Geographic proximity is associated with transmission of suicidal behaviour among siblings.

OBJECTIVE: The aim of this study was to clarify the role of 'contagion', or social transmission, in risk of suicidal behaviour (SB) among siblings. METHODS: We followed Swedish sibling pairs until one of them (S1; N = 111,848) was registered for a suicide attempt or completion. We tested the effect of geographic proximity between siblings on risk of a first SB registration of S1's sibling (S2). To control for familial confounding, we conducted complementary analyses of sibling trios (N = 701), comparing risk in different siblings as a function of their respective proximity to S1. RESULTS: The best-fitting model across sibling pairs included an effect of distance between siblings (HR = 0.96, 95% CI = 0.93-0.99). Hazard ratios declined quickly up to 25 km and largely stabilized beyond 150 km. Across all pairs, a larger age difference between siblings was associated with reduced SB risk (HR = 0.96 95% CI = 0.93-0.98). Findings were consistent within the sibling trios. CONCLUSIONS: Consistent with the concept of suicide contagion, risk of suicidal behaviour subsequent to a sibling's suicide completion or attempt is higher as a function of sibling closeness. These findings are robust to potentially confounding familial factors.

Polygenic risk for severe psychopathology among Europeans is associated with major depressive disorder in Han Chinese women.

BACKGROUND: Previous studies have demonstrated that several major psychiatric disorders are influenced by shared genetic factors. This shared liability may influence clinical features of a given disorder (e.g. severity, age at onset). However, findings have largely been limited to European samples; little is known about the consistency of shared genetic liability across ethnicities. METHOD: The relationship between polygenic risk for several major psychiatric diagnoses and major depressive disorder (MDD) was examined in a sample of unrelated Han Chinese women. Polygenic risk scores (PRSs) were generated using European discovery samples and tested in the China, Oxford, and VCU Experimental Research on Genetic Epidemiology [CONVERGE (maximum N = 10 502)], a sample ascertained for recurrent MDD. Genetic correlations between discovery phenotypes and MDD were also assessed. In addition, within-case characteristics were examined. RESULTS: European-based polygenic risk for several major psychiatric disorder phenotypes was significantly associated with the MDD case status in CONVERGE. Risk for clinically significant indicators (neuroticism and subjective well-being) was also associated with case-control status. The variance accounted for by PRS for both psychopathology and for well-being was similar to estimates reported for within-ethnicity comparisons in European samples. However, European-based PRS were largely unassociated with CONVERGE family history, clinical characteristics, or comorbidity. CONCLUSIONS: The shared genetic liability across severe forms of psychopathology is largely consistent across European and Han Chinese ethnicities, with little attenuation of genetic signal relative to within-ethnicity analyses. The overall absence of associations between PRS for other disorders and within-MDD variation suggests that clinical characteristics of MDD may arise due to contributions from ethnicity-specific factors and/or pathoplasticity.

Genetic effects influencing risk for major depressive disorder in China and Europe.

Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.

SNP-based heritability estimates of the personality dimensions and polygenic prediction of both neuroticism and major depression: findings from CONVERGE.

Biometrical genetic studies suggest that the personality dimensions, including neuroticism, are moderately heritable (~0.4 to 0.6). Quantitative analyses that aggregate the effects of many common variants have recently further informed genetic research on European samples. However, there has been limited research to date on non-European populations. This study examined the personality dimensions in a large sample of Han Chinese descent (N=10 064) from the China, Oxford, and VCU Experimental Research on Genetic Epidemiology study, aimed at identifying genetic risk factors for recurrent major depression among a rigorously ascertained cohort. Heritability of neuroticism as measured by the Eysenck Personality Questionnaire (EPQ) was estimated to be low but statistically significant at 10% (s.e.=0.03, P=0.0001). In addition to EPQ, neuroticism based on a three-factor model, data for the Big Five (BF) personality dimensions (neuroticism, openness, conscientiousness, extraversion and agreeableness) measured by the Big Five Inventory were available for controls (n=5596). Heritability estimates of the BF were not statistically significant despite high power (>0.85) to detect heritabilities of 0.10. Polygenic risk scores constructed by best linear unbiased prediction weights applied to split-half samples failed to significantly predict any of the personality traits, but polygenic risk for neuroticism, calculated with LDpred and based on predictive variants previously identified from European populations (N=171 911), significantly predicted major depressive disorder case-control status (P=0.0004) after false discovery rate correction. The scores also significantly predicted EPQ neuroticism (P=6.3 × 10-6). Factor analytic results of the measures indicated that any differences in heritabilities across samples may be due to genetic variation or variation in haplotype structure between samples, rather than measurement non-invariance. Findings demonstrate that neuroticism can be significantly predicted across ancestry, and highlight the importance of studying polygenic contributions to personality in non-European populations.

A developmental model for alcohol use disorders in Swedish men.

BACKGROUND: Alcohol use disorder (AUD) is a classic multifactorial syndrome and it is critical to understand the diversity of the relevant risk factors and how they inter-relate over development. METHOD: We examined 21 risk factors for AUD in four developmental tiers reflecting (i) birth, (ii) childhood and early adolescence, (iii) late adolescence, and (iv) early adulthood in 47 414 Swedish men of whom 3907 (8.2%) were registered for AUD at or after age 25 with a mean length of follow-up of 33.9 (6.6) years. Structural equational model fitting was performed using Mplus. RESULTS: The best-fitting model provided a good fit to the data and explained 23.4% of the variance in AUD. The five strongest predictors were: externalizing behaviors, criminal behavior, father's alcohol consumption, genetic risk, and low educational attainment. Two developmentally early familial/genetic risk factors had substantial direct paths to AUD: father's alcohol consumption and genetic liability. Other broad developmental pathways to risk for AUD were evident: externalizing, psychosocial and internalizing. Overall, the externalizing pathway to AUD was the strongest. However, these pathways were substantially interwoven over time such that risk factors from one domain were commonly predicted by and/or predicted risk factors from the other broad domains of risk. CONCLUSION: AUD in men is an etiologically complex syndrome influenced by familial-genetic, psychosocial, internalizing, and especially externalizing risk factors that act and interact over development and have complicated mediational pathways.

A novel sibling-based design to quantify genetic and shared environmental effects: application to drug abuse, alcohol use disorder and criminal behavior.

BACKGROUND: Twin studies have been criticized for upwardly biased estimates that might contribute to the missing heritability problem. METHOD: We identified, from the general Swedish population born 1960-1990, informative sibships containing a proband, one reared-together full- or half-sibling and a full-, step- or half-sibling with varying degrees of childhood cohabitation with the proband. Estimates of genetic, shared and individual specific environment for drug abuse (DA), alcohol use disorder (AUD) and criminal behavior (CB), assessed from medical, legal or pharmacy registries, were obtained using Mplus. RESULTS: Aggregate estimates of additive genetic effects for DA, AUD and CB obtained separately in males and females varied from 0.46 to 0.73 and agreed with those obtained from monozygotic and dizygotic twins from the same population. Of 54 heritability estimates from individual classes of informative sibling trios (3 syndromes × 9 classes of trios × 2 sexes), heritability estimates from the siblings were lower, tied and higher than those from obtained from twins in 26, one and 27 comparisons, respectively. By contrast, of 54 shared environmental estimates, 33 were lower than those found in twins, one tied and 20 were higher. CONCLUSIONS: With adequate information, human populations can provide many methods for estimating genetic and shared environmental effects. For the three externalizing syndromes examined, concerns that heritability estimates from twin studies are upwardly biased or were not generalizable to more typical kinds of siblings were not supported. Overestimation of heritability from twin studies is not a likely explanation for the missing heritability problem.

A prospective longitudinal model predicting early adult alcohol problems: evidence for a robust externalizing pathway.

BACKGROUND: Risk factors for alcohol problems (AP) include biological and environmental factors that are relevant across development. The pathways through which these factors are related, and how they lead to AP, are optimally considered in the context of a comprehensive developmental model. METHOD: Using data from a prospectively assessed, population-based UK cohort, we constructed a structural equation model that integrated risk factors reflecting individual, family and peer/community-level constructs across childhood, adolescence and young adulthood. These variables were used to predict AP at the age of 20 years. RESULTS: The final model explained over 30% of the variance in liability to age 20 years AP. Most prominent in the model was an externalizing pathway to AP, with conduct problems, sensation seeking, AP at age 17.5 years and illicit substance use acting as robust predictors. In conjunction with these individual-level risk factors, familial AP, peer relationships and low parental monitoring also predicted AP. Internalizing problems were less consistently associated with AP. Some risk factors previously identified were not associated with AP in the context of this comprehensive model. CONCLUSIONS: The etiology of young adult AP is complex, influenced by risk factors that manifest across development. The most prominent pathway to AP is via externalizing and related behaviors. These findings underscore the importance of jointly assessing both biologically influenced and environmental risk factors for AP in a developmental context.

Genome-wide association data suggest ABCB1 and immune-related gene sets may be involved in adult antisocial behavior.

Adult antisocial behavior (AAB) is moderately heritable, relatively common and has adverse consequences for individuals and society. We examined the molecular genetic basis of AAB in 1379 participants from a case-control study in which the cases met criteria for alcohol dependence. We also examined whether genes of interest were expressed in human brain. AAB was measured using a count of the number of Antisocial Personality Disorder criteria endorsed under criterion A from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). Participants were genotyped on the Illumina Human 1M BeadChip. In total, all single-nucleotide polymorphisms (SNPs) accounted for 25% of the variance in AAB, although this estimate was not significant (P=0.09). Enrichment tests indicated that more significantly associated genes were over-represented in seven gene sets, and most were immune related. Our most highly associated SNP (rs4728702, P=5.77 × 10(-7)) was located in the protein-coding adenosine triphosphate-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1). In a gene-based test, ABCB1 was genome-wide significant (q=0.03). Expression analyses indicated that ABCB1 was robustly expressed in the brain. ABCB1 has been implicated in substance use, and in post hoc tests we found that variation in ABCB1 was associated with DSM-IV alcohol and cocaine dependence criterion counts. These results suggest that ABCB1 may confer risk across externalizing behaviors, and are consistent with previous suggestions that immune pathways are associated with externalizing behaviors. The results should be tempered by the fact that we did not replicate the associations for ABCB1 or the gene sets in a less-affected independent sample.

Alcohol consumption in men is influenced by qualitatively different genetic factors in adolescence and adulthood.

BACKGROUND: Alcohol consumption is influenced by genetic factors. Previous studies have examined the heritability of alcohol consumption, or related phenotypes, from adolescence into adulthood, frequently finding that total heritability changes over time. However, it remains unclear whether the same genes underlie liability to alcohol consumption across development versus whether novel risk genes become important over time. Method A population-based study of adult male twins (n=1790) born in Virginia, USA, retrospectively reported on their average monthly alcohol consumption from early adolescence through adulthood. We used twin modeling methods to explore genetic and environmental influences on alcohol consumption over time. RESULTS: One latent genetic factor accounted for the majority of the heritability in alcohol consumption during mid- to late adolescence, but its influence declined thereafter; from young adulthood forward, heritability was largely attributable to a second genetic factor. The total heritability of alcohol consumption increased from 0 at ages 12-14 years to 0.40 by ages 18-21 years. Shared environmental factors declined in influence over time. CONCLUSIONS: The heritability of alcohol consumption over time is dynamic both quantitatively and qualitatively. These results have important implications for gene identification endeavors. Furthermore, these findings could inform efforts to elucidate developmentally dynamic behaviors, such as antisocial behavior.

A population-based twin study of the genetic and environmental relationship of major depression, regular tobacco use and nicotine dependence.

BACKGROUND: Numerous epidemiological studies have reported a positive association between major depression (MD) and regular tobacco use (RU) or nicotine dependence (ND). However, few have used a genetically informative design to assess whether these traits share a common genetic and/or environmental liability. METHOD: We assessed MD, RU and ND in same-sex twins from the population-based Swedish Twin Registry. In males, we examined both cigarette use and snus (smokeless tobacco) use. We used structural equation modeling to examine the relationship between MD, RU, and ND given RU. RESULTS: The results suggest modest correlations between MD and RU, and between MD and ND. In males, the liability shared between MD and RU is solely genetic for both cigarettes and snus, while MD and ND share both genetic and unique environmental influences. The continuation to ND given RU differed considerably between cigarette and snus users. In females, both MD-RU and MD-ND relationships are partially attributable to genetic and unique environmental correlations. CONCLUSIONS: The relationship among MD, RU and ND is at least partially attributable to shared genetic and environmental risk factors. The genetic and environmental correlations between traits are modest. The nature of the shared liability differs by sex, and in males, by the type of tobacco product used. Differences between previous reports and results presented in the current study are suggestive of population differences in how MD and tobacco use inter-relate.

Ractopamine hydrochloride improves growth performance and carcass composition in immunocastrated boars, intact boars, and gilts.

The beta-agonist ractopamine is a dietary ingredient that improves growth and increases the lean mass with little change in fat mass in gilts and barrows. Limited data in boars indicate that dietary ractopamine may increase lean tissue and decrease fat deposition, whereas there are no data for immunocastrated boars. The aims of this investigation were 1) to assess whether the growth performance of all sexes could be maintained over 31 d by using a step-up dietary ractopamine feeding program of 5 mg/kg of ractopamine for the first 14 d, then increasing the dose to 10 mg/kg for a further 17 d, and 2) to determine if dietary ractopamine would increase lean mass in all sexes and decrease fat mass in boars and immunocastrated boars. The study involved 286 pigs randomized and proportionally allocated by breed into 24 groups of 11 or 12 pigs at 17 wk of age, with equal groups of boars, immunocastrated boars, and gilts. Dietary ractopamine decreased (P = 0.005) ADFI during the first 2 wk, particularly in the intact and immunocastrated boars, with the reduction in ADFI being maintained in the immunocastrated boars after the increment in dietary ractopamine. Daily BW gain was not altered by dietary ractopamine during the first 2 wk, but was increased (P < 0.001) after the increment in dietary ractopamine. Dietary ractopamine decreased (P < or = 0.033) feed conversion ratio in all sexes with the response being greater after the increase in dietary ractopamine. Carcass weight was increased (P < 0.001) by dietary ractopamine in all sexes, whereas back fat tended (P = 0.076) to be reduced in the immunocastrated boars. Dietary ractopamine increased (P = 0.018) lean tissue mass by 4.0, 4.8, and 6.5 kg in the intact boars, gilts, and immunocastrated boars, respectively. In the entire and immunocastrated boars, the increase in lean tissue was accompanied with a decrease (P = 0.004) in fat mass. There was little effect of dietary ractopamine on fat mass in gilts. However, carcass percent fat was decreased (P = 0.004) and percent lean increased (P = 0.006) in all sexes. Immunocastration caused a decrease in lean tissue mass and an increase in fat mass and an increase in ADFI in the last one-half of the study. Dietary ractopamine may decrease fat mass in intact and immunocastrated boars and offers an excellent means of maximizing the effects of immunocastration and minimizing the increase in fat mass sometimes observed in immunocastrated boars.

The plant availability of auto-cast platinum group elements.

The introduction of automobile catalysts has raised environmental concern, as this pollution control technology is also an emission source for platinum group elements (PGE). The main aim of this study was to assess soil and grass PGE concentrations in soils adjacent to five road networks. The soil and grass samples were collected from four distances at each site; they were 0, 1, 2 and 5 m from the road edges. The maximum soil Pt, Rh and Pd concentrations were measured at the road perimeters. Pd concentrations were much higher than Pt or Rh, possibly due to differences in its use, emission and/or soil chemistry. Rh and Pt soil concentrations accounted for 66 and 34% (P < 0.01) of the variability observed, respectively, in their plant concentrations. Grass Pd concentrations had no relationship with its total soil concentrations.

Farmyard point discharges and their influence on nutrient and labile carbon dynamics in a second order stream draining through a dairy unit.

Two small piped sources deriving from a single farmyard together with the receiving second order stream above and below the farmyard region were sampled over a two-year period. Although not measured directly, observations at the time of sampling suggested that maximum drain flow was about 2% of downstream base flow. Both point sources were flowing on each sampling occasion (~62) and usually had concentrations of phosphorus (P), nitrate (NO(3)-N) and biological oxygen demand (BOD) well above those from the upstream site. Individual sample concentrations ranged over more than two orders of magnitude for most determinants and a large proportion of the total P was present as soluble (inorganic and organic) and therefore labile forms. More than 70% of samples collected at the downstream site had concentrations that were >1.2 times those of the corresponding upstream site. On certain sampling occasions >80% of total dissolved phosphorus (TDP) and >90% of the BOD and NO(3) instantaneous load appeared to originate from the farmyard region with the composition of downstream samples being completely overwhelmed after the passage through the farmyard. Extrapolations using instantaneous loads suggest that the farmyard and adjacent areas contributed on average 25-30% of the total and dissolved annual downstream P load of 3 kg P ha(-1) and 1.7 kg P ha(-1), respectively. There was no clear relationship between the relative proportion of the contaminant loading originating from the farmyard region and hydrological events. This emphasises the potential localised significance that small, highly concentrated, continuous or semi-continuous farmyard sources can impact headwater streams during periods of low stream flow.

The distribution of automobile catalysts-cast platinum, palladium and rhodium in soils adjacent to roads and their uptake by grass.

The introduction of automobile catalysts has raised environmental concern, as this pollution control technology is also an emission source for the platinum group elements (PGE). The main aim of this study was to assess the concentrations of Pt, Pd, Rh and Au in soil and grass herbage collected adjacent to 5 roads. Soil and grass samples were collected from 4 fixed distances (0, 1, 2 and 5 m) from the road edge at each site. PGE and Au were determined by ICP-MS in all samples after acid digestion. The maximum soil Pt, Rh and Pd concentrations were measured at the road perimeters. Averaged across the sites, the Pt and Rh concentrations of 15.9+/-7.5 microg Pt kg(-1) and 22.40+/-4.73 microg Rh kg(-1) at 0-m distance decreased to 2.04+/-1.7 microg Pt kg(-1) and 3.51+/-1.96 microg Rh kg(-1), respectively at 5-m away from the roads. Pd concentrations were much higher than Pt or Rh, ranging from 120.8+/-12.0 microg Pd kg(-1) (0-m) to 84.2+/-10.9 microg Pd kg(-1) (5-m), possibly due to differences in its use, emission and/or soil chemistry. Au showed little or no change with distance from the roads. However, the average Au concentration of 18.98+/-0.98 microg Au kg(-1) provides clear evidence of some input possibly due to attrition of automobile electronics. No straightforward influence of traffic flow rates on PGE distribution was found. A combination of dispersal impeding local features and slow moving and stop-and-start traffic conditions or fast moving traffic with flat open spaces may have offset the expected impacts. Rh and Pt soil concentration accounted for 66% and 34% (P<0.01) of the variability observed, respectively in their plant concentrations. Grass Pd and Au concentrations had no relationship with their respective soil concentrations.

Reducing fluxes of faecal indicator compliance parameters to bathing waters from diffuse agricultural sources: the Brighouse Bay study, Scotland.

The European Water Framework Directive requires the integrated management of point and diffuse pollution to achieve 'good' water quality in 'protected areas'. These include bathing waters, which are regulated using faecal indicator organisms as compliance parameters. Thus, for the first time, European regulators are faced with the control of faecal indicator fluxes from agricultural sources where these impact on bathing water compliance locations. Concurrently, reforms to the European Union (EU) Common Agricultural Policy offer scope for supporting on-farm measures producing environmental benefits through the new 'single farm payments' and the concept of 'cross-compliance'. This paper reports the first UK study involving remedial measures, principally stream bank fencing, designed to reduce faecal indicator fluxes at the catchment scale. Considerable reduction in faecal indicator flux was observed, but this was insufficient to ensure bathing water compliance with either Directive 76/160/EEC standards or new health-evidence-based criteria proposed by WHO and the European Commission.

Effect of mixing soil aggregates on the phosphorus concentration in surface waters.

At any time, the phosphorus (P) concentration in surface waters is determined by a complex interaction of inputs of soluble P and sorption-desorption reactions of P with sediments. This study investigated what factors control P in solution when various soil aggregates were mixed, seen as being analogous to selective soil erosion events, transport, and mixing within river systems. Fifteen soils with widely differing properties were each separated into three aggregate size fractions (2-52 microm, 53-150 microm, and 151-2,000 microm). Resin P, water-soluble phosphorus (WSP), and the phosphorus buffer capacity (PBC = resin P/WSP) were measured for each aggregate size fraction and WSP was also measured for 11 mixes of the aggregate fractions. The smallest aggregates tended to be enriched with resin P relative to the larger aggregates and the whole soils, while the opposite was true for WSP. As the PBC was a function of resin P and WSP, the PBC was greatest in the 2- to 52-microm aggregate size fraction in most cases. When two aggregate size fractions were mixed, the measured WSP was always lower than the predicted WSP (i.e., the average of the WSP in the two individual aggregates), indicating that WSP released by one aggregate fraction could be resorbed by another aggregate fraction. This resorption of P may result in lower than expected solution P concentration in some surface waters. The strength with which an eroded aggregate can release or resorb P to or from solution is in part determined by that aggregate's PBC.

Calcite saturation in the River Dee, NE Scotland.

The spatial and temporal variations in calcite (calcium carbonate) solubility within the Dee basin of NE Scotland were assessed using water chemistry data gathered from a network of 59 sites monitored for water quality from June 1996 to May 1997. Calcite solubility, expressed in terms of a saturation index (SIcalcite), was determined from measured streamwater pH, Gran alkalinity and calcium concentrations and water temperature. In general, the waters of the Dee system are undersaturated with respect to calcite, though the saturation index is higher during the summer months indicating a dependency on flow conditions and biological activity. Under low-flow conditions, the streamwaters are dominated by water derived from the lower soil horizons and deeper groundwater stores and therefore, ions such as Gran alkalinity and calcium are at their highest concentrations as they are derived mainly from bedrock weathering. The influence of biological activity on the carbonate system is also evident as the observed pH and estimated EpCO2 values indicate strong seasonal patterns, with the highest pH and lowest EpCO2 values occurring during the summer low-flow periods. Only at three sites in the lowland region of the catchment, during the summer low-flow period, are the waters oversaturated. As such, the Dee system represents an extreme 'end-member' case when compared to many UK rivers that span both under- and oversaturated conditions during the year. Regression analysis highlights a systematic change in the SIcalcite-pH relationship in a broad east-west direction across the Dee system. At sites draining the relatively impermeable upland areas, the regression of SIcalcite against pH gives a straight line with a gradient in the range 1.6-2.4. Correspondingly, under the most extreme alkaline conditions found at sites draining lowland agricultural areas, a straight-line relationship exists but with a gradient of unity. It is concluded that these changes in the SIcalcite-pH relationship are due to variations in the bicarbonate system induced by the flow conditions and biological activity. Given the waters are undersaturated, then calcite precipitation and hence phosphorus co-precipitation cannot occur within the water column.

CD18 activation epitopes induced by leukocyte activation.

The cell surface adhesion molecule LFA-1 coordinates leukocyte trafficking and is a costimulatory molecule for T cell activation. We developed a panel of mAbs that recognize activation epitopes on the CD18 subunit, and show that stimulation of T lymphocytes appears to be accompanied by a conformational change in a subpopulation of LFA-1 that does not require ligand binding. Activation epitope up-regulation requires divalent cations, is sensitive to cellular signal transduction events, and correlates with cell adhesion. In addition, the stimulated appearance of these activation epitopes is absent in cell lines from patients with leukocyte adhesion deficiency-1/variant that has previously been shown to be defective in LFA-1 activation. Thus, these activation epitope Abs can be used to dissect signal transmission to CD18. Evidence suggests that these CD18 activation epitopes are induced early in cellular activation and are independent of actin rearrangement necessary for avid adhesion. We have also determined that function-blocking CD18 Abs inhibit the induction of activation epitopes. One activation epitope Ab binds to a site on CD18 distinct from that of the blocking Abs, indicating that the blocking Abs suppress a conformational change in LFA-1. We also find that these neoepitopes are present on rLFA-1 with high affinity for ICAM-1 and their binding is modulated in parallel with the affinity of LFA-1 for ICAM-1. Collectively, these neoepitope Abs identify a subpopulation of LFA-1 most likely with high affinity for ICAM-1 and necessary for LFA-1 function.

Modelling instream nitrogen variability in the Dee catchment, NE Scotland.

The Integrated Nitrogen in CAtchments model (INCA) was applied to the River Dee, Aberdeenshire, NE Scotland. To a first approximation the model was able to simulate the annual mean streamwater NO3-N concentrations observed along the length of the main channel. This provided the basis for using INCA to subsequently explore the effects of N deposition and land use management on streamwater NO3-N concentrations and loads. On an annual timescale, the model predictions suggest that NO3-N concentrations will decrease by 5% following a 20% reduction in fertiliser application. Furthermore, model results also suggest that a 50% increase in N deposition will cause a 15% increase in the streamwater NO3-N concentrations. The utility of INCA as a tool for catchment management is discussed, current limitations are highlighted and possible improvements are suggested.