About the protein shape of Covid-19

  • #1
hagopbul
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TL;DR Summary
what is the crystalline profile of covid-19
hello i came across an old article about crystalline shape of AEC2 receptor that is been some how associated with covid-19
my question

dose knowing the crystalline profile of protein receptors some how can help with finding a better aid against this kind of outbreaks and how crystalline structure of a protein can find a cure from a viruse outbreak thank you for your time in advance

could we use electro static distribution aspect of the protein to create an antidote for it that not only use geometric aspects but also static electrical profile ?

hagop

https://www.pnas.org/content/pnas/106/47/19970.full.pdf
 
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  • #2
TeethWhitener
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The crystal structure of a protein goes a long way toward determining the mechanism by which it functions. It’s just like anything else: it’s much easier to figure out how something works when you understand how it’s put together.


Summary:: could we use electro static distribution aspect of the protein to create an antidote for it that not only use geometric aspects but also static electrical profile ?
Roughly speaking, yes. Many antivirals are based on the idea of inhibiting proteins that the viruses need to enter a cell, replicate, or assemble.
 
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  • #3
fresh_42
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I'm just watching a press conference of the RKI and it seems that there are still many unknowns. They don't even have the infection rate. China reports a fatal rate of ##0.022##, but didn't report the infection rate. We know the virus replicates in the throat like the ordinary influenza even in very early states of sickness, in contrast to SARS which replicated deep in the lungs. As a consequence we probably face an airborne disease, such that there is actually a threat of a pandemic similar to former influenza outbreaks, although the infection path is still not verified. However, replication in the throat is good evidence. And of course, vaccination is still at least months ahead, years to achieve a FDA approval or equivalent. I have heard in the news today, that an American company admitted its tests wouldn't work in all cases. Unfortunately, they didn't mention whether they get false positive or false negative results. In any case this indicates that knowing one surface protein is far from being sufficient to take counteractions. RKI said that they are still missing profound mechanical data.
 
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  • #4
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Thank you for your time

The second part of my question is instead of waiting to find a protein which has the needed geometric patterns to create an antibiotic , how about using electrostatic characters to make proteins and peptides which stuck on ace2 or any thing like it preventing them from functioning properly .

Could we use plasma deposition to accelerate large molecules on thin film of the virus to help create needed inhabitors
(Self assembly concept)

Best
Hahop
 
  • #5
TeethWhitener
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I'm not sure I understand what you mean. Pharmaceutical companies spend vast amounts of computational resources trying to work out what types of molecules fit most optimally into various protein binding pockets. There are a number of ways to inhibit a protein besides simply blocking its active site. There are also a number of ways to activate the immune system besides binding a specific antibody (I assume you meant antibody and not antibiotic) to a virus or other pathogen.

how about using electrostatic characters to make proteins and peptides which stuck on ace2 or any thing like it preventing them from functioning properly .
ELISA is kind of the reverse of what you're talking about. ELISA is normally used when you know what your target is and you want to know if it's in your sample, not so much if you're trying to find out if a random molecule binds to a target. Keep in mind that the number of possible 10-amino acid peptides is 2010=1013. I don't think anyone manufactures a ten trillion-well plate.

Could we use plasma deposition to accelerate large molecules on thin film of the virus to help create needed inhabitors
How would you choose the molecules? Once chosen, how would you generate them? Once generated, how would you detect that they had bonded?

As far as I can tell, researchers currently have cracked the 2019-nCoV genome and are currently using calculated structures to do drug docking studies. They've done some in silico and in vitro work on known antivirals which have shown some promise. Developing new therapies from scratch is an extremely difficult and time-consuming process, not to mention getting approval to deploy them. Unfortunately, biomedical science can only do so much so fast. At this stage of the game, the most promising intervention is at the level of public health.
 
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  • #6
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... how about using electrostatic characters to make proteins and peptides which stuck on ace2 or any thing like it preventing them from functioning properly .
Yikes! I like my ACE2 doing just what it does without screwing it up and losing its activity as a modulator to the renin-angiotensin system.
 
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  • #8
TeethWhitener
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I think OP was referring to the fact that 2019-nCoV uses ACE2 as a receptor for cell entry. An entry inhibitor that blocks that interaction (presumably on the viral side) is a reasonable target for antivirals—or rather, as reasonable as any other target.
 
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  • #9
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Well, that’s how Chloroquine is supposed to work. It changes the local pH of the binding site and prevents the nCoV from strongly attaching. Remdesivir incorporates a messed up version of adenosine that prevents further replication.
 
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  • #10
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About plasma deposition , in physics thin films , we use various methods of deposition of nano objects , some of that methods related to the field of self assembly nano technology , , what i was saying , we bring a liquid of peptides change it to a vapour then in a vacuum chamber make that ionised vapour deposit over a thin film substrate of that virus with some tweaks could we self assembly some of those peptides to create a geometric form of that needed ,could that method or some thing like that* , be some assistance to create an antibodies for covid-19

* That is a lot of methods for self assembly plasma deposition is one of them
 
  • #11
Ygggdrasil
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About plasma deposition , in physics thin films , we use various methods of deposition of nano objects , some of that methods related to the field of self assembly nano technology , , what i was saying , we bring a liquid of peptides change it to a vapour then in a vacuum chamber make that ionised vapour deposit over a thin film substrate of that virus with some tweaks could we self assembly some of those peptides to create a geometric form of that needed ,could that method or some thing like that* , be some assistance to create an antibodies for covid-19

* That is a lot of methods for self assembly plasma deposition is one of them
I see various issues with that approach.

1) There are a variety of technical issues to get such an approach to work. For example, proteins exist in an aqueous environments and taking them out of aqueous environments can change their shapes. Even placing a protein at an air-water interface can cause a protein to denature. It's also not clear whether the deposited peptides would maintain their shape after being removed from the substrate.

2) Reproducibility and costs. Medicines need to be manufactured reproducibly at scale. If one could get the vapor deposition method to work, it's not clear to me how reproducibly one could produce the potential inhibitors and whether production would scale to produce the many thousands of doses needed to treat people in an outbreak.

3) Well tested alternatives exist. Antibody-based methods already provide a decent method of generating treatments. Animal immune systems are extremely good at generating genetically-encoded reagents to recognize biological molecules and prime immune responses to those molecules. Throughout the years, the biotechnology industry has gotten very good at developing such molecules to treat infectious diseases, and they know how to scale production of these molecules. Similarly, vaccine development has become quite streamlined as well, and companies have already reported developing candidate vaccines against the Wuhan coronavirus. The real bottleneck is clinical testing to ensure safety and efficacy, which brings me to my last point.

4) Safety. I am not aware of any similar methods being used to manufacture phamaceuticals, so any pharmacuetical generated by this method would need to undergo more extensive testing to ensure safety, so it's probably not the best approach for a novel disease where treatments and vaccines are more urgently needed.
 
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  • #12
BillTre
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I am skeptical that vapor deposition of peptides would reflect how they would work on solution (their natural environment).
In an aqueous solution, proteins or peptides (short pieces of protein) either take one or more stable 3D configurations or flop around as an unstructured chain of amino acids.
Those with stable structures maintain their configurations based to a large part on the chemical interactions of their amino acids with water molecules as well as other amino acids in their sequence. Without the water around they may find an alternative stable configuration, but it probably won't be the same as it would be in solution.
Those that flop around as an unstructured chain may be able assume a structure when bound to some other molecule or structure.

Deposition onto some structure of molecules as a thin film may result in some repeatedly produced structure, but it is unlikely to the same as an antibody protein would in solution.

If you did get a useful structure that can bind things as you desire, it will be unlikely it would be an antibody. Antibodies are fairly large proteins which, although having unique parts that bind specific molecular components, have a structure that is mostly shared with other antibody proteins that are important to how the antibody functions and interacts with other components of the immune system. This will not be produced by such a deposition experiment.

On the other hand, there are lots of ways to produce and screen for antibodies that can bind specific molecules. Many, but not all, are initially produced intact animals, making use of the millions or billions of antibody variants that the immune system usually screens through.
Alternatively there are now recombinant methods that can produce antibody variants which can be screened through in vitro (not in the animal).

Methods like these seem to be much more likely to produce functional and useful antibodies.
 
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  • #13
Ygggdrasil
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We now have a structure of the 2019-nCoV spike glycoprotein!

Cryo-EM Structure of the 2019-nCoV Spike in the Prefusion Conformation
Wrapp et al. bioRxiv. Published Feb 15 2020
https://www.biorxiv.org/content/10.1101/2020.02.11.944462v1

Abstract:
The outbreak of a novel betacoronavirus (2019-nCov) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for urgently needed vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure (MCM) development we determined a 3.5 Å-resolution cryo-EM structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also show biophysical and structural evidence that the 2019-nCoV S binds ACE2 with higher affinity than SARS-CoV S. Additionally we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to nCoV-2019 S, suggesting antibody cross-reactivity may be limited between the two virus RBDs. The cryo-EM structure of 2019-nCoV S should enable rapid development and evaluation of MCMs to address the ongoing public health crisis.
 
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  • #14
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We now have a structure of the 2019-nCoV spike glycoprotein!

Cryo-EM Structure of the 2019-nCoV Spike in the Prefusion Conformation
Wrapp et al. bioRxiv. Published Feb 15 2020
https://www.biorxiv.org/content/10.1101/2020.02.11.944462v1

The study has been peer reviewed and officially published in the journal Science: https://science.sciencemag.org/content/early/2020/02/19/science.abb2507

CE&N has a nice story with some background on how the group was able to so quickly solve the structure:
UT Austin’s Jason McLellan and his colleagues have spent many years studying other coronaviruses and had already figured out how to use select mutations to lock Coronavirus spike proteins into a shape that is conducive for structural studies. After they got the genome sequence of the virus, it took the team just two weeks to design and produce samples of the stabilized spike protein. After collecting data on their stabilized spike protein samples using a cryo-electron microcope, the researchers spent 12 days reconstructing the 3-D structure. They published the results on bioRXiv on Feb. 15, and the paper was rushed through peer review before being published by Science on Feb. 19
https://cen.acs.org/analytical-chem...ews&utm_medium=LatestNews&utm_campaign=CENRSS
 
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  • #15
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Couldn't we use magnetic sterling and nano dots as a way to synthesize the needed antibodies ? And how about selective methods to find the needed antibodies from the liquid what methods they use hplc ?
 
  • #16
BillTre
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Couldn't we use magnetic sterling and nano dots as a way to synthesize the needed antibodies ?

You can't make antibodies out of non-protein materials.
Something that just specifically binds something else is not going to be an antibody. Nor will it function and one.
When an antibody binds to it target antigen, the shape of the antibody changes slightly which signals other parts of the immune system to respond with secondary steps to remove or destroy the bound antigen.
This is all built into the structure of the antibody and will not be duplicated by just any molecule or nano-sized creation because it can specifically bind a particular antigen.

how about selective methods to find the needed antibodies from the liquid what methods they use hplc ?
Antibodies that bind particular antigens can be isolated from a complex mixture of antibodies (that bind or don't bind the antigen) by affinity columns.
An antigen is imobolized on the column material, the antibody mixture is added to the column and given the opportunity to bind the antigen, unbound antibodies are washed off while the bound antibodies remain attached to the column, the bound antibodies are the eluted (with solutions that disrupt their binding) and collected for later use.
 
  • #17
hagopbul
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Nano dots can't make antibodies but couldn't that nano dots function as a seed to make peptide solutions deposit needed shape ,

About the separation couldn't we use forth flotation or enhance the forth flotation technology to use it in separation of antibodies
 
  • #18
BillTre
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Nano dots can't make antibodies but couldn't that nano dots function as a seed to make peptide solutions deposit needed shape ,
How would this work?
Normally, protein production works very differently.

About the separation couldn't we use forth flotation or enhance the forth flotation technology to use it in separation of antibodies
Don't know what you are talking about here (forth flotation).
 
  • #19
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Forth flotation is a separation method used to separate fine grains of metals using bubble cavitation , and hydrophobic or hydrophilic properties it is an interesting method could we use it to separate other objects
 
  • #20
hagopbul
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There is self assembly methods we use in solid state research could we use those to arrange peptides in the needed way ?
 
  • #21
TeethWhitener
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There is self assembly methods we use in solid state research could we use those to arrange peptides in the needed way ?
No. Peptides get their shapes from inter and intramolecular forces typically on a much shorter length scale (angstroms to nm) than the self assembly methods typically used in solid state research (10s of nanometers).
 
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  • #22
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I just came around an interesting assessment:
The Harvard epidemiology professor https://www.hsph.harvard.edu/marc-lipsitch/ is exacting in his diction, even for an epidemiologist. Twice in our conversation he started to say something, then paused and said, “Actually, let me start again.” So it’s striking when one of the points he wanted to get exactly right was this: “I think the likely outcome is that it will ultimately not be containable.” ... Lipsitch predicts that, within the coming year, some 40 to 70 percent of people around the world will be infected with the virus that causes COVID-19.
https://www.theatlantic.com/health/archive/2020/02/covid-vaccine/607000/

Unfortunately I couldn't find any peer reviewed papers related to Lipsitch's opinion. The closest I got was
https://jamanetwork.com/journals/jama/fullarticle/2762028

However, if he is right, then we are talking (at the current rate of fatalities of 0.022) about 70 - 120 million deaths.
 
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  • #23
hagopbul
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Hello again

I was reading a report about Covid-19 and saw that it start in the upper respiratory system, couldn't moderate drinking and moderate smoking be some kind of effective against its spread inside the body

For example dose eating something like peacles effects it's spread inside the body

Best
Hagop
 
  • #25
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I'm finding little about adaptive immunity, vis a vis Covid 19. Despite much speculation that the virus will become endemic and join the H#N# varieties, or even become ubiquitous like the adenovirus family, there is scant data about colonization or re-infection of previously cleared or recovered victims.

Just my 2¢ worth, but as the word 'inevitable' enters our day to day conversation about the spread of Covid 19, topics of survivability and prevention ought to keep pace.
 
  • #26
pinball1970
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I just came around an interesting assessment:

https://www.theatlantic.com/health/archive/2020/02/covid-vaccine/607000/

Unfortunately I couldn't find any peer reviewed papers related to Lipsitch's opinion. The closest I got was
https://jamanetwork.com/journals/jama/fullarticle/2762028

However, if he is right, then we are talking (at the current rate of fatalities of 0.022) about 70 - 120 million deaths.
Previous post suggest containment and prevention are the best ways of controlling as opposed to synthesizing something from scratch.
Italy situation is worrying.

https://www.nytimes.com/2020/02/25/business/italy-coronavirus.html

This from the CDC on the US
https://www.livescience.com/coronavirus-spread-us-inevitable.html

@Ygggdrasil noted smoking is not a good move, alcohol though? Moderate?
 
  • #27
Ygggdrasil
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I'm finding little about adaptive immunity, vis a vis Covid 19. Despite much speculation that the virus will become endemic and join the H#N# varieties, or even become ubiquitous like the adenovirus family, there is scant data about colonization or re-infection of previously cleared or recovered victims.

Just my 2¢ worth, but as the word 'inevitable' enters our day to day conversation about the spread of Covid 19, topics of survivability and prevention ought to keep pace.

I don't think there is enough data yet about Covid-19, but based on our experiences with other coronaviruses, infection by coronaviruses can produce immunity, but that immunity is not long lasting, so people can be re-infected multiple times throughout their lifetime (as opposed to a disease like chickenpox, where getting the disease once produces nearly life-long immunity).

STAT news has a nice discussion of the possibilities of the Covid-19 virus becoming endemic, and here is the relevant section regarding immunity to coronaviruses. The full piece is worth a read, however:
“There is some evidence that people can be reinfected with the four coronaviruses and that there is no long-lasting immunity,” Dr. Susan Kline, an infectious disease specialist at of the University of Minnesota. “Like rhinoviruses [which cause the common cold], you could be infected multiple times over your life. You can mount an antibody response, but it wanes, so on subsequent exposure you don’t have protection.” Subsequent infections often produce milder illness, however.
https://www.statnews.com/2020/02/04/two-scenarios-if-new-coronavirus-isnt-contained/
 
  • #28
fresh_42
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Italy is in the news, but the other European countries are affected, too. And they said it's now on all continents. (I guess they have forgotten to mention antarctica as exception, but who knows.) On Teneriffa is an entire hotel with 1,000 people under quarantine.
@Ygggdrasil noted smoking is not a good move, alcohol though? Moderate?
Hardly. Covid-19 basically behaves like influenza, and alcohol as well as smoking reduces body resilience.

The main mean factor is the long incubation period and the fact that people can carry and spread it without being sick themselves. And symptomatic ranges between nothing and severe. China soon officially will have the world's cleanest money!
 
  • #29
hagopbul
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and alcohol as well as smoking reduces body resilience.

how alcohol can reduce body resilience ?
 
  • #31
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The journal Cell published online a report showing that SARS-CoV-2, the virus that causes the COVID-19 disease, requires a host cell enzyme for entry into cells and that clinically approved inhibitors of that enzyme can inhibit virus entry in experiments with cultured cells:

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically-Proven Protease Inhibitor
Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder, Nadine Krüger, Tanja Herrler,Sandra Erichsen, Tobias S. Schiergens, Georg Herrler, Nai-Huei Wu, Andreas Nitsche, Marcel A. Müller, Christian Drosten, Stefan Pöhlmann
Cell DOI: 10.1016/j.cell.2020.02.052
https://marlin-prod.literatumonline.../research/cell/CELL_S0092-8674(20)30229-4.pdf

Abstract:
The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor, ACE2, for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2and SARS-CoV infectionand identify a potential target for antiviral intervention.

The TMPRSS2 inhibitor they use in the paper is camostat mesylate. The drug is not FDA approved for any indications, but it is approved for clinical use in Japan. Efficacy in cell culture experiments does not guarantee that the drug will be safe or effective in humans, but at least it provides another lead to test in clinical trials.
 
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  • #32
Paul C
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Italy is in the news, but the other European countries are affected, too. And they said it's now on all continents. (I guess they have forgotten to mention antarctica as exception, but who knows.) On Teneriffa is an entire hotel with 1,000 people under quarantine.

Noting there are many reports of Covid 19 disease occurrence, You may find this an interesting resource:Coronavirus COVID-19 Global Cases by Johns Hopkins CSSE

https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6
 
  • #33
pinball1970
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Italy is in the news, but the other European countries are affected, too. And they said it's now on all continents. (I guess they have forgotten to mention antarctica as exception, but who knows.) On Teneriffa is an entire hotel with 1,000 people under quarantine.

Hardly. Covid-19 basically behaves like influenza, and alcohol as well as smoking reduces body resilience.

The main mean factor is the long incubation period and the fact that people can carry and spread it without being sick themselves. And symptomatic ranges between nothing and severe. China soon officially will have the world's cleanest money!
I did not mean as part of a well rounded diet!

I meant as a prophylactic, there was an article that suggested alcohol inhibits respiratory infection in moderate use.

I will find it and see if it based on anything substantial in my view then throw it out to you guys.
 
  • #34
fresh_42
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I meant as a prophylactic, there was an article that suggested alcohol inhibits respiratory infection in moderate use.
I doubt this very much. SARS-Cor-2 resides on our oral mucosa where it replicates. So you would probably have to gargle with high percentage rum frequently. But I don't know whether alcohol kills it. It survives for days on surfaces, i.e. it is pretty strong.
 
  • #35
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lipid nanoparticle? Any one heard of it ?
 

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