Summary Background Primary open angle glaucoma and ocular hypertension are habitually treated with eye drops that lower intraocular pressure. Selective laser trabeculoplasty is a safe alternative but is rarely used as first-line treatment. We compared the two. Methods In this observer-masked, randomised controlled trial treatment-naive patients with open angle glaucoma or ocular hypertension and no ocular comorbidities were recruited between 2012 and 2014 at six UK hospitals. They were randomly allocated (web-based randomisation) to initial selective laser trabeculoplasty or to eye drops. An objective target intraocular pressure was set according to glaucoma severity. The primary outcome was health-related quality of life (HRQoL) at 3 years (assessed by EQ-5D). Secondary outcomes were cost and cost-effectiveness, disease-specific HRQoL, clinical effectiveness, and safety. Analysis was by intention to treat. This study is registered at controlled-trials.com (ISRCTN32038223). Findings Of 718 patients enrolled, 356 were randomised to the selective laser trabeculoplasty and 362 to the eye drops group. 652 (91%) returned the primary outcome questionnaire at 36 months. Average EQ-5D score was 0·89 (SD 0·18) in the selective laser trabeculoplasty group versus 0·90 (SD 0·16) in the eye drops group, with no significant difference (difference 0·01, 95% CI −0·01 to 0·03; p=0·23). At 36 months, 74·2% (95% CI 69·3–78·6) of patients in the selective laser trabeculoplasty group required no drops to maintain intraocular pressure at target. Eyes of patients in the selective laser trabeculoplasty group were within target intracoluar pressure at more visits (93·0%) than in the eye drops group (91·3%), with glaucoma surgery to lower intraocular pressure required in none versus 11 patients. Over 36 months, from an ophthalmology cost perspective, there was a 97% probability of selective laser trabeculoplasty as first treatment being more cost-effective than eye drops first at a willingness to pay of £20 000 per quality-adjusted life-year gained. Interpretation Selective laser trabeculoplasty should be offered as a first-line treatment for open angle glaucoma and ocular hypertension, supporting a change in clinical practice. Funding National Institute for Health Research, Health and Technology Assessment Programme.

Polymorphism may play an important role in speciation because new species could originate from the distinctive morphs observed in polymorphic populations. However, much remains to be understood about the process by which morphs found new species. To detail the steps of this mode of speciation, we studied the geographic variation and evolutionary history of a throat color polymorphism that distinguishes the "rock-paper-scissors" mating strategies of the sideblotched lizard, Uta stansburiana. We found that the polymorphism is geographically widespread and has been maintained for millions of years. However, there are many populations with reduced numbers of throat color morphs. Phylogenetic reconstruction showed that the polymorphism is ancestral, but it has been independently lost eight times, often giving rise to morphologically distinct subspecies/species. Changes to the polymorphism likely involved selection because the allele for one particular male strategy, the "sneaker" morph, has been lost in all cases. Polymorphism loss was associated with accelerated evolution of male size, female size, and sexual dimorphism, which suggests that polymorphism loss can promote rapid divergence among populations and aid species formation.lizard | morph | phylogeny | rock-paper-scissors | Uta stansburiana P olymorphic forms within a population could be the starting material for new species (1-4). Tests of how polymorphisms diversify into new lineages have been relatively rare (2, 5, 6), despite increasing recognition that polymorphisms, such as alternative mating strategies, are common within species (7-9). Here we investigate the processes by which a morph in a polymorphic population may diverge to found a new species.Competition within a population can generate morphs possessing alternative adaptations, which may become as phenotypically distinct as separate species and thus primed for speciation (2, 3). WestEberhard theorized how morphs may promote speciation (2, 10) and suggested that selection in new environments may favor a particular morph, destabilizing the dynamics maintaining the polymorphism. If a population loses a morph, this can lead to rapid phenotypic divergence in the remaining morph(s) (2). One cause of rapid divergence is that genetic evolution may be constrained in polymorphic populations, because alleles that increase the fitness of a single morph but decrease the fitness of other morphs may be unable to spread. Loss of a morph allows these alleles to spread, which can result in rapid phenotypic evolution in the direction of specialization on the remaining morph phenotypes, a process called character release (2). Another reason for rapid evolution coincident with morph loss is that colonization of a new ecological environment may select against a particular morph and also favor novel phenotypes in the remaining morphs. In addition, loss of a morph changes the competitive environment, because the fitness of morphs can depend on the frequency of other types in the population (8). Rapid evolution may occur ...

We describe new ESS models of density regulation driven by genic selection to explain the cyclical dynamics of a social system that exhibits a rock-paper-scissors (RPS) set of three alternative strategies. We tracked changes in morph frequency and fitness of Lacerta vivipara and found conspicuous RPS cycles. Morphs of Uta and Lacerta exhibited parallel survival-performance trade-offs. Frequency cycles in both species of lizards are driven by genic selection. In Lacerta, frequency of each allele in adult cohorts had significant impacts on juvenile recruitment, similar to mutualistic, altruistic, and antagonistic relations of RPS alleles in Uta. We constructed evolutionarily stable strategy (ESS) models in which adults impact juvenile recruitment as a function of self versus nonself color recognition. ESS models suggest that the rapid 4-year RPS cycles exhibited by Lacerta are not possible unless three factors are present: behaviors evolve that discriminate self versus nonself morphs at higher rates than random, self- versus non-self-recognition contributes to density regulation, and context-dependent mate choice evolves in females, which choose sire genotypes to enhance progeny survival. We suggest genic selection coupled to density regulation is widespread and thus fundamental to theories of social system evolution as well as theories of population regulation in diverse animal taxa.

The type I B family of phosphatidylinositol phosphate kinases (PIPKs) contain a characteristic region of Membrane Occupation and Recognition Nexus (MORN) motifs at the N terminus. These MORN motifs are not found in PIPKs from other eukaryotes. To understand the impact of the additional N-terminal domain on protein function and subcellular distribution, we expressed truncated and full-length versions of AtPIPK1, one member of this family of PIPKs, in Escherichia coli and in tobacco cells grown in suspension culture. Deletion of the Nterminal MORN domain (amino acids 1-251) of AtPIPK1 increased the specific activity of the remaining C-terminal peptide (⌬MORN) >4-fold and eliminated activation by phosphatidic acid (PtdOH). PtdOH activation could also be eliminated by mutating Pro 396 to Ala (P396A) in the predicted linker region between the MORN and the kinase homology domains. AtPIPK1 is product-activated and the MORN domain binds PtdIns(4,5)P 2 . Adding back the MORN peptide to ⌬MORN or to the PtdOH-activated full-length protein increased activity ϳ2-fold. Furthermore, expressing the MORN domain in vivo increased the plasma membrane PtdInsP kinase activity. When cells were exposed to hyperosmotic stress, the MORN peptide redistributed from the plasma membrane to a lower phase or endomembrane fraction. In addition, endogenous PtdInsP kinase activity increased in the endomembrane fraction of hyperosmotically stressed cells. We conclude that the MORN peptide can regulate both the function and distribution of the enzyme in a manner that is sensitive to the lipid environment. Phosphatidylinositol-4-phosphate (PtdInsP)2 5-kinases catalyze the synthesis of phosphatidylinositol-(4,5)-bisphosphate (PtdIns(4,5)P 2 ), a key component in phosphoinositide (PI) signaling that regulates many cellular processes. In Arabidopsis, there are 11 isoforms of PtdInsP 5-kinases that have been divided into 2 subfamilies depending on the size of the proteins (1). Subfamily A consists of AtPIPK10 and AtPIPK11, which contain 401 and 421 amino acids, respectively. The subfamily B proteins (AtPIPK1-9) are larger, from 705 to 859 amino acids, and contain repeated 23-amino acid Membrane Occupation and Recognition Nexus (MORN) motifs in the N terminus. There are 7 MORN motifs in AtPIPK1-3 and 8 motifs in AtPIPK4 -9. The predicted B subfamily PIPKs from rice (2), tomato, and maize also have multiple MORN motifs in the N terminus based on data base analysis; however, these motifs are not found in PIPKs from other eukaryotes including mammals, Caenorhabditis elegans or yeast. In an attempt to understand what advantage there might be for a majority of the plant PIPKs to have this novel N-terminal extension we investigated the effect of the N-terminal MORN domain of AtPIPK1 on enzyme activity and subcellular distribution. MORN motifs were first described in junctophilin (3) and have since been reported to be present in several proteins involved in membrane fission (4, 5). Junctophilin is an integral endoplasmic reticulum (ER) protein that is a compon...

Population-level comparative analyses can link microevolutionary processes within populations to macroevolutionary patterns of diversification. We used the comparative method to study the evolution of sexual size dimorphism (SSD) among populations of side-blotched lizards (Uta stansburiana). Uta stansburiana is polymorphic for different male mating and female life-history strategies in some populations, but monomorphic in others. We tested whether intrasexual selection among males, fecundity selection on females, and the presence of polymorphic strategies affected levels of SSD. We first resolved a phylogeny for 41 populations across the range of the species and documented a substantial regional structure. Our intraspecific data had significant phylogenetic signal, and correcting for phylogeny using independent contrasts had large effects on our results. Polymorphic populations had male-biased SSD and changes in male body size, levels of tail breaks, and SSD consistent with the intrasexual selection hypothesis. Monomorphic populations had changes in female size, clutch size, and SSD consistent with the fecundity selection hypothesis. Fecundity selection is a likely cause of some monomorphic populations having no SSD or female-biased SSD.Our results suggest that changes in mating strategies are associated with phenotypic diversification and multiple evolutionary forces can shape SSD. Sexual selection arises from competition for mates and can lead to phenotypic diversification within and among species (Darwin 1871;West-Eberhard 1983;Andersson 1994). Most studies of sexual selection have focused either on selection within populations (Sinervo and Lively 1996; Krakauer 2005; Clutton-Brock et al.