Lack of phenotypic and evolutionary cross-resistance against parasitoids and pathogens in Drosophila melanogaster

BackgroundWhen organisms are attacked by multiple natural enemies, the evolution of a resistance mechanism to one natural enemy will be influenced by the degree of cross-resistance to another natural enemy. Cross-resistance can be positive, when a resistance mechanism against one natural enemy also offers resistance to another; or negative, in the form of a trade-off, when an increase in resistance against one natural enemy results in a decrease in resistance against another. Using Drosophila melanogaster, an important model system for the evolution of invertebrate immunity, we test for the existence of cross-resistance against parasites and pathogens, at both a phenotypic and evolutionary level.MethodsWe used a field strain of D. melanogaster to test whether surviving parasitism by the parasitoid Asobara tabida has an effect on the resistance against Beauveria bassiana, an entomopathogenic fungus; and whether infection with the microsporidian Tubulinosema kingi has an effect on the resistance against A. tabida. We used lines selected for increased resistance to A. tabida to test whether increased parasitoid resistance has an effect on resistance against B. bassiana and T. kingi. We used lines selected for increased tolerance against B. bassiana to test whether increased fungal resistance has an effect on resistance against A. tabida.Results/ConclusionsWe found no positive cross-resistance or trade-offs in the resistance to parasites and pathogens. This is an important finding, given the use of D. melanogaster as a model system for the evolution of invertebrate immunity. The lack of any cross-resistance to parasites and pathogens, at both the phenotypic and the evolutionary level, suggests that evolution of resistance against one class of natural enemies is largely independent of evolution of resistance against the other

Big conductance calcium-activated potassium channel openers control spasticity without sedation.

BACKGROUND AND PURPOSE: Our initial aim was to generate cannabinoid agents that control spasticity, occurring as a consequence of multiple sclerosis (MS), whilst avoiding the sedative side effects associated with cannabis. VSN16R was synthesized as an anandamide (endocannabinoid) analogue in an anti-metabolite approach to identify drugs that target spasticity. EXPERIMENTAL APPROACH: Following the initial chemistry, a variety of biochemical, pharmacological and electrophysiological approaches, using isolated cells, tissue-based assays and in vivo animal models, were used to demonstrate the activity, efficacy, pharmacokinetics and mechanism of action of VSN16R. Toxicological and safety studies were performed in animals and humans. KEY RESULTS: VSN16R had nanomolar activity in tissue-based, functional assays and dose-dependently inhibited spasticity in a mouse experimental encephalomyelitis model of MS. This effect occurred with over 1000-fold therapeutic window, without affecting normal muscle tone. Efficacy was achieved at plasma levels that are feasible and safe in humans. VSN16R did not bind to known CB1 /CB2 /GPPR55 cannabinoid-related receptors in receptor-based assays but acted on a vascular cannabinoid target. This was identified as the major neuronal form of the big conductance, calcium-activated potassium (BKCa ) channel. Drug-induced opening of neuronal BKCa channels induced membrane hyperpolarization, limiting excessive neural-excitability and controlling spasticity. CONCLUSIONS AND IMPLICATIONS: We identified the neuronal form of the BKCa channel as the target for VSN16R and demonstrated that its activation alleviates neuronal excitability and spasticity in an experimental model of MS, revealing a novel mechanism to control spasticity. VSN16R is a potential, safe and selective ligand for controlling neural hyper-excitability in spasticity

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD

Evaluating the use of laser processing and polishing techniques to generate micro-patterned surfaces for controlling fibroblast cell behaviour

The aim of this thesis was to develop novel micro and nano polymer substrates through different surface patterning techniques to compare their effect on human lung fibroblast (LL24) and bovine aorta endothelium (BAE-1) cell behaviours. The cells ability to adhere, proliferate and migrate were studied through the use of MTT assays and live cell tracking. Laser processing in a directional manner resulted in polyurethane surfaces having a ploughed field effect with micron-scale features a novel surface. In contrast, abrasive polishing in a directional and random manner resulted in polyurethane surfaces having sub-micron scale features orientated in a linear or random manner. The cell results showed that for both the LL24 and BAE-1 cells the laser and randomly organised abrasive surface prompted cell adhesion when compared to the linear polished surface and non-patterned surfaces. The linear polished features did not enhance cell proliferation for wither cell type when compared to the flat surface. For cell migration a clear difference can be seen between the cell types with the LL24 cells showing a decrease in cell migration on the laser and random abrasive surface. The BAE-1 cells showed enhanced migration on the non-patterned surface when compared to the other surfaces. This work was expanded to include different polished surfaces through the use of different grades of polishing paper. The results for the LL24 cells showed that though the polished surfaces promoted adhesion when compared to the non-patterned surface there was no clear difference between the surfaces for cell proliferation and migration. The BAE-1 cells results showed a similarity to the LL24 cells with the polished surfaces promoting adhesion when compared to the non-patterned surface. There was a clear distinction for the proliferation results with the LL24 cells showing enhanced proliferation on the scratched surface, this is in contrast to the BAE-1 cells which were enhanced on the non-patterned surfaces compared to the scratched surfaces. A final study was performed to introduce the use of machine grinding to generate surfaces with micro-sized features and their ability to affect cell behaviour. Results are presented which show that polyurethane castings of the ground surfaces can promote LL24 cell adhesion and migration, demonstrating that this method can be a cost effective technique to be used in this field

Obesity and pronated foot type may increase the risk of chronic plantar heel pain : a matched case-control study

Background : Chronic plantar heel pain (CPHP) is one of the most common musculoskeletal disorders of the foot, yet its aetiology is poorly understood. The purpose of this study was to examine the association between CPHP and a number of commonly hypothesised causative factors.Methods : Eighty participants with CPHP (33 males, 47 females, mean age 52.3 years, S.D. 11.7) were matched by age (&plusmn; 2 years) and sex to 80 control participants (33 males, 47 females, mean age 51.9 years, S.D. 11.8). The two groups were then compared on body mass index (BMI), foot posture as measured by the Foot Posture Index (FPI), ankle dorsiflexion range of motion (ROM) as measured by the Dorsiflexion Lunge Test, occupational lower limb stress using the Occupational Rating Scale and calf endurance using the Standing Heel Rise Test.Results : Univariate analysis demonstrated that the CPHP group had significantly greater BMI (29.8 &plusmn; 5.4 kg/m2 vs. 27.5 &plusmn; 4.9 kg/m2; P &lt; 0.01), a more pronated foot posture (FPI score 2.4 &plusmn; 3.3 vs. 1.1 &plusmn; 2.3; P &lt; 0.01) and greater ankle dorsiflexion ROM (45.1 &plusmn; 7.1&deg; vs. 40.5 &plusmn; 6.6&deg;; P &lt; 0.01) than the control group. No difference was identified between the groups for calf endurance or time spent sitting, standing, walking on uneven ground, squatting, climbing or lifting. Multivariate logistic regression revealed that those with CPHP were more likely to be obese (BMI &ge; 30 kg/m2) (OR 2.9, 95% CI 1.4 &ndash; 6.1, P &lt; 0.01) and to have a pronated foot posture (FPI &ge; 4) (OR 3.7, 95% CI 1.6 &ndash; 8.7, P &lt; 0.01).Conclusion : Obesity and pronated foot posture are associated with CPHP and may be risk factors for the development of the condition. Decreased ankle dorsiflexion, calf endurance and occupational lower limb stress may not play a role in CPHP.<br /

Mindfulness at Work: Positive Affect, Hope, and Optimism Mediate the Relationship Between Dispositional Mindfulness, Work Engagement, and Well-Being

Mindfulness has been described as a state of awareness characterized by refined attentional skills and a non-evaluative attitude toward internal and external events. Recently it has been suggested that higher levels of mindfulness may be beneficial in the workplace and first programs aiming to increase mindful awareness in occupational settings have been introduced. The current study underpins these developments with empirical evidence regarding the involved psychological processes, by investigating the relationship between dispositional mindfulness, work engagement and well-being in 299 adults in fulltime employment. As hypothesized, the results confirm that self-reported mindfulness predicts work engagement and general well-being. Furthermore, these relationships are mediated by positive job-related affect and psychological capital (hope, optimism, resiliency, and self-efficacy). Investigating mindfulness and psychological capital as multi-faceted concepts by means of structural equation modeling yielded a more precise picture. The ability to step back from automatic, habitual reactions to distress turned out to be the mindfulness facet most central for predicting work engagement and well-being. Furthermore, mindfulness exerts its positive effect on work engagement by increasing positive affect, hope, and optimism, which on their own and in combination enhance work engagement (full mediation). Well-being, on the other hand, is directly influenced by mindfulness, which exerts additional indirect influence via positive affect, hope and optimism (partial mediation). Although exploratory in nature, the results identify non-reactivity and non-judging as important mindfulness skills in the workplace

Impacts of the Tropical Pacific/Indian Oceans on the Seasonal Cycle of the West African Monsoon

The current consensus is that drought has developed in the Sahel during the second half of the twentieth century as a result of remote effects of oceanic anomalies amplified by local land–atmosphere interactions. This paper focuses on the impacts of oceanic anomalies upon West African climate and specifically aims to identify those from SST anomalies in the Pacific/Indian Oceans during spring and summer seasons, when they were significant. Idealized sensitivity experiments are performed with four atmospheric general circulation models (AGCMs). The prescribed SST patterns used in the AGCMs are based on the leading mode of covariability between SST anomalies over the Pacific/Indian Oceans and summer rainfall over West Africa. The results show that such oceanic anomalies in the Pacific/Indian Ocean lead to a northward shift of an anomalous dry belt from the Gulf of Guinea to the Sahel as the season advances. In the Sahel, the magnitude of rainfall anomalies is comparable to that obtained by other authors using SST anomalies confined to the proximity of the Atlantic Ocean. The mechanism connecting the Pacific/Indian SST anomalies with West African rainfall has a strong seasonal cycle. In spring (May and June), anomalous subsidence develops over both the Maritime Continent and the equatorial Atlantic in response to the enhanced equatorial heating. Precipitation increases over continental West Africa in association with stronger zonal convergence of moisture. In addition, precipitation decreases over the Gulf of Guinea. During the monsoon peak (July and August), the SST anomalies move westward over the equatorial Pacific and the two regions where subsidence occurred earlier in the seasons merge over West Africa. The monsoon weakens and rainfall decreases over the Sahel, especially in August.Peer reviewe

Measurements of the pp → ZZ production cross section and the Z → 4ℓ branching fraction, and constraints on anomalous triple gauge couplings at √s = 13 TeV

Four-lepton production in proton-proton collisions, pp -> (Z/gamma*)(Z/gamma*) -> 4l, where l = e or mu, is studied at a center-of-mass energy of 13 TeV with the CMS detector at the LHC. The data sample corresponds to an integrated luminosity of 35.9 fb(-1). The ZZ production cross section, sigma(pp -> ZZ) = 17.2 +/- 0.5 (stat) +/- 0.7 (syst) +/- 0.4 (theo) +/- 0.4 (lumi) pb, measured using events with two opposite-sign, same-flavor lepton pairs produced in the mass region 60 4l) = 4.83(-0.22)(+0.23) (stat)(-0.29)(+0.32) (syst) +/- 0.08 (theo) +/- 0.12(lumi) x 10(-6) for events with a four-lepton invariant mass in the range 80 4GeV for all opposite-sign, same-flavor lepton pairs. The results agree with standard model predictions. The invariant mass distribution of the four-lepton system is used to set limits on anomalous ZZZ and ZZ. couplings at 95% confidence level: -0.0012 < f(4)(Z) < 0.0010, -0.0010 < f(5)(Z) < 0.0013, -0.0012 < f(4)(gamma) < 0.0013, -0.0012 < f(5)(gamma) < 0.0013