25 research outputs found
Antigenic Complementarity in the Origins of Autoimmunity: A General Theory Illustrated With a Case Study of Idiopathic Thrombocytopenia Purpura
We describe a novel, testable theory of autoimmunity, outline novel predictions made by the theory, and illustrate its application to unravelling the possible causes of idiopathic thrombocytopenia purpura (ITP). Pairs of stereochemically complementary antigens induce complementary immune responses (antibody or T-cell) that create loss of regulation and civil war within the immune system itself. Antibodies attack antibodies creating circulating immune complexes; T-cells attack T-cells creating perivascular cuffing. This immunological civil war abrogates the self-nonself distinction. If at least one of the complementary antigens mimics a self antigen, then this unregulated immune response will target host tissues as well. Data demonstrating that complementary antigens are found in some animal models of autoimmunity and may be present in various human diseases, especially ITP, are reviewed. Specific mechanisms for preventing autoimmunity or suppressing existing autoimmunity are derived from the theory, and critical tests proposed. Finally, we argue that Koch's postulates are inadequate for establishing disease causation for multiple-antigen diseases and discuss the possibility that current research has failed to elucidate the causes of human autoimmune diseases because we are using the wrong criteria
Stepping Beyond the Newtonian Paradigm in Biology. Towards an Integrable Model of Life: Accelerating Discovery in the Biological Foundations of Science
The INBIOSA project brings together a group of experts across many disciplines
who believe that science requires a revolutionary transformative
step in order to address many of the vexing challenges presented by the
world. It is INBIOSA’s purpose to enable the focused collaboration of an
interdisciplinary community of original thinkers.
This paper sets out the case for support for this effort. The focus of the
transformative research program proposal is biology-centric. We admit
that biology to date has been more fact-oriented and less theoretical than
physics. However, the key leverageable idea is that careful extension of the
science of living systems can be more effectively applied to some of our
most vexing modern problems than the prevailing scheme, derived from
abstractions in physics. While these have some universal application and
demonstrate computational advantages, they are not theoretically mandated
for the living. A new set of mathematical abstractions derived from biology
can now be similarly extended. This is made possible by leveraging
new formal tools to understand abstraction and enable computability. [The
latter has a much expanded meaning in our context from the one known
and used in computer science and biology today, that is "by rote algorithmic
means", since it is not known if a living system is computable in this
sense (Mossio et al., 2009).] Two major challenges constitute the effort.
The first challenge is to design an original general system of abstractions
within the biological domain. The initial issue is descriptive leading to the
explanatory. There has not yet been a serious formal examination of the
abstractions of the biological domain. What is used today is an amalgam;
much is inherited from physics (via the bridging abstractions of chemistry)
and there are many new abstractions from advances in mathematics (incentivized
by the need for more capable computational analyses). Interspersed
are abstractions, concepts and underlying assumptions “native” to biology
and distinct from the mechanical language of physics and computation as
we know them. A pressing agenda should be to single out the most concrete
and at the same time the most fundamental process-units in biology
and to recruit them into the descriptive domain. Therefore, the first challenge
is to build a coherent formal system of abstractions and operations
that is truly native to living systems.
Nothing will be thrown away, but many common methods will be philosophically
recast, just as in physics relativity subsumed and reinterpreted
Newtonian mechanics.
This step is required because we need a comprehensible, formal system to
apply in many domains. Emphasis should be placed on the distinction between
multi-perspective analysis and synthesis and on what could be the
basic terms or tools needed.
The second challenge is relatively simple: the actual application of this set
of biology-centric ways and means to cross-disciplinary problems. In its
early stages, this will seem to be a “new science”.
This White Paper sets out the case of continuing support of Information
and Communication Technology (ICT) for transformative research in biology
and information processing centered on paradigm changes in the epistemological,
ontological, mathematical and computational bases of the science
of living systems. Today, curiously, living systems cannot be said to
be anything more than dissipative structures organized internally by genetic
information. There is not anything substantially different from abiotic
systems other than the empirical nature of their robustness. We believe that
there are other new and unique properties and patterns comprehensible at
this bio-logical level. The report lays out a fundamental set of approaches
to articulate these properties and patterns, and is composed as follows.
Sections 1 through 4 (preamble, introduction, motivation and major biomathematical
problems) are incipient. Section 5 describes the issues affecting
Integral Biomathics and Section 6 -- the aspects of the Grand Challenge
we face with this project. Section 7 contemplates the effort to
formalize a General Theory of Living Systems (GTLS) from what we have
today. The goal is to have a formal system, equivalent to that which exists
in the physics community. Here we define how to perceive the role of time
in biology. Section 8 describes the initial efforts to apply this general theory
of living systems in many domains, with special emphasis on crossdisciplinary
problems and multiple domains spanning both “hard” and
“soft” sciences. The expected result is a coherent collection of integrated
mathematical techniques. Section 9 discusses the first two test cases, project
proposals, of our approach. They are designed to demonstrate the ability
of our approach to address “wicked problems” which span across physics,
chemistry, biology, societies and societal dynamics. The solutions
require integrated measurable results at multiple levels known as “grand
challenges” to existing methods. Finally, Section 10 adheres to an appeal
for action, advocating the necessity for further long-term support of the
INBIOSA program.
The report is concluded with preliminary non-exclusive list of challenging
research themes to address, as well as required administrative actions. The
efforts described in the ten sections of this White Paper will proceed concurrently.
Collectively, they describe a program that can be managed and
measured as it progresses
Receptor-Mediated Enhancement of Beta Adrenergic Drug Activity by Ascorbate In Vitro and In Vivo
RATIONALE: Previous in vitro research demonstrated that ascorbate enhances potency and duration of activity of agonists binding to alpha 1 adrenergic and histamine receptors. OBJECTIVES: Extending this work to beta 2 adrenergic systems in vitro and in vivo. METHODS: Ultraviolet spectroscopy was used to study ascorbate binding to adrenergic receptor preparations and peptides. Force transduction studies on acetylcholine-contracted trachealis preparations from pigs and guinea pigs measured the effect of ascorbate on relaxation due to submaximal doses of beta adrenergic agonists. The effect of inhaled albuterol with and without ascorbate was tested on horses with heaves and sheep with carbachol-induced bronchoconstriction. MEASUREMENTS: Binding constants for ascorbate binding to beta adrenergic receptor were derived from concentration-dependent spectral shifts. Dose- dependence curves were obtained for the relaxation of pre-contracted trachealis preparations due to beta agonists in the presence and absence of varied ascorbate. Tachyphylaxis and fade were also measured. Dose response curves were determined for the effect of albuterol plus-and-minus ascorbate on airway resistance in horses and sheep. MAIN RESULTS: Ascorbate binds to the beta 2 adrenergic receptor at physiological concentrations. The receptor recycles dehydroascorbate. Physiological and supra-physiological concentrations of ascorbate enhance submaximal epinephrine and isoproterenol relaxation of trachealis, producing a 3-10-fold increase in sensitivity, preventing tachyphylaxis, and reversing fade. In vivo, ascorbate improves albuterol's effect on heaves and produces a 10-fold enhancement of albuterol activity in "asthmatic" sheep. CONCLUSIONS: Ascorbate enhances beta-adrenergic activity via a novel receptor-mediated mechanism; increases potency and duration of beta adrenergic agonists effective in asthma and COPD; prevents tachyphylaxis; and reverses fade. These novel effects are probably caused by a novel mechanism involving phosphorylation of aminergic receptors and have clinical and drug-development applications
Transmission of West Nile Virus by Culex quinquefasciatus Say Infected with Culex Flavivirus Izabal
Unlike most known flaviviruses (Family, Flaviviridae: Genus, Flavivirus), insect-only flaviviruses are a unique group of flaviviruses that only infect invertebrates. The study of insect-only flaviviruses has increased in recent years due to the discovery and characterization of numerous novel flaviviruses from a diversity of mosquito species around the world. The widespread discovery of these viruses has prompted questions regarding flavivirus evolution and the potential impact of these viruses on the transmission of flaviviruses of public health importance such as WNV. Therefore, we tested the effect of Culex flavivirus Izabal (CxFV Izabal), an insect-only flavivirus isolated from Culex quinquefasciatus mosquitoes in Guatemala, on the growth and transmission of a strain of WNV isolated concurrently from the same mosquito species and location. Prior infection of C6/36 (Aedes albopictus mosquito) cells or Cx. quinquefasciatus with CxFV Izabal did not alter the replication kinetics of WNV, nor did it significantly affect WNV infection, dissemination, or transmission rates in two different colonies of mosquitoes that were fed blood meals containing varying concentrations of WNV. These data demonstrate that CxFV probably does not have a significant effect on WNV transmission efficiency in nature
lincRNAs act in the circuitry controlling pluripotency and differentiation
Although thousands of large intergenic non-coding RNAs (lincRNAs) have been identified in mammals, few have been functionally characterized, leading to debate about their biological role. To address this, we performed loss-of-function studies on most lincRNAs expressed in mouse embryonic stem (ES) cells and characterized the effects on gene expression. Here we show that knockdown of lincRNAs has major consequences on gene expression patterns, comparable to knockdown of well-known ES cell regulators. Notably, lincRNAs primarily affect gene expression in trans. Knockdown of dozens of lincRNAs causes either exit from the pluripotent state or upregulation of lineage commitment programs. We integrate lincRNAs into the molecular circuitry of ES cells and show that lincRNA genes are regulated by key transcription factors and that lincRNA transcripts bind to multiple chromatin regulatory proteins to affect shared gene expression programs. Together, the results demonstrate that lincRNAs have key roles in the circuitry controlling ES cell state.Broad InstituteHarvard UniversityNational Human Genome Research Institute (U.S.)Merkin Family Foundation for Stem Cell Researc
Editorial. Special Issue on Integral Biomathics: Can Biology Create a Profoundly New Mathematics and Computation?
The idea behind this special theme journal issue was to continue the work we have
started with the INBIOSA initiative (www.inbiosa.eu) and our small inter-disciplinary
scientific community. The result of this EU funded project was a white paper
(Simeonov et al., 2012a) defining a new direction for future research in theoretical
biology we called Integral Biomathics and a volume (Simeonov et al., 2012b) with
contributions from two workshops and our first international conference in this field
in 2011. The initial impulse for this effort was given a year earlier by a publication of
one of the guest editors of this issue (Simeonov, 2010) in this journal. This time we
wish to provide a broader forum and more space to elaborate in detail some of the
most interesting concepts we have encountered in our discussions, as well as to invite
some new contributions of particular interest in the field. Another goal we had in
mind was to collect and review as many provocative perspectives as possible on the
same key topic we are interested before making a decision to follow a more focused
notion that would lead to a funded research program.
Therefore we welcomed the generous suggestion of Professor Denis Noble, FRS, who
is also editor of this journal to prepare a special theme issue entitled: “Can biology
create a profoundly new mathematics and computation?”
It has taken a while to invite and collect the contributions. Most of them had a couple
of revision cycles and adjustments after having been thoroughly discussed with
colleagues, incl. the editors of this issue. We think that the result we have obtained at
the end is a satisfactory one, since we succeeded to integrate a diversity of original,
but sometimes controversial and mutually excluding concepts organized within
chapters of a self-contained volume. The task of compiling all this was not easy at all.
Despite our efforts to position the articles of different authors and themes in a way
allowing their easy comprehension and relation to each other within the individual
chapters, some of them still require a sort of introduction to dissolve possible
ambiguities. This is what we are going to do in the following few paragraphs with the
hope that the reader (and some of the authors) would excuse our failures