"My synapses are not the same" and post-mRNA cancer increase

Mortality increase

Since I do have plentiful to write, we better do it. Smaller sized, but complex and informative nonetheless. I will also thank the spirit of Julius Evola for sending me this paper from the ethereal, immaterial plane (this is a joke; someone named Evola was kind enough to send me this paywalled paper).

Forgive my expletives, but why the fuck this paper sit in limbo for almost an entire year until peer review ?

Also, a refresher in case you are not very fond of neurobiology and its (unnecessarily complicated) concepts.

Highlight of the paper.

• Changes in electric potential and synaptic morphology due to SARS-CoV-2 infection could lead to cognitive consequences in individuals affected by COVID-19

• Synaptic function and neural electrical activity are fundamental to cognitive processes such as learning, memory, and attention.

• Up-regulation of synaptic components, aberrant presynaptic morphology, and perturbations in local electric field potential indicate that SARS-CoV-2 could disrupt critical neural processes

• A correlation between the proteins studied here and Omicron’s TIM-3-Galectin-9 pathway

Brain exposure to SARS-CoV-2 virions perturbs synaptic homeostasis

There is a lot to unpack here. One of the biggest questions is how and why SARS-CoV-2 induces neurocognitive problems, neuroinflammation, microvascular disease (micro clots damaging things), reactivation of herpesviruses, hypoxia (these are also the author’s words), and in addition, secondary bacterial infections, septic states, endogenous retroviruses all play a part, but how can the virus directly cause cognitive dysfunction/decay, especially in asymptomatic cases is up for inquiry.

The authors used a multi-model approach, meaning they utilized multiple forms of testing, and their first test was SARS-CoV-2 infection using cerebral organoids (brain tissues created in a lab). There was a visible variability previously observed in the infection levels of organoids, from low to very high. Thus demonstrating brain organoids can be infected, but experience poorly viral dissemination.

Next, they analyzed the proteins expressed as a whole and found which proteins were more or less produced, which indicated changes in the presynaptic structure and synaptic proteins were produced in larger quantities, synapses are the small space between nerve cells that transmit signals, and these changes indicated they were enlarged.

Since organoids lack a functional immune system, they added immune cells (human monocytes) that got into the organoid tissue. In line with previous evidence, the monocytes that infiltrated the tissue contained elongated synaptic structures, indicating that microglia (immune cells of the brain) play a role in synaptic pruning upon SARS-CoV-2 infection. Synaptic pruning is one of the steps of the brain's “cleaning” system.

Since organoids are considered an immature version of the human brain, the authors used brain slices (post-mortem) finding that SARS-CoV-2 can infect neural cells but to a very low extent.

The changes described above. Some deep insights in the Down-regulated components section of the image

By comparing their brain slice model with samples from people who died of non-neurological COVID-19 the authors found that their model shared similar trends, depending on the region analyzed, both groups had similar levels of viral RNA, not only did some patients have viral infection in the brain while remaining complete asymptomatic, they lacked sign of active microglia (only found in the blood vessels…), subsequentially they found that you don’t need a lot of viruses for these effects to take place. In simple terms, there is virus there, it is enacting change, but the immune system in the model doesn’t respond that much. From my perspective, this is what we could call a stealth factor.

To understand the relevance of the changes in presynaptic components, they looked into the individual protein among the many they tested and found a specific protein was consistently overexpressed (larger quantities than normal), Latrophilin-3 (LPHN3) a protein that is essential for the function and maintenance of synapses (the space between neurons where information is transferred). Its main receptor a protein called FLRT3 was found to be upregulated in patients with Covid.

By using a test that can measure the activity of LPHN3 (by using changes in cAMP production, a secondary messenger of some sort in the synapses), uncovering that even the inactivated viruses caused these changes and that the enlargement and synaptic abnormality are LPHN3-dependent.

Next, they measured the local electric field potential, a way for cells to communicate externally, via cellular electrical signals, and they could readily discriminate between organoids exposed to SARS-CoV-2 and the ones that weren’t. This means the virus affects the highly dynamic informational flow in our brains. The next paragraph is to me the most important one of the paper and I will leave the entire title of it.

SARS-CoV-2 virions dwell at trans-synaptic sites

Given all the observed changes, both chemical and structural, the next step was analyzing if the virus directly interacted with FLRT3, the receptor mentioned above, and many individual proteins from SARS-CoV-2, the author observed a weak interaction between FLRT3 and the Spike Protein and stated perhaps it is because the interaction is weak, or their testing method.

Nevertheless, they used UV-inactivated fluorescent SARS-CoV-2 virions and observed an accumulation of the virus, over time in the trans-synaptic sites positive for FLRT3. They used live cell imaging to confirm that SARS-CoV-2 virions do indeed dwell and are retained in the synaptic sites and to their (and mine) knowledge this is the first time this mechanism (LPHN3) was found and potentially can explain nervous system pathology concerning viral infections.

The authors propose:

Indeed, one could envision a scenario in which low level of SARS-CoV-2 replication in neurons induces local perturbation of the neural network through physical hindrance at the synapse, and because of the low immune response, microglial cells would take time to clear this local perturbance, leading to transient neurological symptoms

This is very concerning to me because of the change in tropism the virus went through in the last 2 years, preferring the gut and brain, rather than the lungs, the virus doesn’t cause severe disease in most people, but it replicates at an absurd level, and the fact that the “dead virus” and its proteins accumulate precisely where it interferes with electric signals and flow of information is concerning.

The brain can’t mount a robust immune response, otherwise, you quite literally suffer brain damage or death, so anything “inside” the brain takes time to get cleaned and be transported out. I will refer to something else now.

Spike Protein accumulation in the brain

As I wrote recently, I don’t know what is worse, the proteins persisting for months inducing a kaleidoscope of dysfunction, or your body pushing the proteins (especially and uniquely the Spike Protein) through tissue, whatever the cost. I have written extensively on the brain, especially the Covid brain. How many of these detrimental changes were caused by a similar mechanism ?

Perhaps I feel dumber because my brain is quite literally slower, and my synapses are dysfunctional (quite a large number of my readers can tell you I tell them I feel dumber for the past 12 months).

This great overview titled Synaptic dysfunction in neurodegenerative and neurodevelopmental diseases: an overview of induced pluripotent stem-cell-based disease models is a fantastic read on the subject.

Changes and disruption of LPHN3 are known to affect the brain itself and behavior, activity, and cognition, changes in expression also influence Serotonin. Worse of all, I was surprised to find out that LPHN3 and FLRT3 play a role in cancer immunity, via the TIM-3 Galectin-9 pathway, the specific pathway I highlighted recently that is one of Omicron’s hallmarks.

There must be a common denominator connecting all these distinct effects, pathways, and myriad of effects…

This pathway will be extremely important soon enough, via multiple tipping points, in fact, I would call it a nexus point. And since we are talking about cancer.

Increased Age-Adjusted Cancer Mortality After the Third mRNA-Lipid Nanoparticle Vaccine Dose During the COVID-19 Pandemic in Japan

Statistically significant increases in age-adjusted mortality rates of all cancer and some specific types of cancer, namely, ovarian cancer, leukemia, prostate, lip/oral/pharyngeal, pancreatic, and breast cancers, were observed in 2022 after two-thirds of the Japanese population had received the third or later dose of SARS-CoV-2 mRNA-LNP vaccine. These particularly marked increases in mortality rates of these ERα-sensitive cancers may be attributable to several mechanisms of the mRNA-LNP vaccination rather than COVID-19 infection itself or reduced cancer care due to the lockdown. 

The focus here should be the mentioning of ERα-sensitive cancers because this is one of the first papers where a correlation between vaccination and this form of cancer has been proposed. It is important because while the mRNA-LNP platform has over a dozen ways to induce or accelerate cancer on its own, the spike has five dozen, and its endocrine aspect has been heavily overlooked so far.

Quite a while ago, a group found the SARS-CoV-2 Spike Protein binds and modulates Estrogen receptors, and this opened a hell of a can of worms since these receptors control many important biological and cell functions, including one of my favorite pathways, the Kynurenine Pathway. Estrogen receptor alpha also plays a particularly important role in preventing endotoxin-induce myocardial dysfunction. Estrogen receptors also regulate Galectin-3 expression and signaling (important in many cancers).

I wish we had sophisticated enough Machine Learning algos and model and samples before and after vaccination, and distinction on how many infections/reinfections a person had, at large enough quantity (the more data, the better for ML/DL with the correct approach) so we could differentiate between cancer acceleration and oncogenesis (cancer creation). We now have enough compute for these things.

Thank you so much for your support !

A picture of a bunch of beetles I randomly found on Twitter. I love beetles, very Japanese of me (I am not Japanese).