The excitable membrane-biophysical theory and experiment

Very different biophysical theories can lead to similar or even identical predictions for a wide range of experiments. This was true for the original Rashevsky theory of membrane excitation, and the later Hill formulation. Similarly, the Hodgkin-Huxley equations for membrane current are based on two postulates: current proportional to total thermodynamic potential difference across the membrane, and the independence principle. Experiments used to confirm these postulates can be predicted as well by a model in which neither postulate applies.     

Model of autism: increased ratio of excitation/inhibition in key neural systems

Autism is a severe neurobehavioral syndrome, arising largely as an inherited disorder, which can arise from several diseases. Despite recent advances in identifying some genes that can cause autism, its underlying neurological mechanisms are uncertain. Autism is best conceptualized by considering the neural systems that may be defective in autistic individuals. Recent advances in understanding neural systems that process sensory information, various types of memories and social and emotional behaviors are reviewed and compared with known abnormalities in autism. Then, specific genetic abnormalities that are linked with autism are examined. Synthesis of this information leads to a model that postulates that some forms of autism are caused by an increased ratio of excitation/inhibition in sensory, mnemonic, social and emotional systems. The model further postulates that the increased ratio of excitation/inhibition can be caused by combinatorial effects of genetic and environmental variables that impinge upon a given neural system. Furthermore, the model suggests potential therapeutic interventions.     

On a method of storing information

A model for storing information is constructed on the postulates that (i) traces are left within the model by threshold changes, (ii) these traces are widespread, (iii) the cells in the model have properties statistically determined, and (iv) the stream of information is itself the encoding and decoding device. The model properties are studied and are found to contain many of the basic phenomena associated with learning by living organisms. In particular, this method of storing information exhibits a large storage capacity.     

Nucleotide recognition by the initiation factor aIF5B: Free energy simulations of a neoclassical GTPase

The GTPase aIF5B is a universally conserved initiation factor that assists ribosome assembly. Crystal structures of its nucleotide complexes, X‐ray(GTP) and X‐ray(GDP), are similar in the nucleotide vicinity, but differ in the orientation of a distant domain IV. This has led to two, contradictory, mechanistic models. One postulates that X‐ray(GTP) and X‐ray(GDP) are, respectively, the active, “ON” and the inactive, “OFF” states; the other postulates that both structures are OFF, whereas the ON state is still uncharacterized. We study GTP/GDP binding using molecular dynamics and a continuum electrostatic free energy method. We predict that X‐ray(GTP) has a ≈ 3 kcal/mol preference to bind GDP, apparently contradicting its assignment as ON. However, the preference arises mainly from a single, nearby residue from the switch 2 motif: Glu81, which becomes protonated upon GTP binding, with a free energy cost of about 4 kcal/mol. We then propose a different model, where Glu81 protonation/deprotonation defines the ON/OFF states. With this model, the X‐ray(GTP):GTP complex, with its protonated Glu81, is ON, whereas X‐ray(GTP):GDP is OFF. The model postulates that distant conformational changes such as domain IV rotation are “uncoupled” from GTP/GDP exchange and do not affect the relative GTP/GDP binding affinities. We analyze the model using a general thermodynamic framework for GTPases. It yields rather precise predictions for the nucleotide specificities of each state, and the state specificities of each nucleotide, which are roughly comparable to the homologues IF2 and aIF2, despite the lack of any conformational switching in the model. © 2012 Wiley Periodicals, Inc.     

One- and two-receptor models of opioid drug action

The history of models for opioid drug receptors is traced and two currently proposed models are compared, the first envisaging two rigid receptors, one for agonists and one for antagonists, while the second model postulates one single flexible receptor which in its native conformation fits opioid antagonists but is distorted when it binds to agonists. Important recent experiments are satisfactorily interpreted by both models but the flexible one-receptor model requires fewer assumptions and explains more facts.     

A Model of Cell Cleavage

A model is presented which describes, at least to a first approximation, the oserved changes in cell shape and the movement of surface markers associated with cleavage in some types of cells. The model postulates that the constraints governing cell cleavage are minimum surface area and constancy of cell volume. Equations are derived both for the case of symmetric as well as the case of asymmetric cleavage. It is pointed out that the generally symmetric character of cell cleavage is explicable if there is a positive correlation between internal cell pressure and the radii of curvature.     

Two-mutation model for carcinogenesis: joint analysis of premalignant and malignant lesions.

A model for carcinogenesis that postulates two rate-limiting events for malignant transformation is a generalization of the recessive oncogenesis hypothesis, according to which inactivation of homologous tumor suppressor genes leads to cancer. This model has been shown to be consistent with a large body of epidemiologic and experimental data and has recently been used for the analysis of altered hepatic foci in rodents. These foci are considered to be premalignant lesions. In this paper the necessary mathematics for the joint analysis of premalignant and malignant lesions are developed within the framework of this model.     

一种新的DNA复制和转录模型

DNA复制和转录有两种模型,一种是传统的滑动模型,复制和转录发生时参与反应的蛋白质沿DNA模板滑动.在另一种新提出的工厂模型中,固定在核结构上的蛋白质拉动模板来完成DNA的复制和转录.来自生物化学、生物物理学和细胞生物学等的实验证据表明,新的工厂模型是生物活体细胞内真实的复制和转录模式.     

Special Relativity at the Quantum Scale

It has been suggested that the space-time structure as described by the theory of special relativity is a macroscopic manifestation of a more fundamental quantum structure (pre-geometry). Efforts to quantify this idea have come mainly from the area of abstract quantum logic theory. Here we present a preliminary attempt to develop a quantum formulation of special relativity based on a model that retains some geometric attributes. Our model is Feynman''s “checker-board” trajectory for a 1-D relativistic free particle. We use this model to guide us in identifying (1) the quantum version of the postulates of special relativity and (2) the appropriate quantum “coordinates”. This model possesses a useful feature that it admits an interpretation both in terms of paths in space-time and in terms of quantum states. Based on the quantum version of the postulates, we derive a transformation rule for velocity. This rule reduces to the Einstein''s velocity-addition formula in the macroscopic limit and reveals an interesting aspect of time. The 3-D case, time-dilation effect, and invariant interval are also discussed in term of this new formulation. This is a preliminary investigation; some results are derived, while others are interesting observations at this point.     

The apoptosome activates caspase-9 by dimerization

The apical protease of the human intrinsic apoptotic pathway, caspase-9, is activated in a polymeric activation platform known as the apoptosome. The mechanism has been debated, and two contrasting hypotheses have been suggested. One of these postulates an allosteric activation of monomeric caspase-9; the other postulates a dimer-driven assembly at the surface of the apoptosome--the "induced proximity" model. We show that both Hofmeister salts and a reconstituted mini-apoptosome activate caspase-9 by a second-order process, compatible with a conserved dimer-driven process. Significantly, replacement of the recruitment domain of the apical caspase of the extrinsic apoptotic pathway, caspase-8, by that of caspase-9 allows activation of this hybrid caspase by the apoptosome. Consequently, apical caspases can be activated simply by directing their zymogens to the apoptosome, ruling out the requirement for allosteric activation and supporting an induced proximity dimerization model for apical caspase activation in vivo.     

Receptor editing: Genetic reprogramming of autoreactive lymphocytes

The clonal selection theory postulates that immune tolerance mediated selection occurs at the level of the cell. The receptor editing model, instead, suggests that selection occurs at the level of the B-cell receptor, so that self-reactive receptors that encounter autoantigen in the bone marrow are altered through secondary rearrangement. Recent studies in transgenic model systems and normal B cells, both in vivo and in vitro, have demonstrated that receptor editing is a major mechanism for inducing B-cell tolerance.     

A genetical model for vitiligo.

A genetical model is found to provide a good fit to family data on vitiligo. The model postulates that recessive alleles at a set of four unlinked diallelic loci are involved in the causation of the disorder. Under this multiple recessive homozygosis model, for normal X affected families ascertained through the affected parent, the expected segregation probability is .063; the estimated value is 0.53, which is not significantly different from the expected value. For normal X normal families ascertained through an affected offspring, the expected segregation probability is .037; the estimated value is .04.     

New strategy for virus discovery: viruses identified in human feces in the last decade

Emerging and re-emerging viruses continue to surface all over the world.Some of these viruses have the potential for rapid and global spread with high morbidity and mortality,such as the SARS coronavirus outbreak.It is extremely urgent and important to identify a novel virus near-instantaneously to develop an active preventive and/or control strategy.As a cultureindependent approach,viral metagenomics has been widely used to investigate highly divergent and completely new viruses in humans,animals,and even environmental samples in the past decade.A new model of Koch’s postulates,named the metagenomic Koch’s postulates,has provided guidance for the study of the pathogenicity of novel viruses.This review explains the viral metagenomics strategy for virus discovery and describes viruses discovered in human feces in the past 10 years using this approach.This review also addresses issues related to the metagenomic Koch’s postulates and the challenges for virus discovery in the future.     

Analytical comparison between Nixon–Logvinenko’s and Jung–Brown’s theories of slow neurofilament transport in axons

This paper develops analytical solutions describing slow neurofilament (NF) transport in axons. The obtained solutions are based on two theories of NF transport: Nixon–Logvinenko’s theory that postulates that most NFs are incorporated into a stationary cross-linked network and only a small pool is slowly transported and Jung–Brown’s theory that postulates a single dynamic pool of NFs that are transported according to the stop-and-go hypothesis. The simplest two-kinetic state version of the model developed by Jung and Brown was compared with the theory developed by Nixon and Logvinenko. The model for Nixon–Logvinenko’s theory included stationary, pausing, and running NF populations while the model used for Jung–Brown’s theory only included pausing and running NF populations. Distributions of NF concentrations resulting from Nixon–Logvinenko’s and Jung-Brown’s theories were compared. In previous publications, Brown and colleagues successfully incorporated slowing of NF transport into their model by assuming that some kinetic constants depend on the distance from the axon hillock. In this paper we defined the average rate of NF transport as the rate of motion of the center of mass of radiolabeled NFs. We have shown that for this definition, if all kinetic rates are assumed constant, Jung–Brown’s theory predicts a constant average rate of NF transport. We also demonstrated that Nixon–Logvinenko’s theory predicts slowing of NF transport even if all kinetic rates are assumed constant, and the obtained slowing agrees well with published experimental data.     

The reinfection threshold promotes variability in tuberculosis epidemiology and vaccine efficacy

Population patterns of infection are determined largely by susceptibility to infection. Infection and vaccination induce an immune response that, typically, reduces susceptibility to subsequent infections. With a general epidemic model, we detect a 'reinfection threshold', above which reinfection is the principal type of transmission and, consequently, infection levels are much higher and vaccination fails. The model is further developed to address human tuberculosis (TB) and the impact of vaccination. The bacille Calmette-Guérin (BCG) is the only vaccine in current use against TB, and there is no consensus about its usefulness. Estimates of protection range from 0 to 80%, and this variability is aggravated by an association between low vaccine efficacy and high prevalence of the disease. We propose an explanation based on three postulates: (i) the potential for transmission varies between populations, owing to differences in socio-economic and environmental factors; (ii) exposure to mycobacteria induces an immune response that is partially protective against reinfection; and (iii) this protection is not significantly improved by BCG vaccination. These postulates combine to reproduce the observed trends, and this is attributed to a reinfection threshold intrinsic to the transmission dynamics. Finally, we demonstrate how reinfection thresholds can be manipulated by vaccination programmes, suggesting that they have a potentially powerful role in global control.     

A model for regulation of the cell cycle incorporating cyclin A, cyclin B and their complexes

Abstract. t. A mathematical model for the cell cycle is proposed that incorporates the known biochemical reactions involving both cyclin A and cyclin B, the interactions of these cyclins with cdc2 and cdk2, and the controlling effects of cdc25 and weel. The model also postulates the existence of an as yet unknown phosphatase involved in the formation of maturation promoting factor. The model produces solutions that agree qualitatively with a wide variety of experimentally observed cell-cycle behavior. Conditions under which the model could explain the initial rapid divisions of embryonic cells and the transition to the slower somatic cell cycle are also discussed.     

Chromosome mutagenesis and cytogenetic monitoring]

A model of formation of radiation-induced cytogenetic damage is proposed on the basis of our own and literature data. The model postulates that localization of DNA damage and repair process play an important role in the final effect.     

On the Number of Rays in Starfish

Multiradiate starfish evolved independently in fourteen livingfamilies. Twenty living families are strictly 5-rayed. The FIVE-PLUShypothesis is that supernumerary rays develop separately fromthe five primary rays. The ontogeny of the primary rays is proposedto be highly integrated ("en bloc" hypothesis), closely timed(synchronic hypothesis) and a developmental constraint ("tamper-proof"hypothesis). The "en bloc" hypothesis postulates that the fiveprimary rays develop as a unit. The deep structure of this unitis believed to be a 2-1-2, BA-A-BA, organization. The synchronichypothesis postulates that there is only a brief time at metamorphosisduring which the "en bloc" pathway operates. There is a pausebefore the development of supernumerary rays. The "tamper-proof"hypothesis postulates that the "en bloc" pathway has no heritablevariation and cannot be co-opted for the production of supernumeraryrays. There is diversity of timing and pattern in the developmentof supernumerary rays. Postgeneration of rays in the rudimentand intercalary regeneration of rays in the imago are independentray-producing pathways that may have been co-opted variouslyand recurrently in the multiple origins of multiradiate starfish.     

On color perception

A simple geometrical model is presented, which explains the recent two-color projections of Edwin H. Land (Proc. Natl. Acad. Sci.,45, 115, 636, 1959), as well as the classical color mixing experiments. The model leads to a set of transformations similar to the Lorentz transformations of special relativity. This suggests that color is essentially a relative phenomenon. The experimental justifications of the model and the relation of its underlying postulates to the theory of evolution are discussed. Various consequences with regard to contrast enhancement, aperture colors and two-color projections are presented. A discussion of the related previous work is given and some implications for a possible neurophysiological process are indicated.     

Simulation of daytime vigilance by the additive interaction of a homeostatic and a circadian process

The two-process model of sleep regulation postulates that a homeostatic and a circadian process underlie sleep regulation. The timing of sleep and waking is accounted for by the interaction of these two processes. The assumptions of two separate processes or of a single process resulting from their additive interaction are mathematically equivalent but conceptually different. Based on an additive interaction, subjective alertness ratings in a forced desynchrony protocol and subjective sleepiness ratings in a photoperiod experiment were simulated. The correspondence between empirical and simulated data supports the basic assumption of the model. Received: 7 October 1993/Accepted in revised form: 22 January 1994