## fredag 24 juni 2011

### My sons wedding.

Such a beautiful couple. So similar. I wish them all luck. And good weather all the day...

(This is an official picture.)

And I was on time!

## lördag 18 juni 2011

### New eyes?

## tisdag 14 juni 2011

### Interview with Jarmo Mäkelä, the FQXI winner.

Jarmo Mäkelä from Vaasa University of Applied Sciences in Vaasa, Finland, for his essay "Is Reality Digital or Analog" recording a late-night conversation with Isaac Newton. In his essay, Jarmo reports that Newton decidedly told him "Digital, of course".

In Vasabladet today is an article about the FQXI-winner, Jarmo Mäkelä, after a hint from me.

'Physicistwinner likes blackholes' is the title. A scanned picture from the newspaper.

He works as a teacher, sinse 10 years, in math and physics at Vaasa Technical Highschool educating engineers (information and data). He says he enjoys his work. Most of the students comes from abroad, and the teaching language is english. His research is mainly theoretic, as a hobby. He looks at gravitation and blackholes. This prize has no practical influence for his future, but is seen mostly in his CV.

Jarmo is 47 years old, from Seinäjoki (about 50 km's from my work), did his thesis at Jyväskylä University. He has a wife and two kids. Interests: physical exercise, skiing, classic music and history.

Quite scare information.

A search gave these:

From wikipedia:

Jarmo Mäkelä (2010). "Notes Concerning "On the Origin of Gravity and the Laws of Newton" by E. Verlinde (arXiv:1001.0785)". arXiv:1001.3808

We point out that certain equations which, in a very recent paper written by E. Verlinde, are postulated as a starting point for a thermodynamical derivation of classical gravity, are actually consequences of a specific microscopic model of spacetime, which has been published earlier.

E.P. Verlinde. "On the Origin of Gravity and the Laws of Newton".

*JHEP 04, 29 (2011)*. doi:10.1007/JHEP04(2011)029

On arxive he has 24 publications. Alone or with collaborators, many published in journals.

On Distance and Area 1011.2052

Partition Function of Spacetime 0810.4910

A Simple Quantum-Mechanical Model of Spacetime II: Thermodynamics of Spacetime 0805.3955

- I: Microscopic Properties of Spacetime 0805.3952

Pioneer Effect: An Interesting Numerical Coincidence 0710.5460

Quantum-Mechanical Model of Spacetime gr-qc/0701128

Gravitation and Thermodynamics: The Einstein Equation of State Revisited gr-qc/0612078

Area and Entropy: A New Perspective gr-qc/0605098

Radiation of the Inner Horizon of the Reissner-Nordström Black Hole gr-qc/0508095

Accelerating Observers, Area and Entropy gr-qc/0506087

Entropy of Spacelike Two-Surfaces of Spacetime gr-qc/0406032

Spacetime Foam Model of the Schwarzschild Horizon gr-qc/0307025

Thermodynamical Properties of Horizons gr-qc/0205128

Microscopic Properties of Horizons gr-qc/0108037

Quantum-mechanical model of the Kerr-Newman black hole gr-qc/0012055

Constraints on Area Variables in Regge Calculus gr-qc/0011006

Microscopic Black Hole Pairs in Highly-Excited States gr-qc/0006070

How to interpret black hole entropy? gr-qc/9812075

Variation of Area Variables in Regge Calculus gr-qc/9801022

A Quantum Mechanical Model of the Reissner-Nordstrom Black Hole gr-qc/9708029

Black Hole Spectrum: Continuous or Discrete? gr-qc/9609001

Area spectrum of the Schwarzschild black hole gr-qc/9605058

Schroedinger Equation of the Schwarzschild Black Hole gr-qc/9602008

and...

If it pleases the court, so to speak, I too have a series of hypothesis that have to do with the vacuum energy behavior of Jarmo Makela's simply-connected quantized space-time models, but I don't go around shitting up the boards with Lubos Motl-style ex-string theorist borderline crankiness, mostly because no one asked or cares much around here about the Verlinde Hypothesis.

I guess I like him...

## söndag 12 juni 2011

### Demetrios Christodoulou & Richard Hamilton.

The Formation of Black Holes in General Relativity, (monograph, 589 pp.), EMS Monographs in Mathematics, EMS Publishing House (ISBN 978-3-03719-068-5), 2009.

Research field: Partial di fferential equations, geometric analysis, general relativity, fluid mechanics. His publications started from1970 with black holes, which also was his theme for the thesis 1971. Investigations in Gravitational Collapse and the Physics of Black Holes. So I guess he is qualified enough. Mathematical Problems of General Relativity I, 2008, The formation of shocks in 3-dimensional fluids, The Euler equations of compressible fluid flow, 2007, Recent developments in nonlinear hyperbolic PDE, 2001 etc.

On wikipedia: well known in the field of general relativity for his proof, together with Sergiu Klainerman, of the nonlinear stability of the Minkowski spacetime of special relativity in the framework of general relativity. The extraordinarily difficult proof of the stability result is laid out in detail.

- Christodoulou, Demetrios & Klainerman, Sergiu (1993).
*The global nonlinear stability of the Minkowski space*. Princeton: Princeton University Press. ISBN 0-691-08777-6.

- Christodoulou, Demetrios (2000).
*The action principle and partial differential equations*. Princeton: Princeton University Press. ISBN 0-691-04957-2.

Richard Hamilton's mathematical contributions are primarily in the field of differential geometry and more specifically geometric analysis. He is best known for having discovered the Ricci flow and suggesting the research program that ultimately led to the proof, by Grigori Perelman, of the Thurston geometrization conjecture and the solution of the Poincaré conjecture. Research field: Partial differential equations, differential geometry. (Peter Woit is also at the same institution. Algebraic Geometry, Mathematical Physics and Number Theory are other fields.) Woits blog. Not many words for the 1mill prize! The second Nobel?

Several stages of Ricci flow on a 2D manifold. Wikipedia. Informally, the Ricci flow tends to expand negatively curved regions of the manifold, and contract positively curved regions.

Colombia Universitys release. Analytic number theory is the study of the distribution of prime numbers. One of the most important unsolved problems in mathematics is the

*Riemann hypothesis*about the zeros of the Riemann zeta function, which gives a square root type error term for the number of primes in a large interval. One of the greatest applications of Grothendieck's theory of schemes is Deligne's proof of the Riemann hypothesis for L-functions for varieties over finite fields (which was first formulated by Weil). Thanks to the profound insight of Langlands, now embodied in the

*Langlands program*: there is a sweeping vision of connections between automorphic L-functions on the one hand, and

*motivic L-functions*, on the other. This vision encompasses the Artin and Shimura-Taniyama conjectures, both of which played a key role in Wiles' proof of Fermat last theorem. The main technique of Wiles, the deformation of Galois representations, is a new direction, now quite extensively developed

Wiles' proof of his modularity lifting theorems is a perfect illustration of p-adic techniques in number theory where the basic objects are deformation of

*Galois representations*, congruences between modular forms, and their deep connections with special values of L-functions. Another spectacular illustration of the p-adic techniques for automorphic forms attached to higher rank reductive groups is the recent proof of the Sato-Tate conjecture. Mazur's theory of deformations of Galois representations used in Wiles' proof has been inspired by the theory of

*p-adic families of automorphic forms*developed originally by Hida. This theory has been developing for reductive groups of higher rank and has many powerful applications for the understanding of the connections between L-functions (or p-adic L-functions) and Galois representations which are at the heart of modern research in algebraic number theory and arithmetic geometry. The theory of p-adic families has also inspired some of the new developments of p-adic Hodge theory and the so-called p-adic Langlands program which establishes a conjectural connection between p-adic Galois representations of a local field of residual characteristic p and certain p-adic representations of p-adic reductive groups. These subjects where the notion of

*p-adic variation*is involved are advancing very quickly and a substantial breakthrough is expected in the near future.

From 1996 Oswald Veblen Prize motivations.

The Ricci flow equations were introduced to geometers by Hamilton in 1982 (“Three manifolds with positive Ricci curvature”, J. Differential Geometry 17 (1982), 255–306). These equations form a very nonlinear system of differential equations (of essentially parabolic type) for the time evolution of a Riemannian metric on a smooth manifold. The equations assert simply that the time derivative of the metric is equal to minus twice the Ricci curvature tensor. (The Ricci curvature tensor is a symmetric, rank two tensor which is obtained by a natural average of the sectional curvatures.) This flow equation can be thought of as a nonlinear heat equation for the Riemannian metric. After an appropriate, time-dependent rescaling, the static solutions are simply the Einstein metrics. In introducing the Ricci flow equations, Hamilton proved that compact, three-dimensional manifolds with positive definite Ricci curvature are diffeomorphic to spherical space forms. (These are quotients of the three-dimensional sphere by free, finite

group actions.)

... understand the nature of the singularities which arise under the flow. (Hamilton proved that singularities do not arise in three dimensions when the Ricci curvature starts out positive.)

Hamilton has come to understand the geometric constraints on the singularities which arise under the Ricci flow on a compact, threedimensional Riemannian manifold and under a related flow equation (for the “isotropic curvature tensor”) on a compact, four-dimensional manifold. This understanding has allowed him, in many cases, to classify all possible singularities of the flow. In the four-dimensional case, Hamilton was recently able to give a topological characterization of the possible singularities which arise from the isotropic curvature tensor flow if the starting metric has positive isotropic curvature tensor. The conclusion is as follows: If a singularity arises, then it can be described as a lengthening neck in the manifold whose cross-section is an embedded spherical space form with injective fundamental group. Hamilton deduced from this fact that simply connected manifolds with positive isotropic curvature are diffeomorphic to the four-dimensional sphere.

For the compact 3-manifold case, Hamilton, in a recent paper, analyzed the development of singularities in the Ricci flow by studying the evolution of stable, closed geodesics and stable, minimal surfaces under their own, compatible, geometric flows. This analysis of the flows of stable geodesics and minimal surfaces leads to a characterization of the developing singularities in terms of Ricci soliton solutions to the flow equations along degenerating, geometric subsets of the original manifold. (A Ricci soliton is a solution whose motion in time is generated by a 1-parameter group of diffeomorphisms of the underlying manifold.)

etc.

He shared the prize with Gang Tian: The basic Kähler-Einstein problem is to find necessary and sufficient conditions for the existence of a Kähler metric on a given complex manifold whose Ricci curvature is a constant multiple of the metric itself. The sign of the constant is determined by the degree of the manifold’s first Chern class. The case where the sign is negative was solved independently by Aubin and Yau, while the sign zero case (where the first Chern class vanishes) was solved by Yau in his celebrated solution to the Calabi Conjecture.

This is still today very actual.

From the Columbia University research pages:

Topology is concerned with the intrinsic properties of shapes of spaces. One class of spaces which plays a central role in mathematics, and whose topology is extensively studied, are the

*n*dimensional manifolds. These are spaces which locally look like Euclidean n-dimensional space.

Historically, topology has been a nexus point where algebraic geometry, differential geometry and partial differential equations meet and influence each other, influence topology, and are influencedby topology. More recently, topology and differential geometry have provided the language in which to formulate much of modern theoretical high energy physics. This interaction has brought topology, and mathematics more generally, a whole host of new questions and ideas. Because of its central place in a broad spectrum of mathematics there has always been a great deal of interaction between work in topology and work in these neighboring disciplines.

Ironically, in topology, the case of manifolds of dimensions 3 and 4, the physical dimensions in which we live, has eluded undestanding for the longest time. The case of manifolds of dimension

*n=1*is straightforward, and the case where

*n=2*was understood thoroughly in the 19

^{th}century. Moreover, intense activity in the 1960's (including the pioneering work of Browder, Milnor, Novikov, and Smale) expresses the topology of manifolds of dimension

*n>4*in terms of an elaborate but purely algebraic description.

The study of manifolds of dimension

*n=3*and

*4*is quite different from the higher-dimensional cases; and, though both cases

*n=3*and

*4*are quite different in their overall character, both are generally referred to as

*low-dimensional topology*.

Low-dimensional topology is currently a very active part of mathematics, benefiting greatly from its interactions with the fields of partial differential equations, differential geometry, algebraic geometry, modern physics, representation theory, number theory, and algebra.

The case of manifolds of dimension

*n=4*remains the most elusive. In view of the foundational results of Freedman, understanding manifolds up to their topological equivalence is a theory which is similar in character to the higher-dimensional manifold theory. However, the theory of differentiable four-manifolds is quite different. The subject was fundamentally transformed by the pioneering work of Simon Donaldson, who was studying moduli spaces of solutions to certain partial differential equations which came from mathematical physics. Studying algebro-topological properties of these moduli spaces, Donaldson came up with very interesting smooth invariants for four-manifolds which demonstrated the unique and elusive character of smooth four-manifold topology. In the case where the underlying manifold is Kähler, these moduli spaces also admit an interpretation in terms of stable bundles, and hence shed light on the differential topology of smooth algebraic surfaces. Since Donaldson's work, the physicists Seiberg and Witten introduced another smooth invariant of four-manifolds. Since then, the study of four-manifolds and their invariants has undergone several further exciting developments, tying them deeply with ideas from symplectic geometry and pseudo-holomorphic curves, and hence forming further bridges with algebraic and symplectic geometry, but also connecting them more closely with knot theory and three-manifold topology.

Geometry and analysis are vast fields, with myriad facets reflected differently in the leading mathematics departments worldwide. At Columbia, they are closely intertwined, with partial differential equations as the common unifying thread, and fundamental questions from several complex variables, algebraic geometry, topology, theoretical physics, probability, and applied mathematics as guiding goals.

The theory of partial differential equations, PDE, at Columbia is practically indistinguishable from its analytic, geometric, or physical contexts: the d-bar-equation from several complex variables and complex geometry, real and complex Monge-Ampère equations from differential geometry and applied mathematics, Schrodinger and Landau-Ginzburg equations from mathematical physics, and especially the powerful theory of geometric evolution equations from topology, algebraic geometry, general relativity, and gauge theories of elementary particle physics. Of particular interest are manifestations of non-linearity and curvature, long-time behavior and inherently non-perturbative aspects, formation of singularities, generalized and viscosity solutions, and global obstructions to the existence and regularity of solutions. Although real and complex differential geometry can be quite different in orientation - the latter having closer ties with algebraic geometry and number theory - both are strongly represented at Columbia.

Other less analytic aspects of the theory of partial differential equations also thrive at Columbia. Of particular importance is the theory of solitons and integrable models, with their hidden symmetries and deep geometric structures, and stochastic differential equations, with the ever growing manifestations of random phenomena.

From its PDE and differential geometry core, the group branches out for strong interactions with other groups in the department and the university, notably the groups in algebraic geometry, topology, number theory, string theory, and applied mathematics.

In arXive is so many articles, but look at this one from 2009!

arXiv:0905.4215 [ps, pdf, other]

## lördag 11 juni 2011

### The molecular mechanism of innate immunity.

Beutler determined how innate immune system cells detect a potentially invasive microorganism present in the body. The same system that provides awareness of infection may sometimes drive inflammatory or autoimmune diseases such as systemic lupus erythematosus. Beutler has spearheaded the use of a technique called "forward genetics" to study genes used by the mammalian innate immune system to clear pathogens from the body.

The Genetics Department has assembled a highly interactive group of investigators with expertise in the theory and practice of forward genetics: the creation of phenovariance, its detection by phenotypic screening, and its solution by positional cloning or other methods.

While many biologists begin with hypotheses about how a particular biological phenomenon operates, geneticists begin instead with a phenotype: an altered form of the phenomenon in question. Our principal interest is mammalian immune function. If we wish to understand why the mouse immune system responds to a particular molecule, we find an exceptional mouse in which it doesn’t; if we wish to understand why most mice don’t have inflammatory disease, we find an exceptional mouse that does. When a phenotype is caused by a single gene mutation, it is generally possible to find the mutation. Then we have gained fundamental insight into the phenomenon itself.

Using a genetic approach, we established some years ago that the Toll-like receptors (TLRs) serve as the key sensors used by the mammals to perceive infection. This conclusion rested upon the positional cloning of a mutation (

*Lps*) that prevented mice from sensing bacterial lipopolysaccharide [Poltorak et al.,

^{d}*Science*282:2085-2088 (1998)]. Since that time, we have established many of the essential proteins active in TLR signal transduction, but many others remain to be found.

We use random chemical mutagenesis with N-ethyl-N-nitrosourea (ENU) to produce many thousands of mice with germline mutations that affect every aspect of normal biological function. We then screen the mice to detect phenotypic change in the innate immune response. For example, the ability of macrophages to sense molecules of microbial origin (for example, lipopolysaccharide, bacterial lipopeptides, double-stranded RNA, and unmethylated DNA) is measured

*in vitro.*The ability to cope with specific pathogens (especially mouse cytomegalovirus) is measured

*in vivo.*Mice with inflammatory colitis, or strong resistance to specific microbes, or an abnormal complement of immune cells are identified as well. When strong deviation from normal function is detected, transmissibility of the phenotype is examined. If the phenotype is transmissible (i.e., if a

*bona fide*mutation exists), meiotic mapping is performed to confine the mutation to a particular genomic interval. The mutation is then sought among candidate genes within the interval. To date, 274 phenotypes of all kinds have been detected in our laboratory by screening random germline mutant mice, and 140 of these mutations have immunologic effects. 170 mutations have been mapped to chromosomes, and in 145 cases, the molecular identity of the defect has been established. We now know that hundreds of genes serve the innate immune responses to microbial infections, making a life-or-death difference to animals infected with a single defined pathogen. And we have made inroads into the principal pathways of innate immune response.

Along the way, we have found many mutations that have shed light on other biological phenomena: hearing, sight, iron absorption, and development. All of these are regarded with interest, and some have started entirely new lines of biological inquiry.

Research presentation.

Among the largest issues in immunology is the question of self/non-self discrimination. How do we "know" when we have an infection? What are the receptors that alert us? For more than a century, and in fact, since microbes were recognized as the cause of infections, it has been clear that mammals are genetically programmed to recognize them.

Because the innate immune system must act promptly to contain an infection, mammals respond violently to purified molecules of microbial origin such as endotoxin (lipopolysaccharide; LPS). And it has long been known that sensing LPS is required for a mouse to overcome a Gram-negative infection (1;2). It has also been clear that cytokines, produced by mononuclear phagocytes in response to LPS, orchestrate the innate response and can be highly toxic when produced in large amounts (3-5). But the nature of the LPS receptor, which ignites the entire process, was long elusive.

It is now believed that each of the 12 mouse TLRs and 10 human TLRs dectect a limited number of the signature molecules that herald infection (LPS, lipopeptides, flagellin, unmethylated DNA, dsRNA, and ssRNA begin the best known examples). They may also detect molecular ligands of host origin under some circumstances, and may participate in sterile inflammation (observed in autoimmune diseases). The TLRs are the gatekeepers of the most powerful inflammatory responses known, and as such, are probably important in a wide range of diseases. And without TLR signaling, a state of severe immunocompromise exists (8).

The forward genetic approach entails the induction of thousands of random germline point mutations on a defined genetic background (C57BL/6) using N-ethyl-N-nitrosourea (ENU), the phenotypic screening of many thousands of mice for specific defects of immunity, and the positional cloning of those transmissible mutations that are detected. This classical genetic method does not depend upon hypotheses, nor upon assumptions about how innate immunity "should" work. Hence, it is unbiased, and errors of interpretation are extremely rare.

Over time, the effects of hundreds of millions of point mutations that change coding sense have been probed, and approximately 70% of all genes have so far been mutated to a state of detectable phenovariance. In terms of throughput, the ENU mutagenesis effort now underway in the Beutler laboratory is the largest in the world, and presently the only one primarily devoted to the decipherment of innate immunity.

*Signaling pathways utilized by the TLRs and other innate immune sensors are kept under surveillance in screens designed to detect mutations that impair the detection of microbes.*In the TLR signaling screen, signaling from seven TLRs is monitored by measuring tumor necrosis factor (TNF)-α production by peritoneal macrophages from ENU-mutagenized mice ex vivo. This screen has led to the decipherment of pathways for microbe sensing, identifying proteins that could not be "guessed" to participate in signaling (8-10). In addition, the study of several mutants identified in the screen has revealed subtleties in the nature of signaling from several TLRs (9;11;12). For example, the pococurante mutation of MyD88 demonstrated that signaling from TLR2 is inherently different from signaling through the other TLRs, requiring only one of two known sites of receptor-adapter interaction (Figure 1) (11). The Double-stranded DNA Macrophage Screen, to identify components involved in sensing cytoplasmic double-stranded DNA (dsDNA), and the NALP3 Inflammasome Screen, to identify components involved in sensing “danger signals,” are also being carried out in macrophages

*ex vivo*. An

*in vivo*screen for response to injected CpG oligodeoxynucleotides has recently been initiated.

2.

*By infecting mice with authentic pathogens using small inocula that are normally eliminated or contained by mice, mutations that impair host defense may be detected.*Screens for susceptibility to mouse cytomegalovirus infection (MCMV Susceptibility and Resistance Screen), and for clearance of lymphocytic choriomeningitis virus (LCMV Clearance Screen) in vivo are currently underway. These screens rely on the highly reproducible behavior of mice challenged by infection, which assures that phenovariants may be easily discerned (Figure 2). Some of the identified mutations have also come as great surprises (13). For example,

*mayday*mice die between 24 and 72 hours after infection with 5 x 10

^{4}PFU of MCMV, and were found to carry a mutation in the gene encoding an inwardly-rectifying potassium (K+) channel subunit, Kir6.1 (Figure 2) (14). Screens for control of MCMV, adenovirus, influenza, and Rift Valley Fever Virus are being performed in macrophages

*ex vivo*(Ex Vivo Macrophage Screen for Control of Viral Infection).

3. The DSS-induced Colitis Screen is designed to discover mutations resulting in susceptibility to chemically-induced colitis, which is thought to arise from excessive and sustained inflammatory host immune responses against commensal intestinal microbes. The screen monitors weight loss, rather than mortality in the case of MCMV or influenza, as an indication of colitis (Figure 3), and for this reason, sensitizing mutations are easily retrieved. Mutations that inappropriately activate immune responses to normal intestinal flora may be revealed by looking for exceptions to the norm in DSS sensitivity. Because of their potential to activate both innate and adaptive immune systems, mutations identified in each of these screens may also reveal molecules that contribute to autoimmune disease. | ||

| ||

4.

*The nature of the innate:adaptive immune connection is being probed*. Although the innate immune response clearly contributes to the development of an adaptive immune response, the mechanism by which this occurs remains unclear. Together with our colleagues in the Nemazee lab, we have recently shown that TLR signaling is not required for effective antibody production following immunization (15), nor for strong CTL responses (16). Focusing on CTL and NK responses (In Vivo NK Cell and CD8+ T Cell Cytotoxicity Screen), we have identified a number of mutations that impair either or both, consistent with the conclusion that a large number of genes have non-redundant function in supporting cytotoxic lymphoid immunity.

In addition, the functions of many genes are illuminated by the study of mice with visible phenotypes induced by random germline mutagenesis. In these mice, mutations may affect development, morphology, behavior, or even immune function, and are positionally cloned with interest. In this manner, the laboratory pursues a broad range of biological topics. Recently, mutations in TMPRSS6 and SHP1 were found to cause body iron deficiency due to impaired iron uptake (17), and autoimmune and inflammatory disease (18), respectively.

To date, 380 transmissible mutations that cause discernable phenotypes have been set aside for positional cloning in the Beutler laboratory; 238 mutations have been mapped to chromosomes, and in 217 instances, molecular identification of the causative mutation has been made. These mutations fall within 146 genes. 264 of the mutations studied affect immunity, and about half of the mutations affecting immunity that are cloned prove to be novel in the sense that no such phenotype had been predicted by knockout mutations, or knockouts had not been created. Only about 50% recessive saturation of the genome has been achieved to date in any given screen; therefore, it is expected that many key discoveries of function lie in waiting.

The long-range goal of the laboratory is to identify the key genes required for resistance to infection (the mammalian "resistome") and determine how they interact with one another. But as genetics is a form of exploration in which very surprising phenotypes can and do arise, many different lines of inquiry are pursued. In this way the lab has solved basic questions in many different fields. Please visit our Mutagenetix web site to view the expanding list of mutations that we have produced and solved.

Beutlers Publications

Jules Hoffman and his publications, often free.

#### Discovery of insect-innate immune system and Toll receptor

Innate immunity is an essential host-defense system, which participates in the elimination of microbes from the body. The molecular mechanism of the innate immune system, especially the way of recognition of microbes, had been uncovered for a long time. Dr. Jules A. Hoffmann and his colleagues discovered that Drosophila Toll gene plays essential roles in innate immunity by using genetic approaches. Drosophila Toll functions as a sensor for microbes and activates intracellular signaling pathways, thereby inducing anti-microbial peptides. Their discovery is a breakthrough for the investigation of innate immune system of mammals, and leads discovery of mammalian Toll like receptor and role of their anti-microbial functions. Their findings are also contributes to the understanding of human immune systems and used for the development of adjuvant for vaccines and new anti-viral agents.

The evolutionary perspective. 1,

**“The Antimicrobial Defence of Drosophila: a paradigm of innate immunity”**

Today, immunologists consider the innate arm of immunity to be at least as equally important as the adaptive for the overall host defence. The innate immunity comprises a heritable, multifaceted and highly conserved defence system which its molecular basis only now has started to be elucidated. The fundamental questions on how the microbes interact with the host during the first minutes to hours following inoculation, what genes are induced and what molecular effectors are expressed are investigated extensively both in insects and in mammals.

Addressing these issues in the antimicrobial defence of Drosophila, a highly efficient innate defence system, has provided great insight and possibilities in immunology research. The results accumulated so far converge to a theatre where two major pathways act as the major actors of these mechanisms. The first is the Spatzle-Toll cascade, triggered by infection with fungi or gram-positive bacteria, while the second is the Imd (Immune deficiency) cascade, triggered by Gram-negative bacterial invasion. These pathways signal to NF-kB response elements, orchestrating the expression of several hundreds of immune-response genes. As to which protein family serves the infection discrimination function during the microbe invasion, several classes of the Peptidoglycan Recognition Proteins (PGRP) seem to be the possible culprit.

Although the knowledge about the innate immunity emerging from the Drosophila paradigm is still very elementary, several lines of investigation imply that the aforementioned complex signalling cascades are builded and act in a similar fashion in mammals also; every element of the Toll and Imd paths are represented in mammals by the TLR4 and TNF cascades respectively.

Ruslan M. Medzhitov, Yale bulletinMedzhitov has made groundbreaking contributions to the understanding of innate immunity, which provides immediate defense against infection. His studies helped elucidate the critical role of toll-like receptors (TLRs) in sensing microbial infections, mechanisms of TLR signaling, and activation of the inflammatory and immune response.

Arming the Immune System talk. "We don't know how to make vaccines yet".

Toll like receptor and IL-1 receptor signalling, also capsases.

"Toll like receptors and innate immunity". R. Medzhitov. Nature Reviews

Immunology 1, 135, 2001.

Minireview 1997: Innate Immunity: The Virtues of a Nonclonal System of Recognition. Ancient Host Defense Pathway etc. with Il-1,6,8. Toll/NFkB pathway is conserved between insects and mammals and activates nonspecific defense mechanisms in both cases, while in mammals Toll also induces signals required for the activation of the adaptive immune response.

INNATE IMMUNE RECOGNITION, 2002

This man was a bit more interesting.

From Howard Hughes Medical Institute:

Medzhitov’s interest in immunology was ignited in the early 1990s - a bleak time for science in Russia. Medzhitov witnessed this disintegration first-hand. Scientific resources drained away, until just a single battered copy of the weekly journals made the rounds at Moscow University. As a graduate student there, Medzhitov yearned to keep up with the latest advances, and his

weekly hour with Science and Nature wasn't enough. So he headed to the Academy of Natural Sciences, which was then engaged in its own detente with the university. For various bureaucratic reasons, university students weren't allowed access to the library. “So I had to go and flirt with the librarians—there were several of them—and eventually they all knew me and

let me in secretly and told me not to tell anyone,” says Medzhitov.

There, in the stacks, the young biology student stumbled on a copy of Cold Spring Harbor Symposia. In it was the paper that launched his career. Written by the late Yale immunologist Charles Janeway (an HHMI investigator), the article sketched a new theory for how the immune system recognizes and responds to pathogens. Little was known then about the so-called innate immune system and how it identifies and reacts to invaders. Janeway’s ideas

ignited Medzhitov, sending him to his university’s sole e-mail terminal. “I was able to send messages once a week,” says Medzhitov. “And my first message was to Charlie.” Medzhitov asked the professor for more details about his ideas. To Medzhitov’s delight, Janeway responded, and the pair exchanged several more messages.

“Charlie's paper was the only paper that made sense of a lot of things,” says Medzhitov. “That was the point I first thought about being a researcher in immunology. As an undergraduate student, I never had a course on immunology.”

With a career path now in mind, Medzhitov landed a fellowship at the University of California, San Diego. There, working with protein evolution pioneer Russell Doolittle, Medzhitov contacted local immunologist Richard Dutton, who knew Janeway and recommended Medzhitov for a postdoctoral position in Janeway’s lab. Janeway said yes. “I felt very lucky,” says

Medzhitov.

When he arrived at Yale—after a detour to Moscow to defend his thesis and sweat out a government coup and six months of uncertainty—Medzhitov felt overwhelmed. “Janeway’s lab was very famous, and I imagine competition to get in was very high. And I was coming from just a few e-mail exchanges and a recommendation. My challenge was, not only did I not speak English well, I also had never done any experiments. In Russia, there was no money to do anything. All I could do was sit in the library. So I arrived without any experience, basically zero. I had to learn as quickly as I could.”

It turns out that lack of experience helped Medzhitov in another way. Janeway’s theory of how innate immunity acted, by recognizing bits of invading organisms, was “extremely speculative.” And that meant it was risky to work on. But, being “oblivious to concerns about career,” Medzhitov jumped in on the project. “I was just happy to be in a place where I could do science,” he says.

In 1996, after just a few years working together, Janeway and Medzhitov made a breakthrough. They discovered receptors that alerted the second arm of the immune system, the more familiar T cells and B cells that attack pathogens. Studying these proteins, dubbed Toll-like receptors, quickly became one of the hottest areas in biology. “That was an extremely exciting time,” says Medzhitov. “We didn't realize how much would come out of it eventually, that it would become such a huge area of research.”

In the years since then, Medzhitov has piled one discovery after another upon the first, dramatically expanding our understanding of the key roles Toll-like receptors play in infection control, chronic inflammation, and even the growth of tumors. At the same time, he's branched off in a dozen directions:

One example of many, Medzhitov is learning how commensal bacteria—which live in our guts and help us digest food—also help protect our intestines from injury.

Medzhitov now thinks that Toll-like receptors and related proteins may trigger the chronic inflammation that leads to coronary artery disease, Alzheimer’s, and diabetes—some of our biggest killers. “I like a lot of areas of biology and it's hard for me to focus on only one,” he says. Now, with plenty of journals to read and experiments to conduct, he doesn't have to.

### Research Summary

Research in this laboratory focuses on many aspects of innate immunity and includes the following areas:

- Molecular mechanisms of innate immune recognition: Identification and analysis of receptors involved in innate immune recognition (Pattern Recognition Receptors) and signaling pathways activated by these receptors. Of particular interest is the recently identifiedfamily of Toll-like receptors, which plays an essential role in innate immune recognition in both mammals and insects.

- Control of adaptive immune responses by innate immune recognition. Signals induced upon innate immune recognition (co-stimulatory molecules, cytokines and chemokines) are necessary both for the initiation of adaptive immune responses and the control of effector functions. We are interested in molecular mechanisms that translate the signals recognized by Pattern Recognition Receptors into signals that control the activation of naive lymphocytes and their differentiation into effector cells.

- Mechanisms of autoimmunity and allergy. Inflammation is a normal component of the host response to infection. However, excessive inflammation, or inflammation in the absence of infection, may lead to a variety of pathological states, including autoimmunity and allergy. We are studying the cellular and molecular basis of inflammatory disorders that are caused by the dysfunctions of the innate immune system.

### Extensive Research Description

### Innate immune recognition

The innate immune system relies on several distinct strategies of recognition, including pattern recognition and missing self recognition. We are interested in defining cellular and molecular mechanisms of innate immune sensing and signaling. There are several different classes of receptors involved in innate immune recognition. We are interested in the general design of the recognition and signaling modules of the innate immune system, their functional relationships, their roles in host defense and in control of adaptive immunity, and their contributions to immunopathology.

### Host-Pathogen interactions

The disease state caused by microbial infection is a result of either microbial virulence or immunopathology (the host response to infection), or in some cases both. Thus immune sensing and responsiveness to infection are adjusted during evolution to achieve an optimal balance to maximize protection from infection, and to minimize the pathology caused by an overzealous immune response. This balance can presumably vary depending on infection. We are interested in studying the mechanisms (both hard-wired and adaptive) that allow for an optimal trade-off between these two conflicting goals. We are interested in understanding the role of virulence in host-pathogen interactions and the effect of microbial virulence on innate and adaptive immunity. We are also studying the affect of infection on the immune system and how the immune system handles co-infections.

### Inflammation

Inflammation is a fundamental physiological process that underlies a multitude of normal and pathological conditions. We are studying both the basic biology of inflammation and the regulatory mechanisms that control initiation, quality and intensity of inflammatory responses. In particular, we are studying the links between inflammation and metabolism, inflammation and aging, and inflammation and cancer.

### Control of adaptive immunity

Innate immune recognition plays a critical role in the control of adaptive immune responses. Multiple mechanisms underlie the connections between innate and adaptive immune systems, and most of them are poorly understood. We are studying basic mechanisms that couple innate immune recognition with activation and differentiation of adaptive immune responses. We are also studying the links between innate immune system and peripheral tolerance.

### Cell biology of signal transduction

Most of what we know about cell signaling is based on biochemical and genetic studies. While these approaches provide essential information about the composition of signaling pathways, much less progress has been made in understanding the functional organization of signaling pathways, especially in the context of basic cell biological processes, such as protein sorting and vesicular trafficking. We are interested in basic principles that govern the cell biology of signaling transduction pathways.

### Control of gene expression

Stimulation of macrophages through TLRs leads to changes in the expression (induction and suppression) of hundreds of genes. These changes are effected through a diversity of mechanisms. Gene regulation occurs at multiple levels (activation of trasnscription factors, chromatin remodeling and histone modifications) and has both signal-specific and gene-specific components. Different subsets of TLR-inducible genes are subject to differential regulatory influences, which are dependent on the function of the products they encode. We are interested in the basic principles of inducible gene expression, which are currently poorly characterized.

### Cancer biology

We are studying the mechanisms whereby cancer cells can sense their 'oncogenic state' and communicate it to other cells of the host. We are also studying the role of inflammation and tissue repair in tumor progression.

Announcement at Science

All plants and animals have a built-in resistance to pathogens called innate immunity that is more basic and general than the better-known adaptive immunity that responds to specific infections or vaccines. Innate immunity is the first line of defense against pathogens in all plants and animals. Jules Hoffmann of the University of Strasbourg in France first identified a key molecule, called Toll, involved in the innate immune response in fruit flies. Ruslan Medzhitov of Yale University then found homologous molecules, Toll-like receptors, in humans. Bruce Beutler of the Scripps Research Institute in San Diego, California, completed the puzzle by showing how the Toll-like receptors activate the innate immune system.

There are also others involved, of course.

### Verlinde's gravity at Cern.

28 AprProf. Erik Verlinde, "On the Origin of Gravity, Dark Energy and Matter."

Insights from black hole physics and developments in string theory strongly indicate that the gravity is derived from an underlying microscopic description in which it has no a priori meaning. Starting from first principles we argue that inertia and gravity are caused by the fact that phase space volume (or entropy) associated with the underlying microscopic system is influenced by the positions of material objects. Application of these ideas to cosmology leads to surprising new insights into the nature of dark energy and dark matter.

So, he talks of Phase space now... We use concepts and observe phenomena at a macroscopic scale, which are derived from a microscopic scale where they have no a priori meaning. Gravity arises because the amount of phase space (information) available for these degrees of freedom is influenced by the location of matter in space and time.

The talk is here. Video here.

### The Origin of Life discussed at Cern.

"The current status of work on the origin of life" by Stuart Kauffman (FRSC, U Vermont, Santa Fe Institute, Tampere U. Technology) Thursday 19 May 2011 from

**16:30**to

**17:30**(Europe/Zurich) at CERN

A miniconference, but still a step in the right direction. “The aim of this research group is to create theory and experiments to produce at least one, or several, candidate evolving protocells in the next decade.”

While physicists at CERN currently study the origin of the universe and the origin of matter, in the future they may be asked to help crack the origin of life too. On May 20, a small group of chemists and biologists gathered at CERN for a brainstorming workshop discussing ideas about the origin of life, and to hear from CERN experts about how to organize a scientific community from disparate research groups and how to access powerful computational resources.

“There is a serious risk that the answer to the question ‘How on Earth has life appeared on Earth?’ will mainly remain in the realm of philosophy for the years to come unless we can take definitive scientific approaches,” said Stuart Kauffman, an American molecular biologist and complexity theorist who co-organized the workshop with Markus Nordberg, resources coordinator at ATLAS, one of the largest experiments at CERN.

Kauffman and his colleagues believe that the crucial step towards life was the formation of autocatalytic sets. An autocatalytic set is a group of molecules which undergo chemical reactions in which some of the molecules catalyze - that is, significantly increase the rate at which the reaction takes place - other reactions in the set. Importantly, though, all molecules mutually catalyze each other’s creation, meaning that autocatalytic sets are ‘self-sustaining’. It’s thought that molecular reproduction and protocells then emerge from such a system.The text in Cern: called together by Ignatios Antoniadis/PH-TH & Markus Nordberg/PH-ADO.

Work on the Origin of Life is poised to converge onto a fourth phase and, many of us hope, success.

The first phase concerned prebiotic synthesis of the small molecules, amino acids, nucleotides, lipids and others, essential for life and spanned some forty years.

The second overlapping phase was inspired by the symmetric of the DNA or RNA double helix, presumed that life must necessarily be based on some form of template replication of one strand by ligation of free nucleotides to create the second strand, melting of the two strands and cycling again. Spearheaded by L. Orgel, but with many others, this effort has, to date, failed.

The third phase begins with the discovery that RNA molecules can act as enzymes, and posited the RNA world, in which RNA molecules dominated. This has led to slightly successful efforts to evolve an RNA sequence able to template replicate itself. Current success is an evolved ribozyme able to do so for 14 nucleotides.

The forth phase is converging around four ideas: 1) liposomes, hollow bilipid spheres obtainable from lipids in water, can grow and divide. We now widely hope that these can serve as “containers” bounding proto-cells. 2) Sources of free energy, from pyrophosphate to proton pumps. 3) A minimal metabolism in a “messy” systems chemistry which supplies the small amino acids, nucleotides and lipids for proto -life. 4) Collectively autocatalytic sets of polymers, peptides, RNA, or other, which achieve molecular reproduction in dividing liposome containers, hence also open ended evolution. At present, a 9 peptide collectively autocatalytic set has been constructend, achieving catalytic closure, and demonstrated beyond doubt that the DNA or RNA double helix is not needed for molecular reproduction. In addition a two membered DNA autocatalytic set has been constructed and two two membered RNA ribozyme autocatalytic sets have been selected from a large RNA library.

The author, in 1971 and 1986 proposed a theory in which the emergence of collectively autocatalytic sets is a first order phase transition as the diversity of polymers that are also candidates to catalyse the reactions they undergo, increases in diversity. Recent theorems have improved upon this initial model, simulations have shown that small collectively autocatalytic sets can emerge in this process and grow together, and also that, in the presence of inhibition of catalysis and if contained in duplicating containers, can indeed serve as plausible protocells able to evolve indefinitely.

The author has gathered some 17 scientists from around the world to collaborate and compete with one another, CERN/LHC experiments style, in a generative scientific environment.

http://indico.cern.ch/event/137302

Kauffmans talk (bad quality, webcam only):

"The current status of work on the origin of life"

“For a long time, it has been debated how likely it is that such autocatalytic sets exist in arbitrary chemical reaction systems,” said Wim Hordijk, a computational and bioinformatics specialist at the University of Lausanne in Switzerland.

“If I randomly throw a bunch of molecules together, and let them react according to the possible reactions between them, can I expect to see one or more of these autocatalytic sets? Some researchers believe they are very likely to occur. Others believe that it is almost impossible that they appear in a random chemistry – similar, they sometimes argue, to the question of what the probability is that a whirlwind blowing through a scrap yard will put together a Boeing 747,” Hordijk said.

### **Analyzing autocatalytic sets**

Until now, little mathematical analysis has been done on this question. But recently, Hordijk developed computer models to explore possibilities and scenarios for autocatalytic sets, in the hope that it could help others figure out how to set up laboratory experiments that would otherwise be too expensive and time-consuming without this prior knowledge.

“So far we have used our own personal computers or relatively small computer cluster to run our simulations on. However, we have already run into limitations in terms of available computing power,” Hordijk said.

Hordijk and his colleague Mike Steel have developed a model of a chemical reaction system where the probability of an arbitrary molecule being a catalyst for an arbitrary reaction was two in a million, a probability that is “chemically plausible” he said. Running this model on the LHC computing grid, he found that, with this level of catalysis, a set of about 65,000 different molecule types or more will have a high probability of forming an autocatalytic set. This is actually reasonable for a chemist in a laboratory to test, he said.

“We are hoping to use the computing grid to perform [future] simulations and analyses, which would enable us to go much further and deeper than we have been able to do so far. We have already done some small test runs just to make sure our software runs on the LHC grid [facilitated by the ATLAS experiment], which seems to be the case,” Hordijk happily reported.

Other areas being explored include self-reproducing RNA, ‘metabolism first’ theories and self-reproducing liposomes - small vesicles formed when lipid molecules, like fats and oils, align to make a membrane. Almost all the theoretical work is underpinned by complex models that would need large-scale computing power.There are several options for computing power available out there, Bob Jones, project director of CERN’s openlab told the group, including other grid infrastructures, supercomputers, clouds and volunteer computing.

### **“New science can arise in unexpected ways”**

"Our group of seven origin of life workers, representing an initial group of 22 of the top researchers in the field, were truly thrilled by our CERN meeting,” said Kauffman. “If CERN wishes it, we hope to become a small part of the CERN world, for the origin of life is itself a problem in physics. New science can arise in unexpected ways."

First, however, the Origin of Life group needs to make a formal proposal for such a project, and CERN must agree formally to support the work. “We hope this occurs. Such approval will help drive an international effort in origin of life research,” Kauffman said.

So, no results from here in several years.