Modelling the effects of partially observed covariates on Poisson process intensity

We propose an estimating function for parameters in a modelfor Poisson process intensity when time- or space-varying covariatesare observed for both the events of the process and at sampletimes or locations selected from a probability-based samplingdesign. We investigate the large-sample properties of the proposedestimator under increasing domain asymptotics, demonstratingthat it is consistent and asymptotically normally distributed.We illustrate our approach using data from an ecological momentaryassessment of smoking.     

DO REEFS DRIVE DIVERSIFICATION IN MARINE TELEOSTS? EVIDENCE FROM THE PUFFERFISH AND THEIR ALLIES (ORDER TETRAODONTIFORMES)

A major challenge in evolutionary biology lies in explaining patterns of high species numbers found in biodiversity hot spots. Tropical coral reefs underlie most marine hot spots and reef-associated fish faunas represent some of the most diverse assemblages of vertebrates on the planet. Although the standing diversity of modern reef fish clades is usually attributed to their ecological association with corals, untangling temporal patterns of codiversification has traditionally proved difficult. In addition, owing to uncertainty in higher-level relationships among acanthomorph fish, there have been few opportunities to test the assumption that reef-association itself leads to higher rates of diversification compared to other habitats. Here we use relaxed-clock methods in conjunction with statistical measures of species accumulation and phylogenetic comparative methods to clarify the temporal pattern of diversification in reef and nonreef-associated lineages of tetraodontiforms, a morphologically diverse order of teleost fish. We incorporate 11 fossil calibrations distributed across the tetraodontiform tree to infer divergence times and compare results from models of autocorrelated and uncorrelated evolutionary rates. All major tetraodontiform reef crown groups have significantly higher rates of diversification than the order as a whole. None of the nonreef-associated families show this pattern with the exception of the aracanid boxfish. Independent contrasts analysis also reveals a significantly positive relationship between diversification rate and proportion of reef-associated species within each family when aracanids are excluded. Reef association appears to have increased diversification rate within tetraodontiforms. We suggest that both intrinsic factors of reef habitat and extrinsic factors relating to the provincialization and regionalization of the marine biota during the Miocene (about 23-5 MY) played a role in shaping these patterns of diversity.     

Binding thermodynamics of substituted diaminopyrimidine renin inhibitors

Renin is an aspartyl protease involved in the production of angiotensin II, a potent vasoconstrictor. Renin inhibitors can prevent blood vessel constriction and therefore could be useful for the treatment of hypertension. High-throughput screening efforts identified a small molecule renin inhibitor with a core substituted diaminopyrimidine ring. Parallel medicinal chemistry efforts based on this lead resulted in compound 1. A complex of 1 bound to renin was crystallized, and structural data were obtained by X-ray diffraction. The structure indicated that there were adjacent unoccupied binding pockets. Synthetic efforts were initiated to extend functionality into these pockets so as to improve affinity and adjust pharmacokinetic parameters. Thermodynamics data for inhibitor binding to renin were also collected using isothermal titration calorimetry. These data were used to help guide inhibitor optimization by suggesting molecular alterations to improve binding affinity from both thermodynamic and structural perspectives. The addition of a methoxypropyl group extending into the S3 subpocket improved inhibitor affinity and resulted in greater binding enthalpy. Initial additions to the pyrimidine ring template that extended into the large hydrophobic S2 pocket did not improve affinity and dramatically altered the thermodynamic driving force for the binding interaction. Binding of the core template was enthalpically driven, whereas binding of initial inhibitors with S2 extensions was both enthalpically and entropically driven but lost significant binding enthalpy. Additional electrostatic interactions were then incorporated into the S2 extension to improve binding enthalpy while taking advantage of the favorable entropy.     

Circadian rhythms in myocardial metabolism and contractile function: influence of workload and oleate

Multiple extracardiac stimuli, such as workload and circulating nutrients (e.g., fatty acids), known to influence myocardial metabolism and contractile function exhibit marked circadian rhythms. The aim of the present study was to investigate whether the rat heart exhibits circadian rhythms in its responsiveness to changes in workload and/or fatty acid (oleate) availability. Thus, hearts were isolated from male Wistar rats (housed during a 12:12-h light-dark cycle: lights on at 9 AM) at 9 AM, 3 PM, 9 PM, and 3 AM and perfused in the working mode ex vivo with 5 mM glucose plus either 0.4 or 0.8 mM oleate. Following 20-min perfusion at normal workload (i.e., 100 cm H(2)O afterload), hearts were challenged with increased workload (140 cm H(2)O afterload plus 1 microM epinephrine). In the presence of 0.4 mM oleate, myocardial metabolism exhibited a marked circadian rhythm, with decreased rates of glucose oxidation, increased rates of lactate release, decreased glycogenolysis capacity, and increased channeling of oleate into nonoxidative pathways during the light phase. Rat hearts also exhibited a modest circadian rhythm in responsiveness to the workload challenge when perfused in the presence of 0.4 mM oleate, with increased myocardial oxygen consumption at the dark-to-light phase transition. However, rat hearts perfused in the presence of 0.8 mM oleate exhibited a markedly blunted contractile function response to the workload challenge during the light phase. In conclusion, these studies expose marked circadian rhythmicities in myocardial oxidative and nonoxidative metabolism as well as responsiveness of the rat heart to changes in workload and fatty acid availability.     

Yeast dynamin and Ypt6 function in parallel for the endosome‐to‐Golgi retrieval of Snc1

Protein recycling is an important cellular process required for cell homeostasis. Results from prior studies have shown that vacuolar sorting protein‐1 (Vps1), a dynamin homolog in yeast, is implicated in protein recycling from the endosome to the trans‐Golgi Network (TGN). However, the function of Vps1 in relation to Ypt6, a master GTPase in the recycling pathway, remains unknown. The present study reveals that Vps1 physically interacts with Ypt6 if at least one of them is full‐length. We found that overexpression of full‐length Vps1, but not GTP hydrolysis‐defective Vps1 mutants, is sufficient to rescue abnormal phenotypes of Snc1 distribution provoked by the loss of Ypt6, and vice versa. This suggests that Vps1 and Ypt6 function in parallel pathways instead of in a sequential pathway and that GTP binding/hydrolysis of Vps1 is required for proper traffic of Snc1 toward the TGN. Additionally, we identified two novel Vps1‐binding partners, Vti1 and Snc2, which function for the endosome‐derived vesicle fusion at the TGN. Taken together, the present study demonstrates that Vps1 plays a role in later stages of the endosome‐to‐TGN traffic.     

Girdling increases survival and growth of emerald ash borer larvae on Manchurian ash

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A luminescent assay for real-time measurements of receptor endocytosis in living cells

Ligand-mediated endocytosis is a key autoregulatory mechanism governing the duration and intensity of signals emanating from cell surface receptors. Due to the mechanistic complexity of endocytosis and its emerging relevance in disease, simple methods capable of tracking this dynamic process in cells have become increasingly desirable. We have developed a bioluminescent reporter technology for real-time analysis of ligand-mediated receptor endocytosis using genetic fusions of NanoLuc luciferase with various G-protein-coupled receptors (GPCRs). This method is compatible with standard microplate formats, which should decrease work flows for high-throughput screens. This article also describes the application of this technology to endocytosis of epidermal growth factor receptor (EGFR), demonstrating potential applicability of the method beyond GPCRs.     

Modular color evolution facilitated by a complex nanostructure in birds

The way in which a complex trait varies, and thus evolves, is critically affected by the independence, or modularity, of its subunits. How modular designs facilitate phenotypic diversification is well studied in nonornamental (e.g., cichlid jaws), but not ornamental traits. Diverse feather colors in birds are produced by light absorption by pigments and/or light scattering by nanostructures. Such structural colors are deterministically related to the nanostructures that produce them and are therefore excellent systems to study modularity and diversity of ornamental traits. Elucidating if and how these nanostructures facilitate color diversity relies on understanding how nanostructural traits covary, and how these traits map to color. Both of these remain unknown in an evolutionary context. Most dabbling ducks (Anatidae) have a conspicuous wing patch with iridescent color caused by a two‐dimensional photonic crystal of small (100–200 nm) melanosomes. Here, we ask how this complex nanostructure affects modularity of color attributes. Using a combination of electron microscopy, spectrophotometry, and comparative methods, we show that nanostructural complexity causes functional decoupling and enables independent evolution of different color traits. These results demonstrate that color diversity is facilitated by how nanostructures function and may explain why some birds are more color‐diverse than others.     

Foraging a new trail with northern fur seals (Callorhinus ursinus): Lactating seals from islands with contrasting population dynamics have different foraging strategies,and forage at scales previously unrecognized by GPS interpolated dive data

We reconstructed the foraging tracks of lactating northern fur seals (Callorhinus ursinus) from two eastern Bering Sea islands (St. Paul Island and Bogoslof Island) using linear interpolation between GPS locations recorded at a maximum of four times per hour and compared it to tri‐axial accelerometer and magnetometer data collected at 16 Hz to reconstruct pseudotracks between the GPS fixes. The high‐resolution data revealed distances swum per foraging trip were much greater than the distances calculated using linearly interpolated GPS tracks (1.5 times further for St. Paul fur seals and 1.9 times further for Bogoslof fur seals). First passage time metrics calculated from the high resolution data revealed that the optimal scale at which the seals searched for prey was 500 m (radius of circle searched) for fur seals from St. Paul Island that went off‐shelf, and 50 m for fur seals from Bogoslof Island and surprisingly, 50 m for fur seals from St. Paul that foraged on‐shelf. These area‐restricted search scales were significantly smaller than those calculated from GPS data alone (12 km for St. Paul and 6 km for Bogoslof) indicating that higher resolution movement data can reveal novel information about foraging behaviors that have important ecological implications.