## Archive for the ‘dynamical systems’ Category

### Matched asymptotic expansions and the Kaplun-Lagerstrom model

December 13, 2022

In a post I wrote a long time ago I described matched asymptotic expansions as being like black magic. Now I have understood some more about how to get from there to rigorous mathematics. My main guide in doing so has been Chapter 7 of the book ‘Classical Methods in Ordinary Differential Equations’ by Hastings and McLeod. There they give an extensive treatment of a model problem by Kaplun and Lagerstrom. The ultimate source of this is work of Stokes on hydrodynamics around 1850. In his calculations he found some paradoxical phenomena. Roughly speaking, attempting to obtain an asymptotic expansion for a solution led to inconsistencies. These things remained a mystery for many years. A big step forward came in the work of Kaplun and Lagerstrom in 1957. There they introduced an ODE model which, while having no direct physical interpretation, provides a relatively simple mathematical context in which to understand these phenomena. It is this model problem which is treated in detail by Hastings and McLeod. The model is a boundary value problem for the equation $y''+\frac{n-1}{r}y'+\epsilon yy'=0$. We look for a solution with $y(1)=0$ and $\lim_{r\to\infty}y(r)=1$. The first two terms look like the expression for the Laplacian of a spherically symmetric function in $n$ dimensions and for this reason the motivation is strong to look at the cases $n=2$ and $n=3$ which are vaguely related to fluid flow around a cylinder and flow around a sphere, respectively. It turns out that the case $n=2$ is a lot harder to analyse than the case $n=3$. When $n=3$ the problem has a unique solution for $\epsilon>0$. We would like to understand what happens to this solution as $\epsilon\to 0$. It is possible to find an asymptotic expansion in $\epsilon$ but it is not enough to use powers of $\epsilon$ when building the expansion. There occurs a so-called switchback term containing $\log\epsilon$. This is a singular limit although the parameter in the equation only occurs in a lower order term. This happens because the equation is defined on a non-compact region.

Consider the case $n=3$. In applying matched asymptotic expansions to this problem the first step is to do a straightforward (formal) expansion of the equation in powers of $\epsilon$. This gives differential equations for the expansion coefficients. At order zero there is no problem solving the equation with the desired boundary conditions. At order one this changes and it is not possible to implement the desired boundary condition at infinity. This has to do with the fact that in the correct asymptotic expansion the second term is not of order $\epsilon$ but of order $\epsilon\log\epsilon$. This extra term is the switchback term. Up to this point all this is formal. One method of obtaining rigorous proofs for the asymptotics is to use GSPT, as done in two papers of Popovic and Szmolyan (J. Diff. Eq. 199, 290 and Nonlin. Anal. 59, 531). There is an introduction to this work in the book but I felt the need to go deeper and I looked at the original papers as well. To fit the notation of those papers I replace $y$ by $u$. Reducing the equation to first order by introducing $v=u'$ as a new variable leads to a non-autonomous system of two equations. Introducing $\eta=1/r$ as a new dependent variable and using it to eliminate $r$ from the right hand side of the equations in favour of $\eta$ leads to an autonomous system of three equations. This allows the original problem to be reformulated in the following geometric way. The $u$-axis consists of steady states. The point $(1,0,0)$ is denoted by $Q$. The aim is to find a solution which starts at a point of the form $(0,v,1)$ and tends to $Q$ as $r\to\infty$. A solution of this form for $\epsilon$ small and positive is to be found by perturbation of a corresponding solution in the case $\epsilon=0$. For $\epsilon>0$ the centre manifold of $Q$ is two-dimensional and given explicitly by $v=0$. In the case $\epsilon=0$ it is more degenerate and has an additional zero eigenvalue. To prove the existence of the desired connecting orbit we may note that for $\epsilon>0$ this is equivalent to showing that the manifold consisting of solutions starting at points of the form $(0,v,1)$ and the manifold consisting of solutions converging to $Q$ intersect. The first of these manifolds is obviously a deformation of a manifold for $\epsilon=0$. We would like the corresponding statement for the second manifold. This is difficult to get because of the singularity of the limit. To overcome this $\epsilon$ is introduced as a new dynamical variable and a suitable blow-up is carried out near the $u$-axis. In this way it is possible to get to a situation where there are two manifolds which exist for all $\epsilon\ge 0$ and depend smoothly on $\epsilon$. They intersect for $\epsilon=0$ and in fact do so transversely. It follows that they also intersect for $\epsilon$ small and positive. What I have said here only scratches the surface of this subject but it indicates the direction in which progress could be made and this is a fundamental insight.

Advertisement

### The shooting method for ordinary differential equations

November 25, 2022

A book which has been sitting on a shelf in my office for some years without getting much attention is ‘Classical Methods in Ordinary Differential Equations’ by Hastings and McLeod. Recently I read the first two chapters of the book and I found the material both very pleasant to read and enlightening. A central theme of those chapters is the shooting method. I have previously used the method more than once in my own research. I used it together with Juan Velázquez to investigate the existence of self-similar solutions of the Einstein-Vlasov system as discussed here. I used it together with Pia Brechmann to prove the existence of unbounded oscillatory solutions of the Selkov system for glycolysis as discussed here. This method is associated with the idea of a certain type of numerical experiment. Suppose we consider a first order ODE with initial datum $x(0)=\alpha$. Suppose that for some value $\alpha_1$ the solution tends to $+\infty$ for $t\to\infty$ and for another value $\alpha_2>\alpha_1$ the solution tends to $-\infty$. Then we might expect that in between there is a value $\alpha^*$ for which the solution is bounded. We could try to home in on the value of $\alpha^*$ by a bisection method. What I am interested in here is a corresponding analytical procedure which sometimes provides existence theorems.

In the book the procedure is explained in topological terms. We consider a connected parameter space and a property $P$. Let $A$ be the subset where $P$ does not hold. If we can show that $A=A_1\cup A_2$ where $A_1$ and $A_2$ are non-empty and open and $A=A_1\cap A_2=\emptyset$ then $A$ is disconnected and so cannot be the whole of the parameter space. Hence there is at least one point in the complement of $A$ and there property $P$ holds. The most common case is where the parameter space is an interval in the real numbers. For some authors this is the only case where the term ‘shooting method’ is used. In the book it is used in a more general sense, which might be called multi-parameter shooting. The book discusses a number of cases where this type of method can be used to get an existence theorem. The first example is to show that $x'=-x^3+\sin t$ has a periodic solution. In fact this is related to the Brouwer fixed point theorem specialised to dimension one (which of course is elementary to prove). The next example is to show that $x'=x^3+\sin t$ has a periodic solution. After that this is generalised to the case where $\sin t$ is replaced by an arbitrary bounded continuous function on $[0,\infty)$ and we look for a bounded solution. The next example is a kind of forced pendulum equation $x''+\sin x=f(t)$ and the aim is to find a solution which is at the origin at two given times. In the second chapter a wide variety of examples is presented, including those just mentioned, and used to illustrate a number of general points. The key point in a given application is to find a good choice for the subsets. There is also a discussion of two-parameter shooting and its relation to the topology of the plane. This has a very different flavour from the arguments I am familiar with. It is related to Wazewski’s theorem (which I never looked at before) and the Conley index. The latter is a subject which has crossed my path a few times in various guises but where I never really developed a warm relationship. I did spend some time looking at Conley’s book. I found it nicely written but so intense as to require more commitment than I was prepared to make at that time. Perhaps the book of Hastings and McLeod can provide me with an easier way to move in that direction.

### Is mathematics being driven out by computers?

September 28, 2022

In the past two weeks I attended two conferences. The first was the annual meeting of the Deutsche Mathematikervereinigung (DMV, the German mathematical society) in Berlin. The second was the joint annual meeting of the ESMTB (European Society for Mathematical and Theoretical Biology) and the SMB (Society for Mathematical Biology) in Heidelberg. I had the impression that the participation of the SMB was relatively small compared to previous years. (Was this mainly due to the pandemic or due to other problems in international travel?) There were about 500 participants in total who were present in person and about another 100 online. I was disappointed with the plenary talks at both conferences. The only one which I found reasonably good was that of Benoit Perthame. One reason I did not like them was the dominance of topics like machine learning and artificial intelligence. This brings me to the title of this post. I have the impression that mathematics (at least in applied areas) is becoming ever weaker and being replaced by the procedure of developing computer programmes which could be applied (and sometimes are) to the masses of data which our society produces these days. This was very noticeable in these two conferences. I would prefer if we human beings would continue to learn something and not just leave it to the machines. The idea that some day the work of mathematicians might be replaced by computers is an old one. Perhaps it is now happening, but in a different way from that which I would have expected. Computers are replacing humans but not because they are doing everything better. There is no doubt there are some things they can do better but I think there are many things which they cannot. The plenary talks at the DMV conference on topics of this kind were partly critical. There occurred examples of a type I had not encountered before. A computer is presented with a picture of a pig and recognizes it as a pig. Then the picture is changed in a very specific way. The change is quantitatively small and is hardly noticeable to the human eye. The computer identifies the modified picture as an aeroplane. In another similar example the starting picture is easily recognizable as a somewhat irregular seven and is recognized by the computer as such. After modification the computer recognizes it as an eight. This seems to provide a huge potential for mistakes and wonderful opportunities for criminals. I feel that the trend to machine learning and related topics in mathematics is driven by fashion. It reminds me a little of the ‘successes’ of string theory in physics some years ago. Another aspect of the plenary talks at these conferences I did not like was that the speakers seemed to be showing off with how much they had done instead of presenting something simple and fascinating. At the conference in Heidelberg there were three talks by young prizewinners which were shorter than the plenaries. I found that they were on average of better quality and I know that I was not the only one who was of that opinion.

In the end there were not many talks at these conferences I liked much but let me now mention some that I did. Amber Smith gave a talk on the behaviour of the immune system in situations where bacterial infections of the lung arise during influenza. In that talk I really enjoyed how connections were made all the way from simple mathematical models to insights for clinical practise. This is mathematical biology of the kind I love. In a similar vein Stanca Ciupe gave a talk about aspects of COVID-19 beyond those which are common knowledge. In particular she discussed experiments on hamsters which can be used to study the infectiousness of droplets in the air. A talk of Harsh Chhajer gave me a new perspective on the intracellular machinery for virus production used by hepatitis C, which is of relevance to my research. I saw this as something which is special for HCV and what I learned is that it is a feature of many positive strand RNA viruses. I obtained another useful insight on in-host models for virus dynamics from a talk of James Watmough.

Returning to the issue of mathematics and computers another aspect I want to mention is arXiv. For many years I have put copies of all my papers in preprint form on that online archive and I have monitored the parts of it which are relevant for my research interests for papers by other people. When I was working on gravitational physics it was gr-qc and since I have been working on mathematical biology it has been q-bio (quantitative biology) which I saw as the natural place for papers in that area. q-bio stands for ‘quantitative biology’ and I interpreted the word ‘quantitative’ as relating to mathematics. Now the nature of the papers on that archive has changed and it is also dominated by topics strongly related to computers such as machine learning. I no longer feel at home there. (To be fair I should say there are still quite a lot of papers there which are on stochastic topics which are mathematics in the classical sense, just in a part of mathematics which is not my speciality.) In the past I often cross-listed my papers to dynamical systems and maybe I should exchange the roles of these two in future – post to dynamical systems and cross-list to q-bio. If I succeed in moving further towards biology in my research, which I would like to I might consider sending things to bioRxiv instead of arXiv.

In this post I have written a lot which is negative. I feel the danger of falling into the role of a ‘grumpy old man’. Nevertheless I think it is good that I have done so. Talking openly about what you are unsatisfied with is a good starting point for going out and starting in new positive directions.

### The centre manifold theorem and its proof

September 2, 2022

In my research I have often used centre manifolds but I have not thoroughly studied the proof of their existence. The standard reference I have quoted for this topic is the book of Carr. The basic statement is the following. Let $\dot x=f(x)$ be a dynamical system on $R^n$ and $x_0$ a point with $f(x_0)=0$. Let $A=Df(x_0)$. Then $R^n$ can be written as a direct sum of invariant subspaces of $A$, $V_-\oplus V_c\oplus V_+$, such that the real parts of the eigenvalues of the restrictions of $A$ to these subspaces are negative, zero and positive, respectively. $V_c$ is the centre subspace. The centre manifold theorem states that there exists an invariant manifold of the system passing through $x_0$ whose tangent space at $x_0$ is equal to $V_c$. This manifold, which is in general not unique, is called a centre manifold for the system at $x_0$. Theorem 1 on p. 16 of the book of Carr is a statement of this type. I want to make two comments on this theorem. The first is that Carr states and proves the theorem only in the case that the subspace $V_+$ is trivial although he states vaguely that this restriction is not necessary. The other concerns the issue of regularity. Carr assumes that the system is $C^2$ and states that the centre manifold obtained is also $C^2$. In the book of Perko on dynamical systems the result is stated in the general case with the regularity $C^r$ for any $r\ge 1$. No proof is given there. Perko cites a book of Guckenheimer and Holmes and one of Ruelle for this but as far as I can see neither of them contains a proof of this statement. Looking through the literature the situation of what order of differentiability is required to get a result and whether the regularity which comes out is equal to that which goes in or whether it is a bit less seems quite chaotic. Having been frustrated by this situation a trip to the library finally allowed me to find what I now see as the best source. This is a book called ‘Normal forms and bifurcations of planar vector fields’ by Chow, Li and Wang. Despite the title it offers an extensive treatment of the existence theory in any (finite) dimension and proves, among other things, the result stated by Perko. I feel grateful to those authors for their effort.

A general approach to proving the existence of a local centre manifold, which is what I am interested in here, is first to do a cut-off of the system and prove the existence of a global centre manifold for the cut-off system. It is unique and can be obtained as a fixed point of a contraction mapping. A suitable restriction of it is then the desired local centre manifold for the original system. Due to the arbitrariness involved in the cut-off the uniqueness gets lost in this process. A mapping whose fixed points correspond to (global) centre manifolds is described by Carr and is defined as follows. We look for the centre manifold as the graph of a function $y=h(x)$. The cut-off is done only in the $x$ variables. If a suitable function $h$ is chosen then setting $y=h(x)$ gives a system of ODE for $x$ which we can solve with a prescribed initial value $x_0$ at $t=0$. Substituting the solution into the nonlinearity in the evolution equation for $y$ defines a function of time. If this function were given we could solve the equation for $y$ by variation of constants. A special solution is singled out by requiring that it vanishes sufficiently fast as $t\to -\infty$. This leads to an integral equation of the general form $y=I(h)$. If $y=h$, i.e. $h$ is a fixed point of the integral operator then the graph of $h$ is a centre manifold. It is shown that when certain parameters in the problem are chosen correctly (small enough) this mapping is a contraction in a suitable space of Lipschitz functions. Proving higher regularity of the manifold defined by the fixed point requires more work and this is not presented by Carr. As far as I can see the arguments he does present in the existence proof nowhere use that the system is $C^2$ and it would be enough to assume $C^1$ for them to work. It is only necessary to replace $O(|z|^2)$ by $o(|z|)$ in some places.

### Lyapunov-Schmidt reduction and stability

August 30, 2022

I discussed the process of Lyapunov-Schmidt reduction in a previous post. Here I give an extension of that to treat the question of stability. I again follow the book of Golubitsky and Schaeffer. My interest in this question has the following source. Suppose we have a system of ODE $\dot y+F(y,\alpha)=0$ depending on a parameter $\alpha$. The equation for steady state solutions is then $F(y,\alpha)=0$. Sometimes we can eliminate all but one of the variables to obtain an equation $g(x,\alpha)=0$ for a real variable $x$ whose solutions are in one to one correspondence with those of the original equation for steady states. Clearly this situation is closely related to Lyapunov-Schmidt reduction in the case where the linearization has corank one. Often the reduced equation is much easier to treat that the original one and this can be used to obtain information on the number of steady states of the ODE system. This can be used to study multistationarity in systems of ODE arising as models in molecular biology. In that context we would like more refined information related to multistability. In other words, we would like to know something about the stability of the steady states produced by the reduction process. Stablity is a dynamical property and so it is not a priori clear that it can be investigated by looking at the equation for steady states on its own. Different ODE systems can have the same set of steady states. Note, however, that in the case of hyperbolic steady states the stability of a steady state is determined by the eigenvalues of the linearization of the function $F$ at that point. Golubitsky and Schaeffer prove the following remarkable result. (It seems clear that results of this kind were previously known in some form but I did not yet find an earlier source with a clear statement of this result free from many auxiliary complications.) Suppose that we have a bifurcation point $(y_0,\lambda_0)$ where the linearization of $F$ has a zero eigenvalue of multiplicity one and all other eigenvalues have negative real part. Let $x_0$ be the corresponding zero of $g$. The result is that if $g(x)=0$ and $g'(x)\ne 0$ then for $x$ close to $x_0$ the linearization of $F$ about the steady state has a unique eigenvalue close to zero and its sign is the same as that of $g'(x)$. Thus the stability of steady states arising at the bifurcation point is determined by the function $g$.

I found the proof of this theorem hard to follow. I can understand the individual steps but I feel that I am still missing a global intuition for the strategy used. In this post I describe the proof and present the partial intuition I have for it. Close to the bifurcation point the unique eigenvalue close to zero, call it $\mu$, is a smooth function of $x$ and $\alpha$ because it is of multiplicity one. The derivative $g'$ is also a smooth function. The aim is to show that they have the same sign. This would be enough to prove the desired stability statement. Suppose that the gradient of $g'$ at $x_0$ is non-zero. Then the zero set of $g$ is a submanifold in a neighbourhood of $x_0$. It turns out that $\mu$ vanishes on that manifold. If we could show that the gradient of $\mu$ is non-zero there then it would follow that the sign of $\mu$ off the manifold is determined by that of $g'$. With suitable sign conventions they are equal and this is the desired conclusion. The statement about the vanishing of $\mu$ is relatively easy to prove. Differentiating the basic equations arising in the Lyapunov-Schmidt reduction shows that the derivative of $F$ applied to the gradient of a function $\Omega$ arising in the reduction process is zero. Thus the derivative of $F$ has a zero eigenvalue and it can only be equal to $\mu$. For by the continuous dependence of eigenvalues no other eigenvalue can come close to zero in a neighbourhood of the bifurcation point.

After this the argument becomes more complicated since in general the gradients of $g'$ and $\mu$ could be zero. This is got around by introducing a deformation of the original problem depending on an additional parameter $\beta$ and letting $\beta$ tend to zero at the end of the day to recover the original problem. The deformed problem is defined by the function $\tilde F(y,\alpha,\beta)=F(y,\alpha)+\beta y$. Lyapunov-Schmidt reduction is applied to $\tilde F$ to get a function $\tilde g$. Let $\tilde\mu$ be the eigenvalue of $D\tilde F$ which is analogous to the eigenvalue $\mu$ of $DF$. From what was said above it follows that, in a notation which is hopefully clear, $\tilde g_x=0$ implies $\tilde\mu=0$. We now want to show that the gradients of these two functions are non-zero. Lyapunov-Schmidt theory includes a formula expressing $\tilde g_{x\beta}$ in terms of $F$. This formula allows us to prove that $\tilde g_{x\beta}(0,0,0)=\langle v_0^*,v_0\rangle>0$. Next we turn to the gradient of $\tilde \mu$, more specifically to the derivative of $\tilde \mu$ with respect to $\beta$. First it is proved that $\tilde\Omega (0,0,\beta)=0$ for all $\beta$. I omit the proof, which is not hard. Differentiating $\tilde F$ and evaluating at the point $(0,0,\beta)$ shows that $v_0$ is an eigenvalue of $D\tilde F$ there with eigenvalue $\beta$. Hence $\tilde\mu (0,0,\beta)=0$ for all $\beta$. Putting these facts together shows that $\tilde\mu (\tilde \Omega,0,\beta)=\beta$ and the derivative of $\tilde\mu (\tilde \Omega,0,\beta)$ with respect to $\beta$ at the bifurcation point is equal to one.

We now use the following general fact. If $f_1$ and $f_2$ are two smooth functions, $f_2$ vanishes whenever $f_1$ does and the gradients of both functions are non-zero then $f_2/f_1$ extends smoothly to the zero set of $f_1$ and the value of the extension there is given by the ratio of the gradients (which are necessarily proportional to each other). In our example we get $\tilde\mu(\tilde\Omega,\alpha,\beta)=\tilde a(x,\alpha,\beta)\tilde g_x(x,\alpha,\beta)$ with $\tilde a(0,0,0)=[\frac{\partial}{\partial\beta}(\tilde\Omega,0,0)]/\tilde g_{x\beta}(0,0,0)]>0$. Setting $\beta=0$ in the first equation then gives the desired conclusion.

### Another paper on hepatitis C: absence of backward bifurcations

June 13, 2022

In a previous post I wrote about a paper by Alexis Nangue, myself and others on an in-host model for hepatitis C. In that context we were able to prove various things about the solutions of that model but there were many issues we were not able to investigate at that time. Recently Alexis visited Mainz for a month, funded by an IMU-Simons Foundation Africa Fellowship. In fact he had obtained the fellowship a long time ago but his visit was delayed repeatedly due to the pandemic. Now at last he was able to come. This visit gave us the opportunity to investigate the model from the first paper further and we have now written a second paper on the subject. In the first paper we showed that when the parameters satisfy a certain inequality every solution converges to a steady state as $t\to\infty$. It was left open, whether this is true for all choices of parameters. In the second paper we show that it is not: there are parameters for which periodic solutions exist. This is proved by demonstrating the presence of Hopf bifurcations. These are obtained by a perturbation argument starting from a simpler model. Unfortunately we could not decide analytically whether the periodic solutions are stable or unstable. Simulations indicate that they are stable at least in some cases.

Another question concerns the number of positive steady states. In the first paper we showed under a restriction on the parameters that there are at most three steady states. This has now been extended to all positive parameters. We also show that the number of steady states is even or odd according to the sign of $R_0-1$, where $R_0$ is a basic reproductive ratio. It was left open, whether the number of steady states is ever greater than the minimum compatible with this parity condition. If there existed backward bifurcations (see here for the definition) it might be expected that there are cases with $R_0<1$ and two positive solutions. We proved that in fact this model does not admit backward bifurcations. It is known that a related model for HIV with therapy (Nonlin. Anal. RWA 17, 147) does admit backward bifurcations and it would be interesting to have an intuitive explanation for this difference.

In the first paper we made certain assumptions about the parameters in order to be able to make progress with proving things. In the second paper we drop these extra restrictions. It turns out that many of the statements proved in the first paper remain true. However there are also new phenomena. There is a new type of steady state on the boundary of the positive orthant and it is asymptotically stable. What might it mean biologically? In that case there are no uninfected cells and the state is maintained by infected cells dividing to produce new infected cells. This might represent an approximate description of a biological situation where almost all hepatocytes are infected.

### Another conference on biological oscillators at EMBL in Heidelberg

March 11, 2022

I recently attended a conference at EMBL in Heidelberg and I very much enjoyed experiencing a live conference for the first time in a couple of years. I heard similar sentiments expressed by many of the other participants at the meeting. This conference at EMBL was a sequel to one which I previously wrote about here. The present event was in hybrid form with many of the speakers remote. There were nevertheless more than a hundred people attending on site. The conference started with a presymposium. This was intended to teach some mathematics to biologists. I attended it since I saw it as an opportunity to learn more about what kind of mathematics is really of interest to biologists. Among the main themes discussed were the relationships between positive feedback and multistability and between negative feedback and oscillations. First there was a one-hour talk by Hanspeter Herzel. Then there was a practical part where we were supposed to play with a computer programme. I had downloaded the necessary programmes (R and RStudio) as recommended but this part of the event was a failure for me. I am simply lacking in basic computer competence. It was not explained to us how to begin using the programme and I was not able to supply this missing information on my own. The first part, the lecture, was more interesting for me. The speaker mentioned a paper which he wrote with others about circadian oscillations in the number of lymphocytes in different tissues (D. Druzd et al., Immunity 46, 120). I had previously wondered about the possible roles of oscillations in immunology but I never thought of that direction. I spoke to Herzel about this in a coffee break. This demonstrates a huge advantage of live versus online conferences. I am sure that the information he and I exchanged over coffee would never have been communicated if the conference had been only online. There is a standard picture in immunology in which antigen is being continuously transported to lymph nodes, where it can activate lymphocytes. A key point of the paper is that this does not happen at a constant rate. Instead the process is highly oscillatory. Lymphocytes reach their highest level in the lymph nodes mainly at the beginning of the active phase  (i.e. the beginning of the dark phase in the mice in which these observations were carried out). This means that the effectiveness of a vaccination or another chemical intervention may depend strongly on the time at which it is administered. Herzel told me about an example where this has been seen in practise in cancer immunotherapy. I decided that I wanted to investigate this more closely. Before I could do that I heard the talk of Francis Levi, which was exactly on this topic. Returning to the paper quoted above, according to Herzel the mathematical content was very elementary, using a linear model. I am happy that simple mathematical models and ideas can lead to useful biological insights. What I do not find so good is that the information on the mathematics presented in the paper is so minimal, even in the supplementary material. There is one aspect of this story which is unclear to me. It is important for the functioning of the immune system that a given T cell visits many lymph nodes in a day. Thus the delays to the entrance or exit from lymph nodes which are supposed to implement the rhythm must act in some kind of averaged sense.

I also had a chance to talk to Levi over coffee and get some additional insights about some aspects of his lecture. He has been working on chronotherapy in oncology for many years. This means the idea that the effectiveness of a cancer therapy can be very dependent on the time of day it is administered. He has applied these ideas in practise but the ideas have not gained wide acceptance in the community of oncologists. There is a chance that this may change soon due to the appearance of two papers on this subject in the prestigious journal ‘The Lancet Oncology’ in November 2021. One of the papers (22, 1648) is by Levi, the other (22, 1777) by Qian et al.

Now let me mention a couple of the other contributions I liked best. On Monday there was a (remote) talk by Albert Goldbeter on the coupling between the cell cycle and the circadian clock. Here, as elsewhere in this conference, entrainment was a central theme. There was a discussion of the role of multiple limit cycles in these models. There was also a (remote) talk by Jim Ferrell. His subject was cataloguing certain aspects of an organism called the mouse lemur. The idea was to have a list of cell types and hormones and to know which cell types produce and are affected by which hormones. There is a preprint on this subject on BioRxiv. One feature of these primates which I found striking is the following. They are much fatter in winter than in summer and this is related to a huge difference in thyroid hormones. If I remember correctly it is a factor of ten. For comparison, in humans thyroid hormones also vary with the time of year but only on the scale of a couple of per cent. In a talk by Susan Golden (live) on the Kai system in cyanobacteria I was able to experience one of the pioneers in that field.

### Persistence and permanence of dynamical systems

February 10, 2022

In mathematical models for chemical or biological systems the unknowns, which might be concentrations or populations, are naturally positive quantities. It is of interest to know whether in the course of time these quantities may approach zero in some sense. For example in the case of ecological models this is related to the question whether some species might become extinct. The notions of persistence and permanence are attempts to formulate precise concepts which could be helpful in discussing these questions. Unfortunately the use of these terms in the literature is not consistent.

I first consider the case of a dynamical system with continuous time defined by a system of ODE $\dot x=f(x)$. The system is defined on the closure $\bar E$ of a set $E$ which is either the positive orthant in Euclidean space (the subset where all coordinates are non-negative) or the intersection of that set with an affine subspace. The second case is included to allow the imposition of fixed values of some conserved quantities. Let $\partial E$ be the boundary of $E$, where in the second case we mean the boundary when $E$ is considered as a subset of the affine subspace. Suppose that for any $x_0\in \bar E$ there is a unique solution $x(t)$ with $x(0)=x_0$. If $x_0\in E$ let $c_1(x_0)=\liminf d(x(t),\partial E)$, where $x(t)$ is the solution with initial datum $x_0$ and $d$ is the Euclidean distance. Let $c_2(x_0)=\limsup d(x(t),\partial E)$. A first attempt to define persistence (PD1) says that it means that $c_1(x_0)>0$ for all $x_0\in E$. Similarly, a first attempt to define uniform persistence (PD2) is to say that it means that there is some $m>0$ such that $c_1(x_0)\ge m$ for all $x_0\in E$. The system may be called weakly persistent (PD3) if $c_2(x_0)>0$ for all $x_0\in E$ but this concept will not be considered further in what follows. A source of difficulties in dealing with definitions of this type is that there can be a mixing between what happens at zero and what happens at infinity. In a system where all solutions are bounded PD1 is equivalent to the condition that no positive solution has an $\omega$-limit point in $\partial E$. Given the kind of examples I am interested in I prefer to only define persistence for systems where all solutions are bounded and then use the definition formulated in terms of $\omega$-limit points. In that context it is equivalent to PD1. The term permanence is often used instead of uniform persistence. I prefer the former term and I prefer to define it only for systems where the solutions are uniformly bounded at late times, i.e. there exists a constant $M$ such that all components of all solutions are bounded by $M$ for times greater than some $t_0$, where $t_0$ might depend on the solution considered. Then permanence is equivalent to the condition that there is a compact set $K\subset E$ such that for any positive solution $x(t)\in K$ for $t\ge t_0$. A criterion for permanence which is sometimes useful will now be stated without proof. If a system whose solutions are uniformly bounded at infinity has the property that $\overline{\omega(E)}\cap\partial E=\emptyset$ then it is permanent. Here $\omega(E)$ is the $\omega$-limit set of $E$, i.e. the union of the $\omega$-limit sets of solutions starting at points of $E$. If there is a point in $\overline{\omega(E)}\cap\partial E$ there is a solution through that point on an interval $(-\epsilon,\epsilon)$ which is non-negative. For some systems points like this can be ruled out directly and this gives a way of proving that they are permanent.

Let $\phi:[0,\infty)\times \bar E\to \bar E$ be the flow of the dynamical system, i.e. $\phi(t,x_0)$ is the value at time $t$ of the solution with $x(0)=x_0$. The time-one map $F$ of the system is defined as $F(x)=\phi(1,x)$. Its powers define a discrete semi-dynamical system with flow $\psi(n,x)=F^n(x)=\phi(n,x)$, where $n$ is a non-negative integer. For a discrete system of this type there is an obvious way to define $\omega$-limit points, persistence and permanence in analogy to what was done in the case with continuous time. For the last two we make suitable boundedness assumptions, as before. It is then clear that if the system of ODE is persistent or permanent its time-one map has the corresponding property. What is more interesting is that the converse statements also hold. Suppose the the time-one map is persistent. For a given $E$ let $K$ be the closure of the set of points $F^n(x)$. This is a compact set and because of persistence it lies in $E$. Let $K'=\phi (K\times [0,1])$. This is also a compact subset of $E$. If $t$ is sufficiently large then $\phi([t],x)\in K$ where $[t]$ is the largest integer smaller that $t$. This implies that $\phi(t,x)\in K'$ and proves that the system of ODE is persistent. A similar argument shows that if the time-one map is permanent the system of ODE is permanent. We only have to start with the compact set $K$ provided by the permanence of the time-one map.

### Hopf bifurcations and Lyapunov-Schmidt theory

January 1, 2022

In a previous post I wrote something about the existence proof for Hopf bifurcations. Here I want to explain another proof which uses Lyapunov-Schmidt reduction. This is based on the book ‘Singularities and Groups in Bifurcation Theory’ by Golubitsky and Schaeffer. I like it because of the way it puts the theorem of Hopf into a wider context. The starting point is a system of the form $\dot x+f(x,\alpha)=0$. We would like to reformulate the problem in terms of periodic functions on an interval. By a suitable normalization of the problem it can be supposed that the linearized problem at the bifurcation point has periodic solutions with period $2\pi$. Then the periodic solutions whose existence we wish to prove will have period close to $2\pi$. To be able to treat these in a space of functions of period $2\pi$ we do a rescaling using a parameter $\tau$. The rescaled equation is $(1+\tau)\dot x+f(x,\alpha)=0$ where $\tau$ should be thought of as small. A periodic solution of the rescaled equation of period $2\pi$ corresponds to a periodic solution of the original system of period $2\pi/(1+\tau)$. Let $X_1$ be the Banach space of periodic $C^1$ functions on $[0,2\pi]$ with the usual $C^1$ norm and $X_0$ the analogous space of continuous functions. Define a mapping $\Phi:X_1\times{\bf R}\times{\bf R}\to X_0$ by $\Phi(x,\alpha,\tau)=(1+\tau)\dot x+f(x,\alpha)$. Note that it is equivariant under translations of the argument. The periodic solutions we are looking for correspond to zeroes of $\Phi$. Let $A$ be the linearization of $f$ at the origin. The linearization of $\Phi$ at $(0,0,0)$ is $Ly=\frac{dy}{dt}+Ay$. The operator $L$ is a (bounded) Fredholm operator of index zero.

Golubitsky and Schaeffer prove the following facts about this operator. The dimension of its kernel is two. It has a basis such that the equivariant action already mentioned acts on it by rotation. $X_0$ has an invariant splitting as the direct sum of the kernel and range of $L$. Moreover $X_1$ has splitting as the sum of the kernel of $L$ and the intersection $M$ of the range of $L$ with $X_1$. These observations provide us with the type of splitting used in Lyapunov-Schmidt reduction. We obtain a reduced mapping $\phi:{\rm ker}L\times{\bf R}\times{\bf R}\to {\rm ker}L$ and it is equivariant with respect to the action by translations. The special basis already mentioned allows this mapping to be written in a concrete form as a mapping ${\bf R}^2\times{\bf R}\times{\bf R}\to {\bf R}^2$. It can be written as a linear combination of the vectors with components $[x,y]$ and $[-y,x]$ where the coefficients are of the form $p(x^2+y^2,\alpha,\tau)$ and $q(x^2+y^2,\alpha,\tau)$. These functions satisfy the conditions $p(0,0,0)=0$, $q(0,0,0)=0$, $p_\tau(0,0,0)=0$, $q_\tau(0,0,0)=-1$. It follows that $\phi$ is only zero if either $x=y=0$ or $p=q=0$. The first case corresponds to the steady state solution at the bifurcation point. The second case corresponds to $2\pi$-periodic solutions which are non-constant if $z=x^2+y^2>0$. By a rotation we can reduce to the case $y=0, x\ge 0$. Then the two cases correspond to $x=0$ and $p(x^2,\alpha,\tau)=q(x^2,\alpha,\tau)=0$. The equation $q(x^2,\alpha,\tau)=0$ can be solved in the form $\tau=\tau (x^2,\alpha)$, which follows from the implicit function theorem. Let $r(z,\alpha)=p(z,\tau(z,\alpha))$ and $g(x,\alpha)=r(x^2,\alpha)x$. Then $\phi(x,y,\tau,\alpha)=0$ has solutions with $x^2+y^2>0$ only if $\tau=\tau(x^2+y^2,\alpha)$. All zeroes of $\phi$ can be obtained from zeroes of $g$. This means that we have reduced the search for periodic solutions to the search for zeroes of the function $g$ or for those of the function $r$.

If the derivative $r_\alpha(0,0)$ is non-zero then it follows from the implicit function theorem that we can write $\alpha=\mu(x^2)$ and there is a one-parameter family of solutions. There are two eigenvalues of $D_xf$ of the form $\sigma(\alpha)-i\omega(\alpha)$ where $\sigma$ and $\omega$ are smooth, $\sigma (0)=0$ and $\omega (0)=1$. It turns out that $r_\alpha (0,0)=\sigma_\alpha(0,0)$ which provides the link between the central hypothesis of the theorem of Hopf and the hypothesis needed to apply the implicit function theorem in this situation. The equation $r=0$ is formally identical to that for a pitchfork bifurcation, i.e. a cusp bifurcation with reflection symmetry. The second non-degeneracy condition is $r_z(0,0)=0$. It is related to the non-vanishing of the first Lyapunov number.

### Hilbert’s sixteenth problem

September 14, 2021

The International Congress of Mathematicians takes place every four years and is the most important mathematical conference. In 1900 the conference took place in Paris and David Hilbert gave a talk where he presented a list of 23 mathematical problems which he considered to be of special importance. This list has been a programme for the development of mathematics ever since. The individual problems are famous and are known by their numbers in the original list. Here I will write about the 16th problem. In fact the problem comes in two parts and I will say nothing about one part, which belongs to the domain of algebraic geometry. Instead I will concentrate exclusively on the other, which concerns dynamical systems in the plane. Consider two equations $\frac{dx}{dt}=P(x,y)$, $\frac{dy}{dt}=Q(x,y)$, where $P$ and $Q$ are polynomial. Roughly speaking, the problem is concerned with the question of how many periodic solutions this system has. The simple example $P(x,y)=y$, $Q(x,y)=-x$ shows that there can be infinitely many periodic solutions and that the precise question has to be a little different. A periodic solution is called a limit cycle if there is another solution which converges to the image of the first as $t\to\infty$. The real issue is how many limit cycles the system can have. The first question is whether for a given system the number $N$ of limit cycles is always finite. A second is whether an inequality of the form $N\le H(n)$ holds, where $H(n)$ depends only on the degree of the polynomials. $H(n)$ is called the Hilbert number. Linear systems have no limit cycles so that $H(1)=0$. Until recently it was not known whether $H(2)$ was finite. A third question is to obtain an explicit bound for $H(n)$. The first question was answered positively by Écalle (1992) and Ilyashenko (1991), independently.

The subject has a long and troubled history. Already before 1900 Poincaré was interested in this problem and gave a partial solution. In 1923 Dulac claimed to have proved that the answer to the first question was yes. In a paper in 1955 Petrovskii and Landis claimed to have proved that $H(2)=3$ and that $H(n)\le P_3(n)$ for a particular cubic polynomial $P_3$. Both claims were false. As shown by Ilyashenko in 1982 there was a gap in Dulac’s proof. After 60 years there was almost no progress on this problem. Écalle worked on it intensively for a long time. For this reason he produced few publications and almost lost his job. At this point I pause to give a personal story. Some years ago I was invited to give a talk in Bayrischzell in the context of the elite programme in mathematical physics of the LMU in Munich. The programme of such an event includes two invited talks, one from outside mathematical physics (which in this case was mine) and one in the area of mathematical physics (which in this case was on a topic from string theory). In the second talk the concept of resurgence, which was invented by Écalle in his work on Hilbert’s sixteenth problem, played a central role. I see this as a further proof of the universality of mathematics.

The basic idea of the argument of Dulac was as follows. If there are infinitely many limit cycles then we can expect that they will accumulate somewhere. A point where they accumulate will lie on a periodic solution, a homoclinic orbit or a heteroclinic cycle. Starting at a nearby point and following the solution until it is near to the original point leads to a Poincaré mapping of a transversal. In the case of a periodic limiting solution this mapping is analytic. If there are infinitely many limit cycles the fixed points of the Poincaré mapping accumulate. It follows that this mapping is equal to the identity, contradicting the limit cycle nature of the solutions concerned. Dulac wanted to use a similar argument in the other two cases. Unfortunately in that case the Poincaré mapping is not analytic. What we need is a class of functions which on the one hand is general enough to include the Poincaré mappings in this situation and on the on the other hand cannot have an accumulating set of fixed points without being equal to the identity. This is very difficult and is where Dulac made his mistake.

What about the second question? It has been known since 1980 that $P(2)\ge 4$. There is an example with three limit cycles which contain a common steady state and another which does not. It is problematic to find (or to portray) these with a computer since three are very small and one very large. More about the history can be found in an excellent article of Iyashenko (Centennial history of Hilbert’s 16th problem. Bull. Amer. Math. Soc. 39, 301) which was the main source for what I have written. In March 2021 a preprint by Pablo Pedregal appeared (http://arxiv.org/pdf/2103.07193.pdf) where he claimed to have answered the second problem. I feel that some caution is necessary in accepting this claim. A first reason is the illustrious history of mistakes in this field. A second is that Pedregal himself produced a related preprint with Llibre in 2014 which seems to have contained a mistake. The new preprint uses techniques which are far away from those usually applied to dynamical systems. On the one hand this gives some plausibility that it might contain a really new idea. On the other hand it makes it relatively difficult for most people coming from dynamical systems (including myself) to check the arguments. Can anyone out there tell me more?