A method for determining overall protein fold from NMR distance restraints

Summary We describe a simple method for determining the overall fold of a polypeptide chain from NOE-derived distance restraints. The method uses a reduced representation consisting of two particles per residue, and a force field containing pseudo-bond and pseudo-angle terms, an electrostatic term, but no van der Waals or hard shell repulsive terms. The method is fast and robust, requiring relatively few distance restraints to approximate the correct fold, and the correct mirror image is readily determined. The method is easily implemented using commercially available molecular modeling software.     

The sinking ark: pollution and the worldwide loss of biodiversity

Humans are making increasing demands on natural ecosystems. One recent study has concluded that our species is consuming or diverting some 40% of the net photosynthetic productivity of our planet. Many habitats are being converted to simpler systems which provide more harvestable goods to people. As a result, genetic diversity, species and whole ecosystems are disappearing; some scientists suggest that as many as 25% of the world's species could be lost in the next several decades.The sinking ark is usually characterized in terms of pollution, habitat loss, poaching, introduced species and illegal trade in wildlife products, but these are symptoms rather than causes. At a more fundamental level, many of the same factors which have enabled pollution to become such a problem have also been responsible for the loss in biodiversity; the most important factor is that the effects of pollutants on biodiversity have been considered an externality, an unintended side effect of industrial activity which brought measurable benefits to people. Development activities which have depleted biodiversity have proven profitable only because the real costs have been hidden.Keeping the ark afloat will require the Five-I Approach: investigation (learning how natural systems function); information (ensuring that the facts are available to inform decisions); incentives (using economic tools to help conserve biodiversity); integration (promoting a cross-sectoral approach to conserving biodiversity); and international support (building productive collaboration for conserving biodiversity).     

A general approach toward the design of inhibitors of serine proteinases: inhibition of human leukocyte elastase by substituted dihydrouracils

A general approach toward the rational design of potential inhibitors of serine proteinases is described. The approach is exemplified and validated through the use of appropriate heterocyclic systems in inhibiting human leukocytes elastase (HLE).     

COMMENTARY ON ZOHAR'S “PROSPECTS FOR‘GENETIC THERAPY’- CAN A PERSON BENEFIT FROM BEING ALTERED?”

In his paper on the effects of Prenatal Genetic Intervention (PGI) on personal identity, Noam Zohar comes to a conclusion about genetic makeup and the uses of gene therapy quite different from the one I reach in another piece in this issue. Zohar's argument rests on the contention that personal identity changes with alteration of the genome, following what I have identified as the "constitutive" view. To see that this is the pillar supporting the weight of his argument, consider the following. Questions of identity aside, how can it be that altering the genome of children suffering from Lesch-Nyhan syndrome or Tay-Sachs disease so that they now produce the enzyme that they formerly lacked does not benefit them? Clearly, if their identities were not changed, such individuals would in fact realize great benefit from PGI, since the devastating bad effects of the genetic flaw would be avoided. Such a change would certainly make the altered individuals better off, that is, it would benefit them. On this, Zohar and I do not disagree. Persistence of identity through such genetic change is the sticking point.     

Segregation analysis with uncertain ascertainment: application to Fanconi anemia.

A Bayesian solution for making inferences about segregation parameters with no information about the ascertainment is presented. Inferences about the segregation probability and the probability of being sporadic are made through the posterior marginal distribution of these parameters after integrating out the ascertainment probability, the nuisance parameter. The method was tested with real and simulated data and performed well. Original Fanconi anemia data, for which no information about the ascertainment was available, were then analyzed, with results that confirmed a monogenic autosomal recessive mode of inheritance.     

Temporal variation in abundance of the egg predator Carcinonemertes epialti (Nemertea) and its effect on egg mortality of its host,the shore crab,Hemigrapsus oregonensis

An outbreak of the nemertean, Carcinonemertes epialti, was observed on Hemigrapsus oregonensis during October, 1982 at Campbell Cove, Bodega Harbor, California. Mean worm intensity (296 worms/crab) was the highest recorded for this nemertean egg predator on H. oregonensis. During the outbreak, male crabs were found to harbor more worms than both non-ovigerous and ovigerous females. Crab egg mortality was substantial; 83% of the ovigerous females experienced 75–100% brood mortality. The seasonal peak in worm abundance coincided with the seasonal low in crab reproduction at this locality. A method for estimating the impact of C. epialti on H. oregonensis natality was developed using crab size and fecundity, and worm prevalence and intensity. For a non-outbreak sampling period, a mean of 5.6% egg mortality was experienced by infested crabs for the period selected. Thus, brood mortality during the outbreak was much greater than that experienced at non-outbreak periods. Heavy fishing pressure on some commercially important crab species has been suggested as a possible factor inducing worm outbreaks and facilitating their continued persistence. These observations suggest that fisheries are not necessarily responsible for the outbreaks of nemerteans on commercially important crab species. However, fishing pressure may still be a sufficient condition to promote nemertean outbreaks.     

Formation of the transverse nerve in moth embryos : I. A scaffold of nonneuronal cells prefigures the nerve

We have studied the embryonic development of the transverse nerve (TN), an unpaired segmental nerve of the moth Manduca sexta. Two identified motor neurons and 16 identified neuroendocrine neurons project axons within the larval TN; therefore, the TN is both a peripheral nerve and a neurohaemal organ. At 33% of embryogenesis, and prior to the arrival of any neuronal growth cones, the position, shape, and trajectory of the TN are anticipated by two groups of nonneuronal cells that we call the strap and the bridge. At this time the strap and the bridge together consist of approximately 100 cells, all of which express a cell surface epitope recognized by the monoclonal antibody TN-1. As development proceeds, both the number of nonneuronal cells within the strap and the bridge and the fraction that expresses the TN-1 antigen(s) decrease. Moreover, individual cells within the strap become morphologically identifiable before the arrival of the neuronal growth cones. Most of the axons that project to the TN also express the TN-1 antigen(s) during their period of outgrowth. The two motor neuron growth cones are the first to reach the environment of the strap and the bridge, doing so at approximately 37%; having encountered these cellular structures, the growth cones restrict their navigation to this preexisting scaffolding, until they reach their muscle target. The neuroendocrine growth cones arrive later and also grow within the confines of the strap and the bridge (J.N. Carr and P.H. Taghert, 1988, Dev. Biol, 130, 500-512). In this first paper we describe the development of the strap and the bridge, and the interactions of the motor neuron growth cones with these structures. The observations are novel in documenting the extent and precision to which a peripheral nerve pathway is prefigured by a contiguous assemblage of nonneuronal cells.     

Effects of the lampricide, 3-trifluoromethyl-4-nitrophenol (TFM) on the macroinvertebrates of a hardwater river

The effects of the lampricide, TFM, on the benthic macroinvertebrates in the Rouge River, a hardwater tributary to Lake Ontario was examined at 1 untreated and 2 treated sites over a 7 month period. Drift samples were collected from one one of the treated sites during the 5 days bracketing treatment. Significant decreases in relative abundance attributable to TFM were recorded for Chimarra sp., Dugesia sp. and Tubificoidea 2–19 d following treatment. Large reductions were also exhibited by Caenis sp. and Lumbricidae. Two-thirds of the Chironomidae genera and Nematoda tended to decline in abundance 2 d after treatment at only one of the treated sites, probably due to a 2.5 h longer treatment. This decline was followed by a significant increase to greater than pretreatment abundances 17 d later undoubtedly as a result of an upward migration of macroinvertebrates from within the hyporheos. Partial recolonization of the TFM-sensitive benthic taxa was evident 19 d after lampricide treatment with complete recolonization 6.5 months later. With the exception of Caenis sp. those taxa in the present study found to be TFM-sensitive were in accordance with those found in softwater field studies. Chimarra sp., Dugesia sp., Hemerodromia sp., Lumbricidae and Tubificoidea exhibited substantial increases in drift abundance resulting from TFM treatment. Generally drift abundance of the taxa returned to pretreatment levels within 12 h following the completion of treatment. The drift abundance of Chimarra sp. and Dugesia sp. remained above normal throughout the rest of the sampling period likely due to continued irritation or mortalities induced by the presence of TFM in the substrate. Generally, drift was a good indicator of those taxa likely to experience a decline in abundance as a result of TFM treatment.     

The determination of fresh organic carbon weight from formaldehyde preserved macrofaunal samples

Methodologies are presented whereby the fresh organic carbon weight of formaldehyde preserved macrofaunal samples may be estimated. Length-organic carbon weight regressions were determined for the four numerically dominant bivalves in Narragansett Bay, Rhode Island (Nucula annulata, Yoldia limatula, Mulinia lateralis, and Pandora gouldiana) and one commercially important, but less abundant species (Mercenaria mercenaria). Constants were determined to convert the dry weight of preserved softbodied organisms (polychaetes, oligochaetes, amphipods, etc.) to fresh (unpreserved) organic carbon weight. These results can be used by investigators studying the energetics of benthic communities similar to those in Narragansett Bay.