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!

New eyes?

I was visiting the first beauty saloon ever in my life - for my sons wedding. The result was seen mostly on my eyes, somehow bigger and darker. The eyes was quite sharp before too :) Look!

Was it worth the effort? Doubtful!

Interview with Jarmo Mäkelä, the FQXI winner.

Top prize of $10,000 and FQXi Membership goes to ...

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...

Demetrios Christodoulou & Richard Hamilton.

Demetrios Christodoulou one of the Shaw Prize winners has one single article from 2008 on arXive, a whole book on 'The Formation of Black Holes in General Relativity', a book where a result which complements the stability result is proved. Namely, that a sufficiently strong flux of incoming gravitational waves leads to the formation of a black hole. Prologue 34 p, sensible for everyone. Read it!

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.

• "Three-manifolds with positive Ricci curvature"

• Lecture by Hamilton on Ricci flow

• Joint seminars see Relative p-adic Hodge theory or THE FUNDAMENTAL CURVE OF p-ADIC HODGE THEORY

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]

Quaternionic Soliton Equations from Hamiltonian Curve Flows in HP^n

Stephen C. Anco, Esmaeel Asadi

The molecular mechanism of innate immunity.

The Shaw Prize Foundation (the Asia's Nobel Prize) announced that Bruce A. Beutler, chair of the Department of Genetics at The Scripps Research Institute, has been awarded a 2011 Shaw Prize in Life Science and Medicine, for “discovery of the molecular mechanism of innate immunity, the first line of defense against pathogens.” Beutler shares the $1 million prize with Jules A. Hoffmann of the University of Strasbourg (France), and Ruslan M. Medzhitov, the David W. Wallace Professor of Immunobiology at Yale University.

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^d) that prevented mice from sensing bacterial lipopolysaccharide [Poltorak et al., 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.

In the Beutler lab, genetic screens are presently being applied to study four important topics in immunobiology. 1. 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 10⁴ 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. ENU mutations can also render mice highly resistant to infection by specific pathogens, or result in autoimmune and inflammatory disease. The MCMV Susceptibility and Resistance Screen and Influenza Resistance Screen may identify mutations that ultimately point to targets for intervention during infection. Such mutations disclose the existence of a "latent innate immune system," in that not all mechanisms for host resistance have been exploited. Rather, the genome has much untapped potential, and innate immunity is a work in progress. 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.

Figure 3a. Screening of G3 mice for susceptibility to DSS-induced colitis. 1% DSS was administered in the drinking water and body weight was determined daily. C57BL/6 mice receiving 1% DSS (black, n=20) or 0% DSS (gray, n=10) served as controls. Putative mutants are circled.

Using genetics to understand the molecular mechanisms of intestinal bowel disease (IBD). Colitis can be induced by the chemical dextran sodium sulphate (DSS), which is toxic to intestinal epithelial cells (IECs) and compromises the mucosal barrier that usually protects the body from intestinal microflora. Detection of intestinal bacteria by Toll-like receptors (TLRs) present in IECs and immune cells in the lamina propria of the intestine results in activation of the immune system, production of inflammatory cytokines, and corrective responses. By screening ENU-induced mouse mutations (red text) with the DSS-induced Colitis Screen, we have identified a number of components that are important in protecting against IBD. These include TLR signaling, epithelial growth factor receptor (EGFR) signaling, aquaporin 3 (Aqp3), the response to unfolded proteins causing endoplasmic reticulum (ER) stress, and numerous factors involved in vesicle transport and secretion, which are required to release cytotoxic molecules necessary to kill invasive pathogens.

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 bulletin
Medzhitov 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.

Also Verlinde has hold a talk at Cern in 28.4.11.
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.

Biology as a foundation for theoretical physics has taken a step forward.

CERN Colloquium

"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.

Antimatter asymmetry?

From Fermilab Today. CMS scientists recently measured the ratio of W+ to W¯ production in proton collisions at the LHC.

It is often said that a proton is made of three quarks: two of the same type, called up quarks, and one of a different type called a down quark. But that's not the whole story. In the space between these three stable quarks there is a boiling soup of quark–antiquark pairs. That is, a quark and an antimatter quark spontaneously come into existence, drift a while, and then recombine, destroying one another. This happens all the time— in every proton in every atom of every cell of our bodies, and in all of the matter in the universe.

When two protons collide in the LHC, most of the individual quarks miss each other. Often only one quark or antiquark from each proton collides directly. When an up quark collides with an anti-down quark, the two can combine to form a W⁺ boson; similarly, a down quark and an anti-up quark can combine to form a W¯ boson. In both cases, an antiquark is involved. Thus, each of the millions of W bosons produced at the LHC must come from at least one of these transient particles, caught before it had a chance to sink back into the soup.

CMS scientists recently measured the ratio of W⁺ to W¯ production in proton collisions at the LHC. The number of W⁺ bosons exceeds the number of W¯ bosons by about 40 percent, partly because each proton has two stable up-quarks for every stable down-quark. However, the exact ratio also depends on the density of the quark-antiquark soup.

My comment: This express asymmetry in favor of antimatter? Note the different quarks have different mass and hierarchy. Kea today: the remaining mystery is why the scales have the ratios that they do, namely roughly 2 and 36 for the down/lepton and up/lepton scales resp. Here with quarks we talked of protons, fermions. Has they also an hierarchy? l-adic /p-adic?

Counting W⁺ and W¯ bosons yields new insight into the dynamic structure of protons, which is too complicated to compute from first principles with current techniques. It also informs predictions of new physics: The rate at which hypothetical particles would be produced depends on the density of quark-antiquark pairs, for the same reason that W bosons do. It is important to know the thickness of this soup when imagining what else might spring from it.

— Jim Pivarski

Interpretation about Copenhagen interpretation.

Lubos has turned his coat? He looks at the Copenhagen Interpretation, and describes the "Lumo interpretation". This time he finds the same solution as Matti has found long ago. Light-like CD cones. Personal ones. And he looks at paranormal phenomena. Amazing!

I cannot hold back a small comment:
Lubos just realized the fact that selves has their own lightcones of reality and perceptions. So consciousness is different too, and the observer-effect. The collapse gives the information and is a result of the measurement. Information is not material, not bound to material patterns etc. So what is it?

The contenta is that he discovered the Zero Energy Ontology :) Maybe also the p-adic algebra :) Isn't that ironic?

Looks like he finally has began to THINK. I am sure he is good in the thinking process.

If he only stopped insulting people.
Ulla.

But I was wrong.
Lubos did not start thinking.
But I am of course no physicist, remember that Lubos. I have only studied this for some years.

Earlier he looked at the absent dark matter. Ironically TGD has been accused exactly because Matti talks of dark matter much. But what does the dark matter mean? Has it to be exotic? I guess no. So both are right? In fact, Kea also talks of the absense of dark matter. She can explain what it is.

Something Lubos has to do to save his face!

Has he become a real crackpot? He talks himself much of insane crackpots. I hate that word. It has done so much harm. So many carriers spoiled. For what? A fantasy? There is no M-theory, and maybe Lubos has been forced to realize that at last. So he goes back to see where it went wrong.

I am sorry, but this is creating more fuzziness than it solves. Lubos has much left to learn, and he must leave his stubborn belief and start look at realities and experiments in biology, condensed matter and quantum computer theory. I see not much progress in this, just the same old story.


To his text:
Pretty much everyone misunderstands the basic points of the Copenhagen interpretation, Lubos claim. I believe him.

There was no fundamental disagreement about the meaning of quantum mechanics among those people. Obviously, many other people such as Albert Einstein, Erwin Schrödinger, or Louis de Broglie didn't ever accept the Copenhagen interpretation but they didn't have any alternative.

Lots of fringe stuff, garbage, and crackpottery was later written by various people who weren't really part of the Copenhagen school of thought but who found it convenient to abuse the famous brand. That's why one can also hear that the Copenhagen school may (or even must) interpret the wave function as a real wave that collapses much like a skyscraper when it's hit by an aircraft on 9/11.

But nothing like that has ever been a part of the Copenhagen school of thought. If you open any complete enough description of the Copenhagen interpretation or if you look at Bohr's or Heisenberg's own texts, you will invariably see something like the following six principles:

1. A system is completely described by a wave function ψ, representing an observer's subjective knowledge of the system. (Heisenberg)
2. The description of nature is essentially probabilistic, with the probability of an event related to the square of the amplitude of the wave function related to it. (The Born rule, after Max Born)
3. It is not possible to know the value of all the properties of the system at the same time; those properties that are not known with precision must be described by probabilities. (Heisenberg's uncertainty principle)
4. Matter exhibits a wave–particle duality. An experiment can show the particle-like properties of matter, or the wave-like properties; in some experiments both of these complementary viewpoints must be invoked to explain the results, according to the complementarity principle of Niels Bohr.
5. Measuring devices are essentially classical devices, and measure only classical properties such as position and momentum.
6. The quantum mechanical description of large systems will closely approximate the classical description. (The correspondence principle of Bohr and Heisenberg)

Note that the very first point says that the wave function is a collection of numbers describing subjective knowledge. That doesn't mean that in practice, everything will be always subjective - or whatever the spiritual people have attributed to quantum mechanics. Of course that constant interactions between parts of the world - and different people - pretty much guarantee that they have to agree about many "objective properties". But as a matter of principle, this rule is important for quantum mechanics and Werner Heisenberg has never left any doubts that this is how one had to interpret it.

Heisenberg would often describe his interpretation of the wave function using a story about a guy who fled the city and we don't know where he is but when they tell us at the airport they saw him 10 minutes ago, our wave function describing his position immediately collapses to a smaller volume, and so on. This "collapse" may occur faster than light because no real object is "collapsing": it's just a state of our knowledge in our brain.

In practice, everyone can use pretty much the same wave function. But in principle, the wave function is subjective. .. . So A and B will have different wave functions during much of the experiment. It's consistent for B to imagine that A had seen a well-defined property of S before it was measured by B - but B won't increase his knowledge in any way by this assumption, so it is useless. If he applied this "collapsed" assumption to purely coherent quantum systems, he would obtain totally wrong predictions. So the wave function is surely subjective if one wants to obtain a universal description of the world.

This is the problem between SR and GR, the quantum gravity. How can a subjective Universe become part in an objective Universe? A collection of probability amplitudes combined differently, says Lubos, before the squared 'absolute values' of the combinations are interpreted as probabilities. This is the essence. A superposition can remain as a probability amplitude if they are not measured, squared, laid on-shell. The Schrödinger cat can be both living and dead at the same time. The cat can have the superpositions in the entangled quantum wavestate and some probabilities can be measured by him or someone else that is also entangled. This has been shownin quantum computer science. It is possible to know 'more than everything'. Then Lubos continues:

All probabilities of physically meaningful events may be calculated in this way - as the squared absolute value of some linear combination of the probability amplitudes.

This is false. All probabilities cannot be squared, only those that become 'subjective' in 'reality'. The rest continues unmeasured.

The notion of an objective collapse was introduced by John von Neumann in 1932 and he was clearly not a part of the Copenhagen school of thought, says Lubos. So no objective measurement is possible. The measurement is always subjective, and everything that happens with the wave function has to be subjective as well.

The laws of physics predict that with the state above, there is a 36% probability that we will measure the cat to be alive and 64% probability that it is dead. Just to be sure, there is a 0% probability that there will be both an alive cat and a dead cat.

Confusions between probability amplitudes and actual measurements, says Lubos, makes people say the cat is both living and dead. Well, in a way he is right, and at the same time it is like an scientist measuring utterly complex things summaristically. The state of being, ontology, both life and death is something we don't know what it is. If we take something more simple like color? Does it change the outcome? But color is an incoming qualia and also impossible today to say exactly what it is. Bodylength vary with as much as 7 cm depending on position and momentum. Weight vary much more. Is there anything that is stable? Maybe a chrystal? But then there are very few probability amplitudes.... Not even ordinary matter is stable.
So the measurement must be done for the momentum and position, in this time alone. Next time the situation vary. So the outcome is influenced by something else too? An oscillation coming from ?

Only one of the options with the nonzero entries, "dead" or "alive", will occur, and the probabilities are 64% and 36%, respectively.

How can those probabilities be measured? They are only probability amplitudes. The outcome may be a Bell curve? But in what form? Today we simply cannot answer. This must be made by assumptions only.

There is no possible answer of the form "half-dead, half-alive"

I think many cats can be half-dead. Old ones that barely function, new ones that not yet are developed. When is a cat 'almost dead' or dead. For people there are a big debate about this. What is 100% alive? 100% health? This is a bad joke.

The Hamiltonian evolves the density matrix and dictates which states are "observable" in the classical sense. It's very clear that once we learn that the cat is alive, even though the chance was just 36%, the number 64% has to be replaced by 0% while 36% jumps to 100%.

Ooops! What is this? Ad hoc! The 'collapse'! Why not try superposition of states? No collapse happen. The cat can be even 98% dead :)

It makes no sense to claim that it's "predetermined" that the cat would be seen as alive. The free-will theorem, among other, morally equivalent results, shows that the actual decision whether the cat is seen alive or dead has to be made at the very point of the spacetime where the event (measurement) takes place; it can't be a functional of the data (any data) in the past light cone.

This is the problem of the quantum jump, discussed by Matti. Is the jump always straight forward, then there is no change, no probability amplitude. What can invoke on the desition? Certainly the history very much, the habit, attitudes, old thinking. "It has always been like this". This was realized by Einstein. In his black hole thinking it was the environment (gravity?) that 'collapsed' the Minkowskian light cone. Free will must be thought as a desition to jump somewhere not computated in advance? What can do that? A surplus of energy? This question cannot be reduced to this 'measurement' here and now. In a comment Lubos say: the random aspect of any event that is predicted with a different probability than certainty - different from 0% and different from 100% - is decided at the very point of the spacetime where this event or measurement takes place.

If you have a perfect memory, then quantum mechanics predicts that you will remember all your past observations accurately with probability 100%. Because it's 100%, no "random generator" is needed.

The claim I am making - and Conway and Kochen are making - doesn't mean that the present has no relationship to the past. It says that the information that is produced by random outcomes now - and recall that the information is given by

-sum p_i ln(p_i)

so it vanishes if all p_i are equal to 0 or 1 - doesn't have any relationship to the past. It is literally random and decided right now, not as a function of any "hidden variables" that were inherited from the past. This is proved by the free-will theorem. However, the *probabilities* that one gets one thing or another *are* of course calculated from the knowledge about the state in the past, from the initial wave function if you wish. If all the probabilities are 0% or 100%, then the measurement produces no information because it's guaranteed in advance, so the question where this (empty) information came from is vacuous. Well, I am not convinced. A computation is a measurement.

Even more importantly, people often say that "rho = rho1 + rho2" decomposition of the density matrix means that there are "two worlds", one that is described by "rho1" AND one that is described by "rho2". (Similarly for "psi", but for "rho", the comments are more clear.) But this is a complete misunderstanding of what the density matrix and addition means. The density matrix is an operator encoding probabilities - its eigenvalues are predicted probabilities. And we're just adding probabilities, not potatoes.

And he continues on the theme. No, I can't agree. Superposition of states do not have to collapse. There can be and there are two worlds. Or three worlds, one of the 'subject' (observer) one of the 'object' (cat) and one of the probabilities (quantum world). Exactly WHAT is manifesting itself, and why? Note that the quantum world is not interactive with the cat, usually, only through windows. And to measure one character momentarily doesn't mean the whole entangled cat vanish, nor the probabilities vanish, only that the subject gain massless information. This is just rubbish. Look: "It is not possible to know the value of all the properties of the system at the same time; those properties that are not known with precision must be described by probabilities. (Heisenberg's uncertainty principle)" The Universe is digital.

The "Lumo interpretation" clearly:

you describe the system by a density matrix evolving according to the right equation and it is always legitimate to imagine that the world collapsed to an eigenstate of the density matrix and the probabilities of different eigenstates are given by the corresponding eigenvalues of the density matrix. Incidentally, this also works for pure states for which "rho = psi.psi". In that case, "psi" is the only eigenstate of "rho" with the eigenvalue of "1", so you may collapse into "psi" with 100% probability which leaves "rho" completely unchanged. ;-) The only illegitimate thing to imagine is that the world has collapsed into a state which is not an eigenstate of "rho".

Uncertainty principle.
It means that generic pairs of properties,- but pairs of projection operators describing various Yes/No properties of a system - can't have well-defined values at the same moment. Pairs are usually oscillating, as instance solitons. Only (magnetic) monopoles can be 'singular'. What about the possible Higgs boson? Can it be a monopole?

Especially John von Neumann, before he began to say silly things, liked to emphasize that the nonzero commutators and the Heisenberg uncertainty principle is the actual main difference between classical physics and quantum physics. If the commutators were zero, the evolution of the density matrix would be equivalent to the evolution of the classical probabilistic distribution on the phase space.

What is this! A measurement without observer? A dead Universe?

Because the projection operators P and Q corresponding to two Yes/No questions about a physical system typically don't commute with one another...

A non-commutative digital Universe? Made of pairs Yes/No properties? But there must be some correlation? Some entanglement, both cannot be Yes. And two questions can also be dependent on each other. Ok, typically...

This main principle is the main "underlying reason" why the GHZM experiment or Hardy's experiment produce results that are totally incompatible with the classical or pre-classical reasoning. The classical reasoning is wrong, the quantum reasoning is right - and the nonzero commutators in the real world are the main reason why the classical reasoning can't agree with the observations.

Complementarity principle.

Bohr's favorite principle shows that the systems exhibit both particle-like and wave-like properties, but the more clearly you can observe the latter, the more obscure has to be the latter, and vice versa.

Shows no collapse! The wave-like patterns can be described as invisible fields? I remember Lubos disliked the work of the Zeilinger-group in Wien. They have clearly shown the duality and that both can coexist in an oscillation; expanding-compressing space/time.

The measurement devices follow the rules of classical physics. This is another source of misunderstandings, says Lubos. The apparatus behaves as a classical object. So in particular, you may assume that these classical objects - especially your brain, but you don't have to go up to your brain - won't ever evolve into unnatural superpositions of macroscopically distinct states. This was a point in which the Copenhagen interpretation was incomplete. They didn't quite understood decoherence, he claims.

Decoherence shows that the states of macroscopic (or otherwise classical-like) objects whose probabilities are well-defined [does he mean squared, on-shell?] are exactly those that we could identify with the "classical states" - they're eigenstates of the density matrix. The corresponding eigenvalues - diagonal entries of the density matrix in the right basis - are the predicted probabilities.

How can probabilities be well-defined? By the non-existent collapse? No!

However, they were saying that there is such a boundary at which the quantum subtleties may be forgotten for certain purposes and they were damn right. There is such a (fuzzy) boundary and we may calculate it with the decoherence calculus today. The loss of the information about the relative phase of the probability amplitudes between several basis vectors is the only new "thing" that occurs near the boundary.

The boundary is always fuzzy because decoherence is self-evidently a continuous process in which the off-diagonal elements quickly (at a certain time scale) but gradually drop to zero. (in comments)

This is only speculations. On the contrary the fuzziness problem of boundaries points to QM-effects (as instance quantum tunneling, sum over paths).

when the history contains a large collection of decohered outcomes, all observers may ultimately reconstruct the same macroscopic past. It's just the "intermediate state of affairs" before the individual events that are "fuzzy" - in Feynman's approach, one has to sum over all histories how to get from A to B so everything that happens between A and B are just "intermediate results" that don't have any objective properties.

But if the intermediate states gets inputs from outside? Information loss or gain? Look at photosynthesis! There are much happening in the intermediate states. How lock them into a black box? Topology/memory? Entropy?
A commenter, Illuminated:Nature is inherently quantum. But human language and thoughts have a classical structure despite the fact that they emerge from an underlying quantum substrate. So, to describe nature using language, equations and thoughts forces us to come up with a classical description of something which is inherently quantum. From a classical point of view, we have to treat the quantum nature as some black box oracle which takes in classical inputs and spits out classical outputs. If we insist upon coming up with a classical model of something which is inherently quantum, that is like constructing mechanical models of the electromagnetic aether. This leaves us with extremely inefficient classical auxiliary constructs like wave functions or density matrices which are exponentially long vectors, or a functional integral over some extremely large functional space of paths. Asking about the actual value of a particular wave function component, or the nature of the functional space of all paths is like asking about the cogs and gears making up the electromagnetic aether.
If we wish to calculate, until the day practical quantum computer simulations become available, we have to resort to classical equations. That's why we have to resort to wave functions, density matrices and path integrals. But otherwise, we should treat nature as a black box oracle. What do you do with black boxes? You only consider the inputs and outputs.

What the "subjective" nature of wave function means that wave function is really a gadget that collects all the information about the system that may be known to an observer, and that may be used to predict the future. The only subjective thing about it is that at different points of space and time, i.e. at locations of different observers, different things about the past are known and used as the input - initial wave function - while the rest is to be calculated probabilistically.

Predict is to computate probable outcome and project them into the future. Usually we use information in climps, analogies. So there are much implicit information in our predictions. Note the personal light-like CD a la TGD.
In a comment: When you say that the state is "psi", it means that "psi" is what you get by time evolution from all the most recent past data that you could have measured or otherwise learned.

Another observer CD who studies you may, however, use a different state vector such as 0.6 psi1 + 0.8 psi2 where psi1 is the state in which you hold a particle apparently in state psi1 and say that it's in state psi1, and another state where you hold a particle in state psi2 and prepare to do the calculation based on this assumption that it's in state psi2.

The observer CD may only decide that psi1 is correct and psi2 is wrong *after* he actually measures the combined system of you and the particle. Before he actually gets this knowledge, he will be using a different function than you. The wave function that a given observer is using depends on what he already knows about the outcomes that have taken place. This is the sense in which it's subjective.

Brain gets its information in state reduction process, or decoherence. 40Hz state reveals the much work done, suddenly 'collapsed' into 7Hz when the information is gained/selected. But much information (as probabilities) are rejected at the same time. This could also be compared to a 'sum over paths' ? Thanks for this. But this 'observer' CD is from TGD.

For more about the links between decoherence and the second law, see e.g. http://arxiv.org/abs/gr-qc/9402006

In comments: Even a geometrically small brain composed out of a small number of atoms will be able to "perceive" almost perfectly decohered outcomes - one may increase the amount of decoherence by extending the period of time in which the decoherence is taking place. However, again, if the system is small and the time is short so that the decoherence is very far from perfect, the objects shouldn't be imagined to observe sharp outcomes of any measurements. Such objects have to be treated as coherent quantum objects that don't perceive anything and that always have a chance to "forget" what they already learned.

In some sense, it's analogous to virtual particles. Virtual particles may momentarily violate inequalities for the energy, or tunnel through a barrier, and so on, as long as dE.dt doesn't exceed hbar, the mandatory uncertainty limit. Similarly, objects that are too small and don't perfectly decohere may "perceive" some outcome, but their perception may be undone in the future. This is the quantum realm. Sharp perceptions of outcomes that hold and that can't be revised only occur in the classical limit where the decoherence is perfect and completed. In the real world, it's never quite perfect, but because rho(A1,A2) goes like exp(-exp(t)), one gets very quickly extremely close to the ideal limit.

I think of dreaming state contra waked state. Lubos: All the imperfectly decohered perceptions could be subject to revisions - some of them would be illusions. - if you were just a generic microscopic system that has no chance to have macroscopic perceptions, the observer would have to describe you properly in the QM framework using a wave function that never collapses. This is the superorganisms, the bacterias as whole cells, not genomes. Or cells in the body, mitochondrias? What determines the quantum:classic measurements? Not size alone! Also the complexity, networks, expansion- compression. Rigidity:flexibility? Einstein talked of the inertia.
Lea Luke: Concerning the abstract "non-reality" of the complex vector spaces (Hilbert spaces?) themselves: I read that they are real in the sense that they carry momentum and energy even when no particles are there. Lubos answer: it has a relation to classical logic - rules for adding and multiplying probabilities in classical physics. Whenever the questions whose probability we calculate by QM are correctly formulated, the probabilities follow all the classical laws. P(A or B) is equal to P(A)+P(B)-P(A and B), P(U and V) = P(U) P(V) if U,V are independent, and so on, and so on. But the new thing is that in quantum mechanics, probabilities themselves are "composite", they're of the form

P(A) = sum (psi_c psi*_d A_cd)

where A_cd is the matrix representing the projection operator associated with property A. Note that the probability P is schematically "psi squared" - it's made of something more fundamental, something that is complex and may interfere.

The other, often emphasized, difference is that in quantum mechanics, you may *only* talk about the classical probabilities of properties that have already decohered from their alternatives. There is no probability of "intermediate" properties of a system prior to the measurement that would obey the classical laws - there are only wave functions, the more fundamental complex probability amplitudes, and these amplitudes are being added - before they're squared at the moment of the measurement.

Oh, my dear God. Would this psi squared be BETTER than p-adics and primes? These guys REFUSE to discuss with Matti??? I cannot believe my eyes. WHAT are they doing?

Correspondence principle

Both Bohr and Heisenberg also emphasized the correspondence principle, e.g. that the quantum equations reduce to the classical ones in the appropriate limit. If you study e.g. the evolution of the expectation value of "x" and "p", they will evolve according to the classical equations. It's the Ehrenfest theorem.

As discussed in the previous point, it is not enough to show that the world of classical perceptions will occur in the limit as well: we also need to know that the right "basis" will become relevant in the classical limit. Nevertheless, with the extra additions that had been demonstrated in recent decades, I mean decoherence, we know that it is true that the classical perception and choice of states does occur in the appropriate classical limit.

The holographic principle? Quantum world manifest on a surface (2-D, that is spacetime sheets)? What are the rules? This seems nonsense to me. Sorry Lubos.

This boundary doesn't mean that quantum mechanical laws ever break down. They never break down. What's true is that for large enough systems, one may use - and should use - the approximate classical scheme (the word "approximate" sounds too scary but in reality, these approximations are super excellent for all practical and even most of the impractical purposes) of asking questions because one may show that it becomes legitimate.

Comment by pbfred: Einstein forgot about the disadvantages of a principle theory and developed General Relativity which, if not a principle theory, builds on the principles of special relativity which cannot be visualized. This set the stage for Quantum Mechanics which itself is nonvisualizable and base on a good many principles . The biggest one is the Uncertainty Principle. Another is the principle of Wave-Particle Duality. The Pauli Exclusion Principle is just an algorithm that for some reason seems to work. Pauli admits in 1945 that he could find no reason as to why it worked. Of course, this applies to the Uncertainity Principle for it just happens to work--but why does it work?

In the comments from Lubos, a comment about Einstein worshiping:
Einstein has done great things. When I was a high school student, I read his Mein Weltbild obsessively and about 5 times. He was my God. And I did fundamentalistically believe that realism had to be correct up to some point, too. Then I tried to explain the simple patterns in atomic physics etc. and I had to be stealing pieces of quantum mechanics to explain it in my "would-be" realist framework. Of course, at the end, I had to rediscover/steal all of quantum mechanics.

When I just went through all the evidence and the critical properties and experiments, it became manifest that despite the "intuitive naturalness" of Einstein's expectations, he was just wrong. Physics is not about uncritical worshiping of cults. Of course, as time continued, it became clear to me that Einstein was fundamentally wrong about many things. It's not just quantum mechanics. It was his expectation that the strong force and the weak force (nuclear forces) would ultimately go away and become non-fundamental, and so on.

Of course when I was 15, but no longer at 16, I shared those beliefs. But these beliefs are just wrong. Despite his unusual and revolutionary contributions in a certain era, Einstein just wasn't able to stay in the "actual" top of physics after the mid 1920s, despite the fact that he of course remained the most popular and appreciated guy with the media. But science has made lots of progress after 1916 when GR was being completed. In my view, the quantum revolution was more profound than the relativistic one. It wasn't done by one person only - like Einstein's relativity - but the total importance was bigger. One must separate personal appraisals and emotions from science. It's just true that Einstein, despite his giant contributions and likability, wasn't at the top of the physics research since the 1920s. The idea that revolutionaries lose some flexibility to understand important new developments is much more universal. Think about Dirac vs renormalization, Feynman vs strings, and many many other examples.

If someone can't accept such things given the evidence, he's doing cult worshiping and not science. Science doesn't have its infallible prophets. It just doesn't work in this way. So I find the very focus in your comment on exciting emotions about Einstein something that shouldn't be done if we are supposed to talk about science. It's emotional harrassment, not science. Einstein was wrong whether it sounds popular or not.

Brian: " reading this blog is sort of like a physics PhD's version of right-wing talk radio." Ye, why should we? Lubos will never change.