differences remain elusive, and future research will shed light on these variations. Recent sequencing data indicate that the SARS-CoV-2 mutation rate is approximately 25 mutations per year (Mittal, et al 2020).

The teams used different pseudovirus systems and tested them on various kinds of cells, but the experiments pointed to the same conclusion: viruses carrying the G mutation infected cells much more ably than did D viruses — up to ten times more efficiently, in some cases (Q).

In laboratory tests, “all of us agree that D to G is making the particles more infectious”, says Jeremy Luban, a virologist at the University of Massachusetts Medical School in Worcester. “The bottom line is, they’re not the virus,” says Luban.

Note the impact of change in single Nucleotide, A to G

Some labs are now working with infectious SARS-CoV-2 viruses that differ by only a single amino acid. These are tested in laboratory cultures of human lung and airway cells, and lab animals such as ferrets and hamsters. For labs with the experience and the biosafety capabilities to manipulate viruses, “this is like bread-and-butter kind of work”, says Sheahan. The first of those studies, led by researchers at the University of Texas Medical Branch in Galveston, was reported in a Sept 2^nd preprint. It found that viruses with the mutation were more infectious than were D viruses in a human lung cell line and airway tissues and that mutated viruses were present at greater levels in the upper airways of infected hamsters.

We do not find any indication that patients infected with the Spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant (Q).

The analysis was done by Paraskevis et al (2020), suggests that the 2019-nCoV although closely related to BatCoV RaTG13 sequence throughout the genome (sequence similarity 96.3%), shows discordant clustering with the Bat_SARS-like coronavirus sequences.

Specifically, in the 5′-part spanning the first 11,498 nucleotides and the last 3′-part spanning 24,341–30,696 positions, 2019-nCoV and RaTG13 formed a single cluster with Bat_SARS-like coronavirus sequences, whereas, in the middle region spanning the 3′-end of ORF1a, the ORF1b, and almost half of the spike regions, 2019-nCoV and RaTG13 grouped in a separate distant lineage within the sarbecovirus branch.

How the mutation leads a complete copy/pest Kind of sequences

The S protein on the surface of the virus is a key factor involved in infection. It is a trimeric class-I TM glycoprotein responsible for viral entry, and it is present in all kinds of HCoVs, as well as in other viruses such as HIV (HIV glycoprotein 160, Env), influenza virus (influenza hemagglutinin, HA), paramyxovirus (paramyxovirus F), and Ebola (Ebola virus glycoprotein) (Q, Q). Similar to other coronaviruses, the S protein of SARS-CoV-2 mediates receptor recognition, cell attachment, and fusion during viral infection (Q, Q, Q, Q, Q, Q).

All coronaviruses genomes with a variable 6-11 open reading frames (ORFs), which encode non-structural proteins as well as structural proteins: spike glycoprotein (S), a small envelope protein (E), matrix protein (M), and nucleocapsid protein (N).

SARS-CoV-2 is related to SARS-CoV, the virus that causes SARS, in addition to SARS-like bat CoVs (RaTG13/CoVZC45/CoVZCX21). A large proportion of SARS-CoV and SARS-CoV-2 genomes are identical. However, notable differences occur in key locations such as the absence of 8a protein and longer 8b protein in SARS-CoV-2.

In one analysis, there were 380 amino acid substitutions between SARS-CoV-2 and SARS/SARS-like viruses, specifically located in nsp2 & nsp3. 6 substitutions were found in the RBD at amino acid location 357-528, with a further 4 substitutions in the C-terminus region of the S1 domain.

While, Laura D Manzanares-Meza, (2020) claimed that SARS-CoV-2 has a proofreading mechanism, which results in a low mutation rate compared to influenza. E1KC4 and camostat mesylate are potential inhibitors of SARS-CoV-2 S protein, achieving an effect similar to oseltamivir. Due to the SARS-CoV-2 low mutation rate, nucleoside analogs have been developed (such as EIDD-2801), which insert lethal mutations in the viral RNA (Q).

When COVID-19 spread around the globe this year, David Montefiori wondered how the deadly virus behind the pandemic might be changing as it passed from person to person. Montefiori is a virologist who has spent much of his career studying how chance mutations in HIV help it to evade the immune system–Nature (Q).

"I think the genetics will tell you about the virus. I think it would be very difficult to tell you where it got into the human population and how it spread and whether it came from a lab or it didn't come from the lab. I think that's going to be very hard," said Barry Bloom, an immunologist and infectious disease expert at Harvard T.H. Chan School of Public Health.

We can see this occurring with the novel coronavirus right now. It is quickly gaining mutations, called E484K and 501Y, that make it more infectious, and doing so in independent lineages across the globe, according to research by evolutionary microbiologist Vaughn Cooper of the University of Pittsburgh Medical Center. This is happening naturally because millions of infections around the globe have provided millions of opportunities for mutations, virologist Adam Lauring of the University of Michigan told Scientific American,  published in Oped and Analysis section. It is not happening because of a lab leak. However, no answer available so far, "as to why only this virus of its family mutating so fast but others couldn’t". Also, how the mutations are only increasing their virulence and infectivity?

"NOW, let's see the other side of the picture. So what more questions should be asked? could it possible to make it in the laboratory? And the answer is very much yes! The next question is for what? The reason is before the world.....And the last question could be why the world is silent, and the answer is not the world is silent but voices against the origin are made silence."

Conclusively: 

What we would or wouldn’t even know if such change (s) was (were) natural or engineered because even if, it has (have) been engineered, the engineers are not alive to tell us than what to say about the record!

Has Covid-19 leaked Unintentionally or Intentionally?