The Royal Society

The structure and connectivity of the nervous system of the nematodeCaenorhabditis eleganshas been deduced from reconstructions of electron micrographs of serial sections. The hermaphrodite nervous system has a total complement of 302 neurons, which are arranged in an essentially invariant structure. Neurons with similar morphologies and connectivities have been grouped together into classes; there are 118 such classes. Neurons have simple morphologies with few, if any, branches. Processes from neurons run in defined positions within bundles of parallel processes, synaptic connections being madeen passant. Process bundles are arranged longitudinally and circumferentially and are often adjacent to ridges of hypodermis. Neurons are generally highly locally connected, making synaptic connections with many of their neighbours. Muscle cells have arms that run out to process bundles containing motoneuron axons. Here they receive their synaptic input in defined regions along the surface of the bundles, where motoneuron axons reside. Most of the m orphologically identifiable synaptic connections in a typical animal are described. These consist of about 5000 chemical synapses, 2000 neuromuscular junctions and 600 gap junctions.

An information-processing model is outlined that predicts that performance on non-routine tasks can be impaired independently of performance on routine tasks. The model is related to views on frontal lobe functions, particularly those of Luria. Two methods of obtaining more rigorous tests of the model are discussed. One makes use of ideas from artificial intelligence to derive a task heavily loaded on planning abilities. A group of patients with left anterior lesions has a specific deficit on the task. Subsidiary investigations support the inference that this is a planning impairment.

The efficiency of crop production is defined in thermodynamic terms as the ratio of energy output (carbohydrate) to energy input (solar radiation). Temperature and water supply are the main climatic constraints on efficiency. Over most of Britain, the radiation and thermal climates are uniform and rainfall is the main discriminant of yield between regions. Total production of dry matter by barley, potatoes, sugar beet, and apples is strongly correlated with intercepted radiation and these crops form carbohydrate at about 1.4 g per MJ solar energy, equivalent to 2.4% efficiency. Crop growth in Britain may therefore be analysed in terms of ( a ) the amount of light intercepted during the growing season and ( b ) the efficiency with which intercepted light is used. The amount intercepted depends on the seasonal distribution of leaf area which, in turn, depends on temperature and soil water supply. These variables are discussed in terms of the rate and duration of development phases. A factorial analysis of efficiency shows that the major arable crops in Britain intercept only about 40 % of annual solar radiation and their efficiency for supplying energy through economic yield is only about 0.3%. Some of the factors responsible for this figure are well understood and some are immutable. More work is needed to identify the factors responsible for the large differences between average commercial and record yields.

Attempts to correlate values of stomatal conductance and leaf water potential with particular environmental variables in the field are generally of only limited success because they are simultaneously affected by a number of environmental variables. For example, correlations between leaf water potential and either flux of radiant energy or vapour pressure deficit show a diurnal hysteresis which leads to a scatter diagram if many values are plotted. However, a simple model may be adequate to relate leaf water potential to the flow of water through the plant. The stomatal conductance of illuminated leaves is a function of current levels of temperature, vapour pressure deficit, leaf water potential (really turgor pressure) and ambient CO ₂ concentration. Consequently, when plotted against any one of these variables a scatter diagram results. Physiological knowledge of stomatal functioning is not adequate to provide a mechanistic model linking stomatal conductance to all these variables. None the less, the parameters describing the relationships with the variables can be conveniently estimated from field data by a technique of non-linear least squares, for predictive purposes and to describe variations in response from season to season and plant to plant.

The β-lactamases are widely distributed in both Gram-positive and Gram-negative bacteria. They all inactivate penicillins and cephalosporins by opening the β-lactam ring. Many varieties of the enzyme can be distinguished on the basis of their catalytic and molecular properties, but only amino acid sequence determination gives information upon which a molecular phylogeny can be based. The present evidence suggests that the β-lactamases have a polyphyletic origin. All the β-lactamases of currently known amino acid sequence belong to one homology group, here called class A enzymes. Class B consists of the mechanistically distinct Bacillus cereus β-lactamase II, which preliminary partial sequence analysis suggests to be structurally unrelated to the class A enzymes. It is predicted that sequence analysis will show that further classes will need to be created to account for particular β-lactamases of distinctive molecular and mechanistic properties.

A neural model is presented, based largely on evidence from studies in monkeys, postulating that coded representations of stimuli are stored in the higher-order sensory (i.e. association) areas of the cortex whenever stimulus activation of these areas also triggers a cortico-limbo-thalamo-cortical circuit. This circuit, which could act as either an imprinting or rehearsal mechanism, may actually consist of two parallel circuits, one involving the amygdala and the dorsomedial nucleus of the thalamus, and the other the hippocampus and the anterior nuclei. The stimulus representation stored in cortex by action of these circuits is seen as mediating three different memory processes: recognition, which occurs when the stored representation is reactivated via the original sensory pathway; recall, when it is reactivated via any other pathway; and association, when it activates other stored representations (sensory, affective, spatial, motor) via the outputs of the higher-order sensory areas to the relevant structures.

Equations have been developed to describe cardiac action potentials and pacemaker activity. The model takes account of extensive developments in experimental work since the formulation of the M.N.T. (R. E. McAllister, D. Noble and R. W. Tsien, J. Physiol., Lond. 251, 1-59 (1975)) and B.R. (G. W. Beeler and H. Reuter, J. Physiol., Lond . 268, 177-210 (1977)) equations. The current mechanism i _K2 has been replaced by the hyperpolarizing-activated current, i _f . Depletion and accumulation of potassium ions in the extracellular space are represented either by partial differential equations for diffusion in cylindrical or spherical preparations or, when such accuracy is not essential, by a three-compartment model in which the extracellular concentration in the intercellular space is uniform. The description of the delayed K current, i _K , remains based on the work of D. Noble and R. W. Tsien ( J. Physiol., Lond . 200, 205-231 (1969 a )). The instantaneous inward-rectifier, i _K1 , is based on S. Hagiwara and K. Takahashi’s equation ( J. Membrane Biol . 18, 61-80 (1974)) and on the patch clamp studies ofB. Sakmann and G. Trube ( J. Physiol., Lond . 347, 641-658 (1984)) and of Y. Momose, G. Szabo and W. R. Giles ( Biophys. J . 41, 311a (1983)). The equations successfully account for all the properties formerly attributed to i _K2 , as well as giving more complete descriptions of i _K1 and i _K . The sodium current equations are based on experimental data of T. J. Colatsky ( J.Physiol., Lond. 305, 215-234 (1980)) and A. M. Brown, K. S. Lee and T. Powell ( J.Physiol., Lond. , Lond. 318, 479-500 (1981)). The equations correctly reproduce the range and magnitude of the sodium ‘window’ current. The second inward current is based in part on the data of H. Reuter and H. Scholz ( J. Physiol., Lond . 264, 17-47 (1977)) and K. S. Lee and R. W. Tsien ( Nature, Lond . 297,498-501 (1982)) so far as the ion selectivity is concerned. However, the activation and inactivation gating kinetics have been greatly speeded up to reproduce the very much faster currents recorded in recent work. A major consequence of this change is that Ca current inactivation mostly occurs very early in the action potential plateau. The sodium-potassium exchange pump equations are based on data reported by D. C. Gadsby ( Proc. natn. Acad. Sci. U. S. A. 77, 4035-4039 (1980)) and by D. A. Eisner and W. J. Lederer ( J. Physiol., Lond . 303, 441-474 (1980)). The sodium-calcium' exchange current is based on L. J. Mullins’ equations ( J. gen.. Physiol. 70, 681-695 (1977)). Intracellular calcium sequestration is represented by simple equations for uptake into a reticulum store which then reprimes a release store. The repriming equations use the data of W. R. Gibbons & H. A. Fozzard ( J. gen. Physiol . 65, 367-384 (1975 b )). Following Fabiato & Fabiato’s work ( J. Physiol., Lond. 249, 469-495 (I975)), Ca release is assumed to be triggered by intracellular free calcium. The equations reproduce the essential features of intracellular free calcium transients as measured with aequorin. The explanatory range of the model entirely includes and greatly extends that of the M.N.T. equations. Despite the major changes made, the overall time-course of the conductance changes to potassium ions strongly resembles that of the M.N.T. model. There are however important differences in the time courses of Na and Ca conductance changes. The Na conductance now includes a component due to the hyperpolarizing-activated current, i _r , which slowly increases during the pacemaker depolarization. The Ca conductance changes are very much faster than in the M.N.T. model so that in action potentials longer than about 50 ms the primary contribution of the fast gated calcium channel to the plateau is due to a steady-state ‘window’ current or non-inactivated component. Slower calcium or Ca-activated currents, such as the Na-Ca exchange current, or Ca-gated currents, or a much slower Ca channel must then play the dynamic role previously attributed to the kinetics of a single type of calcium channel. This feature of the model in turn means that the repolarization process should be related to the inotropic state, as indicated by experimental work. The model successfully reproduces intracellular sodium concentration changes produced by variations in [Na]0, or Na-K pump block. The sodium dependence of the overshoot potential is well reproduced despite the fact that steady state intracellular Na is proportional to extracellular Na, as in the experimental results of D. Ellis J. Physiol., Lond . 274, 211-240 (1977)). The model reproduces the responses to current pulses applied during the plateau and pacemaker phases. In particular, a substantial net decrease in conductance is predicted during the pacemaker depolarization despite the fact that the controlling process is an increase in conductance for the hyperpolarizing-activated current. The immediate effects of changing extracellular [K] are reproduced, including: (i) the shortening of action potential duration and suppression of pacemaker activity at high [K ]; (ii) the increased automaticity at moderately low [K ]; and (iii) the depolarization to the plateau range with premature depolarizations and low voltage oscillations at very low [K]. The ionic currents attributed to changes in Na-K pump activity are well reproduced. It is shown that the apparent K _m for K activation of the pump depends strongly on the size of the restricted extracellular space. With a 30% space (as in canine Purkinje fibres) the apparent K _m is close to the assumed real value of 1 mM . When the extracellular space is reduced to below 5% , the apparent K _m increases by up to an order of magnitude. A substantial part of the pump is then not available for inhibition by low [K] _b . These results can explain the apparent discrepancies in the literature concerning the K _m for pump activation.

The paper describes the arrangement of the atoms within rhombohedral crystals of 2Zn pig insulin as seen in electron density maps calculated from X-ray data extending to 1.5 Å (1 Å = 10^-10m = 10^-1nm) at room temperature and refined toR= 0.153. The unit cell contains 2 zinc ions, 6 insulin molecules and about 3 x 283 water molecules. The atoms in the protein molecules appear well defined, 7 of the 102 side chains in the asymmetric unit have been assigned alternative disordered positions. The electron density over the water molecules has been interpreted in terms of 349 sites, 217 weighted 1.0, 126 weighted 0.5, 5 at 0.33 and 1 at 0.25 givingca. 282 molecules. The positions and contacts of all the residues belonging to the two A and B chains of the asymmetric unit are shown first and then details of their arrangement in the two insulin molecules, 1 and 2, which are different. The formation from these molecules of a compact dimer and the further aggregation of three dimers to form a hexamer around two zinc ions, follows. It appears that in the packing of the hexamers in the crystal there are conflicting influences; too-close contacts between histidine B5 residues in neighbouring hexamers are probably responsible for movements of atoms at the beginning of the A chain of one of the two molecules of the dimer that initiate movements in other parts, particularly near the end of the B chain. At every stage of the building of the protein structure, residues to chains of definite conformation, molecules, dimers, hexamers and crystals, we can trace the effect of the packing of like groups to like, aliphatic groups together, aromatic groups together, hydrogenbonded structures, positive and negative ions. Between the protein molecules, the water is distributed in cavities and channels that are continuous throughout the crystals. More than half the water molecules appear directly hydrogen bonded to protein atoms. These are generally in contact with other water molecules in chains and rings of increasing disorder, corresponding with their movement through the crystals. Within the established crystal structure we survey next the distribution of hydrogen bonds within the protein molecules and between water and protein and water and water; all but eight of the active atoms in the protein form at least one hydrogen bond. We follow with a discussion of the effect of different contacts on the observed thermal parameters and the possibility of correlating these with movements of the monomer, dimer or hexamer as a whole. The correlation seems best for molecule 1 in the dimer. Finally we examine the relation of the crystal structure as a whole to the biological activity of insulin. The large size of the insulin receptor makes it likely that when it combines to form the receptor complex, it makes a large number of contacts with the surface of the insulin molecule. Some of these points of contact, such as, for example, B24 and B25 phenylalanine, are suggested by the changes in biological activity observed when these residues are modified. The conformational changes in the insulin chains produced by crystal packing can be seen as a model for possible changes induced by insulin contacts with the receptor that eventually we may hope to discover if the insulin-receptor complex is crystallized.

Several recent accidents in complex high-risk technologies had their primary origins in a variety of delayed-action human failures committed long before an emergency state could be recognized. These disasters were due to the adverse conjunction of a large number of causal factors, each one necessary but singly insufficient to achieve the catastrophic outcome. Although the errors and violations of those at the immediate human-system interface often feature large in the post-accident investigations, it is evident that these ‘front-line’ operators are rarely the principal instigators of system breakdown. Their part is often to provide just those local triggering conditions necessary to manifest systemic weaknesses created by fallible decisions made earlier in the organizational and managerial spheres. The challenge facing the human reliability community is to find ways of identifying and neutralizing these latent failures before they combine with local triggering events to breach the system’s defences. New methods of risk assessment and risk management are needed if we are to achieve any significant improvements in the safety of complex, well-defended, socio-technical systems. This paper distinguishes between active and latent human failures and proposes a general framework for understanding the dynamics of accident causation. It also suggests ways in which current methods of protection may be enhanced, and concludes by discussing the unusual structural features of ‘high-reliability’ organizations.