Remodeling of the major light-harvesting antenna protein of PSII protects the young leaves of barley (Hordeum vulgare L.) from photoinhibition under prolonged iron deficiency. Because of the high demand for iron of the photosynthetic apparatus in thylakoid membranes, iron deficiency primarily affects the electron transfer between the two photosystems (PSI and PSII), resulting in photooxidative damage in plants. However, in barley, PSII is protected against photoinhibition, and the plant survives even with a low iron content in its chlorotic leaves. In this study, we report an adaptation mechanism of the photosynthetic apparatus in barley to iron deficiency, which is concomitant with the remodeling of a PSII antenna system. Transcriptome analysis revealed that long-term iron deficiency induced the expression of two genes of the major light-harvesting Chl a/b-binding protein of PSII (LHCII), namely HvLhcb1.11 and HvLhcb1.12. Chl fluorescence analysis of the wild type and Lhcb1-less chlorina mutants clearly showed that non-photochemical quenching (NPQ) of the wild type was increased by approximately 200% by iron deficiency, whereas NPQ of chlorina mutants did not change significantly under iron deficiency. The mutant showed severe photodamage in young leaves under prolonged iron deficiency, suggesting that the HvLhcb1 protein is essential for both thermal dissipation and photoprotection in iron-deficient barley. Analysis of thylakoid protein complexes revealed that the proportion of the monomeric form of Lhcb1 significantly increased in barley grown under iron-deficient conditions. We hypothesize that alteration of the HvLhcb1 subpopulations modifies the organization of LHCII in the thylakoid membranes, which is a key step for thermal dissipation to compensate for excess excitation energy and thereby protect the photosystems from serious damage in iron-deficient barley leaves.


Efficient yeast one-/two-hybrid screening using a library composed only of transcription factors in Arabidopsis thaliana. Yeast one-hybrid screening is widely used for the identification of transcription factors (TFs) that interact with specific DNA sequences. However, screening a whole cDNA library is not efficient for the identification of TFs because TF genes represent only a small percentage of clones in a cDNA library. Here, we present the development of an efficient yeast one-hybrid screening system using a prey library composed only of approximately 1,500 TF cDNAs of Arabidopsis thaliana. This library enabled us to isolate a TF that binds to a specific promoter sequence with high efficiency, even when the promoter region of the gene of interest was directly employed as bait. Furthermore, this library was also successfully applied as a yeast two-hybrid library to find TFs that interact with specific proteins. This efficient system will contribute to the elucidation of gene regulatory networks in plants.


Optimized data fusion for K-means Laplacian clustering. We propose a novel algorithm to combine multiple kernels and Laplacians for clustering analysis. The new algorithm is formulated on a Rayleigh quotient objective function and is solved as a bi-level alternating minimization procedure. Using the proposed algorithm, the coefficients of kernels and Laplacians can be optimized automatically. Three variants of the algorithm are proposed. The performance is systematically validated on two real-life data fusion applications. The proposed Optimized Kernel Laplacian Clustering (OKLC) algorithms perform significantly better than other methods. Moreover, the coefficients of kernels and Laplacians optimized by OKLC show some correlation with the rank of performance of individual data source. Though in our evaluation the K values are predefined, in practical studies, the optimal cluster number can be consistently estimated from the eigenspectrum of the combined kernel Laplacian matrix. The MATLAB code of algorithms implemented in this paper is downloadable from http://homes.esat.kuleuven.be/~sistawww/bioi/syu/oklc.html.


Identification of subfamily-specific sites based on active sites modeling and clustering. Current computational approaches to function prediction are mostly based on protein sequence classification and transfer of annotation from known proteins to their closest homologous sequences relying on the orthology concept of function conservation. This approach suffers a major weakness: annotation reliability depends on global sequence similarity to known proteins and is poorly efficient for enzyme superfamilies that catalyze different reactions. Structural biology offers a different strategy to overcome the problem of annotation by adding information about protein 3D structures. This information can be used to identify amino acids located in active sites, focusing on detection of functional polymorphisms residues in an enzyme superfamily. Structural genomics programs are providing more and more novel protein structures at a high-throughput rate. However, there is still a huge gap between the number of sequences and available structures. Computational methods, such as homology modeling provides reliable approaches to bridge this gap and could be a new precise tool to annotate protein functions. Here, we present Active Sites Modeling and Clustering (ASMC) method, a novel unsupervised method to classify sequences using structural information of protein pockets. ASMC combines homology modeling of family members, structural alignment of modeled active sites and a subsequent hierarchical conceptual classification. Comparison of profiles obtained from computed clusters allows the identification of residues correlated to subfamily function divergence, called specificity determining positions. ASMC method has been validated on a benchmark of 42 Pfam families for which previous resolved holo-structures were available. ASMC was also applied to several families containing known protein structures and comprehensive functional annotations. We will discuss how ASMC improves annotation and understanding of protein families functions by giving some specific illustrative examples on nucleotidyl cyclases, protein kinases and serine proteases. http://www.genoscope.fr/ASMC/.


Molecular basis of the core regulatory network in ABA responses: sensing, signaling and transport. ABA is a major phytohormone that regulates a broad range of plant traits and is especially important for adaptation to environmental conditions. Our understanding of the molecular basis of ABA responses in plants improved dramatically in 2009 and 2010, banner years for ABA research. There are three major components; PYR/PYL/ RCAR (an ABA receptor), type 2C protein phosphatase (PP2C; a negative regulator) and SNF1-related protein kinase 2 (SnRK2; a positive regulator), and they offer a double negative regulatory system, [PYR/PYL/RCAR-| PP2C-| SnRK2]. In the absence of ABA, PP2C inactivates SnRK2 by direct dephosphorylation. In response to environmental or developmental cues, ABA promotes the interaction of PYR/PYL/RCAR and PP2C, resulting in PP2C inhibition and SnRK2 activation. This signaling complex can work in both the nucleus and cytosol, as it has been shown that SnRK2 phosphorylates basic-domain leucine zipper (bZIP) transcription factors or membrane proteins. Several structural analyses of PYR/PYL/RCAR have provided the mechanistic basis for this 'core signaling' model, by elucidating the mechanism of ABA binding of receptors, or the 'gate-latch-lock' mechanism of interaction with PP2C in inhibiting activity. On the other hand, intercellular ABA transport had remained a major issue, as had intracellular ABA signaling. Recently, two plasma membrane-type ABC transporters were identified and shed light on the influx/efflux system of ABA, resolving how ABA is transported from cell to cell in plants. Our knowledge of ABA responses in plants has been greatly expanded from intracellular signaling to intercellular transport of ABA.


Reconceptualising health services for school-age children in the 21st century.


A knotted problem.

A knotted problem.


Archimedes. Question 1. Does oral ondansetron reduce vomiting and the need for intravenous fluids and hospital admission in children presenting with vomiting secondary to gastroenteritis?


The neurodevelopmental sequelae of childhood leukaemia and its treatment. The overall survival of childhood leukaemia has increased dramatically over recent decades. With the increasing number of survivors, chemotherapy protocols are designed not only to improve cure rates but also to minimise long-term sequelae. Central-nervous-system-directed therapy given as intrathecal chemotherapy and/or cranial irradiation plays a crucial part in acute leukaemia treatment but can also result in adverse effects on the developing brain. The elimination of cranial irradiation from current treatment protocols has improved the neurocognitive outcome without compromising survival rates. Although neurodevelopmental long-term sequelae after chemotherapy-only central-nervous-system-directed therapies may be more subtle, survivors of childhood leukaemia will continue to require methodical follow-up and appropriate rehabilitation.


Archimedes. Towards evidence based medicine for paediatricians.


Archimedes. Question 2. Is oral montelukast beneficial in treating acute asthma exacerbations in children?


Perinatal interventions and survival in resource-poor settings: which work, which don't, which have the jury out? Perinatal conditions make the largest contribution to the burden of disease in low-income countries. Although postneonatal mortality rates have declined, stillbirth and early neonatal mortality rates remain high in many countries in Africa and Asia, and there is a concentration of mortality around the time of birth. Our article begins by considering differences in the interpretation of 'intervention' to improve perinatal survival. We identify three types of a single action, a collection of actions delivered in a package and a broader social or system approach. We use this classification to summarise the findings of recent systematic reviews and meta-analyses. After describing the growing evidence base for the effectiveness of community-based perinatal care, we discuss current concerns about integration: of women's and children's health programmes, of community-based and institutional care, and of formal and informal sector human resources. We end with some thoughts on the complexity of choices confronting women and their families in low-income countries, particularly in view of the growth in non-government and private sector healthcare.


Archimedes. Question 3. Should carbamazepine be administered to manage agitation and aggressive behaviour following paediatric acquired brain injury?


No overall progression and occasional repair of erosions despite persistent inflammation in adalimumab-treated rheumatoid arthritis patients: results from a longitudinal comparative MRI, ultrasonography, CT and radiography study. To monitor joint inflammation and destruction in rheumatoid arthritis (RA) patients receiving adalimumab/methotrexate combination therapy using MRI and ultrasonography. To assess the predictive value of MRI and ultrasonography for erosive progression on CT and compare MRI/ultrasonography/radiography for erosion detection/monitoring. Fifty-two erosive biological-naive RA patients were followed with repeated MRI/ultrasonography/radiography (0/6/12 months) and clinical/biochemical assessments during adalimumab/methotrexate combination therapy. No overall erosion progression or repair was observed at 6 or 12 months (Wilcoxon; p > 0.05), but erosion progressors and regressors were observed using the smallest detectable change cut-off. Scores of MRI synovitis, grey-scale synovitis (GSS) and power Doppler ultrasonography decreased after 6 and 12 months (p < 0.05), as did DAS28, HAQ and tender and swollen joint counts (p < 0.001). Patients with progression on CT had higher baseline MRI bone oedema scores. The RR for CT progression in bones with versus without baseline MRI bone oedema was 3.8 (95% CI 1.5 to 9.3) and time-integrated MRI bone oedema, power Doppler and GSS scores were higher in bones/joints with CT progression (Mann-Whitney; p < 0.05). With CT as the reference method, sensitivities/specificities for erosion in metacarpophalangeal joints were 68%/92%, 44%/95% and 26%/98% for MRI, ultrasonography and radiography, respectively. Median intraobserver correlation coefficient was 0.95 (range 0.44-0.99). During adalimumab/methotrexate combination therapy, no overall erosive progression or repair occurred, whereas repair of individual erosions was documented on MRI, and MRI and ultrasonography synovitis decreased. Inflammation on MRI and ultrasonography, especially MRI bone oedema, was predictive for erosive progression on CT, at bone/joint level and MRI bone oedema also at patient level.


Elevated number of recently activated T cells in bone marrow of patients with rheumatoid arthritis: a role for interleukin 15? (1) To compare the absolute T-cell numbers in bone marrow (BM) isolated from patients with rheumatoid arthritis (RA) and osteoarthritis (OA); (2) to measure the levels of soluble interleukin 15 (IL-15) and IL-7; (3) to analyse the expression of activation markers on T cells; (4) to analyse influence of IL-15 stimulation on T-cell proliferation. BM samples were obtained from patients undergoing joint replacement surgery. Concentrations of IL-15 and IL-7 were measured using specific ELISAs. The absolute number of T lymphocytes, their activation status and proliferation were evaluated by flow cytometry. BM from patients with RA contained double the number of CD3 T cells in comparison with OA (6.1 vs 2.7 × 10(6) cells/ml, p<0.008). Ratio CD3CD4:CD3CD8 was increased in RA BM, clearly indicating accumulation of CD3CD4 cells. T cells obtained from patients with RA expressed higher level of early activation markers than from OA. Elevated levels of IL-15 were found in BM plasma from patients with RA in comparison with patients with OA (1304.5±956.3 pg/ml and 760±238.7 pg/ml respectively, p<0.01). These data were confirmed by immunohistochemistry of RA BM from regions proximal and distal to the joint. Although both CD3CD4 and CD3CD8 cells proliferated after IL-15 stimulation in vitro, CD3CD4 cells from patients with RA proliferated more vigorously than those from patients with OA, reflecting the composition of T-cell subsets in BM. These results suggest that locally overproduced IL-15 may be responsible for the activation and proliferation of T cells in situ, reflected by significantly increased number of activated T cells in RA BM, possibly contributing to the pathogenesis of RA.


Improvement of HbA1c during treatment with humanised anti-interleukin 6 receptor antibody, tocilizumab.


The interferon regulatory factor 5 gene confers susceptibility to rheumatoid arthritis and influences its erosive phenotype. Increased expression of type I IFN genes, also referred to as an IFN signature, has been detected in various autoimmune diseases including rheumatoid arthritis (RA). Interferon regulatory factors, such as IRF5, coordinate type I IFN expression. Multiple IRF5 variants were suggested as autoimmunity susceptibility factors. As the linkage proof remains important to establish fully any genetic RA susceptibility factor, the authors took advantage of the largest reported European trio family resource dedicated to RA to test for linkage IRF5 and performed a genotype-phenotype analysis. 1140 European Caucasian individuals from 380 RA trio families were genotyped for IRF5 rs3757385, rs2004640 and rs10954213 single nucleotide polymorphisms (SNP). Single marker analysis provided linkage evidence for each IRF5 SNP investigated. IRF5 linked to RA with two haplotypes: the CTA risk haplotype 'R' (transmission (T)=60.6%, p=23.1×10(-5)) and the AGG protective haplotype 'P' (T=39.6%, p=0.0015). Linkage was significantly stronger in non-erosive disease for both IRF5 R and P haplotypes (T=73.9%, p=4.20×10(-5) and T=19.6%, p=3.66×10(-5), respectively). Multivariate logistic regression analysis found IRF5 linked to RA independently of the rheumatoid factor status. IRF5 RR and PP haplotypic genotypes were associated with RA, restricted to the non-erosive phenotype: p=1.68×10(-4), OR 4.80, 95% CI 2.06 to 11.19; p=0.003, OR 0.17, 95% CI 0.05 to 0.57, respectively. This study provides the 'association and linkage proof' establishing IRF5 as a RA susceptibility gene and the identification of a genetic factor that seems to contribute to the modulation of the erosive phenotype. Further studies are warranted to clarify the role of IRF5 in RA and its subphenotypes.


Urinary type II collagen C-terminal peptide is associated with synovitis and predicts structural bone loss in very early inflammatory arthritis. In rheumatoid arthritis, high levels of the cartilage turnover biomarker C-terminal cross-linking telopeptide of type II collagen (CTX-II) predict an increased risk of radiological progression. In very early inflammatory arthritis erosions are uncommon, therefore CTX-II requires validation against early markers of inflammatory arthritis such as power Doppler ultrasound (PDUS) synovitis and bone mineral density (BMD) loss. In 50 subjects with 12 weeks or less of inflammatory hand symptoms, urinary CTX-II and PDUS were performed at baseline and hand BMD at baseline and 12 months. CTX-II data were log transformed to a normal distribution. Associations between variables were examined using Pearson's r/Spearman's ρ correlations. The mean 12- month change in BMD was -0.0068 g/cm² and the geometric mean for baseline CTX-II/creatinine was 245.89 ng/mmol. Log-transformed baseline CTX-II showed a substantive negative association with change in average BMD over 12 months, controlling for baseline BMD and erythrocyte sedimentation rate (r=-0.359, p=0.044). The median total PDUS score was 3.0 and baseline CTX-II was significantly associated with baseline total PDUS (Spearman's ρ=0.482, p=0.002). Urinary CTX-II correlates with PDUS synovitis and hand BMD reduction very early in the course of inflammatory arthritis, suggesting that CTX-II has potential as a biomarker in very early inflammatory arthritis.


Changes in hip fracture rate before and after total knee replacement due to osteoarthritis: a population-based cohort study. Patients with knee osteoarthritis have an increase in bone mass but no corresponding decrease in risk of fracture. This study describes the rates of hip fracture in subjects with knee osteoarthritis before and after having a total knee replacement (TKR), compared with matched controls. A population-based prospective cohort study was conducted. The study population included, from the General Practice Research Database (UK), patients 40 years and older, undergoing TKR between 1986 and end-2006 for knee osteoarthritis as 'cases' (n=20,033). Five disease-free controls (n=100,165) were randomly selected, and matched for age, gender and practice. Hip fractures were ascertained using READ codes, and yearly rates of hip fracture and rate differences were calculated for the 5 years before and after surgery, using Poisson regression. Stratified analyses were performed by age and history of fracture. Hip fracture rates were non-significantly reduced compared with controls before the operation. In the year after TKR, risk increased significantly (RR 1.58; 95% CI 1.14 to 2.19). Rates then declined to equal those of controls by 3 years, and continued decreasing until the end of follow-up; corresponding RR were not significant. The increased risk is greatest in younger ages and in those without previous fracture. The association between knee osteoarthritis and fractures is time-dependent, which may explain the current controversy in the literature. The association is also modified by TKR: subjects have a higher rate of hip fracture than matched controls after TKR, although the rates may eventually decrease.


Total laparoscopic hysterectomy without general anesthesia.


Benefits of massive weight loss on symptoms, systemic inflammation and cartilage turnover in obese patients with knee osteoarthritis. To investigate the effect of massive weight loss on (1) knee pain and disability, (2) low-grade inflammation and metabolic status and (3) joint biomarkers in obese patients with knee osteoarthritis (OA). 140 patients involved in a gastric surgery programme were screened for painful knee OA, and 44 were included (age 44 ± 10.3 years, body mass index (BMI) 50.7 ± 7.2 kg/m(2)). Clinical data and biological samples were collected before and 6 months after surgery. Before surgery, interleukin 6 (IL-6) levels were correlated with levels of high-sensitivity C reactive protein (hsCRP) (p=0.006) and Helix-II (p=0.01), a biomarker of cartilage turnover, and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function score (p=0.03). Surgery resulted in substantial decrease in BMI (-20%). Levels of insulin and insulin resistance were decreased at 6 months. Knee pain decreased after surgery (24.5 ± 21 mm vs 50 ± 26.6 mm; p<0.001), and scores on all WOMAC subscales were improved. Levels of IL-6 (p<0.0001), hsCRP (p<0.0001), orosomucoid (p<0.0001) and fibrinogen (p=0.04) were decreased after surgery. Weight loss resulted in a significant increase in N-terminal propeptide of type IIA collagen levels (+32%; p=0.002), a biomarker of cartilage synthesis, and a significant decrease in cartilage oligomeric matrix protein (COMP) (-36%; p<0.001), a biomarker of cartilage degradation. Changes in COMP concentration were correlated with changes in insulin levels (p=0.02) and insulin resistance (p=0.05). Massive weight loss improves pain and function and decreases low-grade inflammation. Change in levels of joint biomarkers with weight loss suggests a structural effect on cartilage.


Ethylene stimulation of latex yield depends on the expression of a sucrose transporter (HbSUT1B) in rubber tree (Hevea brasiliensis). Hevea brasiliensis is an important industrial crop for natural rubber production. Latex biosynthesis occurs in the cytoplasm of highly specialized latex cells and requires sucrose as the unique precursor. Ethylene stimulation of latex production results in high sugar flow from the surrounding cells of inner bark towards the latex cells. The aim of this work was to understand the role of seven sucrose transporters (HbSUTs) and one hexose transporter (HbHXT1) in this process. Two Hevea clones were used: PB217 and PB260, respectively described as high and low yielding clones. The expression pattern of these sugar transporters (HbSUTs and HbHXT1) was monitored under different physiological conditions and found to be maximal in latex cells. HbSUT1, one of the most abundant isoforms, displayed the greatest response to ethylene treatment. In clone PB217, ethylene treatment led to a higher accumulation of HbSUT1B in latex cells than in the inner bark tissues. Conversely, stronger expression of HbSUT1B was observed in inner bark tissues than in latex cells of PB260. A positive correlation with HbSUT1B transcript accumulation and increased latex production was further supported by its lower expression in latex cells of the virgin clone PB217.


Evidence for genetically influenced caste determination in phylogenetically diverse species of the termite genus Reticulitermes. A number of social insect species have recently been shown to have genetically influenced caste determination (GCD), challenging the conventional view that caste determination should be strictly environmental. To date, GCD has been found in phylogenetically isolated species; examples of GCD being present in multiple species of a genus are lacking. Through crossing experiments of neotenic (juvenile) reproductives, we have recently provided the first evidence for a royal versus worker GCD in the termite Reticulitermes speratus. To elucidate whether this system is more widespread, we performed crossing experiments using three additional Reticulitermes species. Offspring caste and sex ratios were found to be highly similar to those found previously in R. speratus, raising the possibility that GCD was present in an ancestral lineage of Reticulitermes, and subsequently maintained throughout several episodes of speciation.


Dietary protein content affects evolution for body size, body fat and viability in Drosophila melanogaster. The ability to use different food sources is likely to be under strong selection if organisms are faced with natural variation in macro-nutrient (protein, carbohydrate and lipid) availabilities. Here, we use experimental evolution to study how variable dietary protein content affects adult body composition and developmental success in Drosophila melanogaster. We reared flies on either a standard diet or a protein-enriched diet for 17 generations before testing them on both diet types. Flies from lines selected on protein-rich diet produced phenotypes with higher total body mass and relative lipid content when compared with those selected on a standard diet, irrespective of which of the two diets they were tested on. However, selection on protein-rich diet incurred a cost as flies reared on this diet had markedly lower developmental success in terms of egg-to-adult viability on both medium types, suggesting a possible trade-off between the traits investigated.


Unexpected resilience of species with temperature-dependent sex determination at the Cretaceous-Palaeogene boundary. It has been suggested that climate change at the Cretaceous-Palaeogene (K-Pg) boundary, initiated by a bolide impact or volcanic eruptions, caused species with temperature-dependent sex determination (TSD), including dinosaurs, to go extinct because of a skewed sex ratio towards all males. To test this hypothesis, the sex-determining mechanisms (SDMs) of Cretaceous tetrapods of the Hell Creek Formation (Montana, USA) were inferred using parsimony optimizations of SDMs on a tree, including Hell Creek species and their extant relatives. Although the SDMs of non-avian dinosaurs could not be inferred, we were able to determine the SDMs of 62 species; 46 had genotypic sex determination (GSD) and 16 had TSD. The TSD hypothesis for extinctions performed poorly, predicting between 32 and 34 per cent of survivals and extinctions. Most surprisingly, of the 16 species with TSD, 14 of them survived into the Early Palaeocene. In contrast, 61 per cent of species with GSD went extinct. Possible explanations include minimal climate change at the K-Pg, or if climate change did occur, TSD species that survived had egg-laying behaviour that prevented the skewing of sex ratios, or had a sex ratio skewed towards female rather than male preponderance. Application of molecular clocks may allow the SDMs of non-avian dinosaurs to be inferred, which would be an important test of the pattern discovered here.


Performance of human groups in social foraging: the role of communication in consensus decision making. Early hominids searched for dispersed food sources in a patchy, uncertain environment, and modern humans encounter equivalent spatial-temporal coordination problems on a daily basis. A fundamental, but untested assumption is that our evolved capacity for communication is integral to our success in such tasks, allowing information exchange and consensus decisions based on mutual consideration of pooled information. Here we examine whether communication enhances group performance in humans, and test the prediction that consensus decision-making underlies group success. We used bespoke radio-tagging methodology to monitor the incremental performance of communicating and non-communicating human groups (small group sizes of two to seven individuals), during a social foraging experiment. We found that communicating groups (n = 22) foraged more effectively than non-communicating groups (n = 21) and were able to reach consensus decisions (an 'agreement' on the most profitable foraging resource) significantly more often than non-communicating groups. Our data additionally suggest that gesticulations among group members played a vital role in the achievement of consensus decisions, and therefore highlight the importance of non-verbal signalling of intentions and desires for successful human cooperative behaviour.


Electrical signalling of dominance in a wild population of electric fish. Animals often use signals to communicate their dominance status and avoid the costs of combat. We investigated whether the frequency of the electric organ discharge (EOD) of the weakly electric fish, Sternarchorhynchus sp., signals the dominance status of individuals. We correlated EOD frequency with body size and found a strong positive relationship. We then performed a competition experiment in which we found that higher frequency individuals were dominant over lower frequency ones. Finally, we conducted an electrical playback experiment and found that subjects more readily approached and attacked the stimulus electrodes when they played low-frequency signals than high-frequency ones. We propose that EOD frequency communicates dominance status in this gymnotiform species.


Do I stand out or blend in? Conspicuousness awareness and consistent behavioural differences in hermit crabs. Animals titrate their behaviour against the level of risk and an individual's conspicuousness should influence decisions such as when to flee and for how long to hide. Conspicuousness will vary with variation in substrate colour. Since hermit crabs frequently change the shells they occupy, shell colour will also influence conspicuousness and to be aware of their conspicuousness would require information on both of these factors to be integrated. Reduced boldness in high-contrast shell and substrate combinations compared with situations of low contrast indicates that hermit crabs are aware of current conspicuousness. Differences between individuals remained consistent across conspicuousness levels indicating the presence of animal personalities.


Plant-ants feed their host plant, but above all a fungal symbiont to recycle nitrogen. In ant-plant symbioses, plants provide symbiotic ants with food and specialized nesting cavities (called domatia). In many ant-plant symbioses, a fungal patch grows within each domatium. The symbiotic nature of the fungal association has been shown in the ant-plant Leonardoxa africana and its protective mutualist ant Petalomyrmex phylax. To decipher trophic fluxes among the three partners, food enriched in (13)C and (15)N was given to the ants and tracked in the different parts of the symbiosis up to 660 days later. The plant received a small, but significant, amount of nitrogen from the ants. However, the ants fed more intensively the fungus. The pattern of isotope enrichment in the system indicated an ant behaviour that functions specifically to feed the fungus. After 660 days, the introduced nitrogen was still present in the system and homogeneously distributed among ant, plant and fungal compartments, indicating efficient recycling within the symbiosis. Another experiment showed that the plant surface absorbed nutrients (in the form of simple molecules) whether or not it is coated by fungus. Our study provides arguments for a mutualistic status of the fungal associate and a framework for investigating the previously unsuspected complexity of food webs in ant-plant mutualisms.


Disturbance affects short-term facilitation, but not long-term saturation, of exotic plant invasion in New Zealand forest. We investigate the spread of an exotic herb, Hieracium lepidulum, into a New Zealand Nothofagus forest with the aim of understanding how stand-development of tree populations, propagule pressure and invader persistence, affect invasion across the landscape and within communities. Using data repeatedly collected over 35 years, from 250 locations, we parametrize continuous-time Markov chain models and use these models to examine future projections of the invasion under a range of hypothetical scenarios. We found that the probability of invasion into a stand was relatively high following canopy disturbance and that local abundance of Hieracium was promoted by minor disturbances. However, model predictions extrapolated 45 years into the future show that neither the rate of landscape-level invasion, nor local population growth of Hieracium, was affected much by changing the frequency of canopy disturbance events. Instead, invasion levels were strongly affected by the ability of Hieracium to persist in the understorey following forest canopy closure, and by propagule supply from streams, forest edges and plants already established within the stand. Our results show that disturbance frequency has surprisingly little influence on the long-term trajectory of invasion, while invader persistence strongly determines invasion patterns.


Geographical and temporal flexibility in the response to crosswinds by migrating raptors. Wind and ocean currents may potentially have important effects on travelling animals, as an animal which does not respond to lateral flow will be drifted from its intended direction of movement. By analysing daily movements of migrating ospreys Pandion haliaetus and marsh harriers Circus aeruginosus, as recorded by satellite telemetry, in relation to global wind data, we showed that these raptors allow on average 47 per cent drift. Furthermore, our analyses revealed significant geographical and temporal variation in the response to crosswinds. During some parts of the migration, the birds drifted and in other parts they compensated or even overcompensated. In some regions, the response of marsh harriers depended on the wind direction. They drifted when the wind came from one side and (over)compensated when the wind came from the opposite side, and this flexible response was different in different geographical regions. These results suggest that migrating raptors modulate their response to crosswinds at different places and times during their travels and show that individual birds use a much more varied repertoire of behavioural responses to wind than hitherto assumed. Our results may also explain why contrasting and variable results have been obtained in previous studies of the effect of wind on bird migration.


Sizing up your enemy: individual predation vulnerability predicts migratory probability. Partial migration, in which a fraction of a population migrate and the rest remain resident, occurs in an extensive range of species and can have powerful ecological consequences. The question of what drives differences in individual migratory tendency is a contentious one. It has been shown that the timing of partial migration is based upon a trade-off between seasonal fluctuations in predation risk and growth potential. Phenotypic variation in either individual predation risk or growth potential should thus mediate the strength of the trade-off and ultimately predict patterns of partial migration at the individual level (i.e. which individuals migrate and which remain resident). We provide cross-population empirical support for the importance of one component of this model--individual predation risk--in predicting partial migration in wild populations of bream Abramis brama, a freshwater fish. Smaller, high-risk individuals migrate with a higher probability than larger, low-risk individuals, and we suggest that predation risk maintains size-dependent partial migration in this system.


Chimpanzees help conspecifics obtain food and non-food items. Chimpanzees (Pan troglodytes) sometimes help both humans and conspecifics in experimental situations in which immediate selfish benefits can be ruled out. However, in several experiments, chimpanzees have not provided food to a conspecific even when it would cost them nothing, leading to the hypothesis that prosociality in the food-provisioning context is a derived trait in humans. Here, we show that chimpanzees help conspecifics obtain both food and non-food items--given that the donor cannot get the food herself. Furthermore, we show that the key factor eliciting chimpanzees' targeted helping is the recipients' attempts to either get the food or get the attention of the potential donor. The current findings add to the accumulating body of evidence that humans and chimpanzees share the motivation and skills necessary to help others in situations in which they cannot selfishly benefit. Humans, however, show prosocial motives more readily and in a wider range of contexts.


Heritability of female extra-pair paternity rate in song sparrows (Melospiza melodia). The forces driving the evolution of extra-pair reproduction in socially monogamous animals remain widely debated and unresolved. One key hypothesis is that female extra-pair reproduction evolves through indirect genetic benefits, reflecting increased additive genetic value of extra-pair offspring. Such evolution requires that a female's propensity to produce offspring that are sired by an extra-pair male is heritable. However, additive genetic variance and heritability in female extra-pair paternity (EPP) rate have not been quantified, precluding accurate estimation of the force of indirect selection. Sixteen years of comprehensive paternity and pedigree data from socially monogamous but genetically polygynandrous song sparrows (Melospiza melodia) showed significant additive genetic variance and heritability in the proportion of a female's offspring that was sired by an extra-pair male, constituting major components of the genetic architecture required for extra-pair reproduction to evolve through indirect additive genetic benefits. However, estimated heritabilities were moderately small (0.12 and 0.18 on the observed and underlying latent scales, respectively). The force of selection on extra-pair reproduction through indirect additive genetic benefits may consequently be relatively weak. However, the additive genetic variance and non-zero heritability observed in female EPP rate allow for multiple further genetic mechanisms to drive and constrain mating system evolution.


Neural processing of imminent collision in humans. Detecting a looming object and its imminent collision is imperative to survival. For most humans, it is a fundamental aspect of daily activities such as driving, road crossing and participating in sport, yet little is known about how the brain both detects and responds to such stimuli. Here we use functional magnetic resonance imaging to assess neural response to looming stimuli in comparison with receding stimuli and motion-controlled static stimuli. We demonstrate for the first time that, in the human, the superior colliculus and the pulvinar nucleus of the thalamus respond to looming in addition to cortical regions associated with motor preparation. We also implicate the anterior insula in making timing computations for collision events.


Integrating species traits with extrinsic threats: closing the gap between predicting and preventing species declines. In studies of extinction risk, it is often insufficient to conclude that species with narrow ranges or small clutch sizes require prioritized protection. To improve conservation outcomes, we also need to know which threats interact with these traits to endanger some species but not others. In this study, we integrated the spatial patterns of key threats to Australian amphibians with species' ecological/life-history traits to both predict declining species and identify their likely threats. In addition to confirming the importance of previously identified traits (e.g. narrow range size), we find that extrinsic threats (primarily the disease chytridiomycosis and invasive mosquitofish) are equally important and interact with intrinsic traits (primarily ecological group) to create guild-specific pathways to decline in our model system. Integrating the spatial patterns of extrinsic threats in extinction risk analyses will improve our ability to detect and manage endangered species in the future, particularly where data deficiency is a problem.


Assassin bug uses aggressive mimicry to lure spider prey. Assassin bugs (Stenolemus bituberus) hunt web-building spiders by invading the web and plucking the silk to generate vibrations that lure the resident spider into striking range. To test whether vibrations generated by bugs aggressively mimic the vibrations generated by insect prey, we compared the responses of spiders to bugs with how they responded to prey, courting male spiders and leaves falling into the web. We also analysed the associated vibrations. Similar spider orientation and approach behaviours were observed in response to vibrations from bugs and prey, whereas different behaviours were observed in response to vibrations from male spiders and leaves. Peak frequency and duration of vibrations generated by bugs were similar to those generated by prey and courting males. Further, vibrations from bugs had a temporal structure and amplitude that were similar to vibrations generated by leg and body movements of prey and distinctly different to vibrations from courting males or leaves, or prey beating their wings. To be an effective predator, bugs do not need to mimic the full range of prey vibrations. Instead bugs are general mimics of a subset of prey vibrations that fall within the range of vibrations classified by spiders as 'prey'.


From phenotype to genotype: a Bayesian solution. The study of biological systems commonly depends on inferring the state of a 'hidden' variable, such as an underlying genotype, from that of an 'observed' variable, such as an expressed phenotype. However, this cannot be achieved using traditional quantitative methods when more than one genetic mechanism exists for a single observable phenotype. Using a novel latent class Bayesian model, it is possible to infer the prevalence of different genetic elements in a population given a sample of phenotypes. As an exemplar, data comprising phenotypic resistance to six antimicrobials obtained from passive surveillance of Salmonella Typhimurium DT104 are analysed to infer the prevalence of individual resistance genes, as well as the prevalence of a genomic island known as SGI1 and its variants. Three competing models are fitted to the data and distinguished between using posterior predictive p-values to assess their ability to predict the observed number of unique phenotypes. The results suggest that several SGI1 variants circulate in a few fixed forms through the population from which our data were derived. The methods presented could be applied to other types of phenotypic data, and represent a useful and generic mechanism of inferring the genetic population structure of organisms.


Of lemmings and snowshoe hares: the ecology of northern Canada. Two population oscillations dominate terrestrial community dynamics in northern Canada. In the boreal forest, the snowshoe hare (Lepus americanus) fluctuates in cycles with an 8-10 year periodicity and in tundra regions lemmings typically fluctuate in cycles with a 3-4 year periodicity. I review 60 years of research that has uncovered many of the causes of these population cycles, outline areas of controversy that remain and suggest key questions to address. Lemmings are keystone herbivores in tundra ecosystems because they are a key food resource for many avian and mammalian predators and are a major consumer of plant production. There remains much controversy over the role of predation, food shortage and social interactions in causing lemming cycles. Predation is well documented as a significant mortality factor limiting numbers. Food shortage is less likely to be a major limiting factor on population growth in lemmings. Social interactions might play a critical role in reducing the rate of population growth as lemming density rises. Snowshoe hares across the boreal forest are a key food for many predators and their cycles have been the subject of large-scale field experiments that have pinpointed predation as the key limiting factor causing these fluctuations. Predators kill hares directly and indirectly stress them by unsuccessful pursuits. Stress reduces the reproductive rate of female hares and is transmitted to their offspring who also suffer reduced reproductive rates. The maternal effects produced by predation risk induce a time lag in the response of hare reproductive rate to density, aiding the cyclic dynamics.


Biological diversity in a changing world. From the pioneering explorations of Joseph Banks (later a President of the Royal Society), to the present day, a great deal has been learnt about the extent, distribution and stability of biological diversity in the world. We now know that diverse life can be found even in the most inhospitable places. We have also learned that biological diversity changes through time over both large and small temporal scales. These natural changes track environmental conditions, and reflect ecological and evolutionary processes. However, anthropogenic activities, including overexploitation, habitat loss and climate change, are currently causing profound transformations in ecosystems and unprecedented loss of biological diversity. This series of papers considers temporal variation in biological diversity, examines the extent of human-related change relative to underlying natural change and builds on these insights to develop tools and policies to help guide us towards a sustainable future.


Phylogenetic diversity measures based on Hill numbers. We propose a parametric class of phylogenetic diversity (PD) measures that are sensitive to both species abundance and species taxonomic or phylogenetic distances. This work extends the conventional parametric species-neutral approach (based on 'effective number of species' or Hill numbers) to take into account species relatedness, and also generalizes the traditional phylogenetic approach (based on 'total phylogenetic length') to incorporate species abundances. The proposed measure quantifies 'the mean effective number of species' over any time interval of interest, or the 'effective number of maximally distinct lineages' over that time interval. The product of the measure and the interval length quantifies the 'branch diversity' of the phylogenetic tree during that interval. The new measures generalize and unify many existing measures and lead to a natural definition of taxonomic diversity as a special case. The replication principle (or doubling property), an important requirement for species-neutral diversity, is generalized to PD. The widely used Rao's quadratic entropy and the phylogenetic entropy do not satisfy this essential property, but a simple transformation converts each to our measures, which do satisfy the property. The proposed approach is applied to forest data for interpreting the effects of thinning.


Temporal turnover and the maintenance of diversity in ecological assemblages. Temporal variation in species abundances occurs in all ecological communities. Here, we explore the role that this temporal turnover plays in maintaining assemblage diversity. We investigate a three-decade time series of estuarine fishes and show that the abundances of the individual species fluctuate asynchronously around their mean levels. We then use a time-series modelling approach to examine the consequences of different patterns of turnover, by asking how the correlation between the abundance of a species in a given year and its abundance in the previous year influences the structure of the overall assemblage. Classical diversity measures that ignore species identities reveal that the observed assemblage structure will persist under all but the most extreme conditions. However, metrics that track species identities indicate a narrower set of turnover scenarios under which the predicted assemblage resembles the natural one. Our study suggests that species diversity metrics are insensitive to change and that measures that track species ranks may provide better early warning that an assemblage is being perturbed. It also highlights the need to incorporate temporal turnover in investigations of assemblage structure and function.


Detecting temporal trends in species assemblages with bootstrapping procedures and hierarchical models. Quantifying patterns of temporal trends in species assemblages is an important analytical challenge in community ecology. We describe methods of analysis that can be applied to a matrix of counts of individuals that is organized by species (rows) and time-ordered sampling periods (columns). We first developed a bootstrapping procedure to test the null hypothesis of random sampling from a stationary species abundance distribution with temporally varying sampling probabilities. This procedure can be modified to account for undetected species. We next developed a hierarchical model to estimate species-specific trends in abundance while accounting for species-specific probabilities of detection. We analysed two long-term datasets on stream fishes and grassland insects to demonstrate these methods. For both assemblages, the bootstrap test indicated that temporal trends in abundance were more heterogeneous than expected under the null model. We used the hierarchical model to estimate trends in abundance and identified sets of species in each assemblage that were steadily increasing, decreasing or remaining constant in abundance over more than a decade of standardized annual surveys. Our methods of analysis are broadly applicable to other ecological datasets, and they represent an advance over most existing procedures, which do not incorporate effects of incomplete sampling and imperfect detection.


Integrating spatial and temporal approaches to understanding species richness. Understanding species richness patterns represents one of the most fundamental problems in ecology. Most research in this area has focused on spatial gradients of species richness, with a smaller area of emphasis dedicated to understanding the temporal dynamics of richness. However, few attempts have been made to understand the linkages between the spatial and temporal patterns related to richness. Here, we argue that spatial and temporal richness patterns and the processes that drive them are inherently linked, and that our understanding of richness will be substantially improved by considering them simultaneously. The species-time-area relationship provides a case in point: successful description of the empirical spatio-temporal pattern led to a rapid development and testing of new theories. Other areas of research on species richness could also benefit from an explicitly spatio-temporal approach, and we suggest future directions for understanding the processes common to these two traditionally isolated fields of research.


Biodiversity and biogeography of the atmosphere. The variation of life has predominantly been studied on land and in water, but this focus is changing. There is a resurging interest in the distribution of life in the atmosphere and the processes that underlie patterns in this distribution. Here, we review our current state of knowledge about the biodiversity and biogeography of the atmosphere, with an emphasis on micro-organisms, the numerically dominant forms of aerial life. We present evidence to suggest that the atmosphere is a habitat for micro-organisms, and not purely a conduit for terrestrial and aquatic life. Building on a rich history of research in terrestrial and aquatic systems, we explore biodiversity patterns that are likely to play an important role in the emerging field of air biogeography. We discuss the possibility of a more unified understanding of the biosphere, one that links knowledge about biodiversity and biogeography in the lithosphere, hydrosphere and atmosphere.


Evolutionary dynamics at high latitudes: speciation and extinction in polar marine faunas. Ecologists have long been fascinated by the flora and fauna of extreme environments. Physiological studies have revealed the extent to which lifestyle is constrained by low temperature but there is as yet no consensus on why the diversity of polar assemblages is so much lower than many tropical assemblages. The evolution of marine faunas at high latitudes has been influenced strongly by oceanic cooling during the Cenozoic and the associated onset of continental glaciations. Glaciation eradicated many shallow-water habitats, especially in the Southern Hemisphere, and the cooling has led to widespread extinction in some groups. While environmental conditions at glacial maxima would have been very different from those existing today, fossil evidence indicates that some lineages extend back well into the Cenozoic. Oscillations of the ice-sheet on Milankovitch frequencies will have periodically eradicated and exposed continental shelf habitat, and a full understanding of evolutionary dynamics at high latitude requires better knowledge of the links between the faunas of the shelf, slope and deep-sea. Molecular techniques to produce phylogenies, coupled with further palaeontological work to root these phylogenies in time, will be essential to further progress.


The origins of modern biodiversity on land. Comparative studies of large phylogenies of living and extinct groups have shown that most biodiversity arises from a small number of highly species-rich clades. To understand biodiversity, it is important to examine the history of these clades on geological time scales. This is part of a distinct 'phylogenetic expansion' view of macroevolution, and contrasts with the alternative, non-phylogenetic 'equilibrium' approach to the history of biodiversity. The latter viewpoint focuses on density-dependent models in which all life is described by a single global-scale model, and a case is made here that this approach may be less successful at representing the shape of the evolution of life than the phylogenetic expansion approach. The terrestrial fossil record is patchy, but is adequate for coarse-scale studies of groups such as vertebrates that possess fossilizable hard parts. New methods in phylogenetic analysis, morphometrics and the study of exceptional biotas allow new approaches. Models for diversity regulation through time range from the entirely biotic to the entirely physical, with many intermediates. Tetrapod diversity has risen as a result of the expansion of ecospace, rather than niche subdivision or regional-scale endemicity resulting from continental break-up. Tetrapod communities on land have been remarkably stable and have changed only when there was a revolution in floras (such as the demise of the Carboniferous coal forests, or the Cretaceous radiation of angiosperms) or following particularly severe mass extinction events, such as that at the end of the Permian.


Ecological correlates of range shifts of Late Pleistocene mammals. Understanding and predicting how species' distributions will shift as climate changes are central questions in ecology today. The late Quaternary of North America represents a natural experiment in which we can evaluate how species responded during the expansion and contraction of the glaciers. Here, we ask whether species' range shifts differ because of taxonomic affinity, life-history traits, body size or topographic heterogeneity and whether the species survived the megafaunal extinction. There was no difference in range shifts between victims and survivors of the megafaunal extinction. In general, the change in the size of a species' range is not well correlated with any of the ecological or life-history traits evaluated. However, there are significant relationships between some variables and the movements of the centroids of ranges. Differences in the distances shifted exist among orders, although this is probably a result of body size differences as larger bodied species show larger shifts. Although there are a few exceptions, the distance that species shifted their range was weakly correlated with life-history traits. Finally, species in more topographically heterogeneous areas show smaller shifts than species in less-diverse areas. Overall, these results indicate that when trying to predict species range shifts in the future, body size, lifespan and the topographic relief of the landscape should be taken into account.


A stochastic, evolutionary model for range shifts and richness on tropical elevational gradients under Quaternary glacial cycles. Quaternary glacial-interglacial cycles repeatedly forced thermal zones up and down the slopes of mountains, at all latitudes. Although no one doubts that these temperature cycles have left their signature on contemporary patterns of geography and phylogeny, the relative roles of ecology and evolution are not well understood, especially for the tropics. To explore key mechanisms and their interactions in the context of chance events, we constructed a geographical range-based, stochastic simulation model that incorporates speciation, anagenetic evolution, niche conservatism, range shifts and extinctions under late Quaternary temperature cycles along tropical elevational gradients. In the model, elevational patterns of species richness arise from the differential survival of founder lineages, consolidated by speciation and the inheritance of thermal niche characteristics. The model yields a surprisingly rich variety of realistic patterns of phylogeny and biogeography, including close matches to a variety of contemporary elevational richness profiles from an elevational transect in Costa Rica. Mountaintop extinctions during interglacials and lowland extinctions at glacial maxima favour mid-elevation lineages, especially under the constraints of niche conservatism. Asymmetry in temperature (greater duration of glacial than of interglacial episodes) and in lateral area (greater land area at low than at high elevations) have opposing effects on lowland extinctions and the elevational pattern of species richness in the model--and perhaps in nature, as well.


Anthropogenic impacts on tropical forest biodiversity: a network structure and ecosystem functioning perspective. Huge areas of diverse tropical forest are lost or degraded every year with dramatic consequences for biodiversity. Deforestation and fragmentation, over-exploitation, invasive species and climate change are the main drivers of tropical forest biodiversity loss. Most studies investigating these threats have focused on changes in species richness or species diversity. However, if we are to understand the absolute and long-term effects of anthropogenic impacts on tropical forests, we should also consider the interactions between species, how those species are organized in networks, and the function that those species perform. I discuss our current knowledge of network structure and ecosystem functioning, highlighting empirical examples of their response to anthropogenic impacts. I consider the future prospects for tropical forest biodiversity, focusing on biodiversity and ecosystem functioning in secondary forest. Finally, I propose directions for future research to help us better understand the effects of anthropogenic impacts on tropical forest biodiversity.


Disturbance and change in biodiversity.

Disturbance and change in biodiversity. Understanding how disturbance affects biodiversity is important for both fundamental and applied reasons. Here, I investigate how disturbances with different ecological effects change biodiversity metrics. I define three main types of disturbance effects: D disturbance (shifts in mortality rate), B disturbance (shifts in reproductive rates) and K disturbance (shifts in carrying capacity). Numerous composite disturbances can be defined including any combination of these three types of ecological effects. The consequences of D, B and K disturbances, as well as of composite DBK disturbances are examined by comparing metrics before and after a disturbance, in disturbed and undisturbed communities. I use simulations of neutral communities and examine species richness, total abundance and species abundance distributions. The patterns of change in biodiversity metrics are consistent among different types of disturbance. K disturbance has the most severe effects, followed by D disturbance, and B disturbance has nearly negligible effects. Consequences of composite DBK disturbances are more complex than any of the three types of disturbance, with unimodal relationships along a disturbance gradient arising when D, B and K are negatively correlated. Importantly, regardless of disturbance type, community isolation enhances the negative consequences and hinders the positive effects of disturbances.


Temporal biodiversity change in transformed landscapes: a southern African perspective. Landscape transformation by humans is virtually ubiquitous, with several suggestions being made that the world's biomes should now be classified according to the extent and nature of this transformation. Even those areas that are thought to have a relatively limited human footprint have experienced substantial biodiversity change. This is true of both marine and terrestrial systems of southern Africa, a region of high biodiversity and including several large conservation areas. Global change drivers have had substantial effects across many levels of the biological hierarchy as is demonstrated in this review, which focuses on terrestrial systems. Interactions among drivers, such as between climate change and invasion, and between changing fire regimes and invasion, are complicating attribution of change effects and management thereof. Likewise CO(2) fertilization is having a much larger impact on terrestrial systems than perhaps commonly acknowledged. Temporal changes in biodiversity, and the seeming failure of institutional attempts to address them, underline a growing polarization of world views, which is hampering efforts to address urgent conservation needs.


Population and geographic range dynamics: implications for conservation planning. Continuing downward trends in the population sizes of many species, in the conservation status of threatened species, and in the quality, extent and connectedness of habitats are of increasing concern. Identifying the attributes of declining populations will help predict how biodiversity will be impacted and guide conservation actions. However, the drivers of biodiversity declines have changed over time and average trends in abundance or distributional change hide significant variation among species. While some populations are declining rapidly, the majority remain relatively stable and others are increasing. Here we dissect out some of the changing drivers of population and geographic range change, and identify biological and geographical correlates of winners and losers in two large datasets covering local population sizes of vertebrates since 1970 and the distributions of Galliform birds over the last two centuries. We find weak evidence for ecological and biological traits being predictors of local decline in range or abundance, but stronger evidence for the role of local anthropogenic threats and environmental change. An improved understanding of the dynamics of threat processes and how they may affect different species will help to guide better conservation planning in a continuously changing world.


Transitional states in marine fisheries: adapting to predicted global change. Global climate change has the potential to substantially alter the production and community structure of marine fisheries and modify the ongoing impacts of fishing. Fish community composition is already changing in some tropical, temperate and polar ecosystems, where local combinations of warming trends and higher environmental variation anticipate the changes likely to occur more widely over coming decades. Using case studies from the Western Indian Ocean, the North Sea and the Bering Sea, we contextualize the direct and indirect effects of climate change on production and biodiversity and, in turn, on the social and economic aspects of marine fisheries. Climate warming is expected to lead to (i) yield and species losses in tropical reef fisheries, driven primarily by habitat loss; (ii) community turnover in temperate fisheries, owing to the arrival and increasing dominance of warm-water species as well as the reduced dominance and departure of cold-water species; and (iii) increased diversity and yield in Arctic fisheries, arising from invasions of southern species and increased primary production resulting from ice-free summer conditions. How societies deal with such changes will depend largely on their capacity to adapt--to plan and implement effective responses to change--a process heavily influenced by social, economic, political and cultural conditions.


Characterization of the interactions between architecture and source-sink relationships in winter oilseed rape (Brassica napus) using the GreenLab model. This study aimed to characterize the interaction between architecture and source-sink relationships in winter oilseed rape (WOSR): do the costs of ramification compromise the source-sink ratio during seed filling? The GreenLab model is a good candidate to address this question because it has been already used to describe interactions between source-sink relationships and architecture for other species. However, its adaptation to WOSR is a challenge because of the complexity of its developmental scheme, especially during the reproductive phase. Equations were added in GreenLab to compute expansion delays for ramification, flowering of each axis and photosynthesis of pods including the energetic cost of oil synthesis. Experimental field data were used to estimate morphological parameters while source-sink parameters of the model were estimated by adjustment of model outputs to the data. Ecophysiological outputs were used to assess the sources/sink relationships during the whole growth cycle. First results indicated that, at the plant scale, the model correctly simulates the dynamics of organ growth. However, at the organ scale, errors were observed that could be explained either by secondary growth that was not incorporated or by uncertainties in morphological parameters (durations of expansion and life). Ecophysiological outputs highlighted the dramatic negative impact of ramification on the source-sink ratio, as well as the decrease in this ratio during seed filling despite pod envelope photosynthesis that allowed significant biomass production to be maintained. This work is a promising first step in the construction of a structure-function model for a plant as complex as WOSR. Once tested for other environments and/or genotypes, the model can be used for studies on WOSR architectural plasticity.


The future of the oceans past.

The future of the oceans past. Major macroevolutionary events in the history of the oceans are linked to changes in oceanographic conditions and environments on regional to global scales. Even small changes in climate and productivity, such as those that occurred after the rise of the Isthmus of Panama, caused major changes in Caribbean coastal ecosystems and mass extinctions of major taxa. In contrast, massive influxes of carbon at the end of the Palaeocene caused intense global warming, ocean acidification, mass extinction throughout the deep sea and the worldwide disappearance of coral reefs. Today, overfishing, pollution and increases in greenhouse gases are causing comparably great changes to ocean environments and ecosystems. Some of these changes are potentially reversible on very short time scales, but warming and ocean acidification will intensify before they decline even with immediate reduction in emissions. There is an urgent need for immediate and decisive conservation action. Otherwise, another great mass extinction affecting all ocean ecosystems and comparable to the upheavals of the geological past appears inevitable.


Sexual dimorphism in resource acquisition and deployment: both size and timing matter. The males and females of many dioecious plant species differ from one another in important life-history traits, such as their size. If male and female reproductive functions draw on different resources, for example, one should expect males and females to display different allocation strategies as they grow. Importantly, these strategies may differ not only between the two sexes, but also between plants of different age and therefore size. Results are presented from an experiment that asks whether males and females of Mercurialis annua, an annual plant with indeterminate growth, differ over time in their allocation of two potentially limiting resources (carbon and nitrogen) to vegetative (below- and above-ground) and reproductive tissues. Comparisons were made of the temporal patterns of biomass allocation to shoots, roots and reproduction and the nitrogen content in the leaves between the sexes of M. annua by harvesting plants of each sex after growth over different periods of time. Males and females differed in their temporal patterns of allocation. Males allocated more to reproduction than females at early stages, but this trend was reversed at later stages. Importantly, males allocated proportionally more of their biomass towards roots at later stages, but the roots of females were larger in absolute terms. The study points to the important role played by both the timing of resource deployment and the relative versus absolute sizes of the sinks and sources in sexual dimorphism of an annual plant.


The effect of breathing manner on inferior vena caval diameter. Although the inspiratory 'collapse' of the inferior vena cava (IVC) has been used to signify normal central venous pressure, the effect of the manner of breathing IVC size is incompletely understood. As intra-abdominal pressure rises during descent of the diaphragm, we hypothesized that inspiration through diaphragmatic excursion may have a compressive effect on the IVC. We measured minimal and maximal intrahepatic IVC diameter on echocardiography and popliteal venous return by spectral Doppler during isovolemic inspiratory efforts in 19 healthy non-obese volunteers who were instructed to inhale using either diaphragmatic or chest wall expansion. During inspiration, the maximal diaphragmatic excursion and popliteal vein flow were compared between breathing methods. The IVC 'collapsibility index,' IVCCI, was calculated as (IVC(max)-IVC(min))/IVC(max). The difference in diaphragmatic excursion between diaphragmatic and chest wall breaths in each subject was correlated with the corresponding change in IVCCI. Diaphragmatic breathing resulted in more diaphragmatic excursion than chest wall breathing (median 3.4 cm, range 1.7-5.8 vs. 2.2 cm, range 1.0-5.2, P= 0.0003), and was universally associated with decreased popliteal venous return (19/19 vs. 9/19 subjects, P< 0.004). The difference in diaphragmatic excursion correlated with the difference in IVCCI (Spearman's rho = 0.53, P= 0.024). During inspiration of equivalent tidal volumes, the reduction in IVC diameter and lower extremity venous return was related to diaphragmatic excursion, suggesting that the IVC may be compressed through descent of the diaphragm.


Usefulness of transthoracic Doppler echocardiography for noninvasive assessment of coronary blood flow in a patient with symptomatic myocardial bridging. Myocardial bridging (MB) is a congenital anomaly characterized by systolic compression of the tunnelled arterial segment. MB may cause myocardial ischaemia due to abnormal coronary blood flow. We report a case of MB in which transthoracic Doppler echocardiography was used to evaluate the long-term effect of beta-blocker therapy on abnormal coronary blood flow. In this case, beta-blocker therapy with bisoprolol (5.0 mg/day) for 1 month eliminated the patient's symptoms and normalized coronary blood flow through the tunnelled arterial segment.


Blood pressure targets of antihypertensive treatment: up and down the J-shaped curve.


How reproductive and regenerative medicine meet in a Chinese fertility clinic. Interviews with women about the donation of embryos to stem cell research. The social interface between reproductive medicine and embryonic stem cell research has been investigated in a pilot study at a large IVF clinic in central China. Methods included observation, interviews with hospital personnel, and five in-depth qualitative interviews with women who underwent IVF and who were asked for their consent to the donation of embryos for use in medical (in fact human embryonic stem cell) research. This paper reports, and discusses from an ethical perspective, the results of an analysis of these interviews. The participants talked of extreme social pressure to become pregnant. Once they had a baby, 'spare' embryos lost practical significance due to the Chinese one-child policy. In the context of decision making about donating embryos to research, the women used the clinical distinctions between 'good and bad quality' embryos and also between frozen and transferred embryos, as guiding moral distinctions. In the absence of concrete information about what sort of research their embryos should be used for, the women interviewed either refused consent (for fear that the embryo would be given to another couple) or accepted, expressing motives of solidarity with other women in a similar situation. This reveals that they filled the knowledge gap with an image of research improving fertility treatment.


A controlled evaluation of the WHO Safe Communities model approach to injury prevention: increasing child restraint use in motor vehicles. To measure the effect of the WHO Safe Communities model approach to increasing child restraint use in motor vehicles. Pre- and post-intervention observations of restraint use in motor vehicles in several sites in the target area, and in a comparison area community. Community; southeast Dallas, Texas, 2003-2005. A multifaceted approach to increasing use of child safety seats, booster seats and seat belts that included efforts in schools, day care centres, neighbourhoods and a local public clinic, along with child safety seat classes and a low-cost distribution programme. Prevalence of restraint use among children 0-8 years old riding in motor vehicles. In the target area, the adjusted child restraint use increased by 23.9 percentage points versus 11.8 in the comparison area (difference 12.1; 95% CI 9.9 to 14.3), and adjusted driver seat belt use increased by 16.3 percentage points in the target area versus 4.9 in the comparison area (difference 11.4; 95% CI 11.0 to 11.7). Multivariable multilevel analysis showed that the increase in the target area was significantly greater than in the comparison area for child restraint use (OR 1.6; 95% CI 1.2 to 2.2), as well as for driver seat belt use and proportion of children riding in the back seat. The Safe Communities approach was successful in promoting the use of child restraints in motor vehicles through a multifaceted intervention that included efforts in various community settings, instructional classes and child safety seat distribution.


Persistent left with absent right superior vena cava.


Coffee consumption and the risk of heart failure in Finnish men and women. To evaluate the association of coffee consumption with the risk of heart failure (HF) in the Finnish population. Prospective population-based cohort study. This study, which is a part of FINRISK study, was carried out in Finland. Study cohorts included 59,490 Finnish participants aged 25-74 years who were free of HF at baseline. HF (2020 men and 1807 women) during a mean follow-up of 19.2 years. Multivariable-adjusted (age, study year, body mass index, smoking, education, alcohol consumption, tea consumption, physical activity, systolic blood pressure, history of myocardial infarction, history of valvular heart disease, history of diabetes and total cholesterol) HRs (with 95% CI) of HF associated with the amount of coffee consumption daily (0, 1-2, 3-4, 5-6, 7-9 and ≥10 cups) were 1.00, 0.91 (0.71 to 1.16), 0.88 (0.70 to 1.10), 0.91 (0.73 to 1.13), 0.96 (0.76 to 1.22) and 1.02 (0.80 to 1.30) (p(trend) = 0.485) for men and 1.00, 0.73 (0.56 to 0.97), 0.77 (0.60 to 0.98), 0.68 (0.53 to 0.88), 0.80 (0.61 to 1.04) and 0.88 (0.65 to 1.19) (p(trend) = 0.007) for women, respectively. Stratification by age, smoking status, alcohol consumption, history of type 2 diabetes mellitus and body mass index gave similar results. Coffee consumption does not increase the risk of HF in Finnish men and women. In women, an inverse association was observed between low to moderate coffee consumption and the risk of HF.


Successful treatment of aortic bio-prosthetic valve failure by transcatheter aortic valve implantation.


Engineering the stability and the activity of a glycoside hydrolase. Glycosidases, the enzymes responsible in nature for the catabolism of carbohydrates, are well-studied catalysts widely used in industrial biotransformations and oligosaccharide synthesis, which are also attractive targets for drug development. Glycosidases from hyperthermophilic organisms (thriving at temperatures > 85 °C) are also interesting models to understand the molecular basis of protein stability and to produce robust tools for industrial applications. Here, we review the results obtained in the last two decades by our group on a β-glycosidase from the hyperthermophilic Archaeon Sulfolobus solfataricus. Our findings will be presented in the general context of the stability of proteins from hyperthermophiles and of the chemo-enzymatic synthesis of oligosaccharides.


Involvement of MyoD and PEA3 in regulation of transcription activity of MDR1 gene. Overexpression of multidrug resistance 1 (MDR1) in cancer remains one of the major causes for the failure of chemotherapy. In the present study, we found that MyoD and PEA3 could activate P-glycoprotein (P-gp) expression in SGC7901 cells. Knockdown of MyoD and PEA3 attenuated MDR1 expression and increased the sensitivity of multidrug resistant cancer cells to cytotoxic drugs that were transported by P-gp in SGC7901/VCR cells. MyoD or PEA3 could bind to the E-box and PEA3 sites on the MDR1 promoter and activate its transcription. The regulation of MDR1 expression by MyoD and PEA3 may provide potential ways to overcome MDR in cancer treatment.


Targeted therapy for high-grade glioma with the TGF-β2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. This randomized, open-label, active-controlled, dose-finding phase IIb study evaluated the efficacy and safety of trabedersen (AP 12009) administered intratumorally by convection-enhanced delivery compared with standard chemotherapy in patients with recurrent/refractory high-grade glioma. One hundred and forty-five patients with central reference histopathology of recurrent/refractory glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) were randomly assigned to receive trabedersen at doses of 10 or 80 µM or standard chemotherapy (temozolomide or procarbazine/lomustine/vincristine). Primary endpoint was 6-month tumor control rate, and secondary endpoints included response at further timepoints, survival, and safety. Six-month tumor control rates were not significantly different in the entire study population (AA and GBM). Prespecified AA subgroup analysis showed a significant benefit regarding the 14-month tumor control rate for 10 µM trabedersen vs chemotherapy (p= .0032). The 2-year survival rate had a trend for superiority for 10 µM trabedersen vs chemotherapy (p = .10). Median survival for 10 µM trabedersen was 39.1 months compared with 35.2 months for 80 µM trabedersen and 21.7 months for chemotherapy (not significant). In GBM patients, response and survival results were comparable among the 3 arms. Exploratory analysis on GBM patients aged ≤55 years with Karnofsky performance status >80% at baseline indicated a 3-fold survival at 2 and 3 years for 10 µM trabedersen vs chemotherapy. The frequency of patients with related or possibly drug-related adverse events was higher with standard chemotherapy (64%) than with 80 µM trabedersen (43%) and 10 µM trabedersen (27%). Superior efficacy and safety for 10 µM trabedersen over 80 µM trabedersen and chemotherapy and positive risk-benefit assessment suggest it as the optimal dose for further clinical development in high-grade glioma.


What's there in a name: tropical calcific pancreatitis and idiopathic chronic pancreatitis in India.


Cost benefit of out of hours endoscopy: the options.


Hepatitis B viraemia: its heritability and association with common genetic variation in the interferon gamma signalling pathway. High viraemia of hepatitis B virus (HBV) influences all phases in the development of hepatocellular carcinoma (HCC). This study was designed to estimate the overall contribution of host genetics to HBV viraemia, and investigate the influence of common single-nucleotide polymorphisms (SNPs) in the interferon γ (IFNγ) signalling pathway, which is pivotal in the non-cytolytic clearance of HBV. We first determined familial correlations and heritability (ie, proportion of phenotypic variation that is attributable to additive genetic factors) for HBV viraemia using 280 HCC families, including 766 adult HBV carriers. Then family-based association analysis was conducted for viraemia with a panel of 40 SNPs across ten IFNγ-related genes. For replication, seven tagging SNPs in identified candidate regions were also tested in a further 1011 unrelated individuals with longitudinal data on HBV viraemia over 16 years. After adjustment for HBV genotype and sex, significant correlations for viraemia were detected among both siblings and mother-child pairs. Heritability accounted for approximately 30% (p<0.0002) of the variance of viral load, whereas HBV genotype and sex together explained less than 3%. Heritability estimates increased up to 74.0% after further exclusion of subjects with episodes of liver biochemical abnormalities. Our initial family-based association analysis identified two SNPs (rs2284553 (intronic SNP) and rs9808753 (Q64R)) on the IFNγ receptor 2 (IFNGR2) gene that were robustly associated with viraemia after multitest correction (all p<0.02). The SNPs were also associated with the longitudinal levels of viraemia and the persistence of a high viraemia of ≥4.39 log copies/ml (all p<0.0001) in unrelated individuals. HBV viraemia appears to have substantial heritability. Polymorphisms in the IFNGR2 gene appear to be associated with the variability of viraemia.


Acute, severe constipation in a 58-year-old Japanese patient.


Idiopathic chronic pancreatitis in India.


Confocal laser endomicroscopy is a new imaging modality for recognition of intramucosal bacteria in inflammatory bowel disease in vivo. Interaction of bacteria with the immune system within the intestinal mucosa plays a key role in the pathogenesis of inflammatory bowel disease (IBD). The aim of the current study was to develop a fluorescein-aided confocal laser endomicroscopy (CLE) method to visualise intramucosal enteric bacteria in vivo and to determine the involved mucosal area in the colon and ileum in patients with ulcerative colitis (UC) and Crohn's disease (CD). Initially, E coli strains expressing enhanced green fluorescent protein (pEGFP) were endomicroscopically imaged in mice. In addition, ex vivo and in vivo imaging of fluorescent human enteric bacteria was performed to specify the distinct endomicroscopic appearance of enteral bacteria. Targeted mucosal biopsies towards endomicroscopic identifiable intramucosal bacteria and negative mucosal areas were prospectively obtained during colonoscopy and correlated with bench-top fluorescence microscopy (FISH) to prove the endomicroscopic visualisation of intramucosal bacteria. Finally, a retrospective analysis as well as a prospective study was performed in patients with UC and CD to confirm the presence and distribution of intramucosal bacteria within the gut. Confocal endomicroscopy was able to identify intramucosal pEGFP E coli in mice and strains of enteric microflora in the mucosa of humans. Using FISH as the gold standard, evaluation of 21 patients showed that CLE had a sensitivity of 89% and specificity of 100% to identify intramucosal bacteria. In a retrospective study, 113 patients with CD and UC had intramucosal bacteria significantly more often than 50 control patients (66% vs 60% vs 14%, p<0.001). This result was confirmed in a prospective study in which 10 patients with CD and 10 with UC had a significantly wider distribution of involvement with intramucosal bacteria in the colon and terminal ileum compared with 10 controls (85.2% vs 75.9% vs 16.8%, p<0.0001). CLE is a new tool that can image intramucosal bacteria in vivo in patients with IBD. Intramucosal bacteria are found more frequently and with a wider distribution in patients with IBD than in patients with a normal intestine.


Asteroids in the blood.

Asteroids in the blood.


The NSAID sulindac is chemopreventive in the mouse distal colon but carcinogenic in the proximal colon. The non-steroidal anti-inflammatory drug sulindac is an effective chemopreventive agent in sporadic colorectal cancer but its potential benefit in mismatch repair deficient cancers remains to be defined. We wanted to determine whether genetic defects that are relevant for colorectal cancer, such as Msh2 or p53 deficiency, would influence the efficiency of sulindac chemoprevention or increase the side effects. Msh2 or p53 deficient and wild-type mice received feed containing 160-320 ppm sulindac for up to 25 weeks with or without a concurrent treatment with the carcinogen azoxymethane. Colon tissue was analysed by histopathology and molecular biology methods. We show that sulindac prevented azoxymethane-induced distal colon tumours in all mice. In the proximal colon, however, sulindac induced new inflammatory lesions on the mucosal folds, which further developed into adenocarcinoma in up to 18-25% of the p53 or Msh2 deficient mice but rarely in wild-type mice. This region in the proximal colon was characterised by a distinct profile of pro- and anti-inflammatory factors, which were modulated by the sulindac diet, including upregulation of hypoxia inducible factor 1α and macrophage inflammatory protein 2. These data show that the sulindac diet promotes carcinogenesis in the mouse proximal colon possibly through chronic inflammation. Sulindac has both beneficial and harmful effects in vivo, which are associated with different microenvironments within the colon of experimental mice. Deficiency for the Msh2 or p53 tumour suppressor genes increases the harmful side effects of long-term sulindac treatment in the mouse colon.


Re: Specific targeting of Wnt/β-catenin signaling in human melanoma cells by a dietary triterpene lupeol.


An outbreak of norovirus infection linked to oyster consumption at a UK restaurant, February 2010. We present the investigation of an outbreak of gastroenteritis at a UK restaurant incorporating both epidemiological and microbiological analysis. Structured postal questionnaires were sent to 30 diners who ate at the restaurant during the outbreak period (5-7 February 2010). Stool specimens collected from staff and diners were submitted for bacterial culture and norovirus testing, and 15 Pacific oysters (Crassostrea gigas) from the batch served during the outbreak period were tested for norovirus. A strong association was observed between illness and oyster consumption (odds ratio undefined, confidence interval: 11.7 to infinity, P = 0.00001). Multiple different sequences of norovirus RNA were present in both stool and oyster specimens, typical of a shellfish origin. Several contemporaneous norovirus outbreaks throughout the UK were linked to oysters, particularly, though not exclusively, those sourced from Carlingford Lough in Ireland (as in this study), which were subsequently withdrawn from distribution. Despite the risk to human health, there is significant uncertainty surrounding the quantitative correlation between oyster norovirus levels and consumer illness. Continued research should help further our understanding of this crucial correlation and identify ways in which viral depuration of oysters can be enhanced.


Insufficient role of cell proliferation in aberrant DNA methylation induction and involvement of specific types of inflammation. Chronic inflammation is deeply involved in induction of aberrant DNA methylation, but it is unclear whether any type of persistent inflammation can induce methylation and how induction of cell proliferation is involved. In this study, Mongolian gerbils were treated with five kinds of inflammation inducers [Helicobacter pylori with cytotoxin-associated gene A (CagA), H.pylori without CagA, Helicobacter felis, 50% ethanol (EtOH) and saturated sodium chloride (NaCl) solution]. Two control groups were treated with a mutagenic carcinogen that induces little inflammation (20 p.p.m. of N-methyl-N-nitrosourea) and without any treatment. After 20 weeks, chronic inflammation with lymphocyte and macrophage infiltration was prominent in the three Helicobacter groups, whereas neutrophil infiltration was mainly observed in the EtOH and NaCl groups. Methylation levels of eight CpG islands significantly increased only in the three Helicobacter groups. By Ki-67 staining, cell proliferation was most strongly induced in the NaCl group, demonstrating that induction of cell proliferation is not sufficient for methylation induction. Among the inflammation-related genes, Il1b, Nos2 and Tnf showed increased expression specifically in the three Helicobacter groups. In human gastric mucosae infected by H.pylori, NOS2 and TNF were also increased. These data showed that inflammation due to infection of the three Helicobacter strains has a strong potential to induce methylation, regardless of their CagA statuses, and increased cell proliferation was not sufficient for methylation induction. It was suggested that specific types of inflammation characterized by expression of specific inflammation-related genes, along with increased cell proliferation, are necessary for methylation induction.


Effects of specific DNMT gene depletion on cancer cell transformation and breast cancer cell invasion; toward selective DNMT inhibitors. A hallmark of cancer is aberrant DNA methylation, consisting of global hypomethylation and regional hypermethylation of tumor suppressor genes. DNA methyltransferase inhibitors have been recognized as promising candidate anticancer drugs. Drug development has focused on DNA methylation inhibitors with the goal of activating tumor suppressor genes silenced by DNA methylation. 5-azacytidine (5-AC; Vidaza), a global DNA methyltransferase inhibitor, was Food and Drug Administration approved to treat myelodysplastic syndromes and is clinically tested for solid tumors. In this paper, it was demonstrated that 5'-aza-2'-deoxycytidine (5-azaCdR) activated both silenced tumor suppressor genes and pro-metastatic genes by demethylation, raising the concern that it would promote metastasis. 5-AzaCdR treatment increased the invasiveness of non-invasive breast cancer cell lines MCF-7 cells and ZR-75-1 and dramatically induced pro-metastatic genes; Urokinase plasminogen activator (uPA), matrix metalloproteinase 2 (MMP2), metastasis-associated gene (H-MTS1; S100A4) and C-X-C chemokine receptor 4 (CXCR4). The hypothesis that the blocking of cellular transformation activity of DNA methyltransferase inhibitor could be separated from the pro-metastatic activity was tested using short interfering RNA (siRNA) targeted to the different DNA methyltransferase (DNMT) genes. Although depletion of DNMT1 had the strongest effect on colony growth suppression in cellular transformation assays, it did not result in demethylation and activation of uPA, S100A4, MMP2 and CXCR4 in MCF-7 cells. Depletion of DNMT1 did not induce cellular invasion in MCF-7 and ZR-75-1 non-invasive breast cancer cell lines. These data have implications on the design of new DNA methyltransferase inhibitor and on the proper utilization of current inhibitors.


The effect of eccentric and concentric calf muscle training on Achilles tendon stiffness. To compare in vivo effects of eccentric and concentric calf muscle training on Achilles tendon stiffness, in subjects without tendinopathy. Thirty-eight recreational athletes completed 6 weeks eccentric (6 males, 13 females, 21.6  ±  2.2 years) or concentric training (8 males, 11 females, 21.1  ±  2.0 years). Achilles tendon stiffness, tendon modulus and single-leg jump height were measured before and after intervention. Exercise adherence was recorded using a diary. All data are reported as mean  ±  SD. Groups were matched for height and weight but the eccentric training group were more active at baseline (P < 0.05). Tendon stiffness was higher in the eccentrically trained group at baseline compared to the concentrically trained group (20.9  ±  7.3 N/mm v 13.38  ±  4.66 N/mm; P = 0.001) and decreased significantly after eccentric training (to 17.2 ( ±  5.9) N/mm (P = 0.035)). There was no stiffness change in the concentric group (P = 0.405). Stiffness modulus showed similar changes to stiffness. An inverse correlation was found between initial, and subsequent, reduction in stiffness (r = -0.66). Jump height did not change and no correlation between stiffness change and adherence was observed in either group (r = 0.01). Six weeks of eccentric training can alter Achilles tendon stiffness while a matched concentric programme shows no similar effects. Studies in patients with Achilles tendinopathy are warranted.


Influence of magnetic knee wraps on joint proprioception in individuals with osteoarthritis: a randomized controlled pilot trial. To determine the effects of magnetic knee wraps (MKWs) on joint position sense (JPS) in individuals with mild-to-moderate knee osteoarthritis. Randomized, double-blind, placebo-controlled pilot trial. Rehabilitation clinic of a tertiary hospital. Fifty volunteers with mild-to-moderate knee osteoarthritis participated and 33 (66%) completed the trial; only one (2%) withdrew due to study-related adverse effects. Knee wraps with a static magnetic field (35  mT) were compared with control knee wraps for 12 weeks. The main outcome measure was JPS at first, fourth, and twelfth week while applying of the knee wrap, quantified as the ability to replicate target knee joint angles. The secondary outcome was the Comprehensive Osteoarthritis Test (COAT) total score. In the intention-to-treat analysis with an alpha-level of 0.05, 12-week application of the MKWs did not significantly reduce the mean absolute error (MAE) of JPS (n = 18; P = 0.627); contrarily, the MAE was found to decrease significantly after wearing the sham MKWs (n = 20; P = 0.01). The COAT total score gradually improved in both groups (P < 0.05). When comparing the improvement of MAE and COAT total score at each follow-up between two groups, no significant differences were found; the maximal difference in the improvement of MAE between two groups was noted at week 12 (mean difference: 1.2°; 95% confidence interval -0.4 to 2.9; P = 0.144). In the per-protocol analysis, the study group showed better improvement in the COAT total score at week 12 (P = 0.033). The 35-mT MKWs could not significantly influence knee JPS in individuals with mild-to-moderate knee osteoarthritis.


Effects of the protein kinase inhibitor PKC412 on gene expression and link to physiological effects in zebrafish Danio rerio eleuthero-embryos. To identify molecular effects of the antineoplastic agent protein kinase C inhibitor 412 (PKC412) (midostaurin), we applied gene expression profiling in zebrafish using whole-genome microarrays. Behavioral, developmental, and physiological effects were investigated in order to analyze for correlations between altered gene expression profiles with effects on development and physiology. Zebrafish blastula-stage embryos were exposed for 6 days postfertilization to nominal levels of 2 and 40 μg/l PKC412. Among the 259 and 511 altered transcripts at both concentrations, respectively, the expressions of genes involved in the circadian rhythm were further investigated. Alteration of swimming behavior was not observed. Pathways of interest affected by PKC412 were angiogenesis, apoptosis, DNA damage response, and response to oxidative stress. Angiogenesis was analyzed in double-transgenic zebrafish embryos Tg(fli1a:EGFP)y1;Tg(gata1:dsRed)sd2; no major defects were induced by PKC412 treatment at both concentrations. Apoptosis occurred in olfactory placodes of embryos exposed to 40 μg/l, and DNA damage was induced at both PKC412 concentrations. However, there were no significant effects on reactive oxygen species formation. This study leads to the conclusion that PKC412-induced alterations of gene transcripts are partly paralleled by physiological effects at high, but not at low PKC412 concentrations expected to be of environmental relevance.


Bowel movement and constipation frequencies and the risk of colorectal cancer among men in the Netherlands Cohort Study on Diet and Cancer. The authors investigated the associations between bowel movement and constipation frequencies and colorectal cancer (CRC) endpoints among men in the Netherlands Cohort Study on Diet and Cancer (n = 58,279) and explored whether dietary fiber intake may modify associations. After 13.3 years (1986-1999), 1,207 CRC cases and 1,753 subcohort members were available for case-cohort analyses. Multivariate analyses showed a significantly increased hazard ratio for CRC overall and rectal cancer in men who reported having a bowel movement 1-2 times per day (second-highest category) as compared with once a day (CRC: hazard ratio (HR) = 1.29, 95% confidence interval (CI): 1.09, 1.53 (P(trend) < 0.001); rectal cancer: HR = 1.50, 95% CI: 1.15, 1.95 (P(trend) = 0.001)). Hazard ratios for CRC overall and rectal cancer were significantly decreased and lowest in men who reported suffering from constipation sometimes or more often versus never (CRC: HR = 0.76, 95% CI: 0.58, 0.98 (P(trend) = 0.02); rectal cancer: HR = 0.57, 95% CI: 0.35, 0.90 (P(trend) = 0.01)). No trends in the associations with proximal or distal colon cancer risk were observed. Interactions with dietary fiber intake were not significant. In this study, frequent bowel movements were associated with an increased risk of rectal cancer in men, and constipation was associated with a decreased risk.