Comparison of equine paranasal sinus trephination complications and outcome following standing computed tomography, radiography and sinoscopy guided approaches for the treatment of sinusitis.

OBJECTIVE: The recent availability of standing computed tomography (CT) for equine paranasal sinus disease has enhanced diagnosis and enabled more targeted surgery compared to radiography and sinoscopy. To date, there have been no studies which have critically evaluated the benefit of preoperative CT versus radiography and sinoscopy on complications and outcome in horses undergoing sinus trephination. STUDY DESIGN: Retrospective study. ANIMALS: A total of 229 equids. METHODS: The medical records of equids (229) presented for sinusitis treated via trephination that had CT, radiography and/or sinoscopy at time of surgery between 2009 and 2022 were reviewed. Outcome and complications were evaluated for six different pre- and intraoperative imaging modalities. RESULTS: The six groups did not differ in demographics or disease category, though equids with less weight (p = .0179) and shorter disease duration (p = .0075) were more likely to have radiography and sinoscopy based surgical planning. Short-term postoperative complications occurred in 30.1% and were higher in groups using preoperative CT imaging (p = .01), with hemorrhage being the most common surgical complication. Following initial trephination surgery, 57.0% (127/223) of cases resolved and there was no difference between the imaging groups. Final resolution after follow-up medical or surgical treatment increased to 94.6% (211/223) and was not different between the imaging groups or between primary or secondary sinusitis. Additional nasal fenestrations to improve sinonasal drainage, maxillary septal bulla fenestrations and trephinations to treat nasal conchal bullae were made in the CT groups. CLINICAL SIGNIFICANCE: CT provided additional diagnostic information and enabled different surgical approaches but did not improve resolution in this study population.

White matter, cognition and psychotic-like experiences in UK Biobank.

BACKGROUND: Psychotic-like experiences (PLEs) are risk factors for the development of psychiatric conditions like schizophrenia, particularly if associated with distress. As PLEs have been related to alterations in both white matter and cognition, we investigated whether cognition (g-factor and processing speed) mediates the relationship between white matter and PLEs. METHODS: We investigated two independent samples (6170 and 19 891) from the UK Biobank, through path analysis. For both samples, measures of whole-brain fractional anisotropy (gFA) and mean diffusivity (gMD), as indications of white matter microstructure, were derived from probabilistic tractography. For the smaller sample, variables whole-brain white matter network efficiency and microstructure were also derived from structural connectome data. RESULTS: The mediation of cognition on the relationships between white matter properties and PLEs was non-significant. However, lower gFA was associated with having PLEs in combination with distress in the full available sample (standardized ß = -0.053, p = 0.011). Additionally, lower gFA/higher gMD was associated with lower g-factor (standardized ß = 0.049, p < 0.001; standardized ß = -0.027, p = 0.003), and partially mediated by processing speed with a proportion mediated of 7% (p = < 0.001) for gFA and 11% (p < 0.001) for gMD. CONCLUSIONS: We show that lower global white matter microstructure is associated with having PLEs in combination with distress, which suggests a direction of future research that could help clarify how and why individuals progress from subclinical to clinical psychotic symptoms. Furthermore, we replicated that processing speed mediates the relationship between white matter microstructure and g-factor.

The feasibility and effectiveness of a novel online mental health literacy course in supporting university student mental health: a pilot study.

BACKGROUND: There is a need for effective universal approaches to promote and support university student mental health that are scalable and sustainable. In this pilot study we assess the feasibility and acceptability of a fully-digitalized, comprehensive mental health literacy course co-created with and tailored to the needs of undergraduate students. We also explore preliminary associations with mental health and positive behaviour change. METHODS: An accredited online mental health literacy course was developed using state-of-the-art pedagogical principles and a reverse mentorship approach. The course was offered as an interdisciplinary undergraduate elective. Students completed an online survey before and after the 12-week course that collected demographic information and assessed mental health knowledge, emotional self-awareness, mental health, stigma, and health-related behaviors using validated measures. Dependent group t-tests were used to compare pre- and post-course levels of knowledge, mental health, sleep quality and substance use. Mental health outcomes of students who completed the course were compared to an age and sex-matched sample of students not enrolled in the course and who completed the same survey measures over the same academic year. Multivariable linear regression was used to examine the effect of course participation on outcomes at follow-up. RESULTS: The course had good uptake and was positively reviewed by participants. Specifically, students found the course engaging, relevant, and applicable, and agreed they would recommend it to their peers. Among course participants there was improvement in mental health knowledge (p < 0.001) and emotional self-awareness (p = 0.02) at course completion. Compared to the matched comparison group, taking the course was associated with reduced alcohol (ß = - 0.41, p = 0.01) and cannabis use (ß = - 0.35, p = 0.03), and improved sleep quality (ß = 1.56, p = 0.09) at the end of the term. CONCLUSIONS: Findings suggest that delivering mental health literacy as an online accredited course may be an acceptable and effective way of promoting university student mental health through improved knowledge, emotional self-awareness, and healthy lifestyle choices. As the course is expanded to larger and more diverse student cohorts we will be able to further examine the short and long-term effectiveness of the course in supporting student mental health and the underlying mechanisms.

Associations of social cohesion and quality of life with objective and perceived built environments: a latent profile analysis among seniors.

BACKGROUND: Healthy aging requires support from local built and social environments. Using latent profile analysis, this study captured the multidimensionality of the built environment and examined relations between objective and perceived built environment profiles, neighborhood social cohesion and quality of life among seniors. METHODS: In total, 693 participants aged 66-97 were sampled from two US locales in 2005-2008 as part of the Senior Neighborhood Quality of Life Study (SNQLS). Perceived social cohesion and quality of life were assessed using validated surveys. Six objective (geographic information system (GIS)-based) and seven perceived built environment latent profiles generated in previous SNQLS publications were used for analyses. Mixed-effects models estimated social cohesion and quality of life separately as a function of the built environment profiles. RESULTS: More walkable and destination-rich perceived built environment profiles were associated with higher social cohesion and quality of life. Objective built environment profiles were not associated with social cohesion and only positively associated with quality of life in only one locale (Baltimore/DC). CONCLUSIONS: Latent profile analysis offered a comprehensive approach to assessing the built environment. Seniors who perceived their neighborhoods to be highly walkable and recreationally dense experienced higher neighborhood social cohesion and quality of life, which may set the stage for healthier aging.

Amoebic gill disease increases energy requirements and decreases hypoxia tolerance in Atlantic salmon (Salmo salar) smolts.

Globally, Atlantic salmon (Salmo salar Linnaeus) aquaculture is now routinely affected by amoebic gill disease (AGD; Neoparamoeba perurans). The disease proliferates throughout the summer and is implicated in decreasing tolerance of salmon to environmental perturbations, yet little empirical evidence exists to support these observations. Using salmon acclimated to 15 or 19 °C, our aim was to determine the effects of clinically light-moderate (industry-relevant) AGD on metabolism (MO2rest and MO2max), aerobic scope (MO2max - MO2rest), excess post-exercise oxygen consumption (EPOC), and hypoxia tolerance. An increase in MO2rest (~8% and ~ 13% increase within the 15 and 19 °C acclimation groups, respectively) with increasing disease signs demonstrated an increase in baseline energy requirements as the disease progressed. Conversely, MO2max remained stable at both temperatures (~364 mg O2 kg-1 h-1), resulting in a decline in aerobic scope by 13 and 19% in the 15 and 19 °C groups, respectively. There was evidence of a decrease in hypoxia tolerance as the dissolved oxygen concentrations at loss of equilibrium increased by ~8% with more severe lesion coverage of the gills. These results suggest an increase in basal energy requirements and reduction in hypoxia tolerance as AGD proliferates, lending support to the idea that AGD reduces environmental tolerance. However, the lack of an effect of acclimation temperature indicates that the temperature-disease interaction may be more complicated than currently thought.

Odderon Exchange from Elastic Scattering Differences between pp and pp[over ¯] Data at 1.96 TeV and from pp Forward Scattering Measurements.

We describe an analysis comparing the pp[over ¯] elastic cross section as measured by the D0 Collaboration at a center-of-mass energy of 1.96 TeV to that in pp collisions as measured by the TOTEM Collaboration at 2.76, 7, 8, and 13 TeV using a model-independent approach. The TOTEM cross sections, extrapolated to a center-of-mass energy of sqrt[s]=1.96 TeV, are compared with the D0 measurement in the region of the diffractive minimum and the second maximum of the pp cross section. The two data sets disagree at the 3.4σ level and thus provide evidence for the t-channel exchange of a colorless, C-odd gluonic compound, also known as the odderon. We combine these results with a TOTEM analysis of the same C-odd exchange based on the total cross section and the ratio of the real to imaginary parts of the forward elastic strong interaction scattering amplitude in pp scattering for which the significance is between 3.4σ and 4.6σ. The combined significance is larger than 5σ and is interpreted as the first observation of the exchange of a colorless, C-odd gluonic compound.

Comparison of bacterial diversity and distribution on the gills of Atlantic salmon (Salmo salar L.): an evaluation of sampling techniques.

AIMS: Assess bacterial diversity and richness in mucus samples from the gills of Atlantic salmon in comparison to preserved or fixed gill filament tissues. Ascertain whether bacterial diversity and richness are homogeneous upon different arches of the gill basket. METHODS AND RESULTS: Bacterial communities contained within gill mucus were profiled using 16S rRNA gene sequencing. No significant difference in taxa richness, alpha (P > 0·05) or beta diversity indices (P > 0·05) were found between the bacterial communities of RNAlater preserved gill tissues and swab-bound mucus. A trend of lower richness and diversity indices were observed in bacterial communities from posterior hemibranchs. CONCLUSIONS: Non-lethal swab sampling of gill mucus provides a robust representation of bacterial communities externally upon the gills. Bacterial communities from the fourth arch appeared to be the least representative overall. SIGNIFICANCE AND IMPACT OF THE STUDY: The external mucosal barriers of teleost fish (e.g. gill surface) play a vital role as a primary defence line against infection. While research effort on the role of microbial communities on health and immunity of aquaculture species continues, the collection and sampling processes to obtain these data require evaluation so methodologies are consistently applied across future studies that aim to evaluate the composition of branchial microbiomes.

The role of neuroticism in self-harm and suicidal ideation: results from two UK population-based cohorts.

BACKGROUND: Self-harm is common, debilitating and associated with completed suicide and increased all-cause mortality, but there is uncertainty about its causal risk factors, limiting risk assessment and effective management. Neuroticism is a stable personality trait associated with self-harm and suicidal ideation, and correlated with coping styles, but its value as an independent predictor of these outcomes is disputed. METHODS: Prior history of hospital-treated self-harm was obtained by record-linkage to administrative health data in Generation Scotland:Scottish Family Health Study (N = 15,798; self-harm cases = 339) and by a self-report variable in UK Biobank (N = 35,227; self-harm cases = 772). Neuroticism in both cohorts was measured using the Eysenck Personality Questionnaire-Short Form. Associations of neuroticism with self-harm were tested using multivariable regression following adjustment for age, sex, cognitive ability, educational attainment, socioeconomic deprivation, and relationship status. A subset of GS:SFHS was followed-up with suicidal ideation elicited by self-report (n = 3342, suicidal ideation cases = 158) and coping styles measured by the Coping Inventory for Stressful Situations. The relationship of neuroticism to suicidal ideation, and the role of coping style, was then investigated using multivariable logistic regression. RESULTS: Neuroticism was positively associated with hospital-associated self-harm in GS:SFHS (per EPQ-SF unit odds ratio 1.2 95% credible interval 1.1-1.2, pFDR 0.0003) and UKB (per EPQ-SF unit odds ratio 1.1 95% confidence interval 1.1-1.2, pFDR 9.8 × 10-17). Neuroticism, and the neuroticism-correlated coping style, emotion-oriented coping (EoC), were also associated with suicidal ideation in multivariable models. CONCLUSIONS: Neuroticism is an independent predictor of hospital-treated self-harm risk. Neuroticism and emotion-orientated coping styles are also predictive of suicidal ideation.

Nonlinear dynamics of solitary and optically injected two-element laser arrays with four different waveguide structures: a numerical study.

We study the nonlinear dynamics of solitary and optically injected two-element laser arrays with a range of waveguide structures. The analysis is performed with a detailed direct numerical simulation, where high-resolution dynamic maps are generated to identify regions of dynamic instability in the parameter space of interest. Our combined one- and two-parameter bifurcation analysis uncovers globally diverse dynamical regimes (steady-state, oscillation, and chaos) in the solitary laser arrays, which are greatly influenced by static design waveguiding structures, the amplitude-phase coupling factor of the electric field, i.e. the linewidth-enhancement factor, as well as the control parameter, e.g. the pump rate. When external optical injection is introduced to one element of the arrays, we show that the whole system can be either injection-locked simultaneously or display rich, different dynamics outside the locking region. The effect of optical injection is to significantly modify the nature and the regions of nonlinear dynamics from those found in the solitary case. We also show similarities and differences (asymmetry) between the oscillation amplitude of the two elements of the array in specific well-defined regions, which hold for all the waveguiding structures considered. Our findings pave the way to a better understanding of dynamic instability in large arrays of lasers.

Mapping bifurcation structure and parameter dependence in quantum dot spin-VCSELs.

We consider a modified version of the spin-flip model (SFM) that describes optically pumped quantum dot (QD) spin-polarized vertical-cavity surface-emitting lasers (VCSELs). Maps showing different dynamical regions and those consisting of various key bifurcations are constructed by direct numerical simulations and a numerical path continuation technique, respectively. A comparison between them clarifies the physical mechanism that governs the underlying dynamics as well as routes to chaos in QD spin-VCSELs. Detailed numerical simulations illustrate the role played by the capture rate from wetting layer (WL) to QD ground state, the gain parameter, and the amplitude-phase coupling. By tuning the aforementioned key parameters in turn we show how the dynamical regions evolve as a function of the intensity and polarization of the optical pump, as well as in the plane of the spin relaxation rate and linear birefringence rate, which is of importance in the design of spin lasers promising potential applications. By increasing the capture rate from WL to QD our simulation accurately describes the transition from the QD spin-VCSEL to the quantum well case, in agreement with a previous mathematical derivation, and thus validates the modified SFM equations.

Combined Forward-Backward Asymmetry Measurements in Top-Antitop Quark Production at the Tevatron.

The CDF and D0 experiments at the Fermilab Tevatron have measured the asymmetry between yields of forward- and backward-produced top and antitop quarks based on their rapidity difference and the asymmetry between their decay leptons. These measurements use the full data sets collected in proton-antiproton collisions at a center-of-mass energy of sqrt[s]=1.96 TeV. We report the results of combinations of the inclusive asymmetries and their differential dependencies on relevant kinematic quantities. The combined inclusive asymmetry is A_{FB}^{tt[over ¯]}=0.128±0.025. The combined inclusive and differential asymmetries are consistent with recent standard model predictions.

Measurement of the Effective Weak Mixing Angle in pp[over ¯]→Z/γ

We present a measurement of the effective weak mixing angle parameter sin^{2}θ_{eff}^{ℓ} in pp[over ¯]→Z/γ^{*}→µ^{+}µ^{-} events at a center-of-mass energy of 1.96 TeV, collected by the D0 detector at the Fermilab Tevatron Collider and corresponding to 8.6 fb^{-1} of integrated luminosity. The measured value of sin^{2}θ_{eff}^{ℓ}[µµ]=0.23016±0.00064 is further combined with the result from the D0 measurement in pp[over ¯]→Z/γ^{*}→e^{+}e^{-} events, resulting in sin^{2}θ_{eff}^{ℓ}[comb]=0.23095±0.00040. This combined result is the most precise measurement from a single experiment at a hadron collider and is the most precise determination using the coupling of the Z/γ^{*} to light quarks.

Genetic risk of major depressive disorder: the moderating and mediating effects of neuroticism and psychological resilience on clinical and self-reported depression.

BACKGROUND: Polygenic risk scores (PRS) for depression correlate with depression status and chronicity, and provide causal anchors to identify depressive mechanisms. Neuroticism is phenotypically and genetically positively associated with depression, whereas psychological resilience demonstrates negative phenotypic associations. Whether increased neuroticism and reduced resilience are downstream mediators of genetic risk for depression, and whether they contribute independently to risk remains unknown. METHODS: Moderating and mediating relationships between depression PRS, neuroticism, resilience and both clinical and self-reported depression were examined in a large, population-based cohort, Generation Scotland: Scottish Family Health Study (N = 4166), using linear regression and structural equation modelling. Neuroticism and resilience were measured by the Eysenck Personality Scale Short Form Revised and the Brief Resilience Scale, respectively. RESULTS: PRS for depression was associated with increased likelihood of self-reported and clinical depression. No interaction was found between PRS and neuroticism, or between PRS and resilience. Neuroticism was associated with increased likelihood of self-reported and clinical depression, whereas resilience was associated with reduced risk. Structural equation modelling suggested the association between PRS and self-reported and clinical depression was mediated by neuroticism (43-57%), while resilience mediated the association in the opposite direction (37-40%). For both self-reported and clinical diagnoses, the genetic risk for depression was independently mediated by neuroticism and resilience. CONCLUSIONS: Findings suggest polygenic risk for depression increases vulnerability for self-reported and clinical depression through independent effects on increased neuroticism and reduced psychological resilience. In addition, two partially independent mechanisms - neuroticism and resilience - may form part of the pathway of vulnerability to depression.

Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N=112 117).

Alcohol consumption has been linked to over 200 diseases and is responsible for over 5% of the global disease burden. Well-known genetic variants in alcohol metabolizing genes, for example, ALDH2 and ADH1B, are strongly associated with alcohol consumption but have limited impact in European populations where they are found at low frequency. We performed a genome-wide association study (GWAS) of self-reported alcohol consumption in 112 117 individuals in the UK Biobank (UKB) sample of white British individuals. We report significant genome-wide associations at 14 loci. These include single-nucleotide polymorphisms (SNPs) in alcohol metabolizing genes (ADH1B/ADH1C/ADH5) and two loci in KLB, a gene recently associated with alcohol consumption. We also identify SNPs at novel loci including GCKR, CADM2 and FAM69C. Gene-based analyses found significant associations with genes implicated in the neurobiology of substance use (DRD2, PDE4B). GCTA analyses found a significant SNP-based heritability of self-reported alcohol consumption of 13% (se=0.01). Sex-specific analyses found largely overlapping GWAS loci and the genetic correlation (rG) between male and female alcohol consumption was 0.90 (s.e.=0.09, P-value=7.16 × 10-23). Using LD score regression, genetic overlap was found between alcohol consumption and years of schooling (rG=0.18, s.e.=0.03), high-density lipoprotein cholesterol (rG=0.28, s.e.=0.05), smoking (rG=0.40, s.e.=0.06) and various anthropometric traits (for example, overweight, rG=-0.19, s.e.=0.05). This study replicates the association between alcohol consumption and alcohol metabolizing genes and KLB, and identifies novel gene associations that should be the focus of future studies investigating the neurobiology of alcohol consumption.

Compression socks and the effects on coagulation and fibrinolytic activation during marathon running.

PURPOSE: Compression socks are frequently used in the treatment and prevention of lower-limb pathologies; however, when combined with endurance-based exercise, the impact of compression socks on haemostatic activation remains unclear. OBJECTIVES: To investigate the effect of wearing compression socks on coagulation and fibrinolysis following a marathon. METHODS: Sixty-seven participants [43 males (mean ± SD: age: 46.7 ± 10.3 year) and 24 females (age: 40.0 ± 11.0 year)] were allocated into a compression (SOCK, n = 34) or control (CONTROL, n = 33) group. Venous blood samples were obtained 24 h prior to and immediately POST-marathon, and were analyzed for thrombin-anti-thrombin complex (TAT), tissue factor (TF), tissue factor pathway inhibitor (TFPI), and D-Dimer. RESULTS: Compression significantly attenuated the post-exercise increase in D-Dimer compared to the control group [median (range) SOCK: + 9.02 (- 0.34 to 60.7) ng/mL, CONTROL: + 25.48 (0.95-73.24) ng/mL]. TF increased following the marathon run [median (range), SOCK: + 1.19 (- 7.47 to 9.11) pg/mL, CONTROL: + 3.47 (- 5.01 to 38.56) pg/mL] in all runners. No significant post-exercise changes were observed for TAT and TFPI. CONCLUSIONS: While activation of coagulation and fibrinolysis was apparent in all runners POST-marathon, wearing compression socks was shown to reduce fibrinolytic activity, as demonstrated by lower D-Dimer concentrations. Compression may reduce exercise-associated haemostatic activation when completing prolonged exercise.

Secure communication systems based on chaos in optically pumped spin-VCSELs.

We report on a master and slave configuration consisting of two optically pumped spin-vertical-cavity surface-emitting lasers for chaos synchronization and secure communication. Under appropriate conditions, high-quality chaos synchronization is achieved. We propose two encryption schemes, where either the pump magnitude or polarization is modulated. The results show that these allow for Gb/s transmission of secure data, but exhibit different features: one indicates that the message can be recovered by the total intensity, but not the polarization components, whereas the other shows that the message can be better or exclusively retrieved from the polarization components at high bit rates.

High frequency continuous birefringence-induced oscillations in spin-polarized vertical-cavity surface-emitting lasers.

Sustained, large amplitude and tunable birefringence-induced oscillations are obtained in a spin-vertical cavity surface-emitting laser (spin-VCSEL). Experimental evidence is provided using a spin-VCSEL operating at 1300 nm, under continuous-wave optical pumping and at room temperature. Numerical and stability analyses are performed to interpret the experiments and to identify the combined effects of pump ellipticity, spin relaxation rate, and cavity birefringence. Importantly, the frequency of the induced oscillations is determined by the device's birefringence rate, which can be tuned to very large values. This opens the path for ultrafast spin-lasers operating at record frequencies exceeding those possible in traditional semiconductor lasers and with ample expected impact in disparate disciplines (e.g., datacomms, spectroscopy).

Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci.

Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10(-15)) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ∼1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.

Landscape genetics informs mesohabitat preference and conservation priorities for a surrogate indicator species in a highly fragmented river system.

Poor dispersal species represent conservative benchmarks for biodiversity management because they provide insights into ecological processes influenced by habitat fragmentation that are less evident in more dispersive organisms. Here we used the poorly dispersive and threatened river blackfish (Gadopsis marmoratus) as a surrogate indicator system for assessing the effects of fragmentation in highly modified river basins and for prioritizing basin-wide management strategies. We combined individual, population and landscape-based approaches to analyze genetic variation in samples spanning the distribution of the species in Australia's Murray-Darling Basin, one of the world's most degraded freshwater systems. Our results indicate that G. marmoratus displays the hallmark of severe habitat fragmentation with notably scattered, small and demographically isolated populations with very low genetic diversity-a pattern found not only between regions and catchments but also between streams within catchments. By using hierarchically nested population sampling and assessing relationships between genetic uniqueness and genetic diversity across populations, we developed a spatial management framework that includes the selection of populations in need of genetic rescue. Landscape genetics provided an environmental criterion to identify associations between landscape features and ecological processes. Our results further our understanding of the impact that habitat quality and quantity has on habitat specialists with similarly low dispersal. They should also have practical applications for prioritizing both large- and small-scale conservation management actions for organisms inhabiting highly fragmented ecosystems.

Mapping transmembrane residues of proteinase activated receptor 2 (PAR2) that influence ligand-modulated calcium signaling.

Proteinase-activated receptor 2 (PAR2) is a G protein-coupled receptor involved in metabolism, inflammation, and cancers. It is activated by proteolysis, which exposes a nascent N-terminal sequence that becomes a tethered agonist. Short synthetic peptides corresponding to this sequence also activate PAR2, while small organic molecules show promising PAR2 antagonism. Developing PAR2 ligands into pharmaceuticals is hindered by a lack of knowledge of how synthetic ligands interact with and differentially modulate PAR2. Guided by PAR2 homology modeling and ligand docking based on bovine rhodopsin, followed by cross-checking with newer PAR2 models based on ORL-1 and PAR1, site-directed mutagenesis of PAR2 was used to investigate the pharmacology of three agonists (two synthetic agonists and trypsin-exposed tethered ligand) and one antagonist for modulation of PAR2 signaling. Effects of 28 PAR2 mutations were examined for PAR2-mediated calcium mobilization and key mutants were selected for measuring ligand binding. Nineteen of twenty-eight PAR2 mutations reduced the potency of at least one ligand by >10-fold. Key residues mapped predominantly to a cluster in the transmembrane (TM) domains of PAR2, differentially influence intracellular Ca2+ induced by synthetic agonists versus a native agonist, and highlight subtly different TM residues involved in receptor activation. This is the first evidence highlighting the importance of the PAR2 TM regions for receptor activation by synthetic PAR2 agonists and antagonists. The trypsin-cleaved N-terminus that activates PAR2 was unaffected by residues that affected synthetic peptides, challenging the widespread practice of substituting peptides for proteases to characterize PAR2 physiology.