Additivity in protein-DNA interactions: how good an approximation is it?

Man and Stormo and Bulyk et al. recently presented their results on the study of the DNA binding affinity of proteins. In both of these studies the main conclusion is that the additivity assumption, usually applied in methods to search for binding sites, is not true. In the first study, the analysis of binding affinity data from the Mnt repressor protein bound to all possible DNA (sub)targets at positions 16 and 17 of the binding site, showed that those positions are not independent. In the second study, the authors analysed DNA binding affinity data of the wild-type mouse EGR1 protein and four variants differing on the middle finger. The binding affinity of these proteins was measured to all 64 possible trinucleotide (sub)targets of the middle finger using microarray technology. The analysis of the measurements also showed interdependence among the positions in the DNA target. In the present report, we review the data of both studies and we re- analyse them using various statistical methods, including a comparison with a multiple regression approach. We conclude that despite the fact that the additivity assumption does not fit the data perfectly, in most cases it provides a very good approximation of the true nature of the specific protein–DNA interactions. Therefore, additive models can be very useful for the discovery and prediction of binding sites in genomic DNA.     

Condition‐dependent immune defence in the Magpie: how important is ectoparasitism?

The immune system has high costs of maintenance and production and expression of immune function should be dependent on the condition of the individual. The fitness cost that parasites impose on hosts may then be reflected in the investment that hosts make in immunity. Little is known about sources and consequences of intra- and interspecific variation in the presence and size of organs of the immune system in relation to ectoparasitism. Variation in the presence and size of the bursa of Fabricius and spleen size was measured to assess potential relationships between immune defence, nutritional condition and ectoparasites in the Magpie Pica pica. We found three species of lice (Mallophaga), two species of louse flies (Hippoboscidae), and the larvae of a tick (Ixodidae) infecting magpies. Age explained a significant proportion of variation in prevalence and number of parasite species, first-year birds being more parasitized than adults. Spleen size increased with nutritional condition, and the level of ectoparasitism negatively affected nutritional condition. Only one species of lice (Philopterus picae) was involved; the negative effect of this species on nutritional condition was more pronounced in males than females. These results are consistent with the hypotheses of condition-dependent investment in the immune system and sexual differences in susceptibility to parasite effects. Ectoparasites may thus play a role in modulating the relationship between condition and immune defence. We also found evidence for an interaction between the bursa and the spleen. Magpies with bursa had larger spleens than those where it had atrophied. This interaction did not affect ectoparasitism or nutritional condition.     

Remission in psoriatic arthritis: is it possible and how can it be predicted?

Introduction

Since remission is now possible in psoriatic arthritis (PsA) we wished to examine remission rates in PsA patients following anti tumour necrosis factor alpha (TNFα) therapy and to examine possible predictors of response.

Methods

Analysis of a prospective patient cohort attending a biologic clinic, between November 2004 and March 2008, was performed prior to commencing therapy and at regular intervals. Baseline clinical characteristics including demographics, previous disease-modifying antirheumatic drug (DMARD) response, tender and swollen joint counts, early morning stiffness, pain visual analogue score, patient global assessment, C reactive protein (CRP) and health assessment questionnaire (HAQ) were collected.

Results

A total of 473 patients (152 PsA; 321 rheumatoid arthritis (RA)) were analyzed. At 12 months remission, defined according to the disease activity score using 28 joint count and CRP (DAS28-CRP), was achieved in 58% of PsA patients compared to 44% of RA patients, significant improvement in outcome measures were noted in both groups (P < 0.05). Analysis of a subgroup of PsA and RA patients matched for DAS28-CRP at baseline also showed higher numbers of PsA patients achieving remission. Linear regression analysis identified the HAQ at baseline as the best predictor of remission in PsA patients (P < 0.001).

Conclusions

DAS28 remission is possible in PsA patients at one year following anti-TNF therapy, at higher rates than in RA patients and is predicted by baseline HAQ.     

The non‐existent aging program: how does it work?

Summary Aging and lifespan determination have been viewed, in the most well-accepted theories, as nonprogrammatic, and are thought to result from the evolutionary selection for early fitness at the expense of late survival. Here, recent data implicating potentially programmatic aspects of aging and lifespan determination are discussed, and analogies between programmed cell death and programmed organismal death are offered. It is hoped that the recognition of at least the possibility of a programmatic aspect, or aspects, to the determination of longevity and the process of aging will help to optimize our chances to identify appropriate therapeutic targets both for longevity enhancement and disease prevention.     

Single-molecule biology: what is it and how does it work?

Biochemistry and structural biology are undergoing a dramatic revolution. Until now, we have tried to study subtle and complex biological processes by crude in vitro techniques, looking at average behaviors of vast numbers of molecules under conditions usually remote from those existing in the cell. Researchers have realized the limitations of this approach, but none other has been available. Now, we can not only observe the nuances of the behaviors of individual molecules but prod and probe them as well. Perhaps most important is the emerging ability to carry out such observations and manipulations within the living cell. The long-awaited leap to an in vivo biochemistry is at last underway.     

Poisoning for production: how effective is fox baiting in south‐eastern Australia?

• 1 The European red fox Vulpes vulpes represents a continuing threat to both livestock and native vertebrates in Australia, and is commonly managed by setting ground‐level baits impregnated with 1080 (sodium fluoroacetate) poison. However, the long‐term effectiveness of such control campaigns is likely to be limited due to the ability of foxes to disperse over considerable distances and to swiftly recolonize areas from where they had been removed.
• 2 To investigate the effectiveness of fox baiting in a production landscape, we assessed the potential for foxes to reinvade baited farm property areas within the jurisdiction of the Molong Rural Lands Protection Board (RLPB), an area of 815 000 ha on the central tablelands of New South Wales, Australia. The spatial distribution and timing of fox baiting campaigns between 1998 and 2002 was estimated from RLPB records and mapped using Geographical Information System software. The effectiveness of the control campaign was assessed on the basis of the likely immigration of foxes from non‐baited farms using immigration distances calculated from published relationships between dispersal distance and home range size.
• 3 Few landholders undertook baiting campaigns in any given year, and the area baited was always so small that no baited property would have been sufficiently far from an unbaited property to have been immune from immigrating individuals. It is likely, therefore, that immigration onto farms negated any long‐term effects of baiting operations. This study highlights some of the key deficiencies in current baiting practices in south‐eastern Australia and suggests that pest management programmes should be monitored using such methods to ensure they achieve their goals.

     

The mid‐season crash in aphid populations: why and how does it occur?

Abstract. 1. Aphid populations on agricultural crops in temperature regions collapse over a few days from peak numbers to local extinction soon after mid‐summer (e.g. mid‐July in the U.K.). The populations recover 6–8 weeks later. There is anecdotal or incidental evidence of an equivalent mid‐season population crash of aphids on grasses and forbs in natural vegetation. 2. The ecological factors causing the mid‐season population crash of aphids include a decline in plant nutritional quality and increased natural enemy pressure as the season progresses. Extreme weather events, e.g. severe rainstorms, can precipitate the crash but weather conditions are not a consistent contributory factor. 3. The population processes underlying the crash comprise enhanced emigration, especially by alate (winged) aphids, depressed performance resulting in reduced birth rates, and elevated mortality caused by natural enemies. 4. Mathematical models, previously applied to aphid populations on agricultural crops, have great potential for studies of aphid dynamics in natural vegetation. In particular, they can help identify the contribution of various ecological factors to the timing of the population crash and offer explanations for how slow changes in population processes can result in a rapid collapse of aphid populations.     

Angular disorder in actin: is it consistent with general principles of protein structure?

Harold Erickson has recently provided a useful analysis of helical structures having one class versus two classes of intersubunit bonds. His analysis is based upon an assumption that the subunits themselves are essentially unchanged upon bond formation (polymerization). He shows that such a structure having two classes of bonds (i.e. one in which each subunit interacts with four of its neighbors rather than two) can explain some of the features of actin. While he acknowledges that for actin there could be a conformational change and that, in principle, it could explain such features, he argues that the allowed magnitude of such a conformational change is inadequate. Since kinetics and thermodynamics cannot distinguish between the energy derived from the formation of a bond from that due to a conformational change, the question of whether the features of F-actin are derived from a conformational change or a system of two classes of bonds or both must be answered with high-resolution structural information. Recent studies by K. C. Holmes and others suggest that the second possibility might be closest to the truth. The heart of our disagreement is not whether Erickson's thermodynamic analysis is correct, given rigid subunits, but whether all protein polymers are characterized by rigid subunits with rigid intersubunit contacts. Erickson maintains that the observation of an angular disorder of 12 degrees per subunit within the actin filament conflicts with his formalism of rigid subunit interfaces and must therefore result from the erroneous interpretation of measurements. He presents an alternative model to explain the observations. His model, however, does not account for the observations and we will argue that, ultimately, like the resolution of the matter of the number of classes of bonds and the extent of their contact, the amount of angular disorder will require higher-resolution structural studies.     

Hysteresis and cell cycle transitions: how crucial is it?

Recently, experiments have shown that cyclin-dependent kinase (CDK) activity exhibits hysteresis in its response to total cyclin when cyclin is made nondegradable and controlled externally. This observation was taken to support mathematical modeling predictions regarding the underlying dynamics of the cell cycle. However, cell cycle dynamics can also be generated by other nonhysteretic mechanisms. To examine the robustness of the hysteretic response of CDK activity to total cyclin, we simulated various cell cycle signal transduction networks, and correlated the dynamics to the response function of CDK activity versus total cyclin. By randomly searching the parameter space, we assessed robustness by estimating the frequency of hysteretic versus nonhysteretic dynamical mechanisms. When the dynamical instabilities were caused by feedback loops in CDK phosphorylation and dephosphorylation or by feedback between cyclin and the CDK inhibitor, the response function of CDK activity versus total cyclin correlated well with the dynamical instabilities. However, when the dynamical instabilities originated from feedback between cyclin and APC-CDH1 or RB-E2F, the response function did not correlate with dynamical instabilities. Thus, although a hysteretic response is neither necessary nor sufficient, it is in general a much more robust mechanism for generating cell cycle dynamics than nonhysteretic mechanisms.     

Coexistence of competing parasitoids: which is the fugitive and where does it hide?

Most insects harbour a community of parasitoids that coexist in spite of competition for resources. One potential mechanism for coexistence of competitors is a tradeoff between dispersiveness and local competitive ability. Here we present a study of competition between the specialized parasitoids Hyposoter horticola and Cotesia melitaearum sharing the Glanville fritillary butterfly, Melitaea cinxia . Within one host generation, the parasitoid larvae interact inside the host during each of the three C. melitaearum generations. We founds that in the summer when the host is small, the solitary H. horticola is the superior competitor, suppressing the gregarious C. melitaearum as eggs or small larvae. When multiparasitism occurs in the autumn the two parasitoid species engage in physical combat and C. melitaearum is favoured. Finally, a previous study showed that in the third C. melitaearum generation the univoltine H. horticola grows quickly during its final instar, excluding young C. melitaearum simply through limited time and resources. We found that contrary to expectations of the evolution of gregariousness, C. melitaearum , which lives in sibling groups, has biting mandibles in the first instar while the solitary H. horticola has suctorial mouthparts. Previous studies suggest that the two parasitoids co-exist because H. Horticola is dispersive and C. melitaearum is a strong local competitor. However, putting together the results of this experiment and out recent understanding of the adult wasp foraging behaviours and large scale population dynamics, we conclude that H. horticola is both a superior local competitor and more dispersive than C. melitaearum . Cotesia melitaearum has no impact on the population dynamics of H. horticola , persisting as a fugitive using a small fraction the larvae left unparasitized by H. horticola .     

Intra‐individual polymorphism in chloroplasts from NGS data: where does it come from and how to handle it?

Next‐generation sequencing allows access to a large quantity of genomic data. In plants, several studies used whole chloroplast genome sequences for inferring phylogeography or phylogeny. Even though the chloroplast is a haploid organelle, NGS plastome data identified a nonnegligible number of intra‐individual polymorphic SNPs. Such observations could have several causes such as sequencing errors, the presence of heteroplasmy or transfer of chloroplast sequences in the nuclear and mitochondrial genomes. The occurrence of allelic diversity has practical important impacts on the identification of diversity, the analysis of the chloroplast data and beyond that, significant evolutionary questions. In this study, we show that the observed intra‐individual polymorphism of chloroplast sequence data is probably the result of plastid DNA transferred into the mitochondrial and/or the nuclear genomes. We further assess nine different bioinformatics pipelines’ error rates for SNP and genotypes calling using SNPs identified in Sanger sequencing. Specific pipelines are adequate to deal with this issue, optimizing both specificity and sensitivity. Our results will allow a proper use of whole chloroplast NGS sequence and will allow a better handling of NGS chloroplast sequence diversity.     

Disability; is it permanent?

Too often cases of industrial injuries are submitted for permanent disability rating before maximum recovery is attained and the condition is permanent and stationary. This is frequently a situation that is detrimental to the injured working man, since his physical disability might be further reduced by additional treatment, and his future earning power and economic status thus be improved. Also it may be detrimental to the insurance carrier and/or employer, since in some instances it results in increased permanent disability award payments for portions of the condition which are not truly permanent. Inadequate medical reports also are a frequent cause of unfair awards. The necessary factors used to arrive at proper conclusions, the errors that have been observed and the importance of this problem are discussed.     

Vaccination against shigellosis: is it the path that is difficult or is it the difficult that is the path?

Following several decades of research, there is not yet a convincing vaccine against shigellosis. It is still difficult, in spite of the breadth of strategies (i.e. live attenuated oral, killed oral, subunit parenteral) to select an optimal option. Two approaches are clearly emerging: (i) live attenuated deletion mutants based on rational selection of genes that are key in the pathogenic process, and (ii) conjugated detoxified polysaccharide parenteral vaccines, or more recently conjugated synthetic carbohydrates. Some of these approaches have already undergone phase I and II clinical trials with promising results, but important issues have also emerged, particularly the discrepancy between colonization and immunogenic potential of live attenuated vaccine candidates depending upon the population concerned (i.e. non endemic vs. endemic areas). Efforts are needed to definitely establish the proof of concept of these approaches, and thus the need for clinical trials which should also soon explore the possibility to associate different serotypes, in response to serotype specific protection against shigellosis. More basic research is also required to improve what we can still consider as first-generation vaccines, and to explore possible new paradigms including the search for cross-protective antigens.