A note on the quantum-theoretic basis of primary genetic activity

In previous work (Bull. Math. Biophysics,23, 393–403, 1960) it was shown that, if primary genetic processes are of an essentially microphysical nature, the objects bearing the primary genetic information must act in a catalytic fashion. At the same time it was pointed out that the kind of catalysis involved in the primary genetic process was fundamentally different, in specific ways, from that occurring, e.g., in enzyme systems. The present work demonstrates that, if the information-bearing objects of the general theory are identified with molecules of DNA, and the primary gene products are considered to be RNA of the “messenger” variety, then the predictions of the general theory can be compared with experimental data from various recently isolated polymerase systems, which appear to “copy” a sequence of nucleotides from DNA into RNAin vitro, and with certainin vivo microbial systems. It is found that these data provide detailed support for the conclusions drawn from the general theory. However, it is emphasized that the identification of the information-bearing objects and primary gene products as DNA and RNA respectively, which allows us to compare the theory with the cited data, is by no means the only identification which can be made; i.e., other interpretations of the general theory are certainly not precluded. This research was supported by the United States Air Force through the Air Force Office of Scientific Research of the Air Research and Development Command, under Grant No. AF-AFOSR-9-63.     

A quantum-theoretic approach to enzyme specificity: Proposals for a new type of biochemical control mechanism

A quantum-theoretic approach to the problem of enzymic specificity is presented. The concept of a “measuring system” analogized with the enzyme is utilized. Along these lines a quantum mechanical hypothesis for the mechanism of enzyme reactions was advanced (Enzymologia,35, 117–130, 1968). In the measuring process an ℐ-observable, linked to the proper values of the substrate'sA ₁...A _m observables will indicate the state of the measuring apparatus. On the corresponding Hilbert space of the enzymesubstrate complexH _ES , through the respective statistical operatorU _ES we get a “state” vector [s, a]. Theng:Γ _S xΓ _E →Γ _ES , that is, to an oriented pair 〈s, a〉 ∈Γ _S xΓ _E will correspond a “state” vector [s, a], and to a proper valuei _k of ℐ will correspond, throughg, the respective equivalence classes of Г-spaces. Introducing the concept of enzyme-substrate complex entropyL _ES , a theorem is demonstrated asserting thatL _S =L _ES -L _E + 1/2kn wheren is the number of the degrees of freedom which may fluctuate. The values ofL _ES are denoted “specific values,” and it is demonstrated that a microphysical systemS may be a substrate specific forE, if and only if it can realize one of theL _ES specific values. Along these lines a model of a stochastic process for the enzymic reaction is constructed, and the set of Kolmogorov equations for the respective probabilities is derived. When a “perturbation” is induced in our model, an interesting prediction concerning the fluctuations in the kinetics of the corresponding enzyme is obtained. A relevant experimental proof ensued from these theoretical considerations. When a “gentle perturbation” was induced in a substrate by mild X-ray or UV-irradiations, an interesting oscillatory behavior of enzymic activity was recorded. A biochemical control mechanism is constructed (a simple “flip-flop” type) utilizing nonoverlapping oscillations in the activity of two enzymes at a key metabolic intermediate level. Eventually, a relevant experimental proof for the respective control model is presented.     

A mathematical approach to multiple genetic relationships

A fundamental concept in the treatment of genetic relationships is that of gene identity which first was introduced by Cotterman (1940). Based on this notion several measures of relationship evolved such as the inbreeding coefficient, the coefficient of kinship, and the identity coefficients; by means of these quantities joint and conditional phenotype probabilities could be derived. This paper is an attempt at a general mathematical treatment of genetic relationships: Identity states are defined for any number of individuals, a method is given for the calculation of the corresponding identity coefficients by means of generalized coefficients of kinship, and applications are emphasized.     

A statistical approach to finding overlooked genetic associations

Background  

Complexity and noise in expression quantitative trait loci (eQTL) studies make it difficult to distinguish potential regulatory relationships among the many interactions. The predominant method of identifying eQTLs finds associations that are significant at a genome-wide level. The vast number of statistical tests carried out on these data make false negatives very likely. Corrections for multiple testing error render genome-wide eQTL techniques unable to detect modest regulatory effects.     

A genetic approach to dissect sexually dimorphic behaviors

It has been known since antiquity that gender-specific behaviors are regulated by the gonads. We now know that testosterone is required for the appropriate display of male patterns of behavior. Estrogen and progesterone, on the other hand, are essential for female typical responses. Research from several groups also indicates that estrogen signaling is required for male typical behaviors. This finding raises the issue of the relative contribution of these two hormonal systems in the control of male typical behavioral displays. In this review we discuss the findings that led to these conclusions and suggest various genetic strategies that may be required to understand the relative roles of testosterone and estrogen signaling in the control of gender-specific behavior.     

细胞类型特异的遗传学操作：揭开复杂神经环路的面纱

现代神经科学的一个重要课题足阐明复杂神经环路及其细胞组成形成行为的机制。我们希望可以通过对特定神经元群体的区分和操作在引发行为的神经计算和特定神经元群体活性之间建立一种因果联系。运用BAC重组工程技术,我们建立了超过20个“敲入”驱动品系。在这些驱动品系中,Cre或者是可诱导的CreER能够在特定类掣的GABA能细胞中表达。另外,我们还建立了一些Cre报告小鼠品系和一。个基于病毒转染的蛋白表达系统。这些病毒包含一个Cre-激活的表达元件,可以将一些荧光蛋白或分了开关在体内以很高的效率表达。这种基因操作的策略可以使我们进行如下的一些观察和操作：（1）在突触水平观察中间神经元的形态和他们之间的联系;（2）观察中间神经元的活性及其过往的活动;（3）在生理的时间分辨率上操纵特定细胞群的发放和突触传递。这将使我们对复杂神经环路功能和组织的认识进入。个全新的领域。     

A probabilistic approach to some problems in blood-tissue exchange

The problem of exchange of substances between circulating blood and tissue is discussed in terms of a model with continuously distributed tissue characteristics. Consideration is given to the distribution of perfusion rates, the distribution of metabolism coefficients for a substance consumed at a rate proportional to its concentration, and the distribution of permeability coefficients for a slowly penetrating inert substance. Equations are derived for obtaining crude estimates of the moments of these distributions from exchange data.     

A Markovian approach to the control of genetic regulatory networks

This paper presents an approach for controlling gene networks based on a Markov chain model, where the state of a gene network is represented as a probability distribution, while state transitions are considered to be probabilistic. An algorithm is proposed to determine a sequence of control actions that drives (without state feedback) the state of a given network to within a desired state set with a prescribed minimum or maximum probability. A heuristic is proposed and shown to improve the efficiency of the algorithm for a class of genetic networks.     

A genetic approach to the species problem in wild potato

Wild potatoes are native to the Americas, where they present very wide geographical and ecological distribution. Most are diploid, obligate out-crossers due to a multiallelic gametophytic self-incompatibility (S) locus that prevents self-fertilisation and crossing between individuals carrying identical S-alleles. They have two alternative modes of reproduction: sexual (by seeds) and asexual (by stolons and tubers), which provide, respectively, for genetic flexibility in changing environments and high fitness of adapted genotypes under stable conditions. Since the early twentieth century, their taxonomic classification has been mostly based on morphological phenotypes (Taxonomic Species Concept). More recently, attempts have been made to establish phylogenetic relationships, applying molecular tools in samples of populations (accessions) with a previously assigned specific category. However, neither the reproductive biology and breeding relations among spontaneous populations nor the morphological and genetic variability expected in obligate allogamous populations are considered when the taxonomic species concept is applied. In nature, wild potato populations are isolated through external and internal hybridisation barriers; the latter, which are genetically determined, can be either pre-zygotic (pollen-pistil incompatibility) or post-zygotic (abortion of embryo, endosperm or both tissues, sterility, and hybrid weakness and breakdown in segregating generations). The internal barriers, however, can be incomplete, providing opportunities for hybridisation and introgression within and between populations and ploidy levels in areas of overlap. The widespread occurrence of spontaneous hybrids in nature was recognised in the mid-twentieth century. Using genetic approaches, results have been obtained that provide strong support to the assertion that populations are at different stages of genetic divergence and are not at the end of the evolutionary process, as presupposed by the Taxonomic Species Concept. Furthermore, since wild potatoes have uniparental and biparental overlapping generations, the Biological Species Concept - developed for sexually reproducing biparental organisms - cannot be applied to them. In this paper, morphological, genetic, molecular and taxonomic studies in wild potato are reviewed, considering the genetic consequences of their reproductive biology, in an attempt to shed light on the species problem, because of its relevance in germplasm conservation and breeding.     

A systems biology approach to genetic studies of complex diseases

Revealing mechanisms underlying complex diseases poses great challenges to biologists. The traditional linkage and linkage disequilibrium analysis that have been successful in the identification of genes responsible for Mendelian traits, however, have not led to similar success in discovering genes influencing the development of complex diseases. Emerging functional genomic and proteomic ('omic') resources and technologies provide great opportunities to develop new methods for systematic identification of genes underlying complex diseases. In this report, we propose a systems biology approach, which integrates omic data, to find genes responsible for complex diseases. This approach consists of five steps: (1) generate a set of candidate genes using gene-gene interaction data sets; (2) reconstruct a genetic network with the set of candidate genes from gene expression data; (3) identify differentially regulated genes between normal and abnormal samples in the network; (4) validate regulatory relationship between the genes in the network by perturbing the network using RNAi and monitoring the response using RT-PCR; and (5) genotype the differentially regulated genes and test their association with the diseases by direct association studies. To prove the concept in principle, the proposed approach is applied to genetic studies of the autoimmune disease scleroderma or systemic sclerosis.     

Computation of biopolymers: A general approach to different problems

A comparative analysis of some effective algorithms widely used in analysis, computation and comparison of chain molecules is presented. A notion of a stream in an oriented hypergraph is introduced, which generalizes a notion of a path in a graph. All considered algorithms looking over exponential sets of structures in polynomial time can be described as variants of a general algorithm of analysis of paths in graphs and of streams in oriented hypergraphs.     

A molecular genetic approach to the functioning of the immunity protein to colicin A

Summary A plasmid (pColAF1), derived from pColA, and lacking the region encoding Cai (colicin A immunity protein) and Cal (colicin A lysis protein) has been constructed. The strains carrying pColAF1 produce normal amounts of colicin A which remains in the cell cytoplasm and does not result in loss of viability. Similar results have also been obtained for transposon insertion mutants lacking Cai. Structure prediction analysis indicates that four peptide regions of Cai might span the cytoplasmic membrane. Since the NH₂-and COOH-terminal regions are charged, this analysis suggests a topology of the 178 residues polypeptide chain in which regions 38 to 70 and 124 to 143 might be exposed at the outer side of the cytoplasmic membrane. With mutants constructed using recombinant DNA techniques, we could demonstrate that the removal of a 30 residue COOH-terminal region, and mutations altering the surface exposed loop comprised of aminoacid residues 124–143 abolish the protecting function of Cai.     

An approach to inverse scattering problems

There are several reasons for investigating the inverse scattering problem in medical image processing. A typical case, that of ultrasonic fields, is considered. Assuming that a plane wave illuminates a weakly inhomogeneous two-dimensional object, the fundamental equation is derived for the scattered waves in integral as well as in differential forms. It is shown that the scattered waves observed on a circle surrounding the object is sufficient to specify the structure of the object. This information is summarized in a single term, which is a function of the wavenumber as well as the angles of incidence and observation. A successive approximation is applied to reconstruct the image of the object from this function. Since no analytic solution is available, several methods of approximations are proposed, and examples of computations are shown for the case of a cylindrical object.     

A genetic approach to characterizing complex promoters in E. coli

The chromosomal distributions of five families of mouse r-protein genes (S16, L18, L19, L30 and L32/33) were studied by Southern blot analysis of DNA from a panel of mouse-hamster hybrid cells containing various complements of mouse chromosomes. Our results indicated that members of a particular family are often located on more than one chromosome, that extensive clustering of many r-protein gene families on a few chromosomes is unlikely, and that there is no obligatory linkage of r-protein and rRNA genes.