Monday, January 18, 2021

ROS (01) Insulins are ubiquitous in eukaryotes

I've had this paper lying around for years:

Role of Insulin-Induced Reactive Oxygen Species in the Insulin Signaling Pathway

Figure 4, shown below, sums up why it interests me

Brief aside: The role of glucose in generating ROS from mitochondria is, to me, extremely dubious. It certainly can occur but it needs the activation of the glycerophosphate shuttle, which doesn't get a mention. But the GPS is how we convert cytoplasmic NADH in to mitochondrially inputted FADH2, with ROS generation resulting from the raised FADH2:NADH ratio intrinsic to this conversion acting on the CoQ couple. It will apply in the presence of insulin, not isolated hyperglycaemia. If you slog through the refs trail (not good) you need to realise FBS = insulin/IGF-1. Also few people even think of fatty acids in this respect, a serious omission. Enough of mitochondria, back to the cytoplasm. End aside.

It's worth pointing out that the insulin receptor is thought to act as a G-protein coupled receptor which signals to an NADPH oxidase (probably NOX4) using a specific G protein. The NADPH oxidase generates H2O2 extracellularly (this becomes important in future posts) which re-enters the cell (some papers suggest there is a specific transporter) to oxidise cysteines on protein tyrosine phosphatases, disabling these enzymes. Without PTPases maintaining the suppression of insulin signalling both the insulin receptor and insulin receptor substrates autophosphorylate and so signalling takes off.

That's all pretty straightforward and is verging on textbook.

Nothing happens without ROS generation.

This led me down a rabbit hole, thinking about how primordial insulin signalling might be and how primordial the ROS generation might be. Is insulin core, with ROS as a second messenger? People may have noticed that the most basic signalling is what interests me.

How far back does insulin go? If we have a look at this review

Insulin-like signaling within and beyond metazoans

we can see that there is a recognisable insulin like receptor stemming from the common ancestor leading to both ourselves and sponges. That's pretty far back, marked by the blue lineage arrows in Figure 1 from the review:

Insulin signalling is thought to be present in most, but not quite all, metazoans (blue circle).

The review looks at the evidence for insulin signalling in yeasts, plants and a ciliated protozoan.

Sacchromyces has no suggestion of an insulin receptor. However it responds to exogenous human insulin with a response remarkably recognisable as the response of human cells to insulin.

Plants are more straightforward. They produce an insulin-like cysteine rich peptide which interacts with an insulin-like receptor to induce the effects typically seen in mammalian cells under insulin. In fact using this peptide on adipocytes produces exactly the same effects as human insulin.

Neither the "plant insulin" nor its receptor have anything in common with metazoan insulin/receptor protein amino acid sequences.

Except they have common "shape".  They are immuno-related. They look similar enough (shape/charge distribution) that they can be recognised by the same binding antibody.

Exactly the same findings are duplicatable in the ciliate protozoan T pyriformis as for the Sacchromyces yeast.

So. Different insulin-like hormones, different receptors. Genetically completely unrelated, but causing the cell to respond in the same way.

The simplest answer is convergent evolution, as suggested in the review. I think this is correct. But there is a deeply insightful comment towards the end of the discussion. Almost insightful enough, but ever so slightly not quite there:

"The convergent evolution of ligand-receptor pairs alone cannot explain however the biochemical similarities in the intracellular response to insulin observed outside metazoans, as illustrated above. One way to overcome this seeming inconsistency is by considering that independently evolved upstream components of pathways devoted to processing environmental information may have been tied to evolutionary conserved core metabolic and cellular growth signaling networks".

The most obvious metabolic signalling molecules which adjust core metabolic function and cell growth are the ROS.

Metazoans, plants, yeasts, protozoa; all will use ROS signals to control metabolism and growth. This is the evolutionary conserved process on to which various environmentally responsive ligands and receptors have been co-opted to respond. On at least four separate occasions. My opinion.

A eukaryote is a derivative of a bacterium living inside an archaeon. Information about archaea is remarkably thin on the ground. I expect them to use ROS. Bacteria are more rewarding once you turn to Pubmed.

Perhaps bacteria are where we should be looking to find the origin of the primordial ROS signal.


Thursday, January 14, 2021

Where the UK is heading perhaps (or not)

From January 13th 2021, early in Lockdown 3, UK.

This is Dr Mary Ramsay, head of immunisation for PHE (Public Health England, UK government). She is reiterating exactly the manifesto of the Great Barrington Declaration. I think it was April 2020 that I heard Prof Sunetra Gupta first advocate this concept. Now, in the early days of Lockdown 3, suddenly there is a voice of reason from a government department. It's echoing Vallance/Whitty from March 2020, before they both had all of their immunology knowledge, presumably with most of the rest of their brain function (sarcasm warning again) removed, sometime during Lockdown 1.

Here it is! (I can't see any way to embed and preserve Dr Ramsay's interview clip), it's in a Great Barrington Declaration tweet here

This is the text from the tweet because I always worry tweets may be ephemeral:

"Head of Immunisation for @PHE_uk -Dr Ramsey announced to the Science & Technology Committee that England may follow a focused protection strategy, where protection is given to the vulnerable and the disease is allowed to circulate among the young where its not causing much harm."

The text is true to the verbal narrative in the short clip.

While I'm on the subject of brain removals, people may be aware that daily COVID-19 deaths are currently exceeding those in the spring epidemic in the UK.

at a time when all-cause mortality is absolutely normal for the time of year, as mentioned in the last two posts. As in:

April was something exceptional. If anyone thinks December is in any way comparable to April you can head to the Funny Farm now. That's you, Prof Whitty.

Current COVID-19 death "data" are being used as an excuse for our government, particularly Matt Hancock (the UK Health Minister), to personally incite supermarket store managers to bully and harass people with mask exemptions into wearing masks in-store, if they want to buy food to eat. Apparently further measures are under consideration, god only knows what they will be.

Disgust is too mild a word.

I wonder whether Dr Ramsay will last at PHE? Perhaps the Guardian could run a hatchet job on her.


Tuesday, January 12, 2021

Just an update

Here is the right hand end of the graph from the last post, showing the partially adjusted all cause mortality for the UK in week 52:

Clearly the down tick at the end is the result of PHE struggling to adjust for the incomplete data from a week with a bank holiday followed by a week with two bank holidays. Paperwork, such as registering deaths, tends not to get done at weekends or on bank holidays.

So, theoretically, we could have had any of the red dashed line corrections:

EDIT We now have the 2021 week 2 report with more delayed registrations included. Looks like all cause mortality is now on a par with 2017/18. Still watching...


What happened when the majority (most, though not all, comes through within a week) of data were added in? On the 7th of January an update was posted so here is the original graph directly alongside the new graph. Again, ignore the downstroke:

If anyone is struggling to see the difference I've circled the important areas in red:

To put the current situation in to perspective I've pulled the curve from the last years during which we had a significant winter flu epidemic, 2017/18:

and just to make it even clearer, here's a line to show peak all cause mortality from 2017/18 vs end of Dec 2020:

It's also worth noting, again on a terribly parochial UK basis, that the winter peak in all cause mortality is almost always at the end of the first week of January. As in now, though the numbers will take a week or two to fully come in. This year may be typical, it may not. So far it's typical.

I have absolutely no doubt whatsoever that work in the ITUs (which are busy but not full, on a national basis) is hell at the moment. In hot-spots, worse. Given the level of barrier nursing needed, staff shortages because people are not allowed back to work until they eventually become PCR-ve (which can take months), social distancing within wards etc life must be awful and exhausting. 

I absolutely stand ready to accept that there is a catastrophe ongoing at the moment. It is quite possible that this winter's peak deaths will exceed that of 2017/18.

So far it hasn't.

I would suggest that the Guardian and the BBC may not be the most reliable sources of information about the current situation in the UK.

Just sayin'.


Another (as so often!) addendum:

Here are the ITU admissions for COVID-19 from ICNARC (which I consider to be unbiased reporting) up until just before Christmas:

which looks pretty grim, despite UK ITUs being at under 100% occupancy. But these are just COVID-19 patients. I don't have a similar curve for non-COVID-19 patients, but I do have this graph which includes both groups (and the rest of England), should they go on to die:

The last column is too low in both death categories due to delayed reporting, as always.

It's quite clear that for every death from COVID-19 there is nearly one less death from anything else. It could be that the virus is so lethal it is impossible to die quickly enough from anything else before it gets you.

Or it could be that managing to get a SARS-CoV-2 PCR-ve death certificate is becoming harder and harder to achieve in a hospital setting when PCRs are still being run to 45 cycles during a winter of endemic COVID-19.

Monday, January 04, 2021

Sarcasm Warning

Thank goodness for the lockdowns in 2016, 2017 and 2018. What would have happened without them?

Edit, corrected the dates on the image, apologies. Mea culpa. End edit.

The real, un-scribbled-upon data from Public Health England are here:

Please, please, please be aware that the week 52 data are only ESTIMATED.

The real value might be higher. Equally, it might be lower.

Hat tip to Mike Yeadon.


An afterthought: How do you explain the 2020/21 curve?

I don’t know. However: most “COVID-19 on the death certificate” deaths occur in hospitals and are reputed to be registered very promptly compared to community deaths. There is a massive need for the numbers of COVID-19 fatalities in the current situation, the government needs (and demands) these numbers fast to drive policy. This will inflate the uncorrected data through early December. However non-COVID-19 deaths are currently massively and exceptionally below normal for the time of year and these will only be incorporated in to the data more slowly than the rapidly registered COVID-19 deaths. So through early December the overall value has been correctly reported as being higher than normal because the low number of COVID-19 negative fatalities from the community (or even from hospitals) aren’t yet included. Now they are now coming in. I doubt PHE are remotely interested in assimilating this anomaly in to their estimating process (which will be based on previous years normal delay patterns of registration) but eventually the EuroMoMo absolute death data will have the truth out. Not that it will make any difference.

Why are non-COVID-19 deaths so low? People, sadly, die in some excess during the Winter. If you are hospitalised for anything at all leading to your death, the chances of you reaching your end without achieving a +vePCR test are very low. You will be a COVID-19 death and so you will be missing from other datasets.


End afterthought.