Archive for the ‘ACE-2’ Category
an interminable conversation 9: some basic physics
yer most basic sine graph
Jacinta: So it’s time for us oldies to go to school, and get into physics from scratch, including the maths.
Canto: Yes, we’re not going to go all historical this time, much as we love all the nerdy characters to be encountered, instead we’re going to go with the concepts, from simple to complicated. I’ve found a collection of videos, called ‘crash course physics’, and we’re going to follow the ineffable logic of the presenter, Dr Shini Somara, to reach the pinnacle of sagesse en physique. Starting with basic motion in a straight line.
Jacinta: Exciting. I’ve done that. But in this first episode she deals with cars and acceleration, inter alia, including its maths. Equations! Time, position, velocity and acceleration will be explained/analysed in simple terms for this starter.
Canto: Kinematic equations – we’re going to the Kinema! So, motion in one direction on a straight line. You’re stopped at a red light, and then put your foot on the accelerator when it goes green. Seven seconds later (precisely), there’s a siren behind you – a police car is asking you to stop. They give you a ticket for speeding in a 100kph zone.
Jacinta: So, in 7 seconds you’re up to more than 100kph? I know nothing about cars but that’s – unusual? Is it?
Canto: I’m sure car nerds can tell us, but so can google. There are plenty of cars that can get to 100 in less than 4 secs, even less than 3. Supposedly. Anyway, you’re doubtful about the police claim, but you can’t be sure, your speedometer is stuffed. How can you challenge the police claim, using maths?
Jacinta: You can’t, and anyway in Australia you’d be defected for a stuffed speedo.
Canto: But this is the USA, the land of shitty libertarian laws. So you’re travelling in one direction, one-dimensionally, so to speak. So the key variables here are the afore-mentioned time, position, velocity and acceleration. We also have to bear in mind change in position, aka displacement, which could have a positive or negative value – in this example, clearly positive. Now, velocity is about how that displacement occurs over time. It also can have a positive or negative value. Acceleration is about changes in velocity over time. You can feel that change – positive or negative – when you’re ‘thrown’ forward or backward on acceleration or braking.
Jacinta: So Dr Somara presents graphs that are fairly easy to read for a stationary vehicle, and one moving at a constant velocity. The vertical x-axis measures position or displacement in metres from an initial position, the y axis measures time. A stationary vehicle will show a straight horizontal line from the moment it stopped until it starts to move again. Constant velocity will show a straight line moving diagonally along both axes. An accelerating vehicle will of course show a curving line, curving up to the vertical, while a decelerating one will be curving to the horizontal.
Canto: So that’s a simple position v time graph, now to look at velocity and acceleration slightly differently, with velocity in metres/second on the vertical axis and time on the horizontal, and with acceleration in metres per second per second, that is, metres per second squared, on the vertical axis, and time, in seconds, on the horizontal. So this relates all our variables, time, position, velocity and acceleration. Average velocity is the change in position over time, and acceleration is the change in velocity over time. To get average velocity you divide change in position by change in time.
Jacinta: But as Dr Somara says, subtraction is also a feature – to find out ‘change’ you subtract initial value from final value, which sounds right but somehow seems to contradict the previous….
Canto: One’s talking about a change, the other about an average. They’re quite different. So the change in a particular value, or variable, is symbolised or abbreviated as delta, ∆. So, v = ∆x/∆t, average velocity (the v should have a bar above it, but I haven’t learned how to do that – will I need an extra keyboard?) equals change in position over change in time. For Dr Somari’s example, the car moved from 4 metres to 13 metres (the change in position), i.e. a value of 9 metres for ∆x. This occurred over 3 seconds, apparently, which divides as 3m/sec for average velocity over that period. But of course the car was accelerating during that period. The equation for acceleration is a = ∆v/∆t, for average acceleration.
Jacinta: Okay, and we can, apparently handily, rearrange the equation to get v(average) = v(at time zero) + at. This equation is called the Definition of Acceleration. Tadaaa! Constant acceleration is equal to the change in velocity divided by change in time. This is the first of the two main kinematic equations, which links velocity acceleration and time.
Canto: Okay now our physicist turns to gravity (g), which here on Earth is a force causing acceleration at 9.81 m/sec squared. But then she talks about the second kinematic equation, the Displacement Curve, which involves acceleration, starting velocity and time in order to calculate displacement:
x(position) – x(at time zero, initial position) = v(initial velocity)t +1/2a(acceleration)t(squared).
All of which looks very messy because I haven’t learned how to do the proper notation. Anyway this links acceleration as change in velocity to velocity as change in position. Right?
Jacinta: Uhhh, yeah. And the other kinematic equations, we’re assured, are just rearrangements of this dynamic duo. So apparently this takes us back to our speeding issue at the start. The initial velocity was 0, the time was 7 seconds. The displacement curve²equation/formula can be used to work it all out, or at least the acceleration. Our physicist tells that x – x (initial position) is 122 metres, which equals initial velocity (zero) multiplied by 7 seconds (which must surely be zero?) plus I/2a (which is to be found) multiplied by 7s squared, which is 49 seconds. So 122m = 0 + 49 (49) multiplied by half the acceleration, which by calculation I discovered to be close to 2.5, so the acceleration was approximately 5 metres per second squared.
Canto: It works out! And, following our expert, we can use the Definition of Acceleration formula to arrive at final velocity. It’s basically V + at, or 0 + 5 X 7, so a speed of 35 m/sec, which in km terms is about 126 km/h. Amazing! We got the maths. There is hope!
Jacinta: Well they’re diving into the deep end with crash course physics, as the next video is all about calculus and derivatives. About which I have no idea.
Canto: Yes, maths are the basis of physics, and we lost contact with complex maths decades, though I’m quite good at multiplication. But calculus, duh. Though our teacher tells us that it’s all just about accurately describing change.
Jacinta: Important – she goes on to explain things called derivatives, but I note in the inset:
Not all equations have derivatives! When we say ‘equations’ here, we really mean a function – an equation with only one output for each input. More specifically, we’re talking about functions that have derivatives.
I’m looking forward to clarification of all that.
Canto: So calculus explains the why’s and wherefores of change through derivatives. She also mentions integrals early on, as ways of calculating area under a curve – which we actually mentioned in those terms in a previous post.
Jacinta: We sound smart sometimes. So, derivatives. Dr Somara returns to the car and speeding example. The car drives off after the police incident, accelerating of course. But we don’t have a direct measure of the acceleration, but we know positional change over time. This is apparently equal to amount of time driving, squared, X = t². After 20 secs of driving, some kind of roadside ‘detector’ reveals the car’s speed. The driver takes time to register that she’s going even faster than 126 mph.
Canto: Dumb blond? Maybe not, maybe the detector is dodgy. How to find the velocity at the moment she passes it? Which, according to Dr Somara is the derivative of her change in position. And this is also about limits. These are key ideas:
Limits are based on the idea that if you have an equation on a graph, you can often predict what it’s going to look like at one point, just by knowing what it looks like at the surrounding points.
Jacinta: So our teacher gives the example of graphing x = t² when t approaches the limit of 0. So remember we have our time on the horizontal, and distance covered (or displacement, or positional change – it seems ‘distance’ is a no-no in this maths) on the vertical axis. So, moving back to zero from t=1 and x=1 she finds that when t=0.5, x=0.25, and when t reaches 0.1, x=0.001, so both values approach zero. This apparently shows what happens when you make intervals smaller. Another definition:
An interval is just a range on a graph. It’s the space between two points on the horizontal axis.
Of course, because that’s the time axis, generally. This is great parroting, but then when parrots copy their trainer perfectly they’re regarded as brilliant.
Canto: So we’re calculating the average velocity over a particular interval – from 15 to 20 secs. We use the equation v = ∆x/∆t (∆x is change in position, ∆t is change in time). The change in position, after subtraction, was 175 metres, the change in time 5 secs. So the average velocity works out as 35 m/sec. But this is only an average, and doesn’t take into account acceleration. But using limits gets us closer to the number we want. You can calculate your average over increasingly small intervals to arrive at an increasingly accurate figure.
Jacinta: So, sticking with our teacher, velocity is an equation that describes change in position, acceleration describes change in velocity. Velocity is thus the derivative of position and acceleration is the derivative of velocity. This is expressed in writing, using, for example, the power rule, expressed using variables and their numbered exponents. So x = t² is an equation that works here. To calculate the derivative, you take the exponent, 2, and put it in front of the variable, and subtract 1 from the exponent, and that’s the derivative, 2t. In full, the derivative of x = t² is 2t.
Canto: That’s a trick, as Dr Somara said, but it’s not really explained. She says ‘no matter how [you’re accelerating], your velocity will be 2t – double the number of seconds’. So I think it depends on those seconds. After 5 seconds, say, you’re travelling at 5m/sec, but after 20 secs, your speed is 40m/sec. So dx/dt = 2t ‘which is just a way of saying, mathematically, we’re taking the derivative of x with respect to t’. But it’s also written differently sometimes: if f(t) = t², then f'(t) = 2t. And I’m guessing that f stands for function, but I don’t quite know what a function is.
Jacinta: A function is:
in mathematics, an expression, rule, or law that defines a relationship between one variable (the independent variable) and another variable (the dependent variable). Functions are ubiquitous in mathematics and are essential for formulating physical relationships in the sciences.
That’s from Britannica online. So to continue, if f(t) = t², then f'(t) = 2t. That’s to say, f prime (t) = 2t, according to our teacher, who doesn’t explain ‘prime’. Do we have to do a maths course before we do this physics course? Does it have to do with prime numbers?
Canto: Apparently not. The symbol can serve a number of purposes in maths. Let’s just leave it for now. Using the power rule we can find other derivatives, e.g. x = 7t to-the-power-6. This equation has the variable t, and its exponent 6. We take the exponent and put it in front of the 7t variable, multiplying the number and subtracting 1 from the exponent, 42t to-the power 5. That’s to say dx/dt = 42(t to the power of 5). But maybe that shouldn’t be bracketed. And when the exponent is a fraction or decimal, the derivative of, say t to the power of one half is 1/2t to the negative one half. You always minus one, I don’t know why.
Jacinta: Ours is clearly not to reason why, at least not yet. This derivative trick works for negatives too. In the case of x = t to-minus-2, the derivative (dx/dt) = -2t to minus 3. Not very comprehensible, and then she mentions the dread word, trigonometry, used for calculating triangles, their angles and sides. Apparently physics uses right-angled triangles a lot. We shall see.
Canto: Indeed, let’s get into it. The derivatives of sine x and cosine x. If you have a right-angled triangle with an adjacent angle x, sin(x) = the length of the opposite side divided by the hypotenuse. For cosine, cos(x) it’s the length of the adjacent side divided by the hypotenuse. So, sin(x) = o/h, cos(x) = a/h. ‘So the graphs will tell you what those ratios will be, depending on the angle’.
Jacinta: I’m not sure if I really understand this, but let’s move on into further weird territory, in which sin(x) is plotted on a graph going from -360° to 360° on the x (horizontal) axis (that’s the ‘phase’, in degrees) and -1 to 1 on the y axis. At x = -90° and x = 90° the curve turns – that’s at every 180°. At those points the equations aren’t changing and the derivative is zero. Between the points the derivative oscillates from positive to negative. That derivative is in fact cos(x). I’m not sure why, but the derivative of cos(x) is -sin(x), the derivative of -sin(x) is -cos(x) and the derivative of -cos(x) is sin(x), for future reference. I’m hoping it’ll all become clear some day. Graphing all these will provide the proofs, evidently.
Canto: Yes, so Dr Somara finishes off this vid with another derivative that’s important in calculus, e×, the derivative of which is also e×, always. e, like π, is an irrational number which is quite vital to calculus, apparently. And even finance. Can’t wait to find out. So with the preceding we can, supposedly, take any equation for position and calculate the derivative, and so, velocity. And for velocity, your acceleration. Using integrals, which we’ll soon learn about, we can go backwards from acceleration to velocity, and from velocity to position. Presumably that will be next time.
Jacinta: So easy…
References
covid19: monoclonal antibodies, symptomatic v asymptomatic, corticosteroids, comorbidities
keeping it simple, for now
Jacinta: Let’s look at monoclonal antibodies briefly before we continue with those medcram updates. Francis Collins, the somewhat controversial but scientifically reliable directer of the NIH in the USA, recently described ‘monoclonals derived from people who’ve survived covid19’ as the best hope for treatment in the absence of a vaccine. So what are these monoclonals? There are lots of useful videos on youtube that provide detail. I’m picking one from the JAMA network. The technology for producing these types of antibodies was developed in the mid-seventies. It was called ‘murine hybridoma’ technology, murine meaning ‘mice’. I remember first reading about monoclonal antibodies in a Scientific American article in the early eighties. It went straight over my head of course, but now it’s time to get a grip on them. So mice were injected with an antigen, which in general terms is a pathogen that induces an immune response. In more specific terms an antigen is a molecule or structure, part of a larger pathogenic molecule, that can be bound to by an ‘antigen-specific antibody’ or B cell receptor. B cells are lymphocytes that secrete antibodies. So the researchers induced this response, then isolated B cells from the spleen of the mice, which they fused with myelomas (cancerous plasma cells). Cancer cells are notoriously long-lived – see ‘the Immortal Life of Henrietta Lacks’ – so these fused cells, called ‘hybridomas’, act like B cells in producing antibodies, and like tumour cells in their ability to replicate. So these hybridomas can be grown in culture and each one can produce a single antibody type, which targets a single antigen type. Hence monoclonal. They can clone themselves for a specific antigen. So, once you know your antigen, you can create a ‘monoclonal’ specifically for it, or two or three to choose from. And now, with covid19 and with technological development, we can isolate monoclonal antibodies not from mice but from recovered covid19 patients. So that’s a somewhat over-simplified account – for more detailed info on monoclonal antibodies, this zero to finals video is excellent, and there are doubtless others. The target for this work is generally the S-protein of the SARS-CoV2 virus, with various particular sites being looked at, and a number of teams working on the research. Some are pretty well ready to go, with specific antibodies or sets of antibodies. The argument is that they could be used for high-risk groups such as ICU workers and nursing home clients, as a kind of temporary vaccine.
Canto: Okay, something else to keep track of. So update 93 discusses an article published in Nature Medicine – all the authors appear to be Chinese – which looks at 37 asymptomatic covid19-infected subjects and their antibodies, compared to those of 37 symptomatic subjects.
Jacinta: So they looked at their immunoglubulin G (IgG) levels. These are the most common types of antibody, created and released by plasma B cells. They graphed the IgG during the acute and convalescent phases, and they defined the acute phase as that in which the viral RNA was detectable in a respiratory specimen, and the convalescent phase as from eight weeks post-release from hospital. What the graph shows is that the IgG levels decreased from acute to convalescent in both symptomatic and asymptomatic cases, but more in the symptomatic cases. They also looked at ‘neutralisation rates’, which presumably refers to the effect of antibody activity. A positive effect means more neutralising antibodies are produced. These seemed about the same between the phases for both groups, but another graphic shows that in the convalescent phase, the symptomatic group have substantially more neutralising antibodies. It seems from this admittedly small study that asymptomatic subjects are at risk of reinfection, after a period of time.
Canto: And even symptomatic subjects after recovery, as we have obviously no longitudinal studies on anti-viral IgG levels, as the study points out.
Jacinta: Well that takes us to the next study, from Spain, which managed to round up almost 52000 participants. The study tells us between late April and mid-May the estimated seroprevalence (the percentage of inhabitants that had the virus) for the whole country was around 5%, depending on different test types and results, and with great variation between regions. Findings were that prevalence increased with increasing age. Looking at different jobs, those working in healthcare were clearly more at risk, and to a lesser but still significant degree, those working in nursing homes…
Canto: Which is still largely healthcare, but less trained, and often less prepared for this onslaught…
Jacinta: Point taken. And those living in the larger municipalities were more often infected than those in less densely populated regions. Interestingly, they found that the rapid (and cheap) fingerpoint test, which provides results within ten minutes, was pretty close to being as effective as an immunological assay, which is important as the delay in test results has been a major issue.
Canto: Amazing. Why aren’t they using this all the time? Everywhere?
Jacinta: That’s another issue – maybe later. Anyway, much of this study confirms the many smaller studies that have been conducted. They found that healthcare workers comprised 24% of all confirmed cases. This may be partly because they had more access to testing. There is so much to glean from this study, I can only skim. But here are some very interesting remarks in their conclusion:
One in three infections seems to be asymptomatic, while a substantial number of symptomatic cases remained untested. Despite the high impact of covid19 in Spain, prevalence estimates remain low, and are clearly insufficient to provide herd immunity. This cannot be achieved without accepting the collateral damage of many deaths in the susceptible population and overburdening of health systems. In this situation, social distance methods and efforts to identify and isolate new cases are imperative for future epidemic control.
Canto: So there are no easy solutions, and even a vaccine is not necessarily going to be the magic bullet everyone’s hoping for. The proof of the pudding will be in the eating, and we haven’t eaten any vaccines yet. They won’t be on the menu for a while, and it’ll be a lot longer before we can gauge their nutritional value.
Jacinta: Yes, what you’re saying is, we don’t know how long antibodies to this virus will last. We’re still in unexplored terrain with respect to this very unusual and deadly virus. An article published on the Jama Network quite a while ago is still relevant now in its conclusions, as nothing we’ve so far found disconfirms it:
… the immune response to covid19 is not yet fully understood and definitive data on post-infection immunity are lacking. Amidst the uncertainty of this public health crisis, thoughtful and rigorous science will be essential to inform public health policy, planning and practice.
Canto: Frustrating to many. So with update 94 we’re getting towards mid-July and they’re noting that things are hotting up, as the weather is cooling down, in Australia, though of course it bears no comparison to the US tragedy. They were talking about things getting worse in their autumn, but summer hasn’t given them any sort of break.
Jacinta: So update 94 first looks at inhaled corticosteroids, one of many medications being considered and perhaps used by health professionals, others being ivermectin (a broad-spectrum anti-parasitic drug) and nitric oxide, all without solid RCT-type evidence. Even so, case reports and other low-level studies show promise, and these are arguably desperate times. A study presented by Dr Seheult suggested that some corticosteroids showed positive immunological effects in case reports and in vitro. Interestingly, asthmatics have been prescribed corticosteroids quite regularly…
Canto: As have I, from time to time. At least I think it was corticosteroid…
Jacinta: Well, that’s interesting, I know you’re not asthmatic but with bronchiectasis you have asthma-like symptoms at times. And the good news for you, and generally interesting news for us all, is that ‘asthma patients with covid19 do not appear to have a higher rate of hospitalisation or mortality compared with other covid19 patients’. Indeed it may be the opposite, as data from Wuhan indicates that less than 1% of their hospitalised patients had asthma, compared to 5% in the general population. In New York, too, asthma wasn’t even in the top ten comorbidities, which is pretty striking for a virus that hits the lungs first. Similarly, COPD, which your ailment is surely associated with, comes in below diabetes, renal disease and a whole range of cardiovascular issues as a comorbidity factor. A possible reason for this is that the kind of chronic inflammation produced by asthma and COPD is associated with reduced ACE2 expression, meaning fewer receptors for the virus. So these conditions could actually be protective. And they might also be on corticosteroid inhalers, which may also be protective.
Canto: That sounds great. Let’s leave it there before I hear any bad news…
References
Coronavirus Pandemic Update 93: Antibodies, Immunity, & Prevalence of COVID-19 – New Data from Spain
Coronavirus Pandemic Update 94: Inhaled Steroids COVID-19 Treatment; New Pneumonia in Kazakhstan?
How do monoclonal antibodies work? Rituximab, infliximab, adalimumab and others
Coronavirus Treatment and Prevention with Monoclonal Antibodies
more on oxidative stress and covid-19
So, much of this piece will rely on Dr Seheult’s coronavirus update 65. We have this constant set of reactions in the body that reduce oxygen – adding electrons – until we get to water molecules, producing reactive oxygen species (ROS) along the way. This is often described as the oxygen metabolism process. Reactive oxygen species come essentially in three types, superoxides, hydroxy radicals and hydrogen peroxide. The three forms of the enzyme SOD, superoxide dismutase, convert superoxide into oxygen and hydrogen peroxide (H2O2), and then the H2O2 is reduced to H2O by means of glutathione peroxidase (GPx). The GPx, which is broken down in the process is recharged by the enzyme glutathione reductase (GR), which is in turn recharged by other antioxidant products. Also the enzyme catalase, which requires iron, can break H2O2 down into O2 and H2O.
People with diabetes, hypertension and overweight issues, among other things, may have compromised antioxidant systems (too many ROS), linked to angiotensin-converting enzyme 2 (ACE-2) and angiotensin-2. In creating ROS, oxygen is reduced to superoxide by means of the enzyme NADPH oxidase. So, as part of the renin-angiotensin system, angiotensin-2 (AT-2) is converted to angiotensin 1,7 (AT-1,7) by means of angiotensin-converting enzyme 2 (ACE-2). This is important because AT-1,7 effectively blocks superoxide production, while AT-2 promotes it. The virus SARS-CoV2 binds with, and so inactivates, ACE-2, preventing the production of AT-1,7. This action also means that there will be more AT-2 available, and so more superoxides. SARS-CoV2 also, according to Seheult, causes inflammation by recruiting polymorphonuclear neutrophils (PMNs), which stimulate production of superoxides by means of NADPH oxidase. So this, in essence, is why Covid-19 is bringing about oxidative stress.
Seheult next goes on to look at the research evidence for the preceding. A review article from 2005 points out that evidence from animal studies and cell culture studies shows that NADPH oxidase-derived oxidative stress is increased in vascular cells by AT-2, among other ‘agonists’ (chemicals that bind to receptors, thereby producing a response). Another article from 2012 describes several enzyme systems that act to form ROS, including ‘mitochondrial electron leakage from the electron transport chain’ as described in my previous post on the subject, and in Seheult’s update 63. It points out that ROS levels can rise dramatically in older people suffering from oxidative stress due to heart issues such as ischemia-reperfusion (referring to problems with oxygenated blood supply to the heart or other organs). It also points out that it has been shown experimentally that AT-2 stimulates an increase in ROS. A more recent article pertaining to SARS-CoV2 looked at patients in Wuhan and found a substantial increase in neutrophils in the most severe cases. Neutrophils cause ROS to be generated by NADPH oxidase. So Dr Seheult is carefully building up evidence for the case. The last point to deal with is AT-1,7 effects. Seheult has found a 2008 article entitled ‘Angiotensin converting enzyme 2 confers endothelial protection and attenuates atherosclerosis’. Seheult quotes the last line from the abstract:
These data indicate that ACE-2, in an AT-1,7-dependent fashion, functions to improve endothelial homeostasis via a mechanism that may involve attenuation of NADPHox-induced reactive oxygen species production. ACE-2-based treatment approaches may be a novel approach to limit aberrant vascular responses and atherothrombosis.
Atherothrombosis involves disruption of atherosclerotic plaques, which can be an immediate cause of heart attacks. Another article from 2015 essentially confirms the findings, as indicated by its title, ‘ACE-2 and AT-1,7 protect endothelial cell function and prevent early atherosclerosis by inhibiting inflammatory response’. A more recent article, from January 2020, describes how AT-1,7 administration improves endothelial function in women who have suffered from preeclampsia (vasoconstriction, high blood pressure and organ damage due to pregnancy). To give more detail, women in the last stages of pregnancy often suffer vasoconstriction and high protein levels, which is believed to be related to AT-2 levels. Researchers administered local AT-1,7, which is ‘an endogenous inhibitor of... AT-2′, to see if this reduced vasodilation and other symptoms of preeclampsia. What they found was that ‘AT-1,7 increased endothelium-dependent vasodilation via nitric oxide synthase-mediated pathways and attenuated AT-2-mediated constriction in women who have had preeclampsia, suggesting that AT-1,7 may be a viable therapeutic target for improve d microvascular function in women who have had a preeclamptic pregnancy’.
All of this is interesting in itself, of course, and is a little crash course in how research is helping us to tweak our immune systems, but in relation to Covid-19 these finding are of importance due to the comorbidities and general characteristics of patients being hospitalised with Covid-19. Dr Seheult, in his update 65 video, shows that, contrary to what was initially thought, i.e that Covid-19 is primarily a virus affecting the lungs and respiratory system, it may be much more of a problem for those with hypertension, cardiovascular issues and obesity – all of which are related to oxidative stress, as are diabetes and many forms of cancer. They contribute to endothelial dysfunction, which inevitably leads to oxidative stress, and may lead to thrombosis. Seheult here refers to a lengthy 2018 review article, ‘nutrients and oxidative stress: friend or foe?’, which among other things makes useful dietary suggestions for the combatting of oxidative stress – whole grains, nuts, fruit and vegetables, fish and legumes.
It’s been known for some time that endothelial cell dysfunction (ECD) can lead to thrombosis, as it is a major function of these cells to prevent thrombosis. The abstract from a 2002 study finds that ECD ‘is associated with decreased synthesis and oxidative inactivation of nitric oxide (NO)’ and it lists four types of antioxidant enzymes ‘essential for eliminating ROS that can inactivate NO’. It seems that the promotion of these enzymes can be associated with diet as above and with the reduction of risk factors such as hypertension, hypercholesterolaemia (high blood cholesterol), hyperhomocysteinaemia (homocysteine is an amino acid which can contribute to arterial damage and blood clots, and the condition is often associated with lack of vitamin B-12 or folate), cigarette smoking and diabetes mellitus. NO is the key molecule in maintaining endothelial function through these enzymes.
Now I’m having a look at Dr Seheult’s update 66 on blood pressure medications known as ACE inhibitors or ARBs. He cites an editorial article for the New England Journal of Medicine, on ‘inhibitors of the renin-angiotensin-aldosterone system and Covid-19’. This is a triple hormone system responsible for blood pressure regulation and fluid balance. Now, to return to what was outlined before, angiotensin-2 (AT-2) is converted to AT-1,7 by an angiotensin-converting enzyme (ACE-2). The SARS-CoV2 virus binds to the ACE-2 receptor and inhibits the enzyme’s production. This is problematic because AT-2 stimulates superoxide production (that’s bad), while the antioxidant AT-1,7 blocks it, so reducing oxidative stress. SARS-CoV2 also stimulates the production of PMNs, as above, which activates oxidative stress. Another part of this picture is that AT-1 is converted to AT-2 by ACE. There are blood pressure lowering medications, such as benazepril and lisinopril, aka ACE inhibitors, which reduce the production of AT-2. There are also angiotensin receptor blockers (ARBs), which may up-regulate ACE-2 (it isn’t clear, apparently). ACE inhibitors may do the same. The question being asked is, assuming these medications produce more ACE-2, will this lead to more infections because SARS-CoV2 has more ACE-2 to work with? Clearly it would be important to know whether to maintain these medications or not, that’s to say, whether these medications are a risk factor for contracting the virus or recovering from it. The above-mentioned article discusses three studies from different parts of the world, each involving thousands of participants. They all found no risks associating ACE inhibitors and ARBs with a higher risk of infection, severity of illness or death from Covid-19. One of the studies found that ACE inhibitors and statins were associated with a decreased risk of mortality, but these are observational studies and further research would need to be done.
So the above is a rather technical piece, highly reliant on the experts. I write to inform myself, and I’ve certainly been informed by writing this one. Apologies for its laboriousness, but I’ll be continuing… Please consult the references yourself if there’s anything you don’t understand.
References
Coronavirus Pandemic Update 65: COVID-19 and Oxidative Stress (Prevention & Risk Factors)
Coronavirus Pandemic Update 66: ACE-Inhibitors and ARBs – Hypertension Medications with COVID-1
Covid19: world progress, cytokine storms, our plans
Canto: So while we need to be worried about – and to know something about – the cytokine storm that the Covid19 infection can lead to (and we’ll learn about that soon), there’s also a storm of activity on the SARS-CoV-2-fighting front.
Jacinta: Yes, intravenous zinc was talked about in the Medcram series as an effective tool in fighting viral pneumonia, and a world-first trial is being conducted by Austin Health and Melbourne University to test its effectiveness for Covid-19 sufferers with respiratory problems. We’re still catching up on the Medcram series, and update 52 talks of the drug ivermectin, already on the WHO list of essential medicines. The WHO website, incidentally, is promoting a ‘solidarity’ clinical trial for Covid-19 treatments, involving, singly or in combination, remdesivir, hydroxychloraquine, lopinavir, ritonavir and interferon beta-1a. So that gives some idea of the work that’s going on to fight symptoms and reduce the death rate.
Canto: And, you know, I’ve been feeling guilty about singling out the USA as the worst-case scenario all round. It’s not actually so. It’s not fair to look at total figures and point out that the USA tops the list for Covid19 fatalities, and draw calamitous conclusions. You have to take into account its much larger population compared, for example, to number two on the list, Spain. The US has suffered about 2.5 times the fatalities of Spain, but it has about 7 times the population. In fact, if you look at fatalities as a proportion of population, there are many countries worse off than the USA – namely Spain, Italy, France, the UK, Belgium (the worst hit), the Netherlands, Switzerland, Ireland and Sweden. All European countries, notably.
Jacinta: Yes and I’m sure they’ll all have their particular stories to tell about why this is happening to them, and will be wanting to learn lessons from Taiwan, Hong Kong, South Korea, and even our big faraway island, but I really want to look at solutions, in terms of eradicating the virus, or blocking it, or building up our immunity. Having said that, flattening the curve, and reducing fatalities, is a primary focus, which means continuing the physical distancing and looking for ways to keep economies running while this goes on. In spite of patches of civil libertarian activity here and there, the vast majority of our global population is on the same page with this, I think.
Canto: Well I’m looking at an Axios article from the Johns Hopkins website. It compares global performance under Covid19 to a mock pandemic exercise, Event 201, conducted some six months ago. They’ve found some positives and some negatives in their analysis. Positives – a greater degree of compliance with physical distancing measures than expected, ‘the degree of surge capacity augmentation in the health care system which has been possible’, and the rapid growth of international collaboration among scientists, leading to a quickened progress of trials for possible treatments. Negative – disparate and often contradictory messages from authorities – mostly political authorities – leading to confusion and distrust of governments and other institutions. This is partially explained by the complexity of the virus itself, which has made it difficult to characterise to the general public, and to be fully understood by non-medical authorities, such as political leaders.
Jacinta: It’s a weird situation, as there’s no end in sight, everyone’s worried about ending restrictions too soon, yet everyone’s worried about the economy, and those countries, like Australia, that are heading towards winter, are bracing for heightened problems, while northern hemisphere countries are hoping for summer’s relief but worried about the autumn when it might be hard to cope with a second outbreak, should it come. And medicos are warning that expectations of a vaccine in eighteen months might be overly optimistic. But I want to be optimistic – I want to look at anything that’ll reduce symptoms and save lives. One treatment, among many others it should be noted, is hydroxychloraquine, which is being given so much of a bad press, because of its being over-hyped by a Trump administration intent on getting political points for a silver-bullet cure. There have already been a number of small, less-than-gold-standard studies, some in which the drug is combined with the antibiotic azithromycin, and the results appear to be all over the place. We’re still awaiting the results of randomised, placebo-controlled, double-blinded studies, which are under way.
Canto: I note that a couple of reports on chloraquine and hydroxychloraquine on the JAMA website have been taken down, I suspect because of all the politicising. That’s a shame. Anyway I mentioned the cytokine storm at the beginning of this post, so I’ll try to comprehend it. A clue to the meaning comes in this mid-March article on the Lancet website. In an early sentence it mentions ‘cytokine storm syndrome’, and in the following sentence refers to the treatment of ‘hyperinflammation’. It seems the two terms are interchangeable. Another term, in the very next sentence, is ‘a fulminant and fatal hypercytokinaemia’….
Jacinta: Sounds like they’re just showing off.
Canto: Please don’t say that about our frontline covidtroops. Okay, a better site for understanding cytokines and their storms is this from New Scientist. As we’ve guessed, it’s an over-reaction of the immune system, sometimes fatal. Cytokines are small proteins, produced throughout the body, which trigger inflammation as an immune response. Sometimes the intensity of the cytokine response results in hyperinflammation. So you might say the cytokine storm is the cause and hyperinflammation the effect.
Jacinta: So this raises questions. For example, why do some have what seems an over-production of these cytokines and others don’t, in response to SARS-CoV-2 in particular? And what do these cytokines actually do to cause inflammation?
Canto: You’re asking me? Well, it’s conjectured that younger people don’t have the developed immune system that produces all these cytokines, and that’s why you don’t see symptoms. But that raises the question – do others have over-developed immune systems, but maybe only for this particular virus? Is there a general goldilocks level?
Jacinta: And is there a way of distinguishing between those who succumb to the hyperinflammation, which in turn can cause acute respiratory distress syndrome (ARDS), and those who succumb to the virus itself? Or is it always the immune response that does people in?
Canto: I don’t think so. If the immune response doesn’t work at all, I suspect the virus will spread like a cancer to the rest of the body?
Jacinta: That can’t be right. That’d mean those kids who don’t suffer the cytokine storm, or any immune reaction, would remain infected until it spread through their bodies and they dropped dead. That definitely isn’t happening.
Canto: No, you’re right – they’re developing antibodies, presumably, (and that’s a whole other story), without going through much in the way of suffering. In fact, children’s apparent immunity to the virus is something of a mystery that demands further research. If everyone could develop that kind of immunity…
Jacinta: So many questions we can’t answer. I mean, not just the myriad questions we, as dilettantes and autodidacts, can’t answer, but the fewer but many questions epidemiologists, virologists and ICU workers can’t answer. But I propose that we continue to try and educate ourselves and explore, in our feeble but earnest way. I propose that we dedicate this blog, for the foreseeable, to exploring terms and conditions, so to speak, and treatments, such as ‘cytokine’, ‘ACE-2’, ‘hypoxia’ and ‘quercetin’ and how they relate to or are affected by the Covid-19 infection. Like putting pieces together in a jigsaw puzzle, sort of. It might help us being overwhelmed by the whole picture.
Canto: Okay, let’s try it.
References
Coronavirus pandemic update 52, Medcram youtube video
https://coronavirus.jhu.edu/news
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30628-0/fulltext
https://www.newscientist.com/term/cytokine-storm/
https://www.centerforhealthsecurity.org/event201/
https://jamanetwork.com/journals/jama/pages/coronavirus-alert
Covid 19: How the SARS-CoV-2 virion does its thing
Canto: We’ve been lapping up the excellent Medcram series of videos on the pandemic, and we’re now at episode 32 I think, from March 6, and a week’s a long time in Covid-19-world.
Jacinta: Yes and back then the largest number of confirmed cases outside of China was in South Korea, and that, I now understand, was largely because of the massive testing they’d engaged in – so elsewhere the infection was being under-reported, or barely known about.
Canto: And today, April 23, South Korea has dropped down to 27th on the list of reported cases. Interesting to note that by March 6 South Korea had tested some 140,000 people, almost 100 times more than the USA had done. As we know, the CDC had stuffed up by producing a flawed testing kit, which resulted in crucial delays.
Jacinta: And weren’t the South Korean tests more effective? They used a different type of test didn’t they?
Canto: According to a Bloomberg article referred to in the video, South Korea’s tests had a 95% sensitivity rate, much higher than those of the USA at the time. But neither the article nor the video went into detail about the type of test.
Jacinta: So I think the standard type of test used is called PCR, or RT-PCR, which means reverse transcriptase polymerase chain reaction, but I don’t really know what that means or how the tests work.
Canto: We’ll look at how the tests work later. Let’s use this video 32 to help us understand how this virus gets into a host cell and replicates.
Jacinta: Ok, so we have a cell with its nucleus, and its DNA in there, and outside the nucleus is the cell’s cytoplasm containing organelles such as ribosomes, mitochondria, lysosomes, microtubules and the like. The DNA is transcribed into single-stranded precursor messenger RNA. The RNA is then transported into the cytoplasm, where it’s modified, giving it a ‘five prime cap and a poly-A tail’. So one end has its nucleotide altered by the enzyme guanyl transferase. It has to be a guanine nucleotide connected to the mRNA with a particular triphosphate linkage. The poly-A tail is a string of adenine bases. These modifications form what’s called post-transcriptional RNA processing. Then the ribosome, about which we’ve learned so much from Venki Ramakrishnan, reads the mRNA from the five-prime end to the three-prime end. That’s in the ‘positive’ direction. It reads the nucleotides three at a time and comes up with a code (here it gets a bit vague), so that when three particular nucleotides line up, ‘a specific amino acid has to be placed on there’. And transfer RNA is involved here. So a by-product of this process is a protein (consisting of amino acids), made by the ribosome. That’s translation, not so clearly explained. Anyway, proteins are the central building blocks of our bodies, without which not.
Canto: Okay, sufficient unto the day. And remember, this transcription/translation process is known as ‘the central dogma of molecular biology’, in case you’re tested. Now we’ll turn to the virion. So the cell membrane that the virus needs to penetrate is a lipid bilayer. That bilayer is hydrophilic on the outside (that’s facing out from the cell and into the cell) and lipophilic on the inside. The coronovirus has the same lipid bilayer, with embedded proteins, notably the s-proteins or spike proteins which we know are used to attach to host cells. There are other structural proteins such as m-proteins (membrane proteins) and e-proteins (envelope proteins). Inside is the large RNA genome, protected by n-proteins (nucleocapsid proteins). Presumably there are other proteins too. Now, note that this is one virion, which is the built structure housing the virus (what enables it to survive for however long outside of a host), but also including the virus itself, which is essentially the genome. For the virus to replicate and spread, all those structural proteins have to be reproduced too.
Jacinta: The s-protein just happens to fit, like a key in a lock, a receptor protein in the human host cell membrane called the ACE-2 receptor. These ACE-2 receptors, full name angiotensin-converting enzymes, are found in our lungs, and elsewhere, such as the heart, the kidneys and the intestines. Once this connection is made, the viral RNA is released into the cytosol. And as it happens, this viral RNA also has a 5 prime cap and a poly-A tail just like the host’s mRNA. It isn’t clear from the video whether this is because it gets modified within the cytoplasm or it’s already ‘primed’ so to speak. Anyway, the cell’s ribosomes start to act on this rogue RNA as it would on its own mRNA. Meanwhile the structural proteins from the viral membrane are incorporated into the host membrane, possibly earmarking it for destruction.
Canto: The ribosome makes a protein from the viral RNA, called RNA-dependent RNA polymerase (RdRP), or an RNA replicase. The protein somehow makes another complementary strand of RNA, running in the opposite direction, from which the ribosome makes more protein, which makes more RNA and so forth. This RNA also codes for the structural proteins of the virion (because the RdRP somehow forms shorter strands of RNA, called sub-genomic RNAs, specific to the making of those proteins by the hijacked ribosomes), so enabling the spread of the virus.
Jacinta: The key, the video tells me, is in the name polymerase. That’s an enzyme that puts nucleotides together in long chains. Also, many ribosomes – there are thousands in our cells – are connected to the cell membrane and can help create new virions that can leave the cell in much the opposite way they entered, being packaged and then budded off. Through this hijacking process, one virion can come in, and any number of them can go out, and generally from the lung region. They’re naturally attacked by the immune system causing inflammation, possibly pneumonia and respiratory failure.
Canto: Yes and thanks to Dr Roger Seheult for all this, we hope we’re not misreading his work. He goes on to talk about the possibility of inhibiting this nasty polymerase, RdRP. We might talk about this, or not, in the next post.
References
Coronavirus update 32, with Dr Seheult – series of videos
The gene machine, by Venki Ramakrishnan