Ubiquitination and deubiquitination: targeting of proteins for degradation by the proteasome

The post-translational modification of proteins by covalent attachment of ubiquitin targets these proteins for degradation by the proteasome. An astounding number of proteins are involved in ubiquitination and deubiquitination of proteins. The pathways are combinatorial, and selectivity of proteolysis will depend strongly on the exact combination of ubiquitinating and deubiquitinating enzymes present at any time. In addition to temporal control, it is likely that these modifications are also regulated spatially. In this review, we discuss the regulation of ubiquitination by enzymes of this pathway and highlight some of the outstanding problems in understanding this regulation.     

A pilot study of the use of placental cord blood samples in monitoring for mutational events

A pilot study exploring the examination of placental cord blood samples for mutant proteins with one-dimensional electrophoretic techniques is described. Although technical advances are such that the techniques employed in this study are now partially superceded, the practical problems encountered in this study would be typical of any monitoring program of this type. No mutations altering electrophoretic mobility among a battery of 51 different locus products were encountered in a total of 277,747 locus tests. When these data are combined with similar data from other studies, the mutation rate for electromorphs becomes 0.34 X 10(-5)/locus/generation.     

Characterising the searchability of continuous optimisation problems for PSO

The focus of research in swarm intelligence has been largely on the algorithmic side with relatively little attention being paid to the study of problems and the behaviour of algorithms in relation to problems. When a new algorithm or variation on an existing algorithm is proposed in the literature, there is seldom any discussion or analysis of algorithm weaknesses and on what kinds of problems the algorithm is expected to fail. Fitness landscape analysis is an approach that can be used to analyse optimisation problems. By characterising problems in terms of fitness landscape features, the link between problem types and algorithm performance can be studied. This article investigates a number of measures for analysing the ability of a search process to improve fitness on a particular problem (called evolvability in literature but referred to as searchability in this study to broaden the scope to non-evolutionary-based search techniques). A number of existing fitness landscape analysis techniques originally proposed for discrete problems are adapted to work in continuous search spaces. For a range of benchmark problems, the proposed searchability measures are viewed alongside performance measures for a traditional global best particle swarm optimisation (PSO) algorithm. Empirical results show that no single measure can be used as a predictor of PSO performance, but that multiple measures of different fitness landscape features can be used together to predict PSO failure.     

Aeromedical evacuation of the seriously ill.

Almost any patient may be carried by air, but air transport introduces some special problems owing to the effects of altitude, noise, turbulence, and the special environment. Because of these factors it is important to know when considering a patient''s suitability for air transport the type of aircraft to be used, the flight profile--its duration and expected cabin altitudes--and the facilities available on board. It is essential to carry all equipment (as simple and as portable as possible), drugs, and diets that may be needed, and to be sure that all the skills and nursing help needed to deal with any possible problems are available.     

Pluralism, Antirealism, and the Units of Selection

In an important article, Kim Sterelny and Philip Kitcher (1988) challenge the common assumption that for any biological phenomenon requiring a selectionist explanation, it is possible to identify a uniquely correct account of the relevant selection process. They argue that selection events can be modeled in any of a number of different, equally correct ways. They call their view 'Pluralism,' and explicitly connect it with various antirealist positions in the philosophy of science. I critically evaluate Sterelny and Kitcher's Pluralism along with its attendant antirealist theses. In particular, I argue that there are serious problems with their pluralistic antirealism regarding units of selection. By correctly diagnosing these problems a more adequate position can be constructed. I defend such a position, which I designate Inclusive Hierarchical Monism, and show how it captures the important virtues of Sterelny and Kitcher's approach while avoiding its problems.     

Red deer range and problems of carrying capacity in the Scottish Highlands

Some general principles underlying the concept of carrying capacity and problems in using the term are illustrated by reference to herbivore/vegetation inter-relationships in intensive pasture systems, regimes of range management and wildlife systems. The approach to management of the deer/range system in Scotland does not fit into any of these categories of land use. Ecological deficiencies arise because deer, rather than the soils and vegetation, are regarded as the resource. Hence, management of the range is animal orientated. It is based on techniques such as burning which give temporary benefits to the animal component of the system. It is argued that this inversion of priorities in management has the long-term effect of encouraging vegetational successions that aggravate problems of animal management, especially on the poorer soils. The characteristics of the deer and the vegetation, and trends of change are considered in this context. It is concluded that within the present framework of management there is little scope for radical improvement. A restructuring of the system is required to give greater control over the biological performance of the deer and of the trends in the vegetation.     

Statistical investigations into the measured DALA--discharge in the urine of infants

Using a sample of the size 353 on day-nursery children, the authors show that the DALA-U increase, which is due to the absorption of lead and other substances, does not display any age or sex dependence. A dependence upon the day nursery's location is assumed. The authors elaborate on the statistical problems (normal distribution) and the boundary value problems associated with the various DALA-U values measured. Large sample sizes are required to find a final clarification of the relationships.     

Factors regulating the renal circulation in spontaneously hypertensive rats

Hypertension is one of the leading causes of health morbidity and mortality which are linked to many life threatening diseases such as stroke heart problems and renal dysfunction.The integrity of renal microcirculation is crucial to maintaining the clearance and the excretory function in the normotensive and hypertensive conditions. Furthermore, any alteration in the renal function is involved in the pathophysiology of hypertension.The aim of this review is to provide a brief discussion of some factors that regulate renal haemodynamics in spontaneously hypertensive rats, an animal model of hypertension, and how these factors are linked to the disease.     

Demonstration of a universal surface DNA computer

A fundamental concept in computer science is that of the universal Turing machine, which is an abstract definition of a general purpose computer. A general purpose (universal) computer is defined as one which can compute anything that is computable. It has been shown that any computer which is able to simulate Boolean logic circuits of any complexity is such a general purpose computer. The field of DNA computing was founded in 1994 by Adleman's solution of a 7-bit instance of the Hamiltonian path problem. This work, as well as most of the subsequent experimental and theoretical investigations in the area, focused primarily upon the solution of NP-complete problems, which are a subset of the larger universal class of problems. In the present work a surface DNA computer capable of simulating Boolean logic circuits is demonstrated. This was done by constructing NOR and OR gates and combining them into a simple logic circuit. The NOR gate is one of the universal gates in Boolean logic, meaning that any other logic gate can be built from it alone. The circuit was solved using DNA-based operations, demonstrating the universal nature of this surface DNA computing model.     

A prediction-based resampling method for estimating the number of clusters in a dataset

Background  

Microarray technology is increasingly being applied in biological and medical research to address a wide range of problems, such as the classification of tumors. An important statistical problem associated with tumor classification is the identification of new tumor classes using gene-expression profiles. Two essential aspects of this clustering problem are: to estimate the number of clusters, if any, in a dataset; and to allocate tumor samples to these clusters, and assess the confidence of cluster assignments for individual samples. Here we address the first of these problems.     

Estimating the prevalence of protein sequences adopting functional enzyme folds

Proteins employ a wide variety of folds to perform their biological functions. How are these folds first acquired? An important step toward answering this is to obtain an estimate of the overall prevalence of sequences adopting functional folds. Since tertiary structure is needed for a typical enzyme active site to form, one way to obtain this estimate is to measure the prevalence of sequences supporting a working active site. Although the immense number of sequence combinations makes wholly random sampling unfeasible, two key simplifications may provide a solution. First, given the importance of hydrophobic interactions to protein folding, it seems likely that the sample space can be restricted to sequences carrying the hydropathic signature of a known fold. Second, because folds are stabilized by the cooperative action of many local interactions distributed throughout the structure, the overall problem of fold stabilization may be viewed reasonably as a collection of coupled local problems. This enables the difficulty of the whole problem to be assessed by assessing the difficulty of several smaller problems. Using these simplifications, the difficulty of specifying a working beta-lactamase domain is assessed here. An alignment of homologous domain sequences is used to deduce the pattern of hydropathic constraints along chains that form the domain fold. Starting with a weakly functional sequence carrying this signature, clusters of ten side-chains within the fold are replaced randomly, within the boundaries of the signature, and tested for function. The prevalence of low-level function in four such experiments indicates that roughly one in 10(64) signature-consistent sequences forms a working domain. Combined with the estimated prevalence of plausible hydropathic patterns (for any fold) and of relevant folds for particular functions, this implies the overall prevalence of sequences performing a specific function by any domain-sized fold may be as low as 1 in 10(77), adding to the body of evidence that functional folds require highly extraordinary sequences.     

Integrated communication between the nervous, endocrine and immune systems

Several data accumulated over recent years on the mechanisms underlying the interactions between the brain, hormones and the immune system. These data concern two major avenues of research: the evidence that brain-controlled, behavioral parameters can modulate the response of immunocompetent cells, and an increasing awareness that a number of chemical signals - neurotransmitters, hormones or mediators of immunity - are not, as previously believed, specific of given sets of tissues or of functions, but that, on the contrary, they can be produced and recognized by cellular elements belonging to any of those three systems. There is indeed evidence to indicate that signaling molecules involved in cellular communication are 'banalized': that means that their receptors are liable to be expressed in almost any tissue by a wide variety of cells. This statement, together with the discovery that intercellular regulation is multifactorial - that is, depends at any given time upon messages built up by combinations of signal molecules rather than by isolated transmitters - raises a certain number of theoretical problems as to the manner by which cells extract messages out of an important background noise. In the present paper, some of those theoretical problems will be presented in a summarized form, and their relevance for the interpretation of neuroendocrine or neuroimmunological interactions will be discussed.     

Information: needs for the future

The four central questions surrounding the use of information are: where to find it; how to find it; how to present it; and how to maintain information availability and information literacy. It is usually assumed that the main source of information for most scientists is the peer-reviewed journal literature. Traditional journal publishing is beset with a number of problems. Although electronic publishing might possibly solve some of these, it in turn introduces new problems. Further problems arise with respect to secondary sources which, in some cases, are being supplemented by electronic archives of full-text documents. One fundamental question that arises when considering any large collection of documents or of records about documents is whether or not to index them, and how to index them. The pros and cons of free-text searching versus the use of controlled vocabularies are discussed, as is the importance of harmonising the Three Rs-related terminology of existing and proposed thesauri. However, there is a further problem that documents pertinent to the Three Rs are not always indexed from this point of view. Authors need to be made aware that, if the information is not provided in the abstract, there is no easy way to identify and retrieve this document from a database. Small specialised databases on the Three Rs in relation to specific subject areas could provide a further solution, especially if they provide references to conference proceedings and book chapters, which are not usually found in the large bibliographical databases. The provision of training in the use of information resources, and the establishment and maintenance of these resources require investment of money and professional skills. Finally, the future of Three Rs information depends on a recognition that this in an important topic which deserves more than lip service.     

Invariant recognition of feature combinations in the visual system

 The operation of a hierarchical competitive network model (VisNet) of invariance learning in the visual system is investigated to determine how this class of architecture can solve problems that require the spatial binding of features. First, we show that VisNet neurons can be trained to provide transform-invariant discriminative responses to stimuli which are composed of the same basic alphabet of features, where no single stimulus contains a unique feature not shared by any other stimulus. The investigation shows that the network can discriminate stimuli consisting of sets of features which are subsets or supersets of each other. Second, a key feature-binding issue we address is how invariant representations of low-order combinations of features in the early layers of the visual system are able to uniquely specify the correct spatial arrangement of features in the overall stimulus and ensure correct stimulus identification in the output layer. We show that output layer neurons can learn new stimuli if the lower layers are trained solely through exposure to simpler feature combinations from which the new stimuli are composed. Moreover, we show that after training on the low-order feature combinations which are common to many objects, this architecture can – after training with a whole stimulus in some locations – generalise correctly to the same stimulus when it is shown in a new location. We conclude that this type of hierarchical model can solve feature-binding problems to produce correct invariant identification of whole stimuli. Received: 4 August 1999 / Accepted in revised form: 11 October 2000     

Times of crisis in the evolution of the cephalopoda

The evolutionary history of the ectocochlian cephalopods is punctuated by a number of severe crises during each of which this class came very close to extinction. The crisis events follow each other at intervals of from seven to almost 300 million years and, with one exception, were not synchronous for Nautiloidea and Ammonoidea. Only at the end of the Triassic period did both groups simultaneously face the danger of extinction. Generally, the survivors of crisis situations have simple shell forms and are strikingly similar to each other. To trace the details of cephalopod evolution, the family on the taxonomic level and the stratigraphic stage on the chronological level do not provide scales fine enough to reconstruct the true course of this process. The causes of crises and “mass extinctions” are not yet understood. Most authors have approached this problem in a simplistic manner, searching for a single cause for any, or all, events of this kind. It seems that we do not even have begun to understand what the problems are.     

Nomenclature of precancerous lesions of the uterine cervix. A position paper

There is universal and almost unanimous belief that there is a need for a radical revision of the terminology relating to the epithelial abnormalities of the uterine cervix that precede invasive carcinoma. Although this belief has been held for some years, no generally accepted alternative system has, as yet, been devised. This position paper examines (1) the origin of the existing system of terminology, (2) the problems associated with this system and (3) the requirements of any new, alternative nomenclature. The various alternatives that have been suggested are considered with particular reference to their advantages and disadvantages. Only two such alternatives are considered to be acceptable, and it is suggested that neither is likely to gain universal acceptance at this time. However, it is possible that new diagnostic techniques, with their potential for a more accurate evaluation of cell abnormalities, may facilitate the development or application of an acceptable system of terminology.     

The universal tip: a systematic approach to aesthetic problems of the lower lateral cartilages

A systematic approach to the various common aesthetic problems of the lower lateral cartilages is presented. Since this approach and technique may be applied to a wide variety of problems, we have taken the liberty of calling this the universal tip. These concepts have emerged from study of the literature and have evolved over the past thousand rhinoplasties. A classification of lower lateral cartilage problems includes five basic variations: (1) the wide, amphorous, ill-defined tip, (2) insufficient projection of the tip, (3) overprojection of the tip, (4) dependent tip with lack of definition, and (5) asymmetrical tip. It is important to realize that any of these five categories may be found in various combinations with each other. The details and fundamental steps of this universal tip technique are presented along with illustrative case examples in each of the five basic variations. In approximately 4 percent of patients there is a postoperative asymmetry in the position of cartilaginous flaps in the region of the dome of the lower lateral cartilage. These abnormalities plus abnormal ridges or bossa can usually be corrected at the time of secondary surgery under local anesthesia.     

Senior house officers: the lost tribes.

There are more senior house officers than doctors in any other training grade in Britain but nobody knows what they do in hospitals or has a clear idea what skills they should be learning. Nobody is responsible for them and they suffer from having a poor career structure and inadequate training. Now that there are government initiatives to reduce the hours that junior doctors work and to limit the time it takes to train to become a specialist, the problems that senior house officers face can no longer be ignored. A conference for senior house officers held last week talked about the problems that they face and tried to find some solutions.     

Human aspects of shift work in the developing countries--I: A case study in Bangladesh

There currently is little information available that allows objective prediction of psychosocial risks and benefits associated with the shift work in the developing countries. To provide such information, this study assessed possible differential effects of fatigue associated with the shift workers' attitude, job satisfaction, psychosocial problems, and other difficulties. Data were collected from the subjective responses on various scales using questionnaire among sixty adult male subjects working on a weekly rotating three-shift system in a shoe factory in Bangladesh. The results indicated that shift work is associated with negative aspects of disturbing their family, conjugal and social lives, curtailed leisure activities, created difficulties in meeting their friends, caused irregularity of their mealtime, affected sleep and caused health problems. However, the effect is significant only for such feelings of social and family aspects, as well as sleepy and lively hood but no significant main effects of shift schedule are observed for any of the behavioural and organizational context.     

LCA comparability and the waste index

There are several problems with the current Life-Cycle Assessment (LCA) methods. One of the most serious problems, in our opinion, is incomparability of results. Several industry representatives have expressed that without comparability and benchmark ability LCA will not survive long in the commercial world. It is therefore paramount that comparability is achieved. Incomparability stems from the usage of different functional units, unit processes and, most notably, different impact categorizations. We propose a new index — the Waste Index (WI) — that does not rely upon any of these techniques, but rather measures an imbalance in Nature and relies upon thermodynamics and chemistry — resulting in comparability.