Modelling and simulation of biased agonism dynamics at a G protein-coupled receptor.

Theoretical models of G protein-coupled receptor (GPCR) concentration-response relationships often assume an agonist producing a single functional response via a single active state of the receptor. These models have largely been analysed assuming steady-state conditions. There is now much experimental evidence to suggest that many GPCRs can exist in multiple receptor conformations and elicit numerous functional responses, with ligands having the potential to activate different signalling pathways to varying extents-a concept referred to as biased agonism, functional selectivity or pluri-dimensional efficacy. Moreover, recent experimental results indicate a clear possibility for time-dependent bias, whereby an agonist's bias with respect to different pathways may vary dynamically. Efforts towards understanding the implications of temporal bias by characterising and quantifying ligand effects on multiple pathways will clearly be aided by extending current equilibrium binding and biased activation models to include G protein activation dynamics. Here, we present a new model of time-dependent biased agonism, based on ordinary differential equations for multiple cubic ternary complex activation models with G protein cycle dynamics. This model allows simulation and analysis of multi-pathway activation bias dynamics at a single receptor for the first time, at the level of active G protein (αGTP), towards the analysis of dynamic functional responses. The model is generally applicable to systems with NG G proteins and N* active receptor states. Numerical simulations for NG=N*=2 reveal new insights into the effects of system parameters (including cooperativities, and ligand and receptor concentrations) on bias dynamics, highlighting new phenomena including the dynamic inter-conversion of bias direction. Further, we fit this model to 'wet' experimental data for two competing G proteins (Gi and Gs) that become activated upon stimulation of the adenosine A1 receptor with adenosine derivative compounds. Finally, we show that our model can qualitatively describe the temporal dynamics of this competing G protein activation.

Inter and intra-population phenotypic and genotypic structuring in the European whitefish Coregonus lavaretus, a rare freshwater fish in Scotland.

This study revealed between-lake genetic structuring between Coregonus lavaretus collected from the only two native populations of this species in Scotland, U.K. (Lochs Eck and Lomond) evidenced by the existence of private alleles (12 in Lomond and four in Eck) and significant genetic differentiation (FST = 0·056) across 10 microsatellite markers. Juvenile C. lavaretus originating from eggs collected from the two lakes and reared in a common-garden experiment showed clear phenotypic differences in trophic morphology (i.e. head and body shape) between these populations indicating that these characteristics were, at least partly, inherited. Microsatellite analysis of adults collected from different geographic regions within Loch Lomond revealed detectable and statistically significant but relatively weak genetic structuring (FST = 0·001-0·024) and evidence of private alleles related to the basin structure of the lake. Within-lake genetic divergence patterns suggest three possibilities for this observed pattern: (1) differential selection pressures causing divergence into separate gene pools, (2) a collapse of two formerly divergent gene pools and (3) a stable state maintained by balancing selection forces resulting from spatial variation in selection and lake heterogeneity. Small estimates of effective population sizes for the populations in both lakes suggest that the capacity of both populations to adapt to future environmental change may be limited.

A new genus and species of Cyproideidae (Crustacea: Peracarida: Amphipoda) from a tropical coral reef, SE Gulf of Mexico.

Sisalia carricarti new genus, new species, is described on specimens collected from the Sisal Coral Reef System, Southern Gulf of Mexico, Mexico. The new genus is most morphologically similar to the genus Paracyproidea, but can be distinguished by the article 2 of antenna 2 peduncle, the peduncle of the uropods and length of rami, and telson. Also, the new genus can be distinguished from the rest 18 genera of the family Cyproideidae by the following characteristics: 3-articulate mandible palp, mandible molar big and triturative; palp on maxilla 2 uniarticulate; article 2 of pereopods 3-7 rectilinear, and urosomites 1-3 not elongated. Sisalia carricarti new genus, new species, represents the second known genus and third species of cyproideid amphipods documented from the Inter-American Sea (Gulf of Mexico and Caribbean Sea), and the 19th genus and 44th species of the world cyproideid fauna. The more significant morphological characters and the geographical distribution of the 19 known genera of cyproideid amphipods are also pointed out.

A new bathyal species of Pardaliscoides (Amphipoda, Amphilochidea, Pardaliscidae) from off the southwestern Gulf of Mexico.

A new species of pardaliscid amphipod is described and illustrated from a single male specimen collected from bathyal sediments (2125 m depth) in the southern Gulf of Mexico. The new species is morphologically closest to Pardaliscoides fictotelson Barnard, 1966, previously documented from Southern California, at 218 m depth. The new pardaliscid differs from other species in the genus in having antenna 1 with a 10-articulate accessory flagellum; maxilliped palp very long; pereopods 5-7 elongate, slender; basis pereopod 7 expanded; telson with a short U-shaped cleft and pointed lobes; uropods 1-2 outer ramus curved, peduncle flat, longer than rami; uropod 3 rami flat, fleshy-lined, with marginal distal short robust setae. An identification key for all known species in the Pardaliscoides genus is also provided. The new species increase the number of Pardaliscoides species documented to six worldwide.

Are phenotypic traits useful for differentiating among a priori Coregonus taxa?

A key for three putative species apparently found in three geographic areas, i.e. Coregonus clupeoides (in Scotland), Coregonus stigmaticus (in England), and Coregonus pennantii (in Wales) given in a recent review was tested quantitatively using 544 individuals from nine populations. The classification success of the key was very low (27%). It was concluded that there is currently no robust evidence for the recognition of the three putative species. Furthermore, the use of phenotypic characters alone to distinguish putative species in postglacial fish species such as those of the genus Coregonus that show homoplasy in many of these traits is questioned. In the absence of further evidence, it was concluded that a single highly variable species best describes the pattern of phenotypic variation in these U.K. populations. On this basis it is argued that taxonomic subdivision of U.K. European coregonids is inappropriate and that Coregonus lavaretus should prevail as the species name applicable to all populations.

A new deep-sea species of Vemana J.L. Barnard, 1964 (Amphipoda, Amphilochidea, Vemanidae) from off southern Gulf of Mexico.

Vemanidae Lowry & Myers, 2017, is an amphipod family restricted to the world's deep waters, with four benthic species inhabiting both bathyal and abyssal zones from the Caribbean Sea, South California, and the Mozambique Channel. During an oceanographic campaign carried out in the southern Gulf of Mexico, a single male specimen of a new species of Vemana J.L. Barnard, 1964 was collected from the deep-sea soft bottom, which is described in detail herein. The new species mainly differs from those four Vemana species by coxa 4 posteroventral corner prolonged forming an acute tooth, basis posterior margin of pereopod 7 with 6 evident teeth, antenna 1 flagellar article 1 lower margin with callynophore, and first urosome segment convex with a diminutive hump. The new species is morphologically closest to Vemana lizata Barnard, 1964, which was collected from the Caribbean Sea at 4077 m depth. Besides, a dichotomous key for the identification of the 5 known Vemana species worldwide is provided.

Environmental factors associated with genetic and phenotypic divergence among sympatric populations of Arctic charr (Salvelinus alpinus).

The mechanisms by which phenotypic and genetic divergence may occur among sympatric, conspecific populations have been widely discussed but are still not well understood. Possible mechanisms include assortative mating based on morphology or variation in the reproductive behaviour of phenotypes, and both have been suggested to be relevant to the differentiation of salmonid populations in post-glacial lakes. Here, we studied Arctic charr (Salvelinus alpinus) in Windermere, where putative populations are defined by spatial and temporal variation in spawning. Genetic differentiation was assessed based on nine microsatellite loci, and phenotypic variation was assessed from morphometric characters. We test hypotheses about the relative role of morphology, spawning season and spawning habitat in the evolution of genetic divergence among these populations. Distinct from other lake systems, we find that both morphological and genetic differentiation are restricted primarily to one of two interconnecting basins, that genetic and morphological differentiation are decoupled in this lake and that both phenotype and environment have changed over the last 20 years. The implication is that breeding habitat plays a primary role in isolating populations that differentiate by drift and that phenotypically plastic changes, potentially related to foraging specializations, have either become secondarily decoupled from the genetically defined populations or were never fundamental in driving the evolution of genetic diversity in the Windermere system.

A new deep-sea species of Epimeria Costa in Hope, 1851 (Amphipoda, Amphilochidea, Epimeriidae) from off southwestern Mexico.

A single ovigerous female specimen of a new species of Epimeria Costa in Hope, 1851 was collected from deep sea, off southwestern Mexico, in the eastern Pacific. Epimeria karamani sp. nov., is most similar to females of E. cora J.L. Barnard, 1971, E. pacifica Gurjanova, 1995 and Epimeria morronei Winfield, Ortiz Hendrickx, 2013. However, it differs from these species by: eyes long and slightly kidney-shaped; pleonite 3 strongly carinate, with dorsal tooth produced and acute; urosomite 1 with a wide mid-dorsal notch and a strong, upright blunt tooth; coxa 3 anterior margin slightly truncate and with two processes marginally; coxa 4 ventral margin linear, with facial granules and simple setae; gnathopods palm with distal bifid setae; telson straight medially, distal margin crenulate and with minute setae. The new species described herein increases the number of Epimeria species from the Pacific Ocean to 14, and from the eastern Pacific to three.

Investigation of first year biotic and abiotic influences on the recruitment of pike Esox lucius over 48 years in Windermere, UK.

Estimated pike Esox lucius recruitment varied by a factor of 16 for females from 1944 to 1991 and by a factor of 27 for males from 1943 to 1990 in Windermere, a temperate, mesotrophic U.K. lake. No significant stock-recruitment relationships were found, but analysis with general additive models (GAMs) revealed that early autumnal water temperature, strength and direction of the North Atlantic Oscillation displacement (corresponding to different climatic conditions in winter) and zooplankton abundance but above all, late summer water temperature were important explanatory variables over the entire time series. Female recruitment was also influenced by young-of-the-year winter temperature. There was no evidence that perch Perca fluviatilis year-class strength, lake level or the summer position of the Gulf Stream influenced recruitment. The fitted models explained up to c. 65% of the overall observed variation between years.

Sexual assault and psychiatric disorders among a community sample of women.

The authors examined the relationships between sexual assault and psychiatric disorders in a sample of 1,157 women 18-64 years old in the North Carolina site of the NIMH Epidemiologic Catchment Area Program. The results suggest that sexual assault is a risk factor for a number of psychiatric disorders. In addition, several characteristics of the assault among sexual assault victims were significantly related to one or more psychiatric disorders. However, there was no clear pattern relating characteristics of the assault to the risk of specific psychiatric disorders.

PIP: This paper examines the relationships between sexual assault and psychiatric disorders, as well as the extent to which characteristics of the sexual assault affected these relationships. Data were collected from a sample of 1157 women 18-64 years old in the North Carolina site of the National Institute of Mental Health Epidemiologic Catchment Area Program. Findings revealed that sexual assault was a risk factor for a number of psychiatric disorders but more so for some than for others. Major depression, alcohol abuse or dependence, drug abuse or dependence, panic disorder, post-traumatic stress disorder, and obsessive-compulsive disorder were psychiatric disorders associated with sexual disorders. In addition, strong associations were seen in alcohol abuse or dependence, drug abuse or dependence, panic disorder, post-traumatic stress disorder, and obsessive-compulsive disorder. However, no clear pattern relating characteristics of the assault to the risk of specific psychiatric disorders was noted. Further study employing a very large sample is recommended.

Identification of borderline personality disorder with the NIMH Diagnostic Interview Schedule.

No lay-administered interviews are currently available to identify persons with borderline personality disorder. The authors studied 79 subjects with the NIMH Diagnostic Interview Schedule (DIS), a lay-administered interview, and the Diagnostic Interview for Borderline Patients (DIB) and used the results to construct a DIS-based diagnostic index to identify borderline personality disorder. Using the clinician-administered DIB as the diagnostic standard, the authors found that the DIS borderline index had a sensitivity of 85.7%, a specificity of 86.2%, and a kappa of 0.67. The DIS borderline index is a promising extension of the DIS that will facilitate studies of borderline personality disorder in clinical and community settings.

Epidemiologic data and planning mental health services. A tale of two surveys.

The Epidemiologic Catchment Area Program (ECA) is the most comprehensive community and institutionalized epidemiologic data base currently available for mental health service planning. In this report, the authors compare the ECA with a previous community survey used to plan mental health services--the Stirling County Study--in terms of conceptual framework, research design, results and implementation of service planning. Familiarity with the Stirling County Study can inform users of ECA data regarding the strengths and weaknesses of the ECA data for health services research.

Detached concern and death anxiety of first-year medical students: before and after the gross anatomy course.

The purpose of this study was to gather data from first-year medical students prior to their taking gross anatomy and again at the end of the course to determine if changes occur regarding death anxiety and detached concern toward patients. Chi-square and t-tests were used to assess statistical significance. From the 84 students for whom we had data both prior to and after gross anatomy, only the sociodemographic variable of sex was consistently related to the two dependent variables. Women reported more death anxiety prior to and after the gross anatomy course and were more likely to disagree with the need for detached concern.