by Silviu “Silview” Costinescu_ Buy Me a Coffee at ko-fi.com

An article titled “m6A RNA modification as a new player in R-loop regulation,” was published in the January 2020 edition of Nature Genetics and widely reported in the scientific community. What we learn from it opens the door for crucially important knowledge in the context of this technology being used for Covid vaccines.

Below I copy/pasted the press release that circulated at the time in several top publications:

“Following a new collaboration between UiO and research groups in Nottingham and Oxford, it has now been revealed that RNA has a direct effect on DNA stability, according to Professor Klungland’s research.

He believes the discovery will provide the health service with an important tool, since many studies have shown that the regulation of modifications to RNA is important for the development of cancer.

If genes that are important for the chemical compound 6-methyladenine are completely removed, this results in neurodegeneration in both mice and humans.

Where and how

In areas of DNA where RNA binds to one of the DNA threads in such a way that the complementary DNA thread becomes the sole thread (R-loop structures), the DNA stability will change if RNA is chemically modified by m6A.

Several research groups are now working together to study what effect this can have on the DNA molecule. We already know that R-loop areas are associated with sequences of DNA containing active genes and that this can lead to chromosomal breakage and the loss of genetic information

Prof. Arne Klungland
Modified RNA has a direct effect on DNA
Credit: University of Oslo

New field of research

Normally, epigenetic gene regulation is studied by examining dynamic modifications of DNA and proteins—so-called epigenetic modifications. The modifications can turn genes on or off without changing the underlying genetic code.

Less than 10 years ago, it was discovered that dynamic modifications also exist in RNA and that these have an important role to play in gene regulation

Important modification

The most common modification is on mRNA is 6-metyladenin (m6A). It has now been shown that this modification is essential for the survival of cells and model (non-human) organisms.

Over the last five years, there has been an enormous increase in the amount of research into RNA modifications—a field called epitranscriptomics.

One of the first studies in this field of research was the result of a collaboration between research groups in Chicago, Beijing and Oslo (Zheng, Dahl et al., Molecular Cell, 2012, 49, 18-29).

End of article citation.
I bolded a few paragraphs to make sure you see what I saw:
RNA modification not only can alter DNA, but it’s been already envisioned as a tool for DNA editing.
This argues the whole BS official narrative that the RNA vaccine technology is inoffensive for the DNA

One of the most remarkable findings of this study is that depletion of YTHDF2 and METTL3 (the writer that deposits m6A) increases levels of γH2AX, a marker of DNA double-strand breaks, thus suggesting that pathological R-loop accumulation in the absence of the m6A RNA-methylation pathway challenges genome integrity. This result is in line with findings from many studies that clearly suggest the potential of R-loops to induce DNA double-strand breaks2. Moreover, dysregulation of R-loops is emerging as a critical factor driving genome instability in a large variety of pathological contexts, including after oncogenic stress12, in cells infected with Kaposi’s sarcoma–associated herpesvirus, in neurological disorders associated with trinucleotide-repeat expansion (such as Huntington’s disease and fragile X syndrome) and in multiple other inherited ataxias (for example, ataxia with oculomotor apraxia 2)2. The use of existing drugs targeting the m6A pathway (for example, inhibitors of FTO) could therefore be considered as a new therapeutic approach to treat R-loop-related diseases13.
Beyond genome stability, the finding that m6A methylation controls R-loop levels across the genome considerably expands the biological functions of the m6A-modification pathway to potentially all R-loop-related functions, including DNA topology (because R-loops have recently been proposed to relieve superhelical stress), immunoglobulin class-switch recombination (and therefore the immune response), replication initiation and transcription1,2,14. Additionally, m6A accumulates at sites of ultraviolet-induced DNA damage6, thus raising the interesting possibility that this modification may also regulate R-loops during DNA repair and thus affect the frequency of chromosomal translocations15.
In summary, the results presented by Abakir et al. unveil an unexpected interplay between RNA modifications (the epitranscriptome) and the maintenance of genome integrity. Re-analysis of the pathological contexts implicating dysregulation of the m6A RNA pathway through the prism of genome instability therefore warrants further investigation (Fig. 1).

m6A RNA modification as a new player in R-loop regulation – Aline Marnef & 
Gaëlle Legube, Nature Genetics

Epitranscriptomics: The new RNA code and the race to drug it

A small group of scientists studying chemical modifications on RNA ushered in the field of epitranscriptomics. Now they’re hoping it will create an entirely new way to treat cancer

by Ryan Cross, Chemical & Engineering News, Feb. 18, 2019 

It’s not every day that a biotech investor stumbles across an entirely new field of science. And frankly, Carlo Rizzuto wasn’t even looking for such a thing. When Rizzuto, a partner at the venture capital firm Versant Ventures, embarked on a scouting trip to New York City in 2014, he was simply hoping to discover academic research that was ripe enough to form the basis of a biotech company.

Rizzuto had an appointment with Samie Jaffrey, an RNA scientist at Weill Cornell Medicine. RNA is often described as a cousin to DNA—the stuff that our genes are made of. One kind of RNA, called messenger RNA, acts as the intermediary code that cells use to transfer information stored in DNA into a set of instructions that cells can easily read for making proteins.

After Rizzuto rejected several of his projects, Jaffrey mentioned a relatively young line of work focused on studying chemical modifications to RNA. In 2012, his lab invented a method to map the location of methyl groups that, for some reason, cells were adding to their mRNA. It was reminiscent of another field, called epigenetics, or the study of chemical modifications made to DNA to turn genes on or off. The entirety of RNA in a cell is called the transcriptome, so Jaffrey dubbed the new field “epitranscriptomics.”

Rizzuto perked up. “This is something that we would be very interested in,” he said.09607-cover-jaffrey.jpgCredit: Gotham TherapeuticsSamie Jaffrey, a professor of pharmacology at Weill Cornell Medicine and cofounder of Gotham Therapeutics, explains the m6A modification on RNA. Jaffrey’s lab invented a technique to map the location of m6A on RNA.

Jaffrey was hesitant. “We’re just doing basic stuff now,” he recalls explaining. His lab, and others, was still trying to figure out how this RNA modification system worked. They were building evidence suggesting that enzymes added and removed these methyl marks to control the fate of mRNA, and thus protein production, but many questions remained. Jaffrey implored: “Carlo, what disease would we be curing if we started a company around epitranscriptomics?”

“It doesn’t matter,” Rizzuto replied. “This is so central to molecular biology; it has to be related to fundamental disease processes.”

Then reality kicked in. Venture capital firms like Rizzuto’s aren’t in the business of funding years of basic research just to see if something like epitranscriptomics is involved in disease. “We were looking at a new paradigm for gene-expression regulation,” Rizzuto recalls, but it was too early to start a company. He and Jaffrey agreed to stay in touch.

Rizzuto’s enthusiasm in 2014 has since percolated among scientists and investors learning about epitranscriptomics. Several groups, including Jaffrey’s, have shown that the epitranscriptomic code—the number and location of chemical modifications across a cell’s RNA—is seriously out of whack in some cancers. And with basic tools in hand to read this previously hidden layer of information in cells, biotech companies are now out to alter it. Three start-ups, including one that Jaffrey and Rizzuto helped found, called Gotham Therapeutics, have launched with more than $110 million in total dedicated to epitranscriptomics drug discovery.

There was a similar reaction to epigenetics more than a decade ago, when it became clear that chemical modifications regulating genes are frequently out of whack in cancer. Companies rushed to develop drugs against proteins responsible for making, removing, and recognizing chemical modifications on genes—often referred to as the writer, eraser, and reader proteins. With the discovery of parallel writer, eraser, and reader proteins working on RNA, epitranscriptomics is looking like a promising, untapped area for drug discovery.

But there’s another parallel to epigenetics that’s less optimistic: thus far, epigenetic drugs have been a disappointment. “Epigenetics turned out to be a lot more complicated than the community originally thought,” says Chuan He, a professor of chemistry at the University of Chicago.

He, a scientific founder of the epitranscriptomics company Accent Therapeutics, has been at the forefront of developing the new study of RNA modifications and their role in disease. He, Jaffrey, and many others are confident that understanding and controlling RNA modifications will provide completely new avenues for treating disease. “What this really offers is a totally new biology,” He says. “And whenever there is a new biology emerging there are always opportunities for therapies.”


EPITRANSCRIPTOMICS, ABRIDGED

A series of discoveries and technical advancements over the past decade has spawned a new field called epitranscriptomics, the study of chemical modifications to RNA, and the proteins that write, erase, and read these modifications. In recent years, studies implicating epitranscriptomic proteins in cancer have led to the launch of three biotech companies dedicated to drugging these proteins.

May 2008: Rupert Fray shows that a methyl-adding enzyme is essential for plant development. The study inspires others to look at RNA modifications.

November 2010: Chuan He proposes new field of RNA epigenetics, suggesting that methyl modifications on RNA can be removed.

October 2011: Chuan He’s lab proves that an enzyme called FTO erases methyl modifications on RNA.

April and May 2012: The labs of Gideon Rechavi (April) and Samie Jaffrey (May) publish the first maps of RNA methyl modifications. Jaffrey coins the word “epitranscriptomics.”

October 2014: Howard Chang’s lab shows that METTL3, which adds methyl groups to RNA, is critical for embryonic stem cell development and differentiation.

June 2016: Storm Therapeutics, founded by University of Cambridge scientists Tony Kouzarides and Eric Miska, raises $16 million to drug proteins that make RNA modifications.

September and November 2017: Independent studies from Samie Jaffrey and colleagues (September) and Tony Kouzarides and colleagues (November) show that METTL3 is elevated in acute myeloid leukemia and that suppressing the enzyme forces the cancer cells to become noncancerous.

May 2018: Accent Therapeutics, cofounded by Chuan He, Howard Chang, and Robert Copeland, raises $40 million.

October 2018: Gotham Therapeutics, cofounded by Samie Jaffrey, launches with $54 million.

February 2019: Evidence builds that epitranscriptomics may be important for cancer immunotherapy. Chuan He shows that deleting a reader protein boosts the efficacy of checkpoint inhibitors in mice.

MAKING A MAP

A series of events beginning in 2008 laid the foundation for epitranscriptomics. That year, while He was studying epigenetic enzymes that remove methyl modifications from DNA, he and University of Chicago biologist Tao Pan began doubting that all these enzymes were really working on DNA as others assumed. The evidence was particularly shaky for one enzyme, called fat mass and obesity-associated protein, or FTO.

But a study coming out of the lab of plant biologist Rupert Fray at the University of Nottingham reinforced He and Pan’s suspicions that RNA modifications were underappreciated. Fray showed that plants missing a methyl-adding enzyme—similar to an enzyme called METTL3 in humans—stopped growing at a specific early stage in their development.

Scientists knew that METTL3 placed a methyl on a specific nitrogen in adenosine, one of the four building blocks of RNA. This modified building block is called N6-methyladenosine, or m6A for short. Beyond m6A, chemists had cataloged some 150 different chemical modifications to RNA in bacteria, plants, and animals. If He could find an enzyme that removed the methyl groups, it would suggest that there was an undiscovered RNA control system in cells, analogous to epigenetic controls in DNA.

In 2010, He coined the phrase “RNA epigenetics” in a commentary that outlined his ideas (Nat. Chem. Biol.DOI: 10.1038/nchembio.482). A year later, He and Pan published evidence showing that the FTO enzyme was an eraser—it removed the methyl modifications made by METTL3 (Nat. Chem. Biol. 2011, DOI: 10.1038/nchembio.687).

METTL3 and FTO are both enzymes, which means they should be pretty straightforward to inhibit with small-molecule drugs. That notion would later be frequently cited by the new epitranscriptomics companies, although it would be several years still before these enzymes were connected to disease.

At first, the significance of these enzymes was lost on many researchers. At Weill Cornell, however, Jaffrey immediately recognized that He’s study was part of a new field that was about to explode. His lab had been working on a method to detect and map m6A across a cell’s mRNA. Jaffrey had also seen Fray’s work on m6A in plants and thought that if the modifications existed in humans, they must be doing something important in us too.

At the time, methods for studying m6A were rudimentary. Researchers could detect the presence of m6A in ground-up globs of mRNA run through common chemistry lab techniques like chromatography or mass spectrometry. “But you had no idea which mRNAs were being modified,” Jaffrey says. No one knew if all mRNA had some m6A or if the methyl modifications were found on only certain transcripts, he adds. “And frankly, it wasn’t even terribly clear that m6A levels changed.”This is so central to molecular biology; it has to be related to fundamental disease processes.Carlo Rizzuto, partner, Versant Ventures

So Jaffrey and Kate Meyer, a postdoc in his lab, developed a technique to figure out which mRNAs contained these modifications. They used commercially available antibodies that attach to m6A to fish out fragments of human mRNA for sequencing (Cell 2012, DOI: 10.1016/j.cell.2012.05.003).

That technique allowed the creation of the first map of m6A. The results were stunning. “We thought that m6A was going to be all over the place, kind of random,” Jaffrey says. Instead, the researchers saw that methyl marks tended to cluster near an area called the stop codon, and only on certain mRNA transcripts. “It was so specific, it just knocked our socks off.”

An even closer inspection revealed that many of the mRNAs containing m6A were linked to differentiation and development, the same functions that were affected in Fray’s stunted plant embryos. “We were amazed,” Jaffrey says.

In April 2012, while Jaffrey and Meyer were waiting for their m6A paper to publish, another group, led by Gideon Rechavi at Tel Aviv University, published its own paper on the use of antibodies to map m6A in mouse and human cells (Nature 2012, DOI: 10.1038/nature11112). “It was met with a lot of skepticism,” says Dan Dominissini, the PhD student in Rechavi’s lab who led the project. “People didn’t get why it was important. It took a year to publish.”

The problem was researchers still hadn’t established a clear link between these RNA modifications and disease, or even basic human biology. Moreover, the field wouldn’t have its name of epitranscriptomics for another three weeks, when Jaffrey and Meyer’s paper describing their m6A-mapping technique was published online in May 2012. Although Jaffrey had been scooped, the back-to-back publications put epitranscriptomics on the radar. The field was poised to explode.


Editing the epitranscriptomic code

The most common RNA modification is N6-methyladenosine (m6A), which is made when a protein complex containing the “writer” enzyme METTL3 adds a methyl group to adenosine. Two different “eraser” enzymes, called ALKBH5 and FTO, can remove a methyl group to turn m6A back into adenosine.Credit: ALKBH5, FTO, and METTL3-METTL14 protein images created with the Protein Data Bank, NGL Viewer

SEARCHING FOR DISEASE

In Chicago, He was positioning his lab as the forefront of epitranscriptomics research. His group discovered that an enzyme called ALKBH5, like FTO, erased methyl marks on RNA, turning m6A back into adenosine. Yet even by 2014, two years after the m6A-mapping methods were published, epitranscriptomics wasn’t getting the recognition, or funding, that He thought it deserved. “People thought it was cute,” He says. “But biologists were not convinced of its significance.”

Epitranscriptomics was now a hot topic. As studies began bubbling up exploring the role of RNA modifications, particularly m6A, in a variety of cells and species, investors started putting money into the field. In June 2016, a British start-up called Storm Therapeutics raised $16 million and became the first company dedicated to tackling the new RNA epigenetics.

Although Storm was several years in the making, it wasn’t clear what diseases the company would be curing. Two University of Cambridge scientists, Tony Kouzarides and Eric Miska, began discussing the idea for the company back in 2012, when they had published work on obscure enzymes that chemically modify microRNAs, which regulate the function of other RNAs.

Although the enzymes were linked to cancer, at least in cells growing in a dish, the microRNA studies went largely unnoticed. Kouzarides and Miska thought more undiscovered links between RNA modifications and cancer must exist, but it took a few years to find investors willing to bet on their hypothesis. “I don’t think that there was a huge amount of actual data; it was just the belief that there must be,” Storm’s CEO, Keith Blundy, says. “The idea that all of these chemical modifications on RNA weren’t dysregulated or mutated or changed in cancer was almost unthinkable.”

That belief, which echoes the sentiment that Versant Ventures’ Rizzuto expressed in Jaffrey’s office in 2014, was about to be validated. In the second half of 2016, studies began linking reader and writer proteins to cancer. Jaffrey saw the evidence firsthand in an ongoing study he was conducting in blood cancer. The implications for drug discovery were becoming clear. He reached out to Rizzuto. It was time to move forward.

ANNOTATIONS IN THE BLOOD

The common thread running through epitranscriptomics research was its link to cell differentiation and development. Chang’s and Rechavi’s stem cell studies on m6A gave several research labs—including He’s, Jaffrey’s, and Kouzarides’s—the idea to look at the role of these RNA modifications in a deadly blood cancer called acute myeloid leukemia.

Leukemia is essentially a disease of dysfunctional differentiation. Healthy people’s bones are filled with hematopoietic stem cells that produce white blood cells. In leukemia, these stem cells go haywire. They proliferate and displace other blood cells because they can’t differentiate, or mature, into normal white blood cells.

In December 2016, He’s lab, together with several collaborators, showed that tissue samples taken from people with certain kinds of acute myeloid leukemia displayed high levels of the enzyme FTO—which, five years earlier, He had discovered is an m6A eraser (Cancer Cell 2016, DOI: 10.1016/j.ccell.2016.11.017). A few months later, with a different set of collaborators, He showed that levels of the methyl-removing enzyme ALKBH5 were elevated in glioblastoma stem cells (Cancer Cell 2017, DOI: 10.1016/j.ccell.2017.02.013).09707-cover-rnamethyl.jpgCredit: Journal of the American Chemical SocietyA surface (mesh) structure of an RNA duplex (sticks) with the methyl modification of m6A (balls).

At the beginning of 2017, Lasky, the Column Group investor, reached out to He. Now that epitranscriptomic enzymes were tied to cancer, Lasky’s firm wanted to start a drug company to control RNA modifications. With the new cancer data in hand, He felt that the time was right.

The investors also knew about a publication in the works from Jaffrey and leukemia expert Michael Kharas at Memorial Sloan Kettering Cancer Center. The Column Group and Versant Ventures worked together for a time to begin forming a single epitranscriptomics company with several of the academic leaders. During the summer of 2017 however, the different players split into two camps. The Column Group brought on He and Chang as academic cofounders of Accent Therapeutics. Versant Ventures named Jaffrey the academic founder of Gotham Therapeutics.

While Accent and Gotham were still in stealth mode, Jaffrey published a study showing that genetic mutations led to fixed, elevated levels of METTL3 in acute myeloid leukemia, keeping white blood cells from forming. By reducing METTL3 levels, leukemia cells could be coaxed into undergoing differentiation to become noncancerous cells that eventually die (Nat. Med. 2017, DOI: 10.1038/nm.4416). “It was remarkable because we didn’t even need complete inhibition of METTL3,” Jaffrey says.

Two months later, Kouzarides’s lab at the University of Cambridge published similar results, with additional details on what METTL3 was doing in these cells (Nature 2017, DOI: 10.1038/nature24678). In leukemia, elevated METTL3 encouraged the production of proteins linked to cancer. “It is feeding the cell the very proteins that are driving tumorigenesis,” Gotham CEO Lee Babiss says.

Epitranscriptomics now had drug targets, diseases, and high-profile studies. After recruiting additional investors, Accent launched with $40 million in May 2018, and Gotham launched with $54 million in October. Storm Therapeutics is in the process of raising approximately $65 million for its second round of cash from investors. Although none of these companies will name their targets or first diseases they will attempt to treat, conversations with the companies’ CEOs suggest that developing inhibitors of METTL3 is a goal for all three.

Drug designers have a lot of experience inhibiting enzymes, making METTL3 an attractive first target. But its activity may not be straightforward, says Yunsun Nam, a biophysicist at the University of Texas Southwestern Medical Center. METTL3 grabs the methyl group it adds to RNA from S-adenosylmethionine (SAM), a molecule used by several other enzymes. Companies’ compounds will need to avoid inhibiting these other enzymes as well, she explains.

Nam thinks a workaround could be targeting a protein called METTL14, which is attached to METTL3 as part of a larger m6A-writing complex. “METTL3 and METTL14 are very dependent on each other for stability,” she says.

Even if the companies can develop selective METTL3 inhibitors, it’s unclear how many people would benefit from them. While the leukemia studies by Jaffrey and Kouzarides showed that m6A levels are too high, He’s leukemia and glioblastoma studies showed the opposite, that m6A levels are too low. Other studies have suggested more contradictory results—including that m6A levels may be too high in glioblastoma. In other words, when developing therapies, it will be crucial to know the epitranscriptomic state of one’s cancer cells. Otherwise, giving the wrong person a METTL3 inhibitor might make things worse.

“That’s a possibility,” Robert Copeland, the president and chief scientific officer of Accent, acknowledges. The challenge for Accent and other companies will be to figure out which subset of people with leukemia would benefit from a METTL3 inhibitor, to lower m6A levels, and which would benefit from an FTO inhibitor, to raise m6A levels, Copeland explains. “If the pendulum swings too much one way or too much the other way, you can cause disease.”09707-cover-copelandcxd.jpgCredit: Accent TherapeuticsRobert Copeland, president and chief scientific officer of Accent Therapeutics

EPI-EXPANSION

Although the leaders of Accent, Gotham, and Storm are being secretive about their strategies, they all hint that the potential scope of epitranscriptomics drug discovery is much bigger than just targeting METTL3.

In addition to the m6A erasers, a growing body of work is uncovering the importance of the m6A readers. Earlier this month, He’s lab showed that an m6A reader protein called YTHDF1 is an important control switch in the immune system and that inhibiting it might dramatically boost the efficacy of existing checkpoint inhibitors, a popular class of cancer immunotherapy (Nature 2019, DOI: 10.1038/s41586-019-0916-x). “I think a lot of immunotherapy companies will jump into epitranscriptomics once they read the paper,” He says.

And this isn’t the first known link between epitranscriptomics and immunotherapy, Accent’s Copeland says. His firm has been studying an enzyme called ADAR1—which stands for adenosine deaminase acting on RNA—that modifies adenosine bases in RNA. Studies from academic labs show that some tumors depend on ADAR1 in ways that normal cells do not. One study suggests that blocking ADAR1 could make certain drug-resistant cancers vulnerable to checkpoint inhibitors (Nature 2018, DOI: 10.1038/s41586-018-0768-9).

Other labs entering the fray are uncovering new proteins that read, write, and erase RNA modifications, with links to additional types of cancer and other diseases. The scope of epitranscriptomics could be enormous. “That’s what excites us about the field,” says Blundy, Storm’s CEO. “There are many, many RNA pathways that are regulated through modifications.”

The discoveries aren’t all coming smoothly, however. For example, Jaffrey claims that the main target of the eraser enzyme FTO isn’t actually m6A but a slightly different modification, called m6Am. Others disagree. “There is still some debate, but that is the normal trajectory for a field, especially in the early days,” Jaffrey says.

The field also still has technical hurdles. “Right now the methods to map and detect m6A are crude,” Jaffrey admits. Existing methods require large sample sizes and are ineffective at quantifying how m6A levels change over time on particular mRNA transcripts. His lab is now working on ways to better quantify m6A to diagnose or predict diseases in the clinic. Such tools will be critical for recruiting the right people into clinical studies testing inhibitors of epitranscriptomic proteins.

Another issue is the lack of publicly available small-molecule inhibitors for studying epitranscriptomic proteins. “We don’t even have an inhibitor for research,” says Dominissini, who has also developed new RNA-modification-mapping techniques and now runs his own epitranscriptomics lab at Tel Aviv University. Right now, researchers have to use genetic techniques to remove or block production of writer, eraser, and reader proteins, but what the field really needs are simple small molecules to test the hypotheses that these proteins will make good drug targets, he says. Of course, that’s what the companies are working on.

A similar lack of compounds stalled epigenetics drug discovery more than a decade ago. Pioneers in the epitranscriptomics field are unfazed by these parallels. “I don’t think there is a relationship between the success or failure of an epigenetics drug to an epitranscriptomics drug,” Jaffrey says.

The scientists and companies in the field are running full speed ahead. Hundreds of labs have cited papers from Dominissini, He, and Jaffrey, and all can point to several ongoing studies investigating the role of RNA modifications in other diseases. “It reflects how fast people jumped into the field,” He says. “Epitranscriptomics is booming.”

RNA AS A PATHWAY TO THE BRAIN

A 2018 study from the Scripps Research laboratory of Sathyanarayanan Puthanveettil, PhD, peers deep within the nucleus of developing brain cells and finds that long noncoding RNAs play an important role in the healthy functioning and maintenance of synapses, the communication points between nerve cells in the brain.

“Long noncoding RNAs are often described as ‘the dark matter of the genome.’ So, systematic interrogation of their function will illuminate molecular mechanisms of brain development, storage of long-term memories and degradation of memory during aging and dementia,” Puthanveettil says.

RNA are the master regulators of the cell, tiny chains of nucleotides that read, transcribe and regulate expression of DNA, and build proteins. While scientists have gained great insights recently into the genetics underpinning how brain cells reach out and communicate with each other, the role of noncoding RNA is poorly understood. Research suggests that the longest of these noncoding RNA, those over 200 nucleotides long, help determine which genes are activated and operating in brain cells at various times. But which ones?

Writing in the journal Proceedings of the National Academy of Sciences, Puthanveettil and his colleagues on Scripps Research’s Florida campus report that a specific long non-coding RNA, GM12371, controls expression of multiple genes involved in nervous system development and functioning. Furthermore, it affects the developing neurons’ shape and ability to signal.

In mouse hippocampal cells, learning-related signaling upregulates GM12371, while its reduction produces inactive neurons, ones with sparse branches.

Together, the results suggest that healthy growth and development of brain cells and brain circuits depends not just upon specific proteins but also upon specific long noncoding RNAs, which scientists are now beginning to explore.

What role GM12371 dysfunction may play in diseases of the brain and nervous system demands further study, Puthanveettil says.

“Both coding and noncoding RNAs are increasingly viewed as druggable targets. Identifying their specific roles in the fundamental biology of functioning of neural circuits might eventually open new ways of treating neuropsychiatric disorders, such as autism and Alzheimer’s disease,” Puthanveettil says.

A Chinese team of researchers furthers these findings one year later:

“In the emerging field of epitranscriptomic mechanisms, mRNA m6A modification has potential role in learning and memory. It regulates physiological and stress-induced behavior in the adult mammalian brain, and augments the strength of weak memories. As a newly identified element in the region-specific gene regulatory network in the mouse brain, mRNA m6A modification plays a vital role in the death of dopaminergic neuron.
Mettl3-mediated RNA m6A modification has the direct effect on regulating hippocampal-dependent long-term memory formation. The decrease of Mettl3 in the mice hippocampus may reduce its memory consolidation, and adequate training or restoration would restore the ability of learn and memory.”

“The role of mRNA m6A methylation in the nervous system”, Cell & Bioscience, 2019

From the same Chinese study quoted above:
Epitranscriptomics, also known as “RNA epigenetics”, is a chemical modification for RNA regulation [1]. According to its function, RNA can be divided into two broad categories, including encoding protein mRNA and non-coding RNA. With the deep research of epitranscriptomics, the researchers found methylation modification on mRNA, which is involved in the regulation of eukaryotic gene expression [2,3,4].
The mRNA is a type of RNA with genetic information synthesized by DNA transcription, which acts as a template in protein synthesis and determines the amino acid sequence of the peptide chain [5]. It is an important RNA in the human body. The methylation is the process of catalytically transferring a methyl group from an active methyl compound such as S-adenosylmethionine (SAM) to another compound, which can chemically modify certain proteins or nucleic acids to form a methylated product [6]. In biological systems, methylation influences heavy metal modification, regulation of gene expression, regulation of protein function, RNA processing, etc. [7]. At the early 1970s, scientists discovered the presence of the methylation modification in mRNA [89]. The mRNA methylation modification mainly located in the nitrogen atom of the base group to form m6A, which is enriched in long exons and overrepresented in transcripts with alternative splicing variants [10]. The mRNA methylation modifications also include 5-methylcytosine (m5C), N1-methyladenosine (m1A), 5-hydroxymethylcytosine (5hmC), N6, 2′-O-dimethyladenosine (m6Am), 7-methylguanine (m7G) (Fig. 1). These modifications can affect regulation of various biological processes, such as RNA stability and mRNA translation, and abnormal mRNA methylation is linked to many diseases
“.

Another US study from 2018 deals with “Role of RNA modifications in brain and behavior” and reveals that:
“Much progress in our understanding of RNA metabolism has been made since the first RNA nucleoside modification was identified in 1957. Many of these modifications are found in noncoding RNAs but recent interest has focused on coding RNAs. Here, we summarize current knowledge of cellular consequences of RNA modifications, with a special emphasis on neuropsychiatric disorders. We present evidence for the existence of an “RNA code,” similar to the histone code, that fine-tunes gene expression in the nervous system by using combinations of different RNA modifications. Unlike the relatively stable genetic code, this combinatorial RNA epigenetic code, or epitranscriptome, may be dynamically reprogrammed as a cause or consequence of psychiatric disorders. We discuss potential mechanisms linking disregulation of the epitranscriptome with brain disorders and identify potential new avenues of research”.

But the most important take out from this latter study, for me, is the final conclusion that stresses the need for larger data-bases to advance the research. I find it important because data bases need samples. And samples are often collected with swabs, like those used for Covid testing.

“With the development of more and better epitranscriptome sequencing technologies there will be a need to analyze large sequencing datasets. New bioinformatic tools are needed to supplement the current data analysis pipelines which were initially designed to analyze chromatin immunoprecipitation sequencing (ChIP seq) data. These new tools will need to take into account the complications caused by differential splicing, and amplification bias induced during reverse transcription as well as integrate multiple RNA modifications within the same molecule of RNA, across the entire transcriptome. A comprehensive database for curating and sharing epitranscriptomic data should be established to standardize the experimental and computational procedures that are used in different studies.123 We envision that in the not so distant future many new molecular and bioinformatic tools will become available to facilitate rapid advancements in the field of epitranscriptomics.”

Role of RNA modifications in brain and behavior” – Y. Jung and D. Goldman

Actually China and US have been collaborating for quite a while in getting ahead of the curve in RNA therapies. In 2017, a mixed research team from the two countries noted in a study:

“Over 100 types of chemical modifications have been identified in cellular RNAs. While the 5′ cap modification and the poly(A) tail of eukaryotic mRNA play key roles in regulation, internal modifications are gaining attention for their roles in mRNA metabolism. The most abundant internal mRNA modification is N⁶-methyladenosine (m⁶A), and identification of proteins that install, recognize, and remove this and other marks have revealed roles for mRNA modification in nearly every aspect of the mRNA life cycle, as well as in various cellular, developmental, and disease processes. Abundant noncoding RNAs such as tRNAs, rRNAs, and spliceosomal RNAs are also heavily modified and depend on the modifications for their biogenesis and function. Our understanding of the biological contributions of these different chemical modifications is beginning to take shape, but it’s clear that in both coding and noncoding RNAs, dynamic modifications represent a new layer of control of genetic information.”

Dynamic RNA Modifications in Gene Expression Regulation, 2017, Cell magazine

It’s obvious we’re dealing with an already vast scientific domain that can expand far and wide and has serious positive and negative potential for the human species.
And that’s a completely different story than what the establishment is giving you on the RNA vaccines and technologies.

In closure, I’ll quote none other than the Oxford University, the world-famous covid vaccine developers who have been also at the core of this technology, as proven by their 2018 study “m6A modification of non-coding RNA and the control of mammalian gene expression

“For more than forty years we have known that like DNA, RNA is chemically modified, with evidence of RNA modifications identified from viruses to Arabidopsis, mouse and man. Characterisation of highly abundant modified tRNA and rRNA first informed us of the plethora of structural and functional roles for modified RNA. “

HeatherCoker, GuifengWei, NeilBrockdorff – Department of Biochemistry, University of Oxford

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by Silviu “Silview” Costinescu_ Buy Me a Coffee at ko-fi.com

I keep telling covidiots their actions speak way louder than their propaganda, it’s still rocket science to them. Not many words to add from my side.

These silly dipshits think they can control me with fear. Fear of channel deletion lol. They’ve already deleted all the joy from my life, you don’t do that to people and then hope to scare them with Youtube deletion!
What if WE delete YOU(tube)?


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by Silviu “Silview” Costinescu_ Buy Me a Coffee at ko-fi.com

Allow me to leak some of their more intimate shots

SOURCE

Pfizer Wuhan R&D Center was founded on October 8, 2010, becoming the first world’s top 500 enterprises settled in Wuhan Biolake.

The US Pfizer is transferring its medicine safety business from India to Wuhan, capital of central China’s Hubei, due to the advantages of talent resources and industry environment here.

Five years ago, Pfizer established an affiliate at Wuhan Biolake, a national biological industrial base, and greatly expanded its research and development scale and cooperative sectors in China. The Pfizer Wuhan R&D Center is an important base supporting Pfizer’s global data processing, quality control and medicine safety.

Pfizer has two world class R&D centers in China’s Wuhan and Shanghai, with business operations in over 300 cities. Pfizer’s China Research and Development Center has become one of the company’s seven major R&D centers worldwide.” – government website of the Hubei Province, China

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Reminder : BILL GATES HAS BEEN AN OFFICIAL MEMBER OF CHINESE ACADEMIA FOR YEARS. AND THERE’S MORE…

UPDATE:
As per usual, life doesn’t take long to confirm us

Major leak ‘exposes’ members and ‘lifts the lid’ on the Chinese Communist Party

13/12/2020|

A major leak containing a register with the details of nearly two million CCP members has occurred – exposing members who are now working all over the world, while also lifting the lid on how the party operates under Xi Jinping, says Sharri Markson.

According to Sky News journalist Sherri Markson, “Some of its members – who swear a solemn oath to ‘guard CCP secrets, be loyal to the Party, work hard, fight for communism throughout my life…and never betray the Party’ – are understood to have secured jobs in British consulates.”

Alarmingly, Markson also says Pfizer and AsraZeneca – both currently producing large numbers of COVID-19 vaccine doses – have “employed a total of 123 party loyalists.”

To be continued and updated

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by Silviu “Silview” Costinescu_ Buy Me a Coffee at ko-fi.com

I don’t know if they do it, because no independent researchers examine those swabs, but I have always pointed out that our overlords seem more concerned with testing than with vaccinating. Almost like the vaccines were the bait and tests were the switch. And now we also know they totally CAN do that.
Just follow the science below.

UPDATE: DR. LORRAINE DAY QUOTES AND FURTHER EXPLAINS THIS VERY ARTICLE!

Share the video in higher resolution from our Bitchute or Lbry

November 3, 2020

Researchers engineer tiny machines that deliver medicine efficiently

by Johns Hopkins University School of Medicine

Johns Hopkins Researchers engineer tiny machines that deliver medicine efficiently
A theragripper is about the size of a speck of dust. This swab contains dozens of the tiny devices. Credit: Johns Hopkins University.

Inspired by a parasitic worm that digs its sharp teeth into its host’s intestines, Johns Hopkins researchers have designed tiny, star-shaped microdevices that can latch onto intestinal mucosa and release drugs into the body.

David Gracias, Ph.D., a professor in the Johns Hopkins University Whiting School of Engineering, and Johns Hopkins gastroenterologist Florin M. Selaru, M.D., director of the Johns Hopkins Inflammatory Bowel Disease Center, led a team of researchers and biomedical engineers that designed and tested shape-changing microdevices that mimic the way the parasitic hookworm affixes itself to an organism’s intestines.

Made of metal and thin, shape-changing film and coated in a heat-sensitive paraffin wax, “theragrippers,” each roughly the size of a dust speck, potentially can carry any drug and release it gradually into the body.

The team published results of an animal study this week as the cover article in the journal Science Advances.

Gradual or extended release of a drug is a long-sought goal in medicine. Selaru explains that a problem with extended-release drugs is they often make their way entirely through the gastrointestinal tract before they’ve finished dispensing their medication.

“Normal constriction and relaxation of GI tract muscles make it impossible for extended-release drugs to stay in the intestine long enough for the patient to receive the full dose,” says Selaru, who has collaborated with Gracias for more than 10 years. “We’ve been working to solve this problem by designing these small drug carriers that can autonomously latch onto the intestinal mucosa and keep the drug load inside the GI tract for a desired duration of time.”

Researchers engineer tiny machines that deliver medicine efficiently
When an open theragripper, left, is exposed to internal body temperatures, it closes on the instestinal wall. In the gripper’s center is a space for a small dose of a drug. Credit: Johns Hopkins University

Thousands of theragrippers can be deployed in the GI tract. When the paraffin wax coating on the grippers reaches the temperature inside the body, the devices close autonomously and clamp onto the colonic wall. The closing action causes the tiny, six-pointed devices to dig into the mucosa and remain attached to the colon, where they are retained and release their medicine payloads gradually into the body. Eventually, the theragrippers lose their hold on the tissue and are cleared from the intestine via normal gastrointestinal muscular function.

Taken from the original research annexes

Gracias notes advances in the field of biomedical engineering in recent years.

“We have seen the introduction of dynamic, microfabricated smart devices that can be controlled by electrical or chemical signals,” he says. “But these grippers are so small that batteries, antennas and other components will not fit on them.”

Theragrippers, says Gracias, don’t rely on electricity, wireless signals or external controls. “Instead, they operate like small, compressed springs with a temperature-triggered coating on the devices that releases the stored energy autonomously at body temperature.”

The Johns Hopkins researchers fabricated the devices with about 6,000 theragrippers per 3-inch silicon wafer. In their animal experiments, they loaded a pain-relieving drug onto the grippers. The researchers’ studies found that the animals into which theragrippers were administered had higher concentrates of the pain reliever in their bloodstreams than did the control group. The drug stayed in the test subjects’ systems for nearly 12 hours versus two hours in the control group.

“Swarms of microscopic robots that can be injected”
Tell Melinda Gates we can inject robots these days.

Epub 2008 Dec 13.

Nanoparticles for nasal vaccination

Noemi Csaba  1 Marcos Garcia-FuentesMaria Jose Alonso Affiliations

Abstract

The great interest in mucosal vaccine delivery arises from the fact that mucosal surfaces represent the major site of entry for many pathogens. Among other mucosal sites, nasal delivery is especially attractive for immunization, as the nasal epithelium is characterized by relatively high permeability, low enzymatic activity and by the presence of an important number of immunocompetent cells. In addition to these advantageous characteristics, the nasal route could offer simplified and more cost-effective protocols for vaccination with improved patient compliance. The use of nanocarriers provides a suitable way for the nasal delivery of antigenic molecules. Besides improved protection and facilitated transport of the antigen, nanoparticulate delivery systems could also provide more effective antigen recognition by immune cells. These represent key factors in the optimal processing and presentation of the antigen, and therefore in the subsequent development of a suitable immune response. In this sense, the design of optimized vaccine nanocarriers offers a promising way for nasal mucosal vaccination.


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2015 called…

PubMed, 2015 Jun 9.:

Nanoneurotherapeutics approach intended for direct nose to brain delivery

Shadab Md  1 Gulam Mustafa  2   3 Sanjula Baboota  3 Javed Ali  3 Affiliations Expand

Abstract

Context: Brain disorders remain the world’s leading cause of disability, and account for more hospitalizations and prolonged care than almost all other diseases combined. The majority of drugs, proteins and peptides do not readily permeate into brain due to the presence of the blood-brain barrier (BBB), thus impeding treatment of these conditions.

Objective: Attention has turned to developing novel and effective delivery systems to provide good bioavailability in the brain.

Methods: Intranasal administration is a non-invasive method of drug delivery that may bypass the BBB, allowing therapeutic substances direct access to the brain. However, intranasal administration produces quite low drug concentrations in the brain due limited nasal mucosal permeability and the harsh nasal cavity environment. Pre-clinical studies using encapsulation of drugs in nanoparticulate systems improved the nose to brain targeting and bioavailability in brain. However, the toxic effects of nanoparticles on brain function are unknown.

Result and conclusion: This review highlights the understanding of several brain diseases and the important pathophysiological mechanisms involved. The review discusses the role of nanotherapeutics in treating brain disorders via nose to brain delivery, the mechanisms of drug absorption across nasal mucosa to the brain, strategies to overcome the blood brain barrier, nanoformulation strategies for enhanced brain targeting via nasal route and neurotoxicity issues of nanoparticles.

Epub 2013 Oct 16.

Nanoemulsion-based intranasal drug delivery system of saquinavir mesylate for brain targeting

Hitendra S Mahajan  1 Milind S MahajanPankaj P NerkarAnshuman Agrawal Affiliations Expand

Abstract

The central nervous system (CNS) is an immunological privileged sanctuary site-providing reservoir for HIV-1 virus. Current anti-HIV drugs, although effective in reducing plasma viral levels, cannot eradicate the virus completely from the body. The low permeability of anti-HIV drugs across the blood-brain barrier (BBB) leads to insufficient delivery. Therefore, developing a novel approaches enhancing the CNS delivery of anti-HIV drugs are required for the treatment of neuro-AIDS. The aim of this study was to develop intranasal nanoemulsion (NE) for enhanced bioavailability and CNS targeting of saquinavir mesylate (SQVM). SQVM is a protease inhibitor which is a poorly soluble drug widely used as antiretroviral drug, with oral bioavailability is about 4%. The spontaneous emulsification method was used to prepare drug-loaded o/w nanoemulsion, which was characterized by droplet size, zeta potential, pH, drug content. Moreover, ex-vivo permeation studies were performed using sheep nasal mucosa. The optimized NE showed a significant increase in drug permeation rate compared to the plain drug suspension (PDS). Cilia toxicity study on sheep nasal mucosa showed no significant adverse effect of SQVM-loaded NE. Results of in vivo biodistribution studies show higher drug concentration in brain after intranasal administration of NE than intravenous delivered PDS. The higher percentage of drug targeting efficiency (% DTE) and nose-to-brain drug direct transport percentage (% DTP) for optimized NE indicated effective CNS targeting of SQVM via intranasal route. Gamma scintigraphy imaging of the rat brain conclusively demonstrated transport of drug in the CNS at larger extent after intranasal administration as NE.

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PubMed Epub, 2016 Jun 28:

Hydrogel nanoparticles and nanocomposites for nasal drug/vaccine delivery

Sara Salatin  1   2 Jaleh Barar  1   3 Mohammad Barzegar-Jalali  3 Khosro Adibkia  3   4 Mitra Alami Milani  2   4 Mitra Jelvehgari  5   6 Affiliations Expand

Affiliations

  • 1 Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Science, Tabriz, Iran.
  • 2 Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran.
  • 3 Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Mailbox 51664, Tabriz, Iran.
  • 4 Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
  • 5 Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Mailbox 51664, Tabriz, Iran. mitra_jelvehgari@yahoo.com.
  • 6 Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. mitra_jelvehgari@yahoo.com.

Abstract

Over the past few years, nasal drug delivery has attracted more and more attentions, and been recognized as the most promising alternative route for the systemic medication of drugs limited to intravenous administration. Many experiments in animal models have shown that nanoscale carriers have the ability to enhance the nasal delivery of peptide/protein drugs and vaccines compared to the conventional drug solution formulations. However, the rapid mucociliary clearance of the drug-loaded nanoparticles can cause a reduction in bioavailability percentage after intranasal administration. Thus, research efforts have considerably been directed towards the development of hydrogel nanosystems which have mucoadhesive properties in order to maximize the residence time, and hence increase the period of contact with the nasal mucosa and enhance the drug absorption. It is most certain that the high viscosity of hydrogel-based nanosystems can efficiently offer this mucoadhesive property. This update review discusses the possible benefits of using hydrogel polymer-based nanoparticles and hydrogel nanocomposites for drug/vaccine delivery through the intranasal administration.

Keywords: Brain; Hydrogel; Nanoparticles; Nasal delivery; Vaccine.

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by Silviu “Silview” Costinescu

UK’s Government’s Medicines & Healthcare products Regulatory Agency (MHRA) spends close to $2million on an Artificial Intelligence to monitor “Medicines & Healthcare products Regulatory Agency”. If this isn’t alarming, I don’t know what is. But I know there’s more to the story.

The MHRA urgently seeks an Artificial Intelligence (AI) software tool to process the expected high volume of Covid-19 vaccine Adverse Drug Reaction (ADRs) and ensure that no details from the ADRs’ reaction text are missed.

MRHA
DOWNLOAD PDF

Thanks Graham Pick for the tip!

The acquisition document further provides this explanation:

“For reasons of extreme urgency under Regulation 32(2)(c) related to the release of a Covid-19 vaccine MHRA have accelerated the sourcing and implementation of a vaccine specific AI tool.

Strictly necessary — it is not possible to retrofit the MHRA’s legacy systems to handle the volume of ADRs that will be generated by a Covid-19 vaccine. Therefore, if the MHRA does not implement the AI tool, it will be unable to process these ADRs effectively. This will hinder its ability to rapidly identify any potential safety issues with the Covid-19 vaccine and represents a direct threat to patient life and public health.

Reasons of extreme urgency — the MHRA recognises that its planned procurement process for the SafetyConnect programme, including the AI tool, would not have concluded by vaccine launch. Leading to a inability to effectively monitor adverse reactions to a Covid-19 vaccine.

Events unforeseeable — the Covid-19 crisis is novel and developments in the search of a Covid-19 vaccine have not followed any predictable pattern so far.”

Beneficiary of this contract is a company named Genpact, part of a larger multi-industry group with the same name.
Genpact also does Facebook moderation, which gives it access to Facebook data!

Source

Genpact CEO is close to our old friends from WEF, of course

Here he supports using military to distribute the vaccine that will then provide work for his company:

He seems to applaud a Biden victory in the US presidentials. :

This Tyger dude basically has all the traits and inclinations of the elite mafia that set up Covidiocracy as the new business and live-stock management model for the whole world.

Source

Genpact has acquired 23 companies, including 10 in the last 5 years. A total of 8 acquisitions came from private equity firms. Genpact’s largest acquisition to date was in 2011, when it acquired Headstrong for $550MGenpact has acquired in 11 different US states, and 5 countries. The Company’s most targeted sectors include information technology (28%) and software (28%). – Mergr

Gentec CEO interview

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