On statistical inference for the random set generated Cox process with set-marking

Cox point process is a process class for hierarchical modelling of systems of non-interacting points in Rd under environmental heterogeneity which is modelled through a random intensity function. In this work a class of Cox processes is suggested where the random intensity is generated by a random closed set. Such heterogeneity appears for example in forestry where silvicultural treatments like harvesting and site-preparation create geometrical patterns for tree density variation in two different phases. In this paper the second order property, important both in data analysis and in the context of spatial sampling, is derived. The usefulness of the random set generated Cox process is highly increased, if for each point it is observed whether it is included in the random set or not. This additional information is easy and economical to obtain in many cases and is hence of practical value; it leads to marks for the points. The resulting random set marked Cox process is a marked point process where the marks are intensity-dependent. The problem with set-marking is that the marks are not a representative sample from the random set. This paper derives the second order property of the random set marked Cox process and suggests a practical estimation method for area fraction and covariance of the random set and for the point densities within and outside the random set. A simulated example and a forestry example are given.     

Orientational relaxation time of bottom-heavy squirmers in a semi-dilute suspension

One of the important quantities to characterize unsteady behaviour of a cell suspension is the orientational relaxation time, which is the time scale for a micro-organism to re-orientate to its preferred direction from disorientated conditions. In this paper, a swimming micro-organism is modelled as a squirming sphere with prescribed tangential surface velocity, in which the centre of mass of the sphere is displaced from the geometric centre (bottom-heaviness). The orientational relaxation time of bottom-heavy squirmers in a suspension is investigated both analytically and numerically. The three-dimensional movement of 64 identical squirmers in a fluid otherwise at rest, contained in a cube with periodic boundary conditions, is dynamically computed, for random initial positions and orientations. The effects of volume fraction of squirmers, the bottom-heaviness and the squirming mode on the relaxation time are discussed. The results for a semi-dilute suspension show that both the mean stresslet strength and the orientational relaxation time decrease from those for a dilute suspension. We also observe a stress overshoot in some cases. The mechanism for this is different from that for a visco-elastic fluid, and is explained by the change with time of the orientation of squirmers.     

Journeying Between Desire and Anthropology: A Story in Suspense

Anthropology is a discipline based on the motif of the journey and ‘the myth of the eternal return’. This is the journey out to the ‘other’in order to return to constitute ‘self, and this movement is a movement of desire. The desire is for wholeness, for self‐presence, for a unified self. It is a desire for origins. And this desire is evident in anthropological practices as it is in myths and fairytales—all tell stories that speak of the desire for a separate, an original, self. Yet ‘the myth of the eternal return’reveals that the enactment of the story is itself originating. The origin is not a thing to be hunted down and appropriated—it is no thing. Like the archetypes which flow through stories, it is alive in the telling. The story I tell in this paper is about my own desires. It speaks of the desire to undergo the rite of passage of anthropology, and of how this journey was interrupted by the anthropologist who always journeys before me. And yet. it is through the inextricable relations with the writings of the “other‘ anthropologist that alluring moments of different desiring are fleetingly revealed. In the end. my relations with anthropology tell of a paradox: of the desire for a transcendental journey in order to constitute self and the seductive desire for immersion—to lose self, the story remains in suspense.     

On peristaltic flow and its efficiency

The question of efficiency in performing biological functions is raised in the context of peristaltic fluid transport. To deal with this problem a complete solution for peristaltic flow in a pipe and in a channel, assuming a given time mean flow, is developed, by a double expansion in terms of the Reynolds number and the square of the wave number. This solution is valid for arbitrary waveshapes. We resolve a long-standing problem and show that quite generally the pressure rise per wave length is constant on a cross section. We also show that for a sinusoidal wave (and others) the interaction of Reynolds number and wave number is a third-order effect for this pressure rise. Plow-type waves, nipple-type waves and the sinusoidal wave are compared for maximum efficiency and for minimum energy usage. It is found that large plows are best from mechanical efficiency considerations, but large nipples use the least energy. The biological implications of these results are discussed.     

Anopheles gambiae purine nucleoside phosphorylase: catalysis, structure, and inhibition

The purine salvage pathway of Anopheles gambiae, a mosquito that transmits malaria, has been identified in genome searches on the basis of sequence homology with characterized enzymes. Purine nucleoside phosphorylase (PNP) is a target for the development of therapeutic agents in humans and purine auxotrophs, including malarial parasites. The PNP from Anopheles gambiae (AgPNP) was expressed in Escherichia coli and compared to the PNPs from Homo sapiens (HsPNP) and Plasmodium falciparum (PfPNP). AgPNP has kcat values of 54 and 41 s-1 for 2'-deoxyinosine and inosine, its preferred substrates, and 1.0 s-1 for guanosine. However, the chemical step is fast for AgPNP at 226 s-1 for guanosine in pre-steady-state studies. 5'-Deaza-1'-aza-2'-deoxy-1'-(9-methylene)-Immucillin-H (DADMe-ImmH) is a transition-state mimic for a 2'-deoxyinosine ribocation with a fully dissociated N-ribosidic bond and is a slow-onset, tight-binding inhibitor with a dissociation constant of 3.5 pM. This is the tightest-binding inhibitor known for any PNP, with a remarkable Km/Ki* of 5.4 x 10(7), and is consistent with enzymatic transition state predictions of enhanced transition-state analogue binding in enzymes with enhanced catalytic efficiency. Deoxyguanosine is a weaker substrate than deoxyinosine, and DADMe-Immucillin-G is less tightly bound than DADMe-ImmH, with a dissociation constant of 23 pM for AgPNP as compared to 7 pM for HsPNP. The crystal structure of AgPNP was determined in complex with DADMe-ImmH and phosphate to a resolution of 2.2 A to reveal the differences in substrate and inhibitor specificity. The distance from the N1' cation to the phosphate O4 anion is shorter in the AgPNP.DADMe-ImmH.PO4 complex than in HsPNP.DADMe-ImmH.SO4, offering one explanation for the stronger inhibitory effect of DADMe-ImmH for AgPNP.     

Site-directed mutants of charged residues in the active site of tyrosine hydroxylase

The active site of tyrosine hydroxylase consists of a hydrophobic cleft with an iron atom near the bottom. Within the cleft are several charged residues which are conserved across the family of pterin-dependent hydroxylases. We have studied four of these residues, glutamates 326 and 332, aspartate 328, and arginine 316 in tyrosine hydroxylase, by site-directed substitution with alternate amino acid residues. Replacement of arginine 316 with lysine results in a protein with a Ktyr value that is at least 400-fold greater and a V/Ktyr value that is 4000-fold lower than those found in the wild-type enzyme; substitution with alanine, serine, or glutamine yields insoluble enzyme. Arginine 316 is therefore critical for the binding of tyrosine. Replacement of glutamate 326 with alanine has no effect on the KM value for tyrosine and results in a 2-fold increase in the KM value for tetrahydropterin. The Vmax for DOPA production is reduced 9-fold, and the Vmax for dihydropterin formation is reduced 4-fold. These data suggest that glutamate 326 is not directly involved in catalysis. Replacement of aspartate 328 with serine results in a 26-fold higher KM value for tyrosine, a 8-fold lower Vmax for dihydropterin formation, and a 13-fold lower Vmax for DOPA formation. These data suggest that aspartate 328 has a role in tyrosine binding. Replacement of glutamate 332 with alanine results in a 10-fold higher KM value for 6-methyltetrahydropterin with no change in the KM value for tyrosine, a 125-fold lower Vmax for DOPA formation, and an only 3.3-fold lower Vmax for tetrahydropterin oxidation. These data suggest that glutamate 332 is required for productive tetrahydropterin binding.     

X-inactivation is stably maintained in mouse embryos deficient for histone methyl transferase G9a

One of the two X chromosomes becomes inactivated during early development of female mammals. Recent studies demonstrate that the inactive X chromosome is rich in histone H3 methylated at Lys-9 and Lys-27, suggesting an important role for these modifications in X-inactivation. It has been shown that in the mouse Eed is required for maintenance of X-inactivation in the extraembryonic lineages. Interestingly, Eed associates with Ezh2 to form a complex possessing histone methyltransferase activity predominantly for H3 Lys-27. We previously showed that G9a is one of the histone methyltransferases specific for H3 Lys-9 and is essential for embryonic development. Here we examined X-inactivation in mouse embryos deficient for G9a. Expression of Xist, which is crucial for the initiation of X-inactivation, was properly regulated and the inactivated X chromosome was stably maintained even in the absence of G9a. These results demonstrate that G9a is not essential for X-inactivation.     

Selection on parental performance opposes selection for larger body mass in a wild population of blue tits

There is abundant evidence in many taxa for positive directional selection on body size, and yet little evidence for microevolutionary change. In many species, variation in body size is partly determined by the actions of parents, so a proposed explanation for stasis is the presence of a negative genetic correlation between direct and parental effects. Consequently, selecting genes for increased body size would result in a correlated decline in parental effects, reducing body size in the following generation. We show that these arguments implicitly assume that parental care is cost free, and that including a cost alters the predicted genetic architectures needed to explain stasis. Using a large cross‐fostered population of blue tits, we estimate direct selection on parental effects for body mass, and show it is negative. Negative selection is consistent with a cost to parental care, mainly acting through a reduction in current fecundity rather than survival. Under these conditions, evolutionary stasis is possible for moderately negative genetic correlations between direct and parental effects. This is in contrast to the implausibly extreme correlations needed when care is assumed to be cost‐free. Thus, we highlight the importance of accounting correctly for complete selection acting on traits across generations.     

An approximation method for the determination of diffusion and permeability coefficients in nerve trunks

A recently introduced approximation method is applied in order to obtain an expression for the amount of a substance remaining within a nerve at any time, the nerve having been soaked for a long time in a solution containing the substance until the time zero when it is bathed in the same solution but without the substance. The case of a uniform nerve without a sheath leads to substantially the same results as previously obtained by A. V. Hill (1928) for this case. A solution is given for the case of a nerve without sheath but having fibers which are permeable. In this case it is shown how an effective diffusion coefficient for the interstitial fluid can be obtained, as well as the effective inward and outward fiber permeabilities. A solution is given for the case of a nerve with a sheath in which the substance considered does not penetrate the fibers, and it is shown how the effective diffusion coefficients of the sheath and the interstitial fluid can be obtained.     

Estimation of the dissociation constants of enzyme-substrate complexes from steady-state measurements. Interpretation of pH-independence of Km.

If the Michaelis constant of an enzyme-catalysed reaction is independent of pH under conditions where the catalytic constant varies with pH, it is equal to the thermodynamic dissociation constant of the enzyme-substrate complex. This is true for realistic mechanisms in which binding and catalytic steps, are clearly distinguished, as well as for the simpler mechanisms that have been considered previously. It is also true for a mechanism in which a bell-shaped pH profile for the catalytic constant results from a change of rate-limiting step with pH. The relaxation time for ionization of a typical group in unbuffered solutions at 25 degrees C is of the order of 0.1 ms at the longest, and is much shorter in buffered solutions. Thus ionizations in almost all enzyme mechanisms can properly be treated as equilibria, provided that ionization is not accompanied by a slow, compulsory change in conformation.     

Deadlock Avoidance for Sequential Resource Allocation Systems: Hard and Easy Cases

Deadlock is a major problem for systems that allocate resources in real time. The key issue in deadlock avoidance is whether or not a given resource allocation state is safe: that is, whether or not there exists a sequence of resource allocations that completes all processes. Although safety is established as NP-complete for certain broad resource allocation classes, newly emerging resource allocation scenarios often exhibit unique features not considered in previous work. In these cases, establishing the underlying complexity of the safety problem is essential for developing the best deadlock avoidance approach. This work investigates the complexity of safe resource allocation for a class of systems relevant in automated manufacturing. For this class, the resource needs of each process are expressed as a well-defined sequence. Each request is for a single unit of a single resource and is accompanied by a promise to release the previously allocated resource. Manufacturing researchers have generally accepted that safety is computationally hard, and numerous suboptimal deadlock avoidance solutions have been proposed for this class. Recent results, however, indicate that safety is often computationally easy. The objective of this article is to settle this question by formally establishing the NP-completeness of safety for this class and investigating the boundary between the hard and easy cases. We discuss several special structures that lead to computationally tractable safety characteristics.     

A simpler, more general method of finding the optimal foraging strategy for Bayesian birds

Oaten's (1977) stochastic model for optimal foraging in patches has been solved for a number of particular cases. A few cases, such as Poisson prey distribution and either systematic or random search, are easy to solve. In other cases, such as binomial prey distribution and random search, the form of the optimal strategy may be found using a theorem of McNamara, although more work is required to find which particular rule of the proper form is actually best. More generally (but not completely generally), optimal strategies may be found using dynamic programming. This requires that the number of prey found up to a particular time is a sufficient statistic for the number of prey remaining in a patch. This requirement cannot be dispensed with, but other simplifying assumptions that were used in the past are not necessary. In particular, it is not necessary, even for the sake of convenience, to assume that prey distribution has a form convenient for Bayesian analysis, such as a beta mixture of binomials or a gamma mixture of Poissons. Any prey distribution may be used if whatever prey are in a patch are located at random, and if search either is systematic for discrete time or for continuous time, or is random for continuous time. In earlier work, some pains had to be taken to find the rate of finding prey achieved by a given candidate strategy, but this is not necessary if expected gains and expected times are calculated routinely for each potential stopping point during dynamic programming. A new, simple method of finding optimal strategies is illustrated for discrete time and systematic search. This paper is based on a talk given at the Fifth Hans Kristiansson Symposium held in Lund, Sweden in August, 2003. The subject of the symposium was Bayesian foraging.     

Minimum shear wind strength required for dynamic soaring of albatrosses

The transfer of energy from the moving air in the shear wind above the sea surface to a bird is considered as an energy source for dynamic soaring, with the goal to determine the minimum shear wind strength required for the dynamic soaring of albatrosses. Focus is on energy-neutral trajectories, implying that the energy gain from the moving air is just sufficient to compensate for the energy loss due to drag for a dynamic soaring cycle. A mathematical optimization method is used for computing minimum shear wind energy-neutral trajectories, using a realistic flight mechanics model for the soaring of albatrosses. Thus, the minimum shear wind strength required for dynamic soaring is determined. The minimum shear wind strength is of a magnitude that often exists or is exceeded in areas in which albatrosses are found. This result holds for two control cases dealt with, one of which shows a freely selectable and the other a constant lift coefficient characteristic. The mechanism of energy transfer from the shear flow to the bird is considered, and it is shown that there is a significant energy gain in the upper curve and a loss in the lower curve. As a result, the upper curve can be qualified as the characteristic flight phase of dynamic soaring to achieve an energy gain.     

Positional Information and Positional Signalling in Hydra

A model is proposed for regulation and regeneration of the headend of hydra in terms of positional information, which involvestwo gradients. One is a diffusible substance made at the headend, which may be regarded as a positional signal. The otheris a more stable cellular parameter which is the positionalvalue. The rule for head end formation is that the concentrationof the diffusible substance falls a threshold amount below thepositional value. This model, for which some computer simulationis provided, can account for head end formation in a wide varietyof grafts. Evidence for a diffusable signal is provided by experimentsin which the time/distance relationships for head inhibitionby a grafted head are determined. Changes in positional valueduring regulation have been assayed and are much slower awayfrom the boundary. Polarity is interpreted in terms of the interactionbetween the two gradients. The biochemical basis of the gradientsis not known, but an approach to the problem has been made bytreating hydra with a variety of chemical agents.     

Gene Genealogies within Mutant Allelic Classes

A coalescent theory of the gene genealogy within an allelic class that arises by a unique mutational event is developed and analyzed. To interpret this theory it was necessary to expand on existing theory for populations of varying size. Two features of the gene genealogy--the average pairwise distance and the total tree length--within the mutant class and within the nonmutant class are found. An index, I, is proposed that describes the extent to which a genealogy is similar to one from a population of constant size (for which I = 0) or to a star genealogy (for which I = 1). The value of I is positive in growing populations and is generally positive for the gene genealogy for the mutant class. The value of I is negative for a population decreasing in size and for the nonmutant class, if the mutant arose recently. The results are discussed in the context of the infinite sites model of mutation, which is appropriate for nucleotide sequence data, and the generalized stepwise mutation model, which is appropriate for microsatellite loci. The same genealogical methods are used to find the probability of at least one recombination event between a nucleotide that defines an allelic class and a marker at a nearby linked site.     

The ethics of euthanasia: advocates' perspectives

The Netherlands is currently the only country in the world in which euthanasia is legally permissible. More specifically, Dutch law (briefly explained) allows that a doctor terminates the life of a patient of hers on his voluntary, well-considered and sustained request, if he is suffering unbearably and hopelessly. The aim of this paper is to reconstruct the Dutch debate on the moral permissibility of euthanasia so as to clarify and strengthen the various views that can be advanced in support of euthanasia. On the one view, The Pure Autonomy View (TPAV), the justification of euthanasia rests solely on the principle of respect for autonomy. That is, the reason for performing and permitting euthanasia is the patient's voluntary, well-considered and sustained, in one word: autonomous, request for euthanasia. On the alternative view, The Joint View (TJV), the principle of respect for autonomy and the principle of beneficence morally justify euthanasia together . That is, euthanasia is ethical if and partly because, since the patient is suffering unbearably and hopelessly, euthanasia is in his interest. According to this paper, there is no easy argument for one of these views rather than the other. Instead, as yet both TPAV and TJV seem inherently problematic. TPAV is unable to give a doctor a reason for performing euthanasia that appeals to her in her capacity as a doctor, such as relief of suffering. And TJV begs the question – for example, if a state were to legalize euthanasia on grounds of TJV, it would force the view upon its citizens that it may be in a person's interest to die.     

Homozygosity in a population of variable size and mutation rate

A formula is obtained for the probability that two genes at a single locus, sampled at random from a population at time t, are of particular types. The model assumed is a diffusion approximation to a neutral Wright-Fisher model in which mutation is not necessarily symmetric and the population size is a function of time. It is shown that for symmetric mutation in a population undergoing a step-function type bottleneck, homozygosity increases with decreasing population size. A formula is given for the distribution of the number of segregating sites occurring in two randomly sampled sequences of completely linked sites, with general mutation at a site and identical mutation structure between sites.We give similar results for a population of fixed size but for which the mutation rate is a function of time, and not necessarily symmetric. We confirm the intuitively clear effect that increasing the mutation rate decreases homozygosity.     

Mass Ligand Binding Screening for Receptor Antagonists: Prototype New Drugs and Blind Alleys

Abstract

The ligand binding assay is a powerful tool in the search for antagonists for novel receptors, and for identification of novel classes of antagonists for well-known receptors. Ligand binding mass screening can be adapted for very high throughput. In order for mass screening to be useful, it is necessary to strictly define the binding characteristics for a compound to be considered a putative receptor antagonist. In practice, we have found that synthetic pursuit of a compound with a K_i of ± 1 uM is likely to lead down a blind alley unless very good evidence for specificity is available. Even potent competitors for binding should be thoroughly evaluated in assays of biological activity before a synthetic program is initiated in earnest.     

Thresholds of bifurcation of the degree of circular polarization of the bremsstrahlung-generated pump field harmonics in plasma

It is established that, for a Maxwellian plasma in a monochromatic pump field, the phenomenon of bifurcation of the degree of circular polarization of the field harmonics is of a universal nature. A general equation determining the thresholds for this phenomenon for arbitrary harmonics is derived, and a set of its solutions is presented for illustrative purposes.