Cyclic lactam hybrid α-MSH/Agouti-related protein (AGRP) analogues with nanomolar range binding affinities at the human melanocortin receptors

A novel hybrid melanocortin pharmacophore was designed based on the topographical similarities between the pharmacophores of Agouti related protein (AGRP) an endogenous melanocortin antagonist, and α-melanocyte-stimulating hormone (α-MSH), an endogenous melanocortin agonist. When employed in two different 23-membered macrocyclic lactam peptide templates, the designed hybrid AGRP/MSH pharmacophore yielded non-competitive ligands with nanomolar range binding affinities. The topography-based pharmacophore hybridization strategy will prove useful in development of unique non-competitive melanocortin receptor modulators.     

Ecological and evolutionary consequences of linked life-history stages in the sea

Naturalists and scientists have been captivated by the diversity of marine larval forms since they were discovered following the advent of the microscope. Because they often bear little resemblance to adults, larvae were identified initially as new life forms, classified into different groups based on the similarity of their body plans and given new names that are still with us today. The radically different body plans and lifestyles of marine larvae and adults have led most investigators historically to study the two phases of complex life cycles in isolation. More recently, important ecological insights have sprung from taking a holistic view of marine life cycles. Meanwhile, the evolutionary (phenotypic and genetic) links among life-history phases remain less appreciated. In this review, our objective is to evaluate the evolutionary links within marine life cycles, and explore their ecological and evolutionary consequences. We provide a brief overview of marine life histories, discuss the phenotypic and genetic links between the two phases of the life cycle and pose challenges to advance our understanding of the evolutionary constraints acting on marine life histories.     

Environmental uncertainty and the global biogeography of cooperative breeding in birds

Understanding why organisms as different as amoebas, ants, and birds cooperate remains an important question in evolutionary biology. Although ecology can influence cooperation and conflict within animal societies and has been implicated in species differences in sociality, the environmental predictors of sociality across broad geographic and taxonomic scales remain poorly understood. In particular, the importance of temporal variation in selection pressure has been underestimated in most evolutionary studies. Environmental uncertainty resulting from climatic variation is likely to be an important driver of temporal variation in selection pressure and therefore is expected to impact the evolution of behavioral, morphological, and physiological traits, including cooperation. Using a data set of over 95% of the world's birds, we examine the global geography and environmental, biotic, and historical biogeographic predictors of avian social behavior. We find dramatic spatial variation in social behavior for which environmental and biotic factors--namely, among-year environmental variability in precipitation--are important predictors. Although the clear global biogeographic structure in avian social behavior carries a strong signal of evolutionary history, environmental uncertainty plays an additional key role in explaining the incidence and distribution of avian cooperative breeding behavior.     

P granules extend the nuclear pore complex environment in the C. elegans germ line

The immortal and totipotent properties of the germ line depend on determinants within the germ plasm. A common characteristic of germ plasm across phyla is the presence of germ granules, including P granules in Caenorhabditis elegans, which are typically associated with the nuclear periphery. In C. elegans, nuclear pore complex (NPC)-like FG repeat domains are found in the VASA-related P-granule proteins GLH-1, GLH-2, and GLH-4 and other P-granule components. We demonstrate that P granules, like NPCs, are held together by weak hydrophobic interactions and establish a size-exclusion barrier. Our analysis of intestine-expressed proteins revealed that GLH-1 and its FG domain are not sufficient to form granules, but require factors like PGL-1 to nucleate the localized concentration of GLH proteins. GLH-1 is necessary but not sufficient for the perinuclear location of granules in the intestine. Our results suggest that P granules extend the NPC environment in the germ line and provide insights into the roles of the PGL and GLH family proteins.     

Seasonal photosynthetic gas exchange and water-use efficiency in a constitutive CAM plant, the giant saguaro cactus (Carnegiea gigantea)

Crassulacean acid metabolism (CAM) and the capacity to store large quantities of water are thought to confer high water use efficiency (WUE) and survival of succulent plants in warm desert environments. Yet the highly variable precipitation, temperature and humidity conditions in these environments likely have unique impacts on underlying processes regulating photosynthetic gas exchange and WUE, limiting our ability to predict growth and survival responses of desert CAM plants to climate change. We monitored net CO₂ assimilation (A _net), stomatal conductance (g _s), and transpiration (E) rates periodically over 2 years in a natural population of the giant columnar cactus Carnegiea gigantea (saguaro) near Tucson, Arizona USA to investigate environmental and physiological controls over carbon gain and water loss in this ecologically important plant. We hypothesized that seasonal changes in daily integrated water use efficiency (WUE_day) in this constitutive CAM species would be driven largely by stomatal regulation of nighttime transpiration and CO₂ uptake responding to shifts in nighttime air temperature and humidity. The lowest WUE_day occurred during time periods with extreme high and low air vapor pressure deficit (D _a). The diurnal with the highest D _a had low WUE_day due to minimal net carbon gain across the 24 h period. Low WUE_day was also observed under conditions of low D _a; however, it was due to significant transpiration losses. Gas exchange measurements on potted saguaro plants exposed to experimental changes in D _a confirmed the relationship between D _a and g _s. Our results suggest that climatic changes involving shifts in air temperature and humidity will have large impacts on the water and carbon economy of the giant saguaro and potentially other succulent CAM plants of warm desert environments.     

Refugial isolation and divergence in the Narrowheaded Gartersnake species complex (Thamnophis rufipunctatus) as revealed by multilocus DNA sequence data

Glacial–interglacial cycles of the Pleistocene are hypothesized as one of the foremost contributors to biological diversification. This is especially true for cold‐adapted montane species, where range shifts have had a pronounced effect on population‐level divergence. Gartersnakes of the Thamnophis rufipunctatus species complex are restricted to cold headwater streams in the highlands of the Sierra Madre Occidental and southwestern USA. We used coalescent and multilocus phylogenetic approaches to test whether genetic diversification of this montane‐restricted species complex is consistent with two prevailing models of range fluctuation for species affected by Pleistocene climate changes. Our concatenated nuDNA and multilocus species analyses recovered evidence for the persistence of multiple lineages that are restricted geographically, despite a mtDNA signature consistent with either more recent connectivity (and introgression) or recent expansion (and incomplete lineage sorting). Divergence times estimated using a relaxed molecular clock and fossil calibrations fall within the Late Pleistocene, and zero gene flow scenarios among current geographically isolated lineages could not be rejected. These results suggest that increased climate shifts in the Late Pleistocene have driven diversification and current range retraction patterns and that the differences between markers reflect the stochasticity of gene lineages (i.e. ancestral polymorphism) rather than gene flow and introgression. These results have important implications for the conservation of T. rufipunctatus (sensu novo), which is restricted to two drainage systems in the southwestern US and has undergone a recent and dramatic decline.     

A conformational switch in the CRIB-PDZ module of Par-6

Here, we report a novel mechanism of PDZ (PSD-95/Dlg/ZO-1) domain regulation that distorts?a conserved element of PDZ ligand recognition. The polarity regulator Par-6 assembles a conserved multiprotein complex and is directly modulated by the?Rho GTPase Cdc42. Cdc42 binds the adjacent Cdc42/Rac interactive binding (CRIB) and PDZ domains of Par-6, increasing C-terminal ligand binding affinity by 10-fold. By solving structures of the isolated PDZ domain and a disulfide-stabilized CRIB-PDZ, we detected a conformational switch that controls affinity by altering the configuration of the conserved "GLGF" loop. As a result, lysine 165 is displaced from the PDZ core by an adjacent hydrophobic residue, disrupting coordination of the PDZ ligand-binding cleft. Stabilization of the CRIB:PDZ interface restores K165 to its canonical location in the binding pocket. We conclude that a unique "dipeptide switch" in the Par-6 PDZ transmits a signal for allosteric activation to the ligand-binding pocket.     

When is a maternal effect adaptive?

Maternal effects have become an important field of study in evolutionary ecology and there is an ongoing debate regarding their adaptive significance. Some maternal effects can act to increase offspring fitness and are called 'adaptive maternal effects'. However, other maternal effects decrease offspring fitness and there is confusion regarding whether certain maternal effects are indeed adaptive or merely physiological inevitabilities. Here we suggest that the focus on the consequences of maternal effects for offspring fitness only and the use of 'snapshot' estimates of fitness have misdirected our effort to understand the evolution of maternal effects. We suggest that selection typically acts on maternal effects to maximise maternal rather than (or in addition to) offspring fitness. We highlight the importance of considering how maternal effects influence maternal fitness across a mother's lifetime and describe four broad types of maternal effects using an outcome-based approach. Overall, we suggest that many maternal effects will have an adaptive basis for mothers, regardless of whether these effects increase or decrease survival or reproductive success of individual offspring.     

Mutational bias for body size in rhabditid nematodes

Mutational bias is a potentially important agent of evolution, but it is difficult to disentangle the effects of mutation from those of natural selection. Mutation-accumulation experiments, in which mutations are allowed to accumulate at very small population size, thus minimizing the efficiency of natural selection, are the best way to separate the effects of mutation from those of selection. Body size varies greatly among species of nematode in the family rhabditidae; mutational biases are both a potential cause and a consequence of that variation. We report data on the cumulative effects of mutations that affect body size in three species of rhabditid nematode that vary fivefold in adult size. Results are very consistent with previous studies of mutations underlying fitness in the same strains: two strains of Caenorhabditis briggsae decline in body size about twice as fast as two strains of C. elegans, with a concomitant higher point estimate of the genomic mutation rate; the confamilial Oscheius myriophila is intermediate. There is an overall mutational bias, such that mutations reduce size on average, but the bias appears consistent between species. The genetic correlation between mutations that affect size and those underlying fitness is large and positive, on average.     

Biomechanics of the rabbit knee and ankle: muscle, ligament, and joint contact force predictions

Mathematical models of small animals that predict in vivo forces acting on the lower extremities are critical for studies of musculoskeletal biomechanics and diseases. Rabbits are advantageous in this regard because they remodel their cortical bone similar to humans. Here, we enhance a recent mathematical model of the rabbit knee joint to include the loading behavior of individual muscles, ligaments, and joint contact at the knee and ankle during the stance phase of hopping. Geometric data from the hindlimbs of three adult New Zealand white rabbits, combined with previously reported intersegmental forces and moments, were used as inputs to the model. Muscle, ligament, and joint contact forces were computed using optimization techniques assuming that muscle endurance is maximized and ligament strain energy resists tibial shear force along an inclined plateau. Peak forces developed by the quadriceps and gastrocnemius muscle groups and by compressive knee contact were within the range of theoretical and in vivo predictions. Although a minimal force was carried by the anterior cruciate and medial collateral ligaments, force patterns in the posterior cruciate ligament were consistent with in vivo tibial displacement patterns during hopping in rabbits. Overall, our predictions compare favorably with theoretical estimates and in vivo measurements in rabbits, and enhance previous models by providing individual muscle, ligament, and joint contact information to predict in vivo forces acting on the lower extremities in rabbits.