Long-term outcome of peripheral T-cell lymphomas: Ten-year follow-up of the International Prospective T-cell Project.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of haematological cancers with generally poor clinical outcomes. However, a subset of patients experience durable disease control, and little is known regarding long-term outcomes. The International T-cell Lymphoma Project (ITCLP) is the largest prospectively collected cohort of patients with PTCLs, providing insight into clinical outcomes at academic medical centres globally. We performed a long-term outcome analysis on patients from the ITCLP with available 10-year follow-up data (n = 735). The overall response rate to first-line therapy was 68%, while 5- and 10-year overall survival estimates were 49% and 40% respectively. Most deaths occurred prior to 5 years, and for patients alive at 5 years, the chance of surviving to 10 years was 84%. However, lymphoma remained the leading cause of death in the 5- to 10-year period (67%). Low-risk International Prognostic Index and Prognostic Index for T-cell lymphoma scores both identified patients with improved survival, while in multivariate analysis, age >60 years and Eastern Cooperative Oncology Group performance status 2-4 were associated with inferior outcomes. The favourable survival seen in patients achieving durable initial disease control emphasizes the unmet need for optimal front-line therapeutic approaches in PTCLs.

Caffeic acid phenethyl ester analogues as selective inhibitors of 12-lipoxygenase product biosynthesis in human platelets.

The inflammatory response is an essential process for the host defence against pathogens. Lipid mediators are important in coordinating the pro-inflammatory and pro-resolution phases of the inflammatory process. However, unregulated production of these mediators has been associated with chronic inflammatory diseases such as arthritis, asthma, cardiovascular diseases, and several types of cancer. Therefore, it is not surprising that enzymes implicated in the production of these lipid mediators have been targeted for potential therapeutic approaches. Amongst these inflammatory molecules, the 12-hydroxyeicosatetraenoic acid (12(S)-HETE) is abundantly produced in several diseases and is primarily biosynthesized via the platelet's 12-lipoxygenase (12-LO) pathway. To this day, very few compounds selectively inhibit the 12-LO pathway, and most importantly, none are currently used in the clinical settings. In this study, we investigated a series of polyphenol analogues of natural polyphenols that inhibit the 12-LO pathway in human platelets without affecting other normal functions of the cell. Using an ex vivo approach, we found one compound that selectively inhibited the 12-LO pathway, with IC50 values as low as 0.11 µM, with minimal inhibition of other lipoxygenase or cyclooxygenase pathways. More importantly, our data show that none of the compounds tested induced significant off-target effects on either the platelet's activation or its viability. In the continuous search for specific and better inhibitors targeting the regulation of inflammation, we characterized two novel inhibitors of the 12-LO pathway that could be promising for subsequent in vivo studies.

Hydrozoan sperm-specific SPKK motif-containing histone H2B variants stabilise chromatin with limited compaction.

Many animals achieve sperm chromatin compaction and stabilisation by replacing canonical histones with sperm nuclear basic proteins (SNBPs) such as protamines during spermatogenesis. Hydrozoan cnidarians and echinoid sea urchins lack protamines and have evolved a distinctive family of sperm-specific histone H2Bs (spH2Bs) with extended N termini rich in SPK(K/R) motifs. Echinoid sperm packaging is regulated by spH2Bs. Their sperm is negatively buoyant and fertilises on the sea floor. Hydroid cnidarians undertake broadcast spawning but their sperm properties are poorly characterised. We show that Hydractinia echinata and H. symbiolongicarpus sperm chromatin possesses higher stability than somatic chromatin, with reduced accessibility to transposase Tn5 integration and to endonucleases in vitro. In contrast, nuclear dimensions are only moderately reduced in mature Hydractinia sperm. Ectopic expression of spH2B in the background of H2B.1 knockdown results in downregulation of global transcription and cell cycle arrest in embryos, without altering their nuclear density. Taken together, SPKK-containing spH2B variants act to stabilise chromatin and silence transcription in Hydractinia sperm with only limited chromatin compaction. We suggest that spH2Bs could contribute to sperm buoyancy as a reproductive adaptation.

Inflammatory markers and BDNF in obstructive sleep apnea (OSA) in Parkinson's disease (PD).

OBJECTIVE: Obstructive sleep apnea (OSA) exacerbates Parkinson's disease (PD) manifestations including cognitive dysfunction. Both OSA and PD have been associated with inflammation. Brain-derived neurotrophic factor (BDNF) has been implicated in cognitive function. We aimed to investigate inflammatory cytokines and BDNF in relation to OSA and PD symptoms. METHODS: In a prospective observational study, patients with PD underwent overnight polysomnography. Morning serum levels of interleukin (IL)-1ß, IL-6, IL-8, TNFα, and BDNF were quantified at baseline (n = 64) and 6 months (n = 38). Outcomes included non-motor and motor standard scores; Montreal Cognitive Assessment (MoCA); and Epworth Sleepiness scale (ESS). Associations were assessed using linear regression, adjusting for age, sex and body mass index. RESULTS: At baseline, IL-6 was associated with the Apnea-Hypopnea Index (ß = 0.013, p = 0.03), and the Oxygen Desaturation Index (ß = 0.028, p = 0.002). No other associations between cytokines and sleep parameters were found. Motor dysfunction was associated with IL-6 (ß = 0.03, p = 0.001). ESS was associated non-significantly with IL-6 (ß = 0.04, p = 0.07) and BDNF (ß = 555, p = 0.06). At follow-up, change in IL-6 was associated with change in non-motor (ß = 0.08, p = 0.007), and motor (ß = 0.03, p = 0.001) symptoms. Change in BDNF was associated with change in ESS (ß = 1450, p = 0.02). INTERPRETATION: We found an association between IL-6 levels and both OSA severity and PD motor dysfunction. At follow-up, increasing IL-6 correlated with deterioration of motor and non-motor PD symptoms. Increasing BDNF correlated with increasing sleepiness. Further work with a larger sample size is needed, but our results support the hypothesis that OSA-related inflammation plays a role in PD manifestations and progression.

Airway Epithelial Cells Drive Airway Smooth Muscle Cell Phenotype Switching to the Proliferative and Pro-inflammatory Phenotype.

The increased mass of airway smooth muscle (ASM) in the airways of asthmatic patients may contribute to the pathology of this disease by increasing the capacity for airway narrowing. Evidence for the airway epithelium as a participant in ASM remodeling is accruing. To investigate mechanisms by which airway epithelial cells induce ASM cell (ASMC) proliferation, we have employed a co-culture model to explore markers of ASMC proliferative phenotype. Co-culture with epithelial cells led to incorporation of bromodeoxyuridine into ASMCs, indicating augmented proliferation and an associated increase in mRNA of the pro-proliferative co-transcription factor Elk1. Although the mitogen heparin-binding epidermal growth factor (HB-EGF) was augmented in the co-culture supernatant, the ASMC epidermal growth factor receptor (EGFR), an effector of HB-EGF induced proliferation, did not mediate epithelial-induced proliferation. The co-culture increased the expression of ASMC mRNA for the pro-inflammatory cytokines IL-6 and IL-8 as well as the pro-proliferative microRNA miR-210. The transcriptional repressor Max-binding protein (Mnt), a putative target of miR-210, was transcriptionally repressed in co-cultured ASMCs. Together, these data indicate that the airway epithelium-induced proliferative phenotype of ASMCs is not driven by EGFR signaling, but rather may be dependent on miR210 targeting of tumor suppressor Mnt.

Influence of mini-screw implant-assisted intrusion on orthodontically induced inflammatory root resorption: a systematic review.

AIM: To systematically review indexed literature related to the influence of mini-screw implant (MSI)-assisted intrusion on orthodontically induced inflammatory root resorption (OIIRR). METHODS: Indexed databases were searched without time and language restrictions using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The inclusion criteria were: (a) original studies; (b) patients/subjects undergoing MSI-assisted intrusion; and (c) tomographic and/or histological assessment of OIIRR. Letters to the Editor, commentaries, case reports/series, reviews, and studies based on two-dimensional radiographic assessment of OIIRR were excluded. For experimental and clinical studies, the risk of bias assessment was performed using the Systematic Review Centre for Laboratory animal Experimentation risk of bias tool and the Risk of Bias in Non-randomized Studies of Interventions guidelines, respectively. RESULTS: The initial search yielded 453 studies, out of which 6 (3 clinical and 3 on animal-models) were included. The clinical studies were performed on males and females with a mean age ranging between 16.07 and 25.5 years. Duration of the clinical studies ranged from 3.8 to 9 months. The animal studies were performed on mini-pigs, rats, and dogs. The mean age in the studies on rats and mini-pigs was 2.76 and 18 months, respectively. In the study on canine models, mean age was not reported. In all studies, MSI-assisted intrusion was shown to cause OIIRR. Power analysis was performed in one study. All studies had a moderate risk of bias. CONCLUSIONS: MSI-assisted intrusion is a risk factor for OIIRR; however, from a clinical perspective, further well-designed and power-adjusted studies are needed.

1,3-Thia-zole-4-carbo-nitrile.

The title compound, C4H2N2S, is a 1,3-thia-zole substituted in the 4-position by a nitrile group. In the crystal, C-H⋯N hydrogen bonds and aromatic π-π stacking inter-actions are observed.

Sinapic acid phenethyl ester as a potent selective 5-lipoxygenase inhibitor: Synthesis and structure-activity relationship.

Given the hepatotoxicity and an unfavorable pharmacokinetic profile of zileuton (Zyflo® ), currently the only approved and clinically used 5-Lipoxygenase (5-LO) inhibitor, the search for potent and safe 5-LO inhibitors is highly demanded. The action of several phenolic acid phenethyl esters as potential 5-Lipoxygenase (5-LO) inhibitors has been investigated. For this purpose, a series of 14 phenethyl esters was synthesized and their impact on 5-LO inhibition was evaluated. The effects of position and number of hydroxyl and methoxy groups on the phenolic acid were investigated. The shortening of the linker between the carbonyl and the catechol moiety as well as the presence of the α,ß-unsaturated carbonyl group was also explored. The sinapic acid phenethyl ester (10), which can be named SAPE (10) by analogy to caffeic acid phenethyl ester (CAPE), inhibited 5-LO in a concentration-dependent manner and outperformed both zileuton (1) and CAPE (2). With an IC50 of 0.3 µm, SAPE (10) was threefold more potent than CAPE (2) and 10-fold more potent than zileuton (1), the only 5-LO inhibitor approved for clinical use. Unlike CAPE (2), SAPE (10) had no effect on 12-lipoxygenase (12-LO) and less effect on cyclooxygenase 1 (COX-1) which makes it a more selective 5-LO inhibitor.

Viral proteins as a potential driver of histone depletion in dinoflagellates.

Within canonical eukaryotic nuclei, DNA is packaged with highly conserved histone proteins into nucleosomes, which facilitate DNA condensation and contribute to genomic regulation. Yet the dinoflagellates, a group of unicellular algae, are a striking exception to this otherwise universal feature as they have largely abandoned histones and acquired apparently viral-derived substitutes termed DVNPs (dinoflagellate-viral-nucleoproteins). Despite the magnitude of this transition, its evolutionary drivers remain unknown. Here, using Saccharomyces cerevisiae as a model, we show that DVNP impairs growth and antagonizes chromatin by localizing to histone binding sites, displacing nucleosomes, and impairing transcription. Furthermore, DVNP toxicity can be relieved through histone depletion and cells diminish their histones in response to DVNP expression suggesting that histone reduction could have been an adaptive response to these viral proteins. These findings provide insights into eukaryotic chromatin evolution and highlight the potential for horizontal gene transfer to drive the divergence of cellular systems.

Variations on Negative Stain Electron Microscopy Methods: Tools for Tackling Challenging Systems.

Negative stain electron microscopy (EM) allows relatively simple and quick observation of macromolecules and macromolecular complexes through the use of contrast enhancing stain reagent. Although limited in resolution to a maximum of ~18 - 20 Å, negative stain EM is useful for a variety of biological problems and also provides a rapid means of assessing samples for cryo-electron microscopy (cryo-EM). The negative stain workflow is straightforward method; the sample is adsorbed onto a substrate, then a stain is applied, blotted, and dried to produce a thin layer of electron dense stain in which the particles are embedded. Individual samples can, however, behave in markedly different ways under varying staining conditions. This has led to the development of a large variety of substrate preparation techniques, negative staining reagents, and grid washing and blotting techniques. Determining the most appropriate technique for each individual sample must be done on a case-by-case basis and a microscopist must have access to a variety of different techniques to achieve the highest-quality negative stain results. Detailed protocols for two different substrate preparation methods and three different blotting techniques are provided, and an example of a sample that shows markedly different results depending on the method used is shown. In addition, the preparation of some common negative staining reagents, and two novel Lanthanide-based stains, is described with discussion regarding the use of each.

Interleukin-17A and vascular remodelling in severe asthma; lack of evidence for a direct role.

BACKGROUND: Bronchial vascular remodelling may contribute to the severity of airway narrowing through mucosal congestion. Interleukin (IL)-17A is associated with the most severe asthmatic phenotype but whether it might contribute to vascular remodelling is uncertain. OBJECTIVE: To assess vascular remodelling in severe asthma and whether IL-17A directly or indirectly may cause endothelial cell activation and angiogenesis. METHODS: Bronchial vascularization was quantified in asthmatic subjects, COPD and healthy subjects together with the number of IL-17A+ cells as well as the concentration of angiogenic factors in the sputum. The effect of IL-17A on in vitro angiogenesis, cell migration and endothelial permeability was assessed directly on primary human lung microvascular endothelial cells (HMVEC-L) or indirectly with conditioned medium derived from normal bronchial epithelial cells (NHBEC), fibroblasts (NHBF) and airway smooth muscle cells (ASMC) after IL-17A stimulation. RESULTS: Severe asthmatics have increased vascularity compared to the other groups, which correlates positively with the concentrations of angiogenic factors in sputum. Interestingly, we demonstrated that increased bronchial vascularity correlates positively with the number of subepithelial IL-17A+ cells. However IL-17A had no direct effect on HMVEC-L function but it enhanced endothelial tube formation and cell migration through the production of angiogenic factors by NHBE and ASMC. CONCLUSIONS & CLINICAL RELEVANCE: Our results shed light on the role of IL-17A in vascular remodelling, most likely through stimulating the synthesis of other angiogenic factors. Knowledge of these pathways may aid in the identification of new therapeutic targets.

Human ß-defensin-3 induces IL-8 release and apoptosis in airway smooth muscle cells.

BACKGROUND: Human airway smooth muscle cells (ASMCs) may have a pro-inflammatory role through the release of inflammatory mediators. Increasing evidence indicates that human ß-defensins (HBDs) are related to pathogenesis of asthma. OBJECTIVES: To examine the plasma level of HBD-1, HBD-2 and HBD-3 in asthmatic patients and the expression of their mouse orthologues in the lung tissue of a mouse model of chronic severe asthma. Further to investigate the effect of HBD-3 on the release of the pro-inflammatory cytokine IL-8 and to explore the mechanisms. METHODS: The plasma levels of HBD-1, HBD-2 and HBD-3 from 34 healthy controls and 25 asthmatic patients were determined by ELISA. The expression of mouse ß-defensins MBD-1, MBD-3 and MBD-14 in the lung tissue of asthmatic mice was detected by Western blot. The ASMCs were cultured with HBD-3 for 24 hour, and then the supernatant level of IL-8 was evaluated by ELISA and the cell viability was examined by WST-1 assay. The signalling pathway was investigated with blocking antibodies or pharmacological inhibitors. RESULTS: The plasma levels of HBD-1 and HBD-3 were elevated in asthmatic patients, and the expression of MBD-14, the mouse orthologue for HBD-3, was increased in asthmatic mice. HBD-3-induced IL-8 production in a CCR6 receptor-specific manner and was dependent on multiple signalling pathways. Moreover, HBD-3-induced cell apoptosis concurrently, which was dependent on the ERK1/2 MAPK pathway. Mitochondrial ROS regulated both HBD-3-induced IL-8 production and cell apoptosis. CONCLUSIONS AND CLINICAL RELEVANCE: These observations provide clear evidence of an important new mechanism for the promotion of airway inflammation and tissue remodelling with potential relevance for the treatment of asthma.

Genetic basis of between-individual and within-individual variance of docility.

Between-individual variation in phenotypes within a population is the basis of evolution. However, evolutionary and behavioural ecologists have mainly focused on estimating between-individual variance in mean trait and neglected variation in within-individual variance, or predictability of a trait. In fact, an important assumption of mixed-effects models used to estimate between-individual variance in mean traits is that within-individual residual variance (predictability) is identical across individuals. Individual heterogeneity in the predictability of behaviours is a potentially important effect but rarely estimated and accounted for. We used 11 389 measures of docility behaviour from 1576 yellow-bellied marmots (Marmota flaviventris) to estimate between-individual variation in both mean docility and its predictability. We then implemented a double hierarchical animal model to decompose the variances of both mean trait and predictability into their environmental and genetic components. We found that individuals differed both in their docility and in their predictability of docility with a negative phenotypic covariance. We also found significant genetic variance for both mean docility and its predictability but no genetic covariance between the two. This analysis is one of the first to estimate the genetic basis of both mean trait and within-individual variance in a wild population. Our results indicate that equal within-individual variance should not be assumed. We demonstrate the evolutionary importance of the variation in the predictability of docility and illustrate potential bias in models ignoring variation in predictability. We conclude that the variability in the predictability of a trait should not be ignored, and present a coherent approach for its quantification.

Structure-activity relationship of caffeic acid phenethyl ester analogs as new 5-lipoxygenase inhibitors.

Leukotrienes (LTs) are a class of lipid mediators implicated in numerous inflammatory disorders. Caffeic acid phenethyl ester (CAPE) possesses potent anti-LTs activity through the inhibition of 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of LTs. In this study, we describe the design and synthesis of CAPE analogs as radical scavengers and 5-LO inhibitors. Caffeic esters bearing propargyl and allyl linkers between the caffeoyl and aryl moieties (4a-i and 5a-i, respectively) were synthesized by Sonogashira and Heck cross-coupling reactions to probe the effects of flexibility and aryl substitution on 5-LO inhibition. Caffeoyl alcohol and ethers (6, 7a-b) as well as caffeoyl aldehyde and ketones (8a-e) were synthesized to elucidate the importance of the ester linkage for inhibitory activity. All tested compounds proved to be good radical scavengers (IC50 of 10-30 µm). After preliminary anti-LTs activity screening in HEK293 cell models, 5-LO inhibition potential of selected compounds was determined in human polymorphonuclear leukocytes (PMNL). Most screened compounds outperformed CAPE 3 in concentration-dependent assays on PMNL, with ester dimers 4i and 5i along with caffeoyl ethers 7a-b being roughly eight-, seven-, and 16-fold more potent than Zileuton, with IC50 values of 0.36, 0.43, and 0.18 µm, respectively.

Exacerbation risk in severe asthma is stratified by inflammatory phenotype using longitudinal measures of sputum eosinophils.

BACKGROUND: Airway inflammatory phenotyping is increasingly applied to subjects with asthma. However, its relationship to clinical outcomes in difficult asthma is incompletely elucidated. OBJECTIVE: The goal of our study was to determine the relationship between exacerbation rates and phenotypes of difficult asthma based on the longitudinal measures of sputum eosinophils and neutrophils. METHODS: Subjects in the longitudinal observational study from two tertiary care centres that completed 1 year of observation and provided at least three sputum samples were classified by inflammatory phenotypes using previously established thresholds. Kaplan-Meier curves and univariable and multivariable Cox proportional hazard models were used to determine the association between inflammatory phenotypes and exacerbation rate. RESULTS: During the study, 115 exacerbations occurred in 73 severe asthmatic subjects. Subjects with the persistently eosinophilic phenotype had a significantly shorter time to first exacerbation and greater risk of exacerbation over a 1-year period than those with the non-eosinophilic phenotype based on the univariable and multivariable Cox proportional hazard model (hazard ratio [HR], 3.24; 95% confidence interval [CI], 1.35-7.72; adjusted HR, 3.90; 95% CI, 1.34-11.36). No significant differences in time to first exacerbation or exacerbation risk over a 1-year period were observed among the neutrophilic phenotypes. CONCLUSIONS: The persistent eosinophilic phenotype is associated with increased exacerbation risk compared with the non-eosinophilic phenotype in severe asthma. No differences in time to first exacerbation or exacerbation risk over a 1-year period were detected among neutrophilic phenotypes.

Phenotyping of difficult asthma using longitudinal physiological and biomarker measurements reveals significant differences in stability between clusters.

BACKGROUND: Although the heterogeneous nature of asthma has prompted asthma phenotyping with physiological or biomarker data, these studies have been mostly cross-sectional. Longitudinal studies that assess the stability of phenotypes based on a combination of physiological, clinical and biomarker data are currently lacking. Our objective was to assess the longitudinal stability of clusters derived from repeated measures of airway and physiological data over a 1-year period in moderate and severe asthmatics. METHODS: A total of 125 subjects, 48 with moderate asthma (MA) and 77 with severe asthma (SA) were evaluated every 3 months and monthly, respectively, over a 1-year period. At each 3-month time point, subjects were grouped into 4 asthma clusters (A, B, C, D) based on a combination of clinical (duration of asthma), physiological (FEV1 and BMI) and biomarker (sputum eosinophil count) variables, using k-means clustering. RESULTS: Majority of subjects in clusters A and C had severe asthma (93 % of subjects in cluster A and 79.5 % of subjects in cluster C at baseline). Overall, a total of 59 subjects (47 %) had stable cluster membership, remaining in clusters with the same subjects at each evaluation time. Cluster A was the least stable (21 % stability) and cluster B was the most stable cluster (71 % stability). Cluster stability was not influenced by changes in the dosage of inhaled corticosteroids. CONCLUSION: Asthma phenotyping based on clinical, physiologic and biomarker data identified clusters with significant differences in longitudinal stability over a 1-year period. This finding indicates that the majority of patients within stable clusters can be phenotyped with reasonable accuracy after a single measurement of lung function and sputum eosinophilia, while patients in unstable clusters will require more frequent evaluation of these variables to be properly characterized.

Role of local eosinophilopoietic processes in the development of airway eosinophilia in prednisone-dependent severe asthma.

BACKGROUND: In severe asthmatics with persistent airway eosinophilia, blockade of interleukin-5 has significant steroid-sparing effects and attenuates blood and sputum eosinophilia. The contribution of local maturational processes of progenitors within the airways relative to the recruitment of mature cells from the peripheral circulation to the development of airway eosinophilia is not known. We hypothesize that local eosinophilopoiesis may be the predominant process that drives persistent airway eosinophilia and corticosteroid requirement in severe asthmatics. OBJECTIVES: In a cross-sectional study, the number and growth potential of eosinophil-lineage-committed progenitors (EoP) were assayed in 21 severe eosinophilic asthmatics, 19 mild asthmatics, eight COPD patients and eight normal subjects. The effect of anti-IL-5 treatment on mature eosinophils and EoP numbers was made in severe eosinophilic asthmatics who participated in a randomized clinical trial of mepolizumab (substudy of a larger GSK sponsored global phase III trial, MEA115575) where subjects received mepolizumab (100 mg, n = 9) or placebo (n = 8), as six monthly subcutaneous injections. RESULTS: Mature eosinophil and EoP numbers were significantly greater in the sputum of severe asthmatics compared with all other subject groups. In colony-forming assays, EoP from blood of severe asthmatics demonstrated a greater response to IL-5 than mild asthmatics. Treatment of severe asthmatics with mepolizumab significantly attenuated blood eosinophils and increased EoP numbers consistent with blockade of systemic eosinophilopoiesis. There was however no significant treatment effect on mature eosinophils, sputum EoP numbers or the prednisone maintenance dose. CONCLUSIONS AND CLINICAL RELEVANCE: Patients with severe eosinophilic asthma have an exaggerated eosinophilopoeitic process in their airways. Treatment with 100 mg subcutaneous mepolizumab significantly attenuated systemic differentiation of eosinophils, but did not suppress local airway eosinophil differentiation to mature cells. Targeting IL-5-driven eosinophil differentiation locally within the lung maybe of relevance for optimal control of airway eosinophilia and asthma.

Heritability and genetic correlations of personality traits in a wild population of yellow-bellied marmots (Marmota flaviventris).

Describing and quantifying animal personality is now an integral part of behavioural studies because individually distinctive behaviours have ecological and evolutionary consequences. Yet, to fully understand how personality traits may respond to selection, one must understand the underlying heritability and genetic correlations between traits. Previous studies have reported a moderate degree of heritability of personality traits, but few of these studies have either been conducted in the wild or estimated the genetic correlations between personality traits. Estimating the additive genetic variance and covariance in the wild is crucial to understand the evolutionary potential of behavioural traits. Enhanced environmental variation could reduce heritability and genetic correlations, thus leading to different evolutionary predictions. We estimated the additive genetic variance and covariance of docility in the trap, sociability (mirror image stimulation), and exploration and activity in two different contexts (open-field and mirror image simulation experiments) in a wild population of yellow-bellied marmots (Marmota flaviventris). We estimated both heritability of behaviours and of personality traits and found nonzero additive genetic variance in these traits. We also found nonzero maternal, permanent environment and year effects. Finally, we found four phenotypic correlations between traits, and one positive genetic correlation between activity in the open-field test and sociability. We also found permanent environment correlations between activity in both tests and docility and exploration in the MIS test. This is one of a handful of studies to adopt a quantitative genetic approach to explain variation in personality traits in the wild and, thus, provides important insights into the potential variance available for selection.

Synthesis and biological activity of arylspiroborate salts derived from caffeic Acid phenethyl ester.

Two novel boron compounds containing caffeic acid phenethyl ester (CAPE) derivatives have been prepared and characterized fully. These new compounds and CAPE have been investigated for potential antioxidant and antimicrobial properties and their ability to inhibit 5-lipoxygenase and whether chelation to boron improves their biological activity. Sodium salt 4 was generally more active than ammonium salt 5 in the biological assays and surpassed the radical scavenging ability of CAPE. Compounds 4 and 5 were more active than CAPE and Zileuton in human polymorphonuclear leukocytes. These results clearly show the effectiveness of the synthesized salts as transporter of CAPE.