Dear Colleagues, I’d like to share a possible sensation as of today if true:
http://phys.org/news/2016-05-complex-life-billion-years-earlier.html What would this mean in terms of our discussion about life and medicine? Best. Plamen On Tue, May 17, 2016 at 6:27 PM, Dr. Plamen L. Simeonov < plamen.l.simeo...@gmail.com> wrote: > This is a very interesting note for me, John! > So, the modern symptomatic medicine, the collection of data about illness > characteristics has its roots in philosophy? > > Best, > > Plamen > > > ____________________________________________________________ > > > On Tue, May 17, 2016 at 6:16 PM, John Collier <colli...@ukzn.ac.za> wrote: > >> Ironically, “semiotic” originally was a medical term referring to signs >> (symptoms) of disease. John Locke (my favourite modern philosopher) >> introduced the term as we use it today, and may have derived it from the >> Greek *seme*. But he also knew a lot about medicine (and just about >> everything else at the time, but he apparently lacked a sense of humour). >> >> >> >> From an online dictionary (the other I found had the first known use in >> 1880. Which is clearly wrong. So beware!): >> >> 1615-20; (def 3) < Greek *sēmeiōtikós* significant, equivalent to >> *sēmeiō-,*verbid stem of *sēmeioûn* to interpret as a sign (derivative of >> Greek *sēmeîon*sign) + *-tikos* -tic >> <http://www.dictionary.com/browse/-tic>; (def 4) < Greek *sēmeiōtik**ḗ* >> *,* noun use of feminine of*sēmeiōtikós,* adapted by John Locke (on the >> model of Greek *logik**ḗ* logic <http://www.dictionary.com/browse/logic>, >> etc.; see -ic <http://www.dictionary.com/browse/-ic> ) to mean “the >> doctrine of signs”; (defs 1, 2) based on Locke'scoinage or a reanalysis >> of the Gk word >> >> >> >> Also, from a medical dictionary: >> >> semiotic >> >> /se·mi·ot·ic/ (se″me-ot´ik) >> >> *1. **pertaining* to signs or symptoms. >> >> *2. **pathognomonic* >> <http://medical-dictionary.thefreedictionary.com/pathognomonic>. >> >> Dorland's Medical Dictionary for Health Consumers. © 2007 by Saunders, an >> imprint of Elsevier, Inc. All rights reserved. >> >> >> >> For which, if like me, you may further need: >> >> pathognomonic >> >> [path″og-no-mon´ik] >> >> specifically *distinctive* >> or characteristic of a disease or pathologic condition; denoting a sign or >> symptom on which adiagnosis can be made. >> >> >> >> >> >> John Collier >> >> Professor Emeritus and Senior Research Associate >> >> University of KwaZulu-Natal >> >> http://web.ncf.ca/collier >> >> >> >> *From:* Fis [mailto:fis-boun...@listas.unizar.es] *On Behalf Of *Stanley >> N Salthe >> *Sent:* Tuesday, 17 May 2016 4:21 PM >> *To:* Dr. Plamen L. Simeonov <plamen.l.simeo...@gmail.com>; fis < >> fis@listas.unizar.es> >> *Subject:* [Fis] _ Re: _ Re: _ Re: _ Towards a 3φ integrative medicine >> >> >> >> Plamen, Pedro -- >> >> >> >> It seems to me that perhaps Medicine should not look to mathematics for >> support or underpinning so much as to SEMIOTICS (that is, Peircean >> semiotics, being worked today as biosemiotics). Biosemiotics is, in the >> verbal conceptual realm, almost as complex and messy as medicine, and so >> the two might be matched up fruitfully! >> >> >> >> STAN >> >> >> >> On Tue, May 17, 2016 at 9:03 AM, Dr. Plamen L. Simeonov < >> plamen.l.simeo...@gmail.com> wrote: >> >> Daer Pedro, >> >> thank you for your entertaining way of presenting my Sisyphus theme about >> medicine in a nutshell, which was mostly enjoyable to read. Actually, you >> are right, medicine is "messy", which qualifies it more like a liberal art >> discipline rather than science, full of workshop type of hustle and bustle, >> ad hoc insights of mystic adepts followed by faithful scholars and mixed >> with cutting edge technology wherever possible (in the Western world). It >> appears that every effort to organize it in the manner we know in >> mathematics and physics is doomed to failure. I realise that the subject's >> depth reflected in my presentation is indeed overwhelming. Yet, it was not >> my intention to put a Sisyphus rock upon this forum. Thank you for your and >> Koichiro's simplified pedestrian analysis of the theme. We can go with thes >> rephrased set of questions further. >> >> >> >> >> >> On Tue, May 17, 2016 at 12:51 PM, Pedro C. Marijuan < >> pcmarijuan.i...@aragon.es> wrote: >> >> Dear Plamen, >> >> Thanks for the synthetic attempt. You have put together pretty complex >> strands of thought that become too demanding for a general response. I will >> concentrate in a few points. >> >> What is Medicine? In what extent is it amenable to "integration"? Is >> reductionism an anathema in medicine? Can we regularly ascend from cellular >> info flows to organs/systems, and to healthy individuals/environments? >> >> >> >> These are good general questions, but I'd rather wish to focus on one >> specific problem, e.g. the one of the metastatic melanoma that Koichiro >> addressed in his example and try to "dissect" it as in the article in his >> example. It is clear to me that I cannot focus on one single thing and >> brainstorm on it all the time. But the idea behind this concluding workshop >> was to be less philosophical and more practical in trying to investigate if >> we can reshape medicine as an extension of biology. After all, huge amounts >> of money are given for research here, more than in any other field, as far >> as I know. Are these investments justifyable in the way this "engineering >> science" is performing today? Is there anything that could make this >> discipline more predictable, at least at the curruculum level? >> >> >> The history of Medicine shows messiness in the highest degree. To note >> that it was not included in the Trivium/Quadrivium medieval scheme of >> knowledge, and was only accepted within the "mechanical arts" after Hugh of >> St. Victor compilation (XIII Century), many decades after the first >> Faculties of Medicine were created in Italy. Why medicine is so messy? Just >> go the wiki pages on the topic: hundreds of subspecialties are listed, and >> under all those terms we imply all the internal and external ("natural") >> phenomena that can derail and put out of track the advancement of a life >> cycle. Each one of those specialties has to arrange its own world of >> knowledge, with lots of analytical and synthetic avenues not amenable to >> neat overall schemes and to formal approaches except in some reduced >> pockets. Successful reductionist strategies and analytical techniques are >> piled up with holistic views, and reams of tacit knowledge (indeed medicine >> is a very stratified small world of "lords", "masters", "disciples", >> "servants", and "beginners"). >> >> >> >> This is all true. But it is also true that medicine has been always very >> important for us human beings. >> >> >> >> So, like in engineering, one has to be suspicious of far reaching >> implications for the term "integrative". Not necessarily in this case with >> the "3φ" connotation. >> >> >> >> Indeed, there coud be a "3φ", a "4φ", or a "3φ+ 1ψ", ... etc. Greek >> alphabet built polynomial connotations encoded in this prefix. The question >> is wether we can use such kind of combination from the known natural >> science disciplines and extend them by some humanitarian fields in order to >> address key issues in an organised and diligent manner in medicine. We know >> well that there are both serios conflicts between some branches and efforts >> to reconcile them. The prefix I used was to make clear that we are asking >> for a novel kind of integration, if possible. Yet this prefix definition >> should not be considered "fixed" once for ever. >> >> But the strong reliance on criticality could be subject to scrutiny. >> Quite many cellular / biomolecular phenomena do not especially rely on >> criticality --perhaps the most essential ones, related to "codes", genomic >> maintenance, protein synthesis, protein degradation, signaling, apoptosis, >> etc. Why the integrative strategy should rely on a term that >> notwithstanding strong physical grounds, has relatively thin explanatory >> capability in the biological? >> >> >> >> Criticality is a phenomenon that holds both for living and non-living >> matter. This is something that "matters". Of course, one could take >> "autopoiesis" instead, which is also a good choice. I am not sure how far >> we can go with this this "criticality" bus. I had to start somewhere my >> talk, and I made this choice to facilitate the transition to medicine. If >> anyone has a better suggestion, I do not mind. >> >> >> It is a long story of looking for responses "where the physical/math >> light is" and not where the biol. problems are. >> >> >> >> I agree. This is the real issue. How can ""3φ", "4φ", or "3φ+ 1ψ + µ " >> help us is the question. >> >> My view, I can be wrong but I have worked considerably on the matter, is >> that cellular signaling, the crisscrossing of info flows that provide the >> singular intelligence and adaptability of organisms, is not well >> articulated yet. Neither in evo-devo, nor in physiology, medicine and >> health. In this regard all the present parlance on information processing >> that accompanies the tremendous technological info-tech revolution does not >> represent a help, maybe the opposite. >> >> >> >> Unfortunately, you appear to be right. I am also not convinced that Big >> Data is blessing rather than a curse. >> >> >> The deep info problems are taken as already solved and articulated >> synthesis are undertaken as mere agglutinations. Maybe the problem is too >> deeply complex, and medicine is as always too messy. >> >> >> >> The question we could try to answer here is: can we do something to >> disentangle the spaghetti dish of medicine? >> >> >> Sorry if seemingly I have joined the "Cassandra" club! >> >> >> >> I don't think so. Yours are fair concerns. >> >> Best, >> >> Plamen >> >> >> >> Best--Pedro >> >> >> >> >> >> El 14/05/2016 a las 9:49, Dr. Plamen L. Simeonov escribió: >> >> Dear Colleagues, >> >> >> >> My contribution will finalize the discussion on phenomenology in the >> domains of biology, mathematics, cyber/biosemiotics and physics by the >> previous speakers (Maxine, Lou, Sœren and Alex) with a “challenging topic” >> in *3φ integrative medicine*. *You may wish to skip the small font text >> notes following each underscored phrase like the one below.* >> >> >> >> *Note 1:* Although this term is often used as synonym for holistic >> healing (s. ref. list A), its meaning in this context with the prefix 3φ >> goes much “deeper” into the disciplines’ integration leaving no room for >> speculations by mainstream scientists. The concept is a linguistic choice >> of mine for the intended merge of the complexity sciences *ph*ysics and >> *ph*ysiology with *ph*enomenology for application in modern medicine >> along the line of integral biomathics (s. ref. list B). >> >> >> >> It is rooted in the last presentation of Alex Hankey, since it naturally >> provides the link from physics to physiology and medicine, and thus to an >> anthropocentric domain implying a leading part of phenomenological studies. >> To begin, I compiled a précis of Alex’ thesis about self-organized >> criticality (s. ref. list C) from his paper “A New Approach to Biology and >> Medicine” -- the download link to it was distributed in a previous email of >> him -- and extended it with my reflections including some questions I hope >> you will resonate on. >> >> >> >> I am curious of your opinion about how to apply the scientific method, >> and in particular mathematics and information science, to study illness and >> recovery as complex phenomena. >> >> >> >> *Alex Hankey: self-organized criticality and regulation in living systems* >> >> >> >> *There is a continuous growth and change at the end of a phase transition >> in an organism, i.e. at its critical point, which is the end point of phase >> equilibrium.* >> >> >> >> *Both endo and exo, genetics and epigenetics are important for life.* >> >> >> >> *Self-organized criticality* is a characteristic state of a system at >> its critical point generated by self-organization during a long transient >> period at the complexity edge between order/stability/predictability and >> disorder/chaos/unpredictability. >> >> >> >> *Regulation of growth, form and function as a balance between health and >> illness.* The role of regulation and homeostasis in maintaining the >> structure and function of living systems is critical. Every deviation from >> a regulated state of being leads to imbalances, failures and subsystem >> dysfunction that is usually transitory, but could also become >> life-threatening, if the organism cannot find a way to restore quickly to a >> balanced, healthy state. Living beings are robust and fault-tolerant with >> respect to hazards; they possess multiple alternative pathways for >> supplying and maintaining their existential functions. However, some state >> transitions in response to severe harms can become practically >> irreversible, because of the deep evolutionary interlocking between the >> participating entities and processes. Sometimes the normal functioning of >> the organism cannot be easily restored by its natural repair processes, >> especially when adversities reoccur frequently, and the organism fails ill. >> >> >> >> *Synchronicity of action and information between the building blocks of a >> living system.* There is a need for every physiological function to be >> correctly coordinated with all other “peer” functions. Information flows >> within a living system interconnect all physiological functions and organs >> at multiple levels into a single mesh of regulatory interconnections. >> Multiple feedback-control loops enable the cross-functional interlocking of >> both healthy and ill state changes of the organism. >> Adjacent/peripheral/secondary homeostasis processes act as fine-tuning >> catalyzers of substrate ratios and process rates exchanged within the >> living system. Imbalances of these quantities lead to excess/blockage or >> scarcity/draining of essential nourishment and information exchange >> pathways. >> >> >> >> *Regulation at criticality* not only fine-tunes a process, it *optimizes* >> it for survival: with respect to a given generation’s available >> possibilities in the light of the past generations’ possibilities. To >> survive an organism or a species needs to develop optimal >> *response-ability* to environmental distress. >> >> >> >> *New ecological definition of life according to Hankey: self-regulating, >> self-reproducing systems that maximize efficiency of function to maximize >> competitiveness in their chosen environment. * >> >> >> >> *Summary: Elements of self-organized criticality* >> >> >> >> 1. Criticality >> 2. Edge of the chaos >> 3. Self-organized criticality >> 4. 1/f fractal patterns of response >> >> >> >> *… and beyond* >> >> >> >> I wish to add a 5th aspect to this definition from the perspective of >> integral biomathics: >> >> >> >> 1. *Phenomenology* >> >> >> >> The latter is a largely studied matter in contemporary medicine (s. ref. >> list D), at least at the macro, interpersonal *level*. >> >> >> >> *Note 2*: A level refers to the compositional hierarchy defining levels >> by scale. >> >> >> >> *The key question in such a “deep holistic” physically-phenomenological >> physiology (*3φ*)** is how to define or comprehend (self-organized) >> criticality operationally within the unifying framework of biomathematics >> and biocomputation*. Indeed, a single temporary imbalance within a >> living system regarded as disease involves multiple agents, perspectives >> and interpretations at all levels altogether, moreover *simultaneously*. >> >> >> >> *Note 3*: Simultaneously at different levels involves very different >> sized 'moments' at the different scales. >> >> >> >> So, how should we approach and take into account the other levels/scales >> in order to derive a reliable diagnosis and *therapy*? >> >> >> >> *Note 4*: The notion of “subject” becomes plural (“subjects”) as >> superposition of quantum states to survive the integration of the multiple >> first-person subjective descriptions and the standard third-person >> objective one. >> >> >> >> Until now criticality has been *non-phenomenological*. >> >> >> >> *Note 5:* In their 2012 paper “No entailing laws, but enablement in the >> evolution of the biosphere” Longo, Montévil and Kauffman claim that >> biological evolution “marks the end of a physics world view of law entailed >> dynamics” (http://arxiv.org/abs/1201.2069). They argue that the >> evolutionary phase space or space of possibilities constituted of >> interactions between organisms, biological niches and ecosystems is “ever >> changing, intrinsically indeterminate and even (mathematically) >> unprestatable”.Hence, the authors' claim that it is impossible to know >> “ahead of time the 'niches' which constitute the boundary conditions on >> selection” in order to formulate laws of motion for evolution. They call >> this effect “radical emergence”, from life to life. Yet this applies to >> abiotic dissipative structures like tornadoes as well. Living beings are >> not radically different in this respect. In their study of biological >> evolution, Longo and colleagues carried close comparisons with physics. >> They investigated the mathematical constructions of phase spaces and the >> role of symmetries as invariant preserving transformations, and introduced >> the notion of “enablement” to restrict causal analyses to Batesonian >> differential cases (1972: “the difference that makes a difference”). The >> authors have shown that mutations or other “causal differences” at the core >> of evolution enable the establishment of non-conservation principles, in >> contrast to physical dynamics, which is largely based on conservation >> principles as symmetries. Their new notion of “extended criticality” also >> helps to understand the distinctiveness of the living state of matter when >> compared to the non-animal one. However, their approach to both physics and >> biology is also *non-phenomenological*. The possibility for endo states >> that can trigger the “(genetic/epigenetic) switches of mutation” has not >> been examined in their model. This is intended to be different in 3φ* >> integrative medicine*. >> >> If we split a human body into macro (patient), mezzo (systems) and micro >> levels (cells) three distinct questions regarding phenomenology arise: i) >> *how* these levels pervade into each other with larger scale providing >> context (boundary conditions) and lowest scale providing raw materials for >> middle scale to function, monitor and control vital processes, ii) >> *who/which* are the agents taking care for this to happen spontaneously, >> and iii) *what kind and role* plays information in the context of i) and >> ii). After all what we are concerned about is modeling the agency of the >> systems in the mezzo level. >> >> >> >> Where should we go from here? >> >> >> >> In particular, I am interested to know *what kind of >> scientific-phenomenological methodology can be developed and applied for >> investigating *the following three major groups of ailments: >> >> >> >> 1. *oncological diseases* with a particular focus on spatial and >> temporal heterogeneity both in terms of flawed histological structures and >> biochemical reactions; >> >> >> 1. *neuro-degenerative disorders* such as vascular dementia, >> Parkinson and Alzheimer diseases: >> >> >> 1. *altered organ and physiological system failures* such as the >> Multiple Organ Dysfunction Syndrome (MODS), cardiovascular and autoimmune >> diseases. >> >> >> >> In the first group, the *extreme diversity of cancer tissue structures >> and circulating tumor cells (CTC) concentrations over both spatial and >> temporal scales* makes the reliable classification, diagnosis, >> model/hypothesis generation, forecast and treatment of individual patients >> very difficult. This is a real challenge for modern pathology. Another >> problem is that pathologists are actually dealing with random tissue and >> blood samples over irregular periods, which hinder the exact 3D >> histological reconstruction of the tumor formations and tracing their >> development over time and space. Using additional means such as diagnostic >> sonography, CT, MRT and PET images do not improve sufficiently the >> hypotheses about the individual cancer morphology and development. All this >> makes tumor classification and diagnosis, even when analyzing >> high-resolution digital images from biopsy slices by means of virtual >> microscopy, very difficult and often a guesswork also for experts. The >> recent advances in high-performance medical scanning and automation >> systems, computerized visualization and graphical modeling tools, as well >> the collection of huge amounts of anonymous patient data in specialized >> medical databases make the impression that the solution of these problems >> is only a question of more automation, performance, investment and time. >> However, many pathologists begin to realize a third problem, namely that >> *tumors >> appear to be unique in their histological structure and development*, >> related to the personal history and the overall state of health of the >> individual patients. This argument reveals the need for developing a more >> personalized and differentiated medicine that goes over scales without >> becoming purely symptomatic, causality-driven and reductionistic. >> >> >> >> Recent research in the other two fields leads to the same conclusion. >> Therefore, I think that we may be able to develop and test hypotheses about >> emergence and development of deficiency and illness that will lead to >> individual therapies in *3φ* integrative medicine. Your ideas regarding >> this assumption are very welcome. >> >> >> >> Some interesting questions bridging the previous discussion sessions to >> this one are: >> >> >> >> - Why does a human embryo repeat the evolutionary history of its >> species when going through its development stages? Is it because it is more >> secure to project and set up the execution of a future life plan by tracing >> and bodily memorizing a series of evolutionary encoded (successful) “locks” >> through equilibrium states at the edge of criticality? >> >> >> >> - Which is the *vital *role of recursion and repetition of life >> processes including their material and information exchange flows in the >> criticality driven self-regulation for recovery from imbalances and the >> reversibility and healing of diseases? How can we effectively model such >> processes? >> >> - Do we make difference between a physicist’s time and a >> biologist’s time in complex living systems? >> >> >> >> * I look forward to your feedback and notes on the subject.* >> >> >> >> *References:* >> >> *A. Integrative Medicine* >> >> Integrative Medicine: https://en.wikipedia.org/wiki/Integrative_medicine >> <http://www.wikiwand.com/en/Integrative_medicine> >> >> What Is Integrative Medicine?: >> >> >> http://www.webmd.com/a-to-z-guides/features/alternative-medicine-integrative-medicine >> >> >> >> Integrative Medicine Research: >> >> http://www.journals.elsevier.com/integrative-medicine-research/ >> >> >> >> Advances in Integrative Medicine >> >> http://www.journals.elsevier.com/advances-in-integrative-medicine >> >> >> >> *B. Integral Biomathics* >> >> Integral Biomathics: >> >> https://en.wikipedia.org/wiki/Integral_Biomathics >> <http://www.wikiwand.com/en/Integral_Biomathics> >> >> Integral Biomathics: A Post-Newtonian View into the Logos of Bios >> >> https://arxiv.org/ftp/cs/papers/0703/0703002.pdf >> >> On Some Recent Insights in Integral Biomathics: >> >> https://arxiv.org/ftp/arxiv/papers/1306/1306.2843.pdf. >> >> Integral Biomathics Reloaded: 2015 (free access until July 19th 2016): >> >> http://www.sciencedirect.com/science/article/pii/S0079610715001509 >> >> >> >> *C. Self-organized criticality**:* >> >> >> >> Self-organized criticality: >> >> https://en.wikipedia.org/wiki/Self-organized_criticality >> <http://www.wikiwand.com/en/Self-organized_criticality> >> >> >> >> Self-organized criticality (SOC): >> >> http://www.johnboccio.com/courses/SOC26/15-SOC.pdf >> >> >> >> Self-organized criticality: >> >> >> http://web.mit.edu/8.334/www/grades/projects/projects12/V.%20A.%20Golyk.pdf >> >> >> >> Self-organized criticality – what it is and what it isn’t >> >> >> http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.96.8017&rep=rep1&type=pdf. >> >> >> >> >> *D. Phenomenology in Medicine* >> >> >> >> The meaning of illness: a phenomenological approach to the >> physician/patient relationship: >> https://baylor-ir.tdl.org/baylor-ir/handle/2104/8286 ; >> http://hdl.handle.net/2104/8286. >> >> >> >> Body Matters: A Phenomenology of Sickness, Disease, and Illness: >> >> http://philpapers.org/rec/AHOBMA. >> >> >> >> Suffering Transfigured: Phenomenological Personalism In the >> Doctor-Patient Relationship: >> http://elischolar.library.yale.edu/cgi/viewcontent.cgi?article=1658&context=ymtdl >> . >> >> The challenge of neuroscience: Psychiatry and phenomenology today: >> https://www.klinikum.uni-heidelberg.de/fileadmin/zpm/psychatrie/fuchs/Challenge_of_Neuroscience.pdf. >> >> >> >> >> Rediscovering Psychopathology: The Epistemology and Phenomenology of the >> Psychiatric Object: >> http://cfs.ku.dk/staff/zahavi-publications/Rediscovering_Psychopathology.pdf >> . >> >> PHENOMENOLOGY IN PSYCHIATRY: >> http://www.wpanet.org/uploads/Sections/Philosopy_and_Humanities/Phenomenology-in-Psychiatry.pdf. >> >> >> >> >> *Plamen* >> >> ____________________________________________________________ >> >> 2015 JPBMB Special Issue on Integral Biomathics: Life Sciences, >> Mathematics and Phenomenological Philosophy >> <http://www.sciencedirect.com/science/journal/00796107/119/3> >> >> (note: free access to all articles until July 19th, 2016) >> >> >> >> 2013 JPBMB Special Issue on Integral Biomathics: Can Biology Create a >> Profoundly New Mathematics and Computation? >> <http://www.sciencedirect.com/science/journal/00796107/113/1> >> >> >> >> 2012 Integral Biomathics: Tracing the Road to Reality >> <http://www.springer.com/engineering/computational+intelligence+and+complexity/book/978-3-642-28110-5> >> >> >> >> 2011 INtegral BIOmathics Support Action (INBIOSA) <http://www.inbiosa.eu> >> >> >> ____________________________________________________________ >> >> >> >> >> >> >> >> -- >> >> ------------------------------------------------- >> >> Pedro C. Marijuán >> >> Grupo de Bioinformación / Bioinformation Group >> >> Instituto Aragonés de Ciencias de la Salud >> >> Centro de Investigación Biomédica de Aragón (CIBA) >> >> Avda. San Juan Bosco, 13, planta X >> >> 50009 Zaragoza, Spain >> >> Tfno. +34 976 71 3526 (& 6818) >> >> pcmarijuan.i...@aragon.es >> >> http://sites.google.com/site/pedrocmarijuan/ >> >> ------------------------------------------------- >> >> >> _______________________________________________ >> Fis mailing list >> Fis@listas.unizar.es >> http://listas.unizar.es/cgi-bin/mailman/listinfo/fis >> >> >> >> >> _______________________________________________ >> Fis mailing list >> Fis@listas.unizar.es >> http://listas.unizar.es/cgi-bin/mailman/listinfo/fis >> >> >> > >
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