Receptor signaling: when dimerization is not enough.

Activation of receptors that signal via tyrosine kinase domains has been thought to involve receptor dimerization and transphosphorylation of juxtaposed catalytic domains. Recent results suggest things might be more complex - specific intersubunit conformational changes within a dimer can also be important.     

The retrograde response: when mitochondrial quality control is not enough

Mitochondria are responsible for generating adenosine triphosphate (ATP) and metabolic intermediates for biosynthesis. These dual functions require the activity of the electron transport chain in the mitochondrial inner membrane. The performance of these electron carriers is imperfect, resulting in release of damaging reactive oxygen species. Thus, continued mitochondrial activity requires maintenance. There are numerous means by which this quality control is ensured. Autophagy and selective mitophagy are among them. However, the cell inevitably must compensate for declining quality control by activating a variety of adaptations that entail the signaling of the presence of mitochondrial dysfunction to the nucleus. The best known of these is the retrograde response. This signaling pathway is triggered by the loss of mitochondrial membrane potential, which engages a series of signal transduction proteins, and it culminates in the induction of a broad array of nuclear target genes. One of the hallmarks of the retrograde response is its capacity to extend the replicative life span of the cell. The retrograde signaling pathway interacts with several other signaling pathways, such as target of rapamycin (TOR) and ceramide signaling. All of these pathways respond to stress, including metabolic stress. The retrograde response is also linked to both autophagy and mitophagy at the gene and protein activation levels. Another quality control mechanism involves age-asymmetry in the segregation of dysfunctional mitochondria. One of the processes that impinge on this age-asymmetry is related to biogenesis of the organelle. Altogether, it is apparent that mitochondrial quality control constitutes a complex network of processes, whose full understanding will require a systems approach. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.     

Dealing with DNA lesions: When one cell cycle is not enough

Subversion of genome integrity fuels cellular adaptation and is a prerequisite for organismal evolution, yet genomic lesions are also the harmful driving force of cancer and other age-related human diseases. Genome integrity maintenance is inherently linked to genome organization and nuclear architecture, which are substantially remodeled during the cell cycle. Here we discuss recent findings on how actively dividing cells cope with endogenous genomic lesions that occur frequently at repetitive, heterochromatic, and late replicating regions as byproducts of genome duplication. We discuss how such lesions, rather than being resolved immediately when they occur, are dealt with in subsequent cell cycle phases, and even after mitotic cell division, and how this in turn affects genome organization, stability, and function.     

Oogenesis: when most is good enough

In male meiosis an unaligned chromosome blocks meiotic progression. However, oocytes with one or more misaligned chromosomes can complete meiosis. This difference reflects a more permissive role of the spindle assembly checkpoint, rather than solely reflecting the ability of some univalents to adopt a meiosis II-like orientation on the spindle.     

When enough is not enough: shorebirds and shellfishing

In a number of extensive coastal areas in northwest Europe, large numbers of long-lived migrant birds eat shellfish that are also commercially harvested. Competition between birds and people for this resource often leads to conflicts between commercial and conservation interests. One policy to prevent shellfishing from harming birds is to ensure that enough food remains after harvesting to meet most or all of their energy demands. Using simulations with behaviour-based models of five areas, we show here that even leaving enough shellfish to meet 100% of the birds' demands may fail to ensure that birds survive in good condition. Up to almost eight times this amount is needed to protect them from being harmed by the shellfishery, even when the birds can consume other kinds of non-harvested prey.     

When counting cattle is not enough: multiple perspectives in agricultural and veterinary research

A traditional approach in agricultural and veterinary research is focussing on the biological perspective where large cattle-databases are used to analyse the dairy herd. This approach has yielded valuable insights. However, recent research indicates that this knowledge-base can be further increased by examining agricultural and veterinary challenges from other perspectives. In this paper we suggest three perspectives that may supplement the biological perspective in agricultural and veterinary research; the economic-, the managerial-, and the social perspective. We review recent studies applying or combining these perspectives and discuss how multiple perspectives may improve our understanding and ability to handle cattle-health challenges.     

Multi-locus species delimitation in closely related animals and fungi: one marker is not enough

Despite taxonomy’s 250‐year history, the past 20 years have borne witness to remarkable advances in technology and techniques, as well as debate. DNA barcoding has generated a substantial proportion of this debate, with its proposition that a single mitochondrial sequence will consistently identify and delimit species, replacing more evidence‐rich and time‐intensive methods. Although mitochondrial DNA (mtDNA) has since been the focus of voluminous discussion and case studies, little effort has been made to comprehensively evaluate its success in delimiting closely related species. We have conducted the first broadly comparative literature review addressing the efficacy of molecular markers for delimiting such species over a broad taxonomic range. By considering only closely related species, we sought to avoid confusion of success rates with those due to deeply divergent taxa. We also address whether increased population‐level or geographic sampling affects delimitation success. Based on the results from 101 studies, we found that all marker groups had approximately equal success rates (～70%) in delimiting closely related species and that the use of additional loci increased average delimitation success. We also found no relationship between increased sampling of intraspecific variability and delimitation success. Ultimately, our results support a multi‐locus integrative approach to species delimitation and taxonomy.     

Assigning pathogenicity to mitochondrial tRNA mutations: when "definitely maybe" is not good enough

Some mutations in mitochondrial tRNA (mt-tRNA) genes cause devastating disease, whereas others have no clinical consequences. We understand little of the factors determining the pathogenicity of specific mt-tRNA mutations, making prediction of clinical outcome extremely difficult. Using extensive sequence databases, we compared the characteristics of neutral variations with those of pathogenic mutations. We recommend that the location of the proposed mutation within the secondary structure of the mt-tRNA molecule and the disruption it causes to Watson-Crick base pairing should be considered when assessing the pathological significance of a novel mt-tRNA mutation.     

Accumulating evidence in ecology: Once is not enough

Many published studies in ecological science are viewed as stand‐alone investigations that purport to provide new insights into how ecological systems behave based on single analyses. But it is rare for results of single studies to provide definitive results, as evidenced in current discussions of the “reproducibility crisis” in science. The key step in science is the comparison of hypothesis‐based predictions with observations, where the predictions are typically generated by hypothesis‐specific models. Repeating this step allows us to gain confidence in the predictive ability of a model, and its corresponding hypothesis, and thus to accumulate evidence and eventually knowledge. This accumulation may occur via an ad hoc approach, via meta‐analyses, or via a more systematic approach based on the anticipated evolution of an information state. We argue the merits of this latter approach, provide an example, and discuss implications for designing sequences of studies focused on a particular question. We conclude by discussing current data collection programs that are preadapted to use this approach and argue that expanded use would increase the rate of learning in ecology, as well as our confidence in what is learned.     

Physiological significance of alpha(2)-adrenergic receptor subtype diversity: one receptor is not enough

Alpha(2)-adrenergic receptors mediate part of the diverse biological effects of the endogenous catecholamines epinephrine and norepinephrine. Three distinct subtypes of alpha(2)-adrenergic receptors, alpha(2A), alpha(2B), alpha(2C), have been identified from multiple species. Because of the lack of sufficiently subtype-selective ligands, the specific biological functions of these receptor subtypes were largely unknown until recently. Gene-targeted mice carrying deletions in the genes encoding for individual alpha(2)-receptor subtypes have added important new insight into the physiological significance of adrenergic receptor diversity. Two different strategies have emerged to regulate adrenergic signal transduction. Some biological functions are controlled by two counteracting alpha(2)-receptor subtypes, e.g., alpha(2A)-receptors decrease sympathetic outflow and blood pressure, whereas the alpha(2B)-subtype increases blood pressure. Other biological functions are regulated by synergistic alpha(2)-receptor subtypes. The inhibitory presynaptic feedback loop that tightly regulates neurotransmitter release from adrenergic nerves also requires two receptor subtypes, alpha(2A) and alpha(2C). Similarly, nociception is controlled at several levels by one of the three alpha(2)-receptor subtypes. Further investigation of the specific function of alpha(2)-subtypes will greatly enhance our understanding of the relevance of closely related receptor proteins and point out novel therapeutic strategies for subtype-selective drug development.     

Medical audit data: counting is not enough.

OBJECTIVE--To assess the meaningfulness of a year''s worth of audit data relating to all the inpatients of one consultant general surgeon and to question the usefulness of certain outcome measures. DESIGN--Analysis of records entered on to audit computer (Dunnfile) and relating to inpatient episodes for one consultant general surgeon over one year. Data obtained were compared with ward records and the patient administration system to check their accuracy. SETTING--The three hospitals and 12 wards in Brighton health district where the surgeon admitted patients. SUBJECTS--859 Records relating to inpatient episodes from 1 January to 31 December 1988. These covered 655 main procedures and 79 secondary procedures performed at the same time. MAIN OUTCOME MEASURES--Procedures were analysed by complexity of operation (BUPA code) and grade of surgeon; complications were counted and rates constructed by surgeon and by BUPA code: returns to theatre were analysed. RESULTS--Simple counts revealed some data, such as the fact that one registrar performed more major operations (32) than the senior registrars (22 and 14), and an analysis of complications showed that he had a lower complication rate (11.4% v 20.0% and 19.4%). But the simple complication rate disclosed nothing about whether the complication was avoidable. Likewise, the number of returns to theatre needed further qualification. Analysis of data collection for February to April 1988 showed a 30% deficit of information on the audit system compared with ward records and prompted a re-examination of everyone''s role in collecting data. After the year''s audit there was still a 17% shortfall compared with the district''s patient administration system, though some of this was accounted for by a backlog of work. CONCLUSIONS--It is difficult to ensure adequate data collection and entails everyone in an unfamiliar discipline. Connecting the audit system to the patient administration system would help. Despite the limitations of crude analyses of workload and complications rates, the audit data helped to measure activity and in the management of the firm. Nevertheless, time and care have to be taken in presenting and interpreting audit data carefully. IMPLICATIONS--Counting is not enough.     

Combining many multiple alignments in one improved alignment

MOTIVATION: The fact that the multiple sequence alignment problem is of high complexity has led to many different heuristic algorithms attempting to find a solution in what would be considered a reasonable amount of computation time and space. Very few of these heuristics produce results that are guaranteed always to lie within a certain distance of an optimal solution (given a measure of quality, e.g. parsimony). Most practical heuristics cannot guarantee this, but nevertheless perform well for certain cases. An alignment, obtained with one of these heuristics and with a bad overall score, is not unusable though, it might contain important information on how substrings should be aligned. This paper presents a method that extracts qualitatively good sub-alignments from a set of multiple alignments and combines these into a new, often improved alignment. The algorithm is implemented as a variant of the traditional dynamic programming technique. RESULTS: An implementation of ComAlign (the algorithm that combines multiple alignments) has been run on several sets of artificially generated sequences and a set of 5S RNA sequences. To assess the quality of the alignments obtained, the results have been compared with the output of MSA 2.1 (Gupta et al., Proceedings of the Sixth Annual Symposium on Combinatorial Pattern Matching, 1995; Kececioglu et al., http://www.techfak.uni-bielefeld. de/bcd/Lectures/kececioglu.html, 1995). In all cases, ComAlign was able to produce a solution with a score comparable to the solution obtained by MSA. The results also show that ComAlign actually does combine parts from different alignments and not just select the best of them. AVAILABILITY: The C source code (a Smalltalk version is being worked on) of ComAlign and the other programs that have been implemented in this context are free and available on WWW (http://www.daimi.au.dk/ ?caprani). CONTACT: klaus@bucka-lassen.dk; jotun@pop.bio.au.dk;ocaprani@daimi.au.dk