Pleiotropy of FRIGIDA enhances the potential for multivariate adaptation.

An evolutionary response to selection requires genetic variation; however, even if it exists, then the genetic details of the variation can constrain adaptation. In the simplest case, unlinked loci and uncorrelated phenotypes respond directly to multivariate selection and permit unrestricted paths to adaptive peaks. By contrast, 'antagonistic' pleiotropic loci may constrain adaptation by affecting variation of many traits and limiting the direction of trait correlations to vectors that are not favoured by selection. However, certain pleiotropic configurations may improve the conditions for adaptive evolution. Here, we present evidence that the Arabidopsis thaliana gene FRI (FRIGIDA) exhibits 'adaptive' pleiotropy, producing trait correlations along an axis that results in two adaptive strategies. Derived, low expression FRI alleles confer a 'drought escape' strategy owing to fast growth, low water use efficiency and early flowering. By contrast, a dehydration avoidance strategy is conferred by the ancestral phenotype of late flowering, slow growth and efficient water use during photosynthesis. The dehydration avoidant phenotype was recovered when genotypes with null FRI alleles were transformed with functional alleles. Our findings indicate that the well-documented effects of FRI on phenology result from differences in physiology, not only a simple developmental switch

Corticosterone Regulates Both Naturally Occurring and Cocaine‐Induced Dopamine Signaling by Selectively Decreasing Dopamine Uptake

Stressful and aversive events promote maladaptive reward‐seeking behaviors such as drug addiction by acting, in part, on the mesolimbic dopamine system. Using animal models, data from our laboratory and others show that stress and cocaine can interact to produce a synergistic effect on reward circuitry. This effect is also observed when the stress hormone corticosterone is administered directly into the nucleus accumbens (NAc), indicating that glucocorticoids act locally in dopamine terminal regions to enhance cocaine\u27s effects on dopamine signaling. However, prior studies in behaving animals have not provided mechanistic insight. Using fast‐scan cyclic voltammetry, we examined the effect of systemic corticosterone on spontaneous dopamine release events (transients) in the NAc core and shell in behaving rats. A physiologically relevant systemic injection of corticosterone (2 mg/kg i.p.) induced an increase in dopamine transient amplitude and duration (both voltammetric measures sensitive to decreases in dopamine clearance), but had no effect on the frequency of transient release events. This effect was compounded by cocaine (2.5 mg/kg i.p.). However, a second experiment indicated that the same injection of corticosterone had no detectable effect on the dopaminergic encoding of a palatable natural reward (saccharin). Taken together, these results suggest that corticosterone interferes with naturally occurring dopamine uptake locally, and this effect is a critical determinant of dopamine concentration specifically in situations in which the dopamine transporter is pharmacologically blocked by cocaine

Multiple origins, one evolutionary trajectory: gradual evolution characterizes distinct lineages of allotetraploid "Brachypodium"

The “genomic shock” hypothesis posits that unusual challenges to genome integrity such as whole genome duplication may induce chaotic genome restructuring. Decades of research on polyploid genomes have revealed that this is often, but not always the case. While some polyploids show major chromosomal rearrangements and derepression of transposable elements in the immediate aftermath of whole genome duplication, others do not. Nonetheless, all polyploids show gradual diploidization over evolutionary time. To evaluate these hypotheses, we produced a chromosome-scale reference genome for the natural allotetraploid grass Brachypodium hybridum, accession “Bhyb26.” We compared 2 independently derived accessions of B. hybridum and their deeply diverged diploid progenitor species Brachypodium stacei and Brachypodium distachyon. The 2 B. hybridum lineages provide a natural timecourse in genome evolution because one formed 1.4 million years ago, and the other formed 140 thousand years ago. The genome of the older lineage reveals signs of gradual post-whole genome duplication genome evolution including minor gene loss and genome rearrangement that are missing from the younger lineage. In neither B. hybridum lineage do we find signs of homeologous recombination or pronounced transposable element activation, though we find evidence supporting steady post-whole genome duplication transposable element activity in the older lineage. Gene loss in the older lineage was slightly biased toward 1 subgenome, but genome dominance was not observed at the transcriptomic level. We propose that relaxed selection, rather than an abrupt genomic shock, drives evolutionary novelty in B. hybridum, and that the progenitor species’ similarity in transposable element load may account for the subtlety of the observed genome dominance

Risk of opioid misuse in people with cancer and pain and related clinical considerations: a qualitative study of the perspectives of Australian general practitioners.

OBJECTIVE:To explore the perspectives of general practitioners (GPs) concerning the risk of opioid misuse in people with cancer and pain and related clinical considerations. DESIGN:A qualitative approach using semistructured telephone interviews. Analysis used an integrative approach. SETTING:Primary care. PARTICIPANTS:Australian GPs with experience of prescribing opioids for people with cancer and pain. RESULTS:Twenty-two GPs participated, and three themes emerged. Theme 1 (Misuse is not the main problem) contextualised misuse as a relatively minor concern compared with pain control and toxicity, and highlighted underlying systemic factors, including limitations in continuity of care and doctor expertise. Theme 2 ('A different mindset' for cancer pain) captured participants' relative comfort in prescribing opioids for pain in cancer versus non-cancer contexts, and acknowledgement that compassion and greater perceived community acceptance were driving factors, in addition to scientific support for mechanisms and clinical efficacy. Participant attitudes towards prescribing for people with cancer versus non-cancer pain differed most when cancer was in the palliative phase, when they were unconcerned by misuse. Participants were equivocal about the risk-benefit ratio of long-term opioid therapy in the chronic phase of cancer, and were reluctant to prescribe for disease-free survivors. Theme 3 ('The question is always, 'how lazy have you been?') captured participants' acknowledgement that they sometimes prescribed opioids for cancer pain as a default, easier option compared with more holistic pain management. CONCLUSIONS:Findings highlight the role of specific clinical considerations in distinguishing risk of opioid misuse in the cancer versus non-cancer population, rather than diagnosis per se. Further efforts are needed to ensure continuity of care where opioid prescribing is shared. Greater evidence is needed to guide opioid prescribing in disease-free survivors and the chronic phase of cancer, especially in the context of new treatments for metastatic disease

Maintaining musculoskeletal health using a behavioural therapy approach : a population-based randomised controlled trial (the MAmMOTH Study)

Acknowledgements: The study was funded by Arthritis Research UK (now Versus Arthritis) grant number: 20748. Costs for delivery of the intervention were provided by NHS Grampian, NHS Greater Glasgow and Clyde, and NHS Highland. The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. We acknowledge the contribution of the trial steering committee to the successful conduct of the study. The members were Professor Ernest Choy (Cardiff University), Professor Tamar Pincus (Royal Holloway, University of London) and Gordon Taylor (Bath University). We thank Brian Taylor and Mark Forrest from the Centre for Healthcare Randomised Trials (CHaRT) at the University of Aberdeen for their technical assistance and Professor Graeme MacLennan, Director of CHaRT, for methodological input. Professor John Norrie (originally University of Aberdeen now University of Edinburgh) and Dr. Majid Artus (originally Keele University, now the Osmaston surgery, Derbyshire) were study investigators at the time of grant award but subsequently left the study. We thank Kathy Longley (a representative of Fibromyalgia Action UK) for her input to the grant application and the project as well as from members of the public on the University of Aberdeen College of Life Sciences and Medicine Research Interest Group. The prioritisation of “Prevention of chronic pain” arose from a 2012 meeting of the Arthritis Research UK Clinical Study Group in Pain to which patients contributed.Peer reviewedPostprintsupplementary_datasupplementary_dat

The Genetic Architecture of Shoot and Root Trait Divergence Between Mesic and Xeric Ecotypes of a Perennial Grass

Environmental heterogeneity can drive patterns of functional trait variation and lead to the formation of locally adapted ecotypes. Plant ecotypes are often differentiated by suites of correlated root and shoot traits that share common genetic, developmental, and physiological relationships. For instance, although plant water loss is largely governed by shoot systems, root systems determine water access and constrain shoot water status. To evaluate the genetic basis of root and shoot trait divergence, we developed a recombinant inbred population derived from mesic and xeric ecotypes of the perennial grass Panicum hallii. Our study sheds light on the genetic architecture underlying the relationships between root and shoot traits. We identified several genomic “hotspots” which control suites of correlated root and shoot traits, thus indicating genetic coordination between plant organ systems in the process of ecotypic divergence. Genomic regions of colocalized quantitative trait locus (QTL) for the majority of shoot and root growth related traits were independent of colocalized QTL for shoot and root resource acquisition traits. The allelic effects of individual QTL underscore ecological specialization for drought adaptation between ecotypes and reveal possible hybrid breakdown through epistatic interactions. These results have implications for understanding the factors constraining or facilitating local adaptation in plants

Components of the ribosome biogenesis pathway underlie establishment of telomere length set point in Arabidopsis

Telomeres cap the physical ends of eukaryotic chromosomes to ensure complete DNA replication and genome stability. Heritable natural variation in telomere length exists in yeast, mice, plants and humans at birth; however, major effect loci underlying such polymorphism remain elusive. Here, we employ quantitative trait locus (QTL) mapping and transgenic manipulations to identify genes controlling telomere length set point in a multi-parent Arabidopsis thaliana mapping population. We detect several QTL explaining 63.7% of the total telomere length variation in the Arabidopsis MAGIC population. Loss-of-function mutants of the NOP2A candidate gene located inside the largest effect QTL and of two other ribosomal genes RPL5A and RPL5B establish a shorter telomere length set point than wild type. These findings indicate that evolutionarily conserved components of ribosome biogenesis and cell proliferation pathways promote telomere elongation

Applying the Knowledge-to-Action Framework to Implement Gait and Balance Assessments in Inpatient Stroke Rehabilitation

Objectives The overall objectives of this project were to implement and sustain use of a gait assessment battery (GAB) that included the Berg Balance Scale, 10-meter walk test, and 6-minute walk test during inpatient stroke rehabilitation. The study objective was to assess the effect of the study intervention on clinician adherence to the recommendations and its effect on clinician perceptions and the organization. Design Pre- and post-training intervention study. Setting Subacute inpatient rehabilitation facility. Participants Physical therapists (N=6) and physical therapist assistants (N=2). Intervention The intervention comprised a bundle of activities, including codeveloping and executing the plan with clinicians and leaders. The multicomponent implementation plan was based on the Knowledge-to-Action Framework and included implementation facilitation, implementation leadership, and a bundle of knowledge translation interventions that targeted barriers. Implementation was an iterative process in which results from one implementation phase informed planning of the next phase. Main Outcome Measures Clinician administration adherence, surveys of perceptions, and organizational outcomes. Results Initial adherence to the GAB was 46% and increased to more than 85% after 6 months. These adherence levels remained consistent 48 months after implementation. Clinician perceptions of measure use were initially high (>63%), with significant improvements in knowledge and use of one measure after implementation. Conclusions We successfully implemented the assessment battery with high levels of adherence to recommendations, likely because of using the bundle of knowledge translation activities, facilitation, and use of a framework to codevelop the plan. These changes in practice were sustainable, as determined by a 4-year follow-up

Receiving Preferred Treatment not Associated with Positive Outcome in a Randomized Trial

Background: In a randomized trial of treatments for chronic widespread pain (CWP), participants were asked their treatment preference just prior to randomisation (baseline). This analysis examined whether treatment preference was associated with baseline factors and whether receiving a preferred treatment affected outcomes. Methods: The MUSICIAN trial was a 2 × 2 randomized trial of cognitive behavioural therapy (CBT) or exercise for people with CWP. Participants were randomly allocated to one of three active treatments [CBT (n = 112), exercise (n = 109), both exercise and CBT (n = 112)] or usual care (n = 109). Before allocation participants were asked, if they had a choice, which active treatment they would choose. A positive outcome was self-reported improvement in health of much or very much better 6, 9 and 30 months after entering the study. Associations between preference and baseline characteristics were examined, including age, gender, chronic pain grade (CPG), passive and active coping, fatigue, psychological distress, sleep problems and kinesiophobia. Differences in gender and CPG between preferences were tested by chi-square tests. For continuous variables, comparison was by analysis of variance and, where a difference was observed, Tukey’s honest significant difference was used to identify which preferences differed and then the standardized mean difference (d) with 95% CIs were calculated. Among those allocated to active treatments, logistic regression was used to calculate odds ratios, adjusted for factors associated with preference, with 95% CIs of positive outcome in those receiving their preferred treatment and not receiving preferred treatment as the referent group. Results: Of 442 participants, 144 (33%) expressed preference for exercise, 20 (5%) for CBT, 199 (45%) for combined exercise and CBT and 79 (18%) expressed no preference. Compared with females, males were more likely to prefer exercise only (44 vs 28%) and less likely to prefer combined treatment (35 vs 50%). Those preferring CBT, compared with those preferring exercise, were higher in passive coping [d = 0.9 (95% CI 0.41, 1.37)], fatigue [0.8 (0.34, 1.31)], psychological distress [0.7 (0.26, 1.21)], sleep problems [0.7 (0.18, 1.12)] and kinesiophobia [0.6 (0.17, 1.12)]. Those preferring CBT also had greater scores on passive coping than those preferring combined treatment [0.6 (95% CI 0.11, 1.03)] or no preference [0.5 (−0.01, 0.98)] and greater kinesiophobia than those with no preference [0.5 (−0.05, 0.95)]. Of participants allocated to CBT, exercise or combined treatment, 7, 39 and 50%, respectively, had a preference for their allocated treatment. There was no clear association between achieving a positive outcome and whether or not someone received their preferred treatment (see Table 1). Conclusion: Exercise and exercise combined with CBT were the most preferred treatments. Participants with specific preferences differed from each other with respect to factors which might influence outcome. However, receiving preferred treatment did not appear to influence treatment response. Disclosure statement: M.B. has received funding for the MUSICIAN Study from Arthritis Research UK. G.J.M. has received funding for the MUSICIAN Study from Arthritis Research UK. All other authors have declared no conflicts of interest