Fixed-bin analysis for statistical evaluation of continuous distributions of allelic data from VNTR loci, for use in forensic comparisons.

The detection of DNA polymorphisms by RFLP analysis is having a major impact on identity testing in forensic science. At present, this approach is the best effort a forensic scientist can make to exclude an individual who has been falsely associated with an evidentiary sample found at a crime scene. When an analysis fails to exclude a suspect as a potential contributor of an evidentiary sample, a means should be provided to assess suitable weight to the putative match. Most important, the statistical analysis should not place undue weight on a genetic profile derived from an unknown sample that is attributed to an accused individual. The method must allow for limitations in conventional agarose-submarine-gel electrophoresis and Southern blotting procedure, limited sample population data, possible subpopulation differences, and potential sampling error. A conservative statistical method was developed based on arbitrarily defined fixed bins. This approach permits classification of continuous allelic data, provides for a simple and portable data-base system, and is unlikely to underestimate the frequency of occurrence of a set of alleles. This will help ensure that undue weight is not placed on a sample attributed to an accused individual.     

Short-term activity cycles in ants: A phase-response curve and phase resetting in worker activity

Single, isolated worker ants are known to become spontaneously active and to respond to interactions with other, active ants. Here I explore the consequences of an interaction between two worker ants on the timing of activity. Isolated worker ants become active after an interval that is characteristic for each individual. The effect of an interaction between two worker ants is strongly dependent on when the interaction takes place. The effect of an interaction is always to decrease the expected interval until the onset of activity. By studying the effect of an interaction on subsequent intervals of activity, it is possible to reject the hypothesis that the change in timing of activity is due to a change in the characteristic period of activity. Rather, the data are consistent with the hypothesis that an interaction causes a phase shift in the normal activity oscillation. The phase-response curve is derived from the observational data. A knowledge of the dynamics of the interactions of individual ants is necessary in order to begin to reconstruct the patterns of colony behavioral activity.     

Echocardiography.

Imaging echocardiography is an important extension of the clinical examination and will answer most questions in an emergency-for example, whether an enlarged cardiac shadow on the chest radiograph represents ventricular dilatation or an effusion. Doppler ultrasonography is essential for hospitals with an interest in cardiology because it provides direct haemodynamic data that are complementary to imaging. It requires more skill than imaging and may also be time consuming. Colour flow Doppler mapping is speedy and simple to use and aids the interpretation of continuous wave Doppler. It is therefore a natural companion to conventional Doppler, but there would have to be a high clinical load to justify its purchase.     

An analysis of extended and exponentially-fed-batch cultures.

Under certain conditions it is shown that an extended culture is equivalent to an exponentially-fed-batch culture, that an exponentially-fed-batch culture (and an extended culture) can be maintained at a steady state and that an exponentially-fed-batch culture may be mimicked by a continuous-flow culture with a constant dilution rate. Operational conditions required to maintain steady states are specified.     

1H, 13C and 15N backbone and side chain resonance assignments of a 28 kDa active mutant of maize ribosome-inactivating protein (MOD)

We report the full resonance assignments of MOD, which is an active mutant of maize ribosome-inactivating protein (mRIP). mRIP is a unique RIP which is synthesized as an inactive precursor and processed by removal of an internal inactivation region to yield an active form.     

The logical structure of irreversible systems transformations: A theorem concerning Dollo's law and chaotic movement

The argument of historical irrevocability as an explanation for the irreversibility of organismic evolution is reconsidered. It is examined under which conditions a chain of transformations never can lead to a state equivalent to a previous one. It is shown to be sufficient to take into consideration that the environment of an organ also consists of the other organs in an organism. Under this prerequisite it is impossible to reach an ancestral state once more. This type of irreversibility depends solely on the mutual interdependency of characters within one organism. No reference to statistical arguments is necessary. The relationship between chaotic dynamic systems and the present theory is discussed.     

Kinetics of the conversion of glucose to gluconic acid by Pseudomonas ovalis

The concept of a “critical oxygen concentration” is conventionally considered to hold for the submerged aerobic fermentation of glucose to gluconic acid. Above the critical level the fermentation rate is supposedly independent of oxygen concentration. In this work it is shown that, at a given agitation rate, the fermentation is independent of dissolved oxygen when above the critical. However, an increase in the agitation rate results in an increase in the fermentation rate. This increase was shown to be accompanied by an increase in the gluconolactone concentration in the broth. Gluconolactone, an intermediate in the reaction pathway, is hydrolyzed nonenzymatically to gluconic acid. Evidence is presented to suggest that the increased gas-liquid interfacial area brought about by increased agitation causes an increased net rate of lactone formation. This in turn results in an increased rate of hydrolysis of the lactone to gluconic acid. A model is presented hypothesizing that negatively charged cells adsorb at the gas-liquid interface. These cells attract hydrogen ions, causing a lowering of the pH in the film around the bubbles. It is this lowered pH which is considered to bring about increased fermentation rates when the interfacial area is increased. Supporting evidence is presented.     

Xenogenetics in multifactorial disease susceptibility

Susceptibility to multifactorial disease includes both genetic and environmental components. These two aspects of susceptibility are interlinked through genetic control of an individual's response to the environment. As a first step in identifying disease susceptibility genes that influence the response of an individual to foreign compounds (xenobiotics), it is necessary to study disorders in which there is an identified environmental trigger. Establishing a DNA resource from individuals with known environmental exposure (‘a xenogenetic register’) for diseases with an established environmental aetiology is an essential step in beginning to understand how environmental factors contribute to the susceptibility to polygenic diseases. A complementary approach to identification of environmental factors is suggested using a comparison of genetically homogeneous subdivisions of individuals with polygenic disease where there is no clue to the environmental trigger.     

Reconstructing an ultrametric galled phylogenetic network from a distance matrix

Given a distance matrix M that specifies the pairwise evolutionary distances between n species, the phylogenetic tree reconstruction problem asks for an edge-weighted phylogenetic tree that satisfies M, if one exists. We study some extensions of this problem to rooted phylogenetic networks. Our main result is an O(n(2) log n)-time algorithm for determining whether there is an ultrametric galled network that satisfies M, and if so, constructing one. In fact, if such an ultrametric galled network exists, our algorithm is guaranteed to construct one containing the minimum possible number of nodes with more than one parent (hybrid nodes). We also prove that finding a largest possible submatrix M' of M such that there exists an ultrametric galled network that satisfies M' is NP-hard. Furthermore, we show that given an incomplete distance matrix (i.e. where some matrix entries are missing), it is also NP-hard to determine whether there exists an ultrametric galled network which satisfies it.     

Immune Response to Combination Therapy for Non-Hodgkin Lymphomas

A parametric model of tumor response to combination therapy in the presence of an immune system is described. Synergistic mechanisms which induce tumor regression are simulated with a coupled set of equations. The simulations are first compared to tumor history data obtained with a SCID mouse model to determine key parameters; predictions are then made for an immune-competent animal. The minimum immune cell birth rate relative to malignant B-cell birth rate necessary to induce tumor regression is determined, and optimization of drug combinations in the presence of an immune response is explored. The delayed effect of an immune response relative to drug scheduling is examined, and a mechanism for disease transformation in heterogeneous tumors is proposed.     

Risk assessment for quantitative responses using a mixture model

A problem that frequently occurs in biological experiments with laboratory animals is that some subjects are less susceptible to the treatment than others. A mixture model has traditionally been proposed to describe the distribution of responses in treatment groups for such experiments. Using a mixture dose-response model, we derive an upper confidence limit on additional risk, defined as the excess risk over the background risk due to an added dose. Our focus will be on experiments with continuous responses for which risk is the probability of an adverse effect defined as an event that is extremely rare in controls. The asymptotic distribution of the likelihood ratio statistic is used to obtain the upper confidence limit on additional risk. The method can also be used to derive a benchmark dose corresponding to a specified level of increased risk. The EM algorithm is utilized to find the maximum likelihood estimates of model parameters and an extension of the algorithm is proposed to derive the estimates when the model is subject to a specified level of added risk. An example is used to demonstrate the results, and it is shown that by using the mixture model a more accurate measure of added risk is obtained.     

Biological properties of two models of calcitonin gene related peptide with idealized amphiphilic alpha-helices of different lengths

Previous studies on calcitonin gene related peptide (CGRP) have demonstrated that it has the characteristics of an amphiphilic peptide, and from an examination of the sequence, we have proposed that it contains an amphiphilic alpha-helix. We have synthesized two analogues of CGRP which have different lengths of idealized amphiphilic alpha-helical secondary structure. The first model, CGRM-1, has been substituted with residues generating an idealized amphiphilic alpha-helix in the region between residues 8 and 25, equivalent to approximately five turns of an alpha-helix. This peptide is not an agonist in any of our bioassays, but it does bind with low affinity to rCGRP receptors in crude liver membranes. Our second model, CGRM-2, has an idealized amphiphilic alpha-helix between residues 8 and 18, which is equivalent to approximately three turns of an alpha-helix. In an in vitro rat vas deferens assay, this peptide is an agonist with a potency one-fourth that of the native hormone. However, the potency of CGRM-2 in an adenylate cyclase assay is much lower, only 1/140th the potency of CGRP. Both model peptides display amphiphilic characteristics commensurate with their design. We conclude that there is an amphiphilic alpha-helix in rCGRP between residues 8 and 18 and that this helix terminates in the vicinity of residue 18.     

Progressive chorioretinal degeneration in a female carrier of the choroideremia gene: A case report

Choroideremia is a generalized hereditary degeneration following an X-linked recessive trait. Its pathogenesis is related to an early atrophy of the choroidal circulation at the choriocapillaris and at the retinal pigment epithelium. Because it is inherited as an X-linked trait, it affects males most severely with female carriers generally being relatively asymptomatic. A report of an extremely rare case of a presumed female carrier with male-like visual symptoms and clinical signs is presented. In addition to a discussion of this atypical case of a female carrier with progressive degeneration, an overview of the disease is presented, including clinical features, pathophysiology, differential diagnoses and management.     

Coupling of DNA replication and cell division: sulB is an allele of ftsZ.

Treatments that damage DNA in Escherichia coli result in the inhibition of cell division. This inhibition is controlled by the lexA-recA regulatory circuit and can be specifically uncoupled by the mutations sulA (sfiA) and sulB (sfiB), which map at 21 and 2 min, respectively. Presently it is thought that sulA codes for an inducible inhibitor of cell division, the expression of which is controlled directly by the lexA repressor. In this report, it is shown that sulB is an allele of ftsZ, an essential cell division gene. A sulB mutation leads to an altered ftsZ gene product which is slightly thermosensitive and has an altered mobility on polyacrylamide gels. It is suggested that the altered ftsZ gene product is resistant to the sulA inhibitor, thus permitting cell division after induction of the SOS response. It is also shown that an increase in the gene dosage of ftsZ delays the onset of filamentation after SOS induction.     

Simulation of human sleep: ultradian dynamics of electroencephalographic slow-wave activity

The typical declining trend of electroencephalographic (EEG) slow-wave activity (SWA) within a sleep period is represented in the two-process model of sleep regulation by an exponentially decaying process (Process S). The model has been further elaborated to simulate not only the global changes of SWA, but also the dynamics within non-rapid-eye-movement (non-REM) sleep episodes. In this new model, the initial intraepisodic buildup of SWA is determined by the combined action of an exponentially increasing process and a saturation process, whereas its fall at the end of an episode is due to an exponentially decreasing process. The global declining trend of SWA over consecutive episodes results from the monotonic decay of the intraepisodic saturation level. In contrast to Process S in the two-process model, this decay is not represented by an exponential function, but is proportional to the momentary level of SWA. REM sleep episodes are triggered by an external function. The model allows one to simulate the ultradian pattern of SWA for baseline nights as well as changes induced by a prolonged waking period, a daytime nap, a partial slow-wave sleep deprivation, or an antidepressant drug.     

The kinetics of diffusion between a spherical cell and a surrounding medium with different diffusion properties

The diffusion equation according to Fick’s law is solved for a spherical cell, surrounded by an infinite medium with different diffusion properties. The method of Laplace transform is used to obtain the formal solution, however, no inversion can be found for all times and an expansion suitable for small times is performed. The final expression found is expanded further to be more suited for the determination of the diffusion coefficient from an experimental curve. Application to a biological problem is dissussed.     

Evidence that N-methyl-N'-nitro-N-nitrosoguanidine induces adaptive response in Bacillus thuringiensis

Bacillus thuringiensis is shown to have an inducible error-free repair system for alkylation damage as found in Escherichia coli and Bacillus subtilis. Growth of cells in the presence of low concentrations of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) induces an adaptive response which is characterized by an increase in resistance to killing and mutagenesis by challenge with higher concentrations of MNNG. In addition, we have noted with interest that adaptive low doses seem to produce lesions at a rate sufficient to induce an increase of mutation frequency, and inhibition of cell division. The possibility of an interaction between SOS and adaptive responses with these low doses of MNNG is discussed.     

Narcotic cue and narcotic state.

There is an increasing interest in the ability of drugs to exert stimulus control over operant responding. By stimulus control is meant here that there is an apparent relation between the stimulus constituted by drug administration, and the subsequent occurrence of an operant response. The purpose of the present review is to analyze the available literature data on stimulus control by narcotic analgesic drugs, and to discuss some of the conclusions reached thus far.     

Notation-dependent and -independent representations of numbers in the parietal lobes

It is a commonly held view that numbers are represented in an abstract way in both parietal lobes. This view is based on failures to find differences between various notational representations. Here we show that by using relatively smaller voxels together with an adaptation paradigm and analyzing subjects on an individual basis it is possible to detect specialized numerical representations. The current results reveal a left/right asymmetry in parietal lobe function. In contrast to an abstract representation in the left parietal lobe, the numerical representation in the right parietal lobe is notation dependent and thus includes nonabstract representations. Our results challenge the commonly held belief that numbers are represented solely in an abstract way in the human brain.