Disrupting and diversifying the values, voices and governance principles that shape biodiversity science and management.

With climate, biodiversity and inequity crises squarely upon us, never has there been a more pressing time to rethink how we conceptualize, understand and manage our relationship with Earth's biodiversity. Here, we describe governance principles of 17 Indigenous Nations from the Northwest Coast of North America used to understand and steward relationships among all components of nature, including humans. We then chart the colonial origins of biodiversity science and use the complex case of sea otter recovery to illuminate how ancestral governance principles can be mobilized to characterize, manage and restore biodiversity in more inclusive, integrative and equitable ways. To enhance environmental sustainability, resilience and social justice amid today's crises, we need to broaden who benefits from and participates in the sciences of biodiversity by expanding the values and methodologies that shape such initiatives. In practice, biodiversity conservation and natural resource management need to shift from centralized, siloed approaches to those that can accommodate plurality in values, objectives, governance systems, legal traditions and ways of knowing. In doing so, developing solutions to our planetary crises becomes a shared responsibility. This article is part of the theme issue 'Detecting and attributing the causes of biodiversity change: needs, gaps and solutions'.

The shadow model: how and why small choices in spatially explicit species distribution models affect predictions.

The use of species distribution models (SDMs) has rapidly increased over the last decade, driven largely by increasing observational evidence of distributional shifts of terrestrial and aquatic populations. These models permit, for example, the quantification of range shifts, the estimation of species co-occurrence, and the association of habitat to species distribution and abundance. The increasing complexity of contemporary SDMs presents new challenges-as the choices among modeling options increase, it is essential to understand how these choices affect model outcomes. Using a combination of original analysis and literature review, we synthesize the effects of three common model choices in semi-parametric predictive process species distribution modeling: model structure, spatial extent of the data, and spatial scale of predictions. To illustrate the effects of these choices, we develop a case study centered around sablefish (Anoplopoma fimbria) distribution on the west coast of the USA. The three modeling choices represent decisions necessary in virtually all ecological applications of these methods, and are important because the consequences of these choices impact derived quantities of interest (e.g., estimates of population size and their management implications). Truncating the spatial extent of data near the observed range edge, or using a model that is misspecified in terms of covariates and spatial and spatiotemporal fields, led to bias in population biomass trends and mean distribution compared to estimates from models using the full dataset and appropriate model structure. In some cases, these suboptimal modeling decisions may be unavoidable, but understanding the tradeoffs of these choices and impacts on predictions is critical. We illustrate how seemingly small model choices, often made out of necessity or simplicity, can affect scientific advice informing management decisions-potentially leading to erroneous conclusions about changes in abundance or distribution and the precision of such estimates. For example, we show how incorrect decisions could cause overestimation of abundance, which could result in management advice resulting in overfishing. Based on these findings and literature gaps, we outline important frontiers in SDM development.

Modeling Thrombin Generation in Plasma under Diffusion and Flow.

We investigate the capacity of published numerical models of thrombin generation to reproduce experimentally observed threshold behavior under conditions in which diffusion and/or flow are important. Computational fluid dynamics simulations incorporating species diffusion, fluid flow, and biochemical reactions are compared with published data for thrombin generation in vitro in 1) quiescent plasma exposed to patches of tissue factor and 2) plasma perfused through a capillary coated with tissue factor. Clot time is correctly predicted in individual cases, and some models qualitatively replicate thrombin generation thresholds across a series of tissue factor patch sizes or wall shear rates. Numerical results suggest that there is not a genuine patch size threshold in quiescent plasma-clotting always occurs given enough time-whereas the shear rate threshold observed under flow is a genuine physical limit imposed by flow-mediated washout of active coagulation factors. Despite the encouraging qualitative results obtained with some models, no single model robustly reproduces all experiments, demonstrating that greater understanding of the underlying reaction network, and particularly of surface reactions, is required. In this direction, additional simulations provide evidence that 1) a surface-localized enzyme, speculatively identified as meizothrombin, is significantly active toward the fluorescent thrombin substrate used in the experiments or, less likely, 2) thrombin is irreversibly inhibited at a faster-than-expected rate, possibly explained by a stimulatory effect of plasma heparin on antithrombin. These results highlight the power of simulation to provide novel mechanistic insights that augment experimental studies and build our understanding of complex biophysicochemical processes. Further validation work is critical to unleashing the full potential of coagulation models as tools for drug development and personalized medicine.

The Discovery of Electrokinetic Phenomena: Setting the Record Straight.

Electro-osmosis and electrophoresis were discovered by F. F. Reuss in Moscow in 1807. Or so the story goes. This Essay critically examines the contributions of three scientists to the discovery of electrokinetic phenomena. The evidence suggests that Reuss did indeed discover electro-osmosis, which takes its name (indirectly) from the work of Porrett. Contrary to current consensus, Gautherot made the earliest known observation of electrophoresis.

Microfluidic circuit analysis I: ion current relationships for thin slits and pipes.

Existing microfluidic circuit theories consider conservation of volume and conservation of total charge at each channel intersection (node) that exists within a circuit. However, in a strict sense conservation of number (or charge) for each ion species that is present should also be applied. To be able to perform such a conservation the currents due to the movement of each ion species (electrokinetic ion currents) that occur within each channel need to be known. Hence, we here present analytical and numerical methods for calculating these ion currents (and fluid flowrates) in Newtonian binary electrolyte solutions flowing within two-dimensional thin slits and pipes. Analytical results are derived in the limits of low potential, high potential, and thin double layers. We show that irrespective of double layer overlap, the Boltzmann distribution is valid provided that a local geometric mean is used for the reference ion concentration. While the real significance of the work lies in its application to multi-channel microfluidic circuit theory (see the accompanying paper of Biscombe et al. [1]), the present results show that even in single channels, ion current behaviour can be surprisingly complex.

Microfluidic circuit analysis II: implications of ion conservation for microchannels connected in series.

A mathematical framework for analysing electrokinetic flow in microchannel networks is outlined. The model is based on conservation of volume and total charge at network junctions, but in contrast to earlier theories also incorporates conservation of ion charge there. The model is applied to mixed pressure-driven/electro-osmotic flows of binary electrolytes through homogeneous microchannels as well as a 4:1:4 contraction-expansion series network. Under conditions of specified volumetric flow rate and ion currents, non-linear steady-state phenomena may arise: when the direction of the net co-ion flux is opposite to the direction of the net volumetric flow, two different fully developed, steady-state flow solutions may be obtained. Model predictions are compared with two-dimensional computational fluid dynamics (CFD) simulations. For systems where two steady states are realisable, the ultimate steady behaviour is shown to depend in part upon the initial state of the system.

Genome screen for quantitative trait loci underlying normal variation in femoral structure.

Femoral structure contributes to bone strength at the proximal femur and predicts hip fracture risk independently of bone mass. Quantitative components of femoral structure are highly heritable traits. To identify genetic loci underlying variation in these structural phenotypes, we conducted an autosomal genome screen in 309 white sister pairs. Seven structural variables were measured from femoral radiographs and used in multipoint sib-pair linkage analyses. Three chromosomal regions were identified with significant evidence of linkage (log10 of the odds ratio [LOD] > 3.6) to at least one femoral structure phenotype. The maximum LOD score of 4.3 was obtained for femur neck axis length on chromosome 5q. Evidence of linkage to chromosome 4q was found with both femur neck axis length (LOD = 3.9) and midfemur width (LOD = 3.5). Significant evidence of linkage also was found to chromosome 17q, with a LOD score of 3.6 for femur head width. Two additional chromosomal regions 3q and 19p gave suggestive (LOD > 2.2) evidence of linkage with at least two of the structure phenotypes. Chromosome 3 showed evidence of linkage with pelvic axis length (LOD = 3.1), midfemur width (LOD = 2.8), and femur head width (LOD = 2.3), spanning a broad (60 cm) region of chromosome 3q. Linkage to chromosome 19 was supported by two phenotypes, femur neck axis length (LOD = 2.8) and femur head width (LOD = 2.8). This study is the first genome screen for loci underlying variation in femoral structure and represents an important step toward identifying genes contributing to the risk of osteoporotic hip fracture in the general population.

Subtle changes among presymptomatic carriers of the Huntington's disease gene.

OBJECTIVES: To compare the neurological and psychometric characteristics of presymptomatic gene carriers and non-gene carriers who are at risk for developing Huntington's disease so as to characterise early signs of disease and to identify markers of neurological function that could be used to assess the impact of experimental therapies on the progression of disease, even among those who are clinically presymptomatic. METHODS: A sample of people at risk for Huntington's disease was genotyped and evaluated using subscales of the Wechsler adult intelligence scale-revised (WAIS-R), a quantified neurological rating scale, and computerised physiological measures including speed of movement and reaction time. RESULTS: Genotyping and clinical examination determined that 171 participants were presymptomatic gene carriers (PSGCs) and 414 participants were non-gene carriers (NGCs). The PSGCs performed significantly worse when compared with the NGCs on the digit symbol, picture arrangement, and arithmetic subscales of the WAIS-R (p<0.02) and for the physiological measures: button tapping, auditory reaction time, visual reaction time with decision, and movement time with and without decision (p<0.05). Although no PSGCs had sufficient neurological findings to warrant a diagnosis of Huntington's disease on clinical examination, the PSGCs had more frequent possible or definite abnormality for oculomotor function, chorea, muscle stretch reflexes, gait, and station stability, and rapid alternating movements (p

Genome screen for QTLs contributing to normal variation in bone mineral density and osteoporosis.

A major determinant of the risk for osteoporosis is peak bone mineral density (BMD), which is largely determined by genetic factors. We recently reported linkage of peak BMD in a large sample of healthy sister pairs to chromosome 11q12-13. To identify additional loci underlying normal variations in peak BMD, we conducted an autosomal genome screen in 429 Caucasian sister pairs. Multipoint LOD scores were computed for BMD at four skeletal sites. Chromosomal regions with LOD scores above 1.85 were further pursued in an expanded sample of 595 sister pairs (464 Caucasians and 131 African-Americans). The highest LOD score attained in the expanded sample was 3.86 at chromosome 1q21-23 with lumbar spine BMD. Chromosome 5q33-35 gave a LOD score of 2.23 with femoral neck BMD. At chromosome 6p11-12, the 464 Caucasian pairs achieved a LOD score of 2.13 with lumbar spine BMD. Markers within the 11q12-13 region continued to support linkage to femoral neck BMD, although the peak LOD score was decreased to 2.16 in the sample of 595 sibling pairs. Our study is the largest genome screen to date for genes underlying variations in peak BMD and represents an important step toward identifying genes contributing to osteoporosis in the general population.

Confirmation of subtle motor changes among presymptomatic carriers of the Huntington disease gene.

OBJECTIVE: To confirm that subtle changes in motor function and reaction time are present in presymptomatic individuals carrying the expanded Huntington disease (HD) allele. DESIGN: A case-control, double-blind study comparing presymptomatic HD gene carriers (PSGCs) and nongene carriers (NGCs) at risk for HD. SETTING: The Department of Medical and Molecular Genetics at a general clinical research center in a midwestern city. PARTICIPANTS: Two hundred sixteen individuals at risk for HD who were asymptomatic by self-report and who did not have manifest HD on results of clinical examination, including PSGCs (n = 61) and NGCs (n = 155). MEASURES: Molecular testing was used to determine the number of CAG repeats in the HD gene. A quantified neurologic examination and a battery of physiological measures of central nervous system function measuring speed of movement and reaction time were administered. RESULTS: On neurologic examination, the PSGCs exhibited significantly more definite or possible abnormalities than NGCs for overall oculomotor function, saccade velocity, optokinetic nystagmus, chorea of the extremities, and dystonia of the extremities (P<.05). The PSGCs also had significantly slower performance for auditory reaction time, visual reaction time, visual reaction time with decision, movement time, movement time with decision, and button-tapping time, compared with the NGCs (P<.05). CONCLUSIONS: Subtle changes in motor function, speed of movement, and reaction time are present in HD gene carriers who do not exhibit definite choreiform movements and who do not have sufficient signs to make a clinical diagnosis of HD. In addition, a trend toward slower speed of movement and reaction time was observed among this population as their neurologic abnormalities increased.

Sib pair linkage and association studies between bone mineral density and the interleukin-6 gene locus.

A major determinant of the risk for osteoporosis in later life is bone mineral density (BMD) attained during early adulthood. Bone mineral density is a complex trait that, presumably, is influenced by multiple genes. Interleukin-6 (IL-6) is an attractive candidate gene for osteoporosis susceptibility, because it has effects on bone cells and has been implicated in the pathogenesis of osteoporosis. Furthermore, previous investigators have identified an association between a 3' UTR polymorphism of the IL-6 gene and BMD. In this study, we searched for linkage and association between this IL-6 gene polymorphism and peak BMD in a large population (812 individuals) of healthy premenopausal sibpairs. Although previous investigators identified only 6 IL-6 alleles, we identified 17 alleles by modifying electrophoretic conditions and evaluating a very large population. We found no evidence for either linkage or association between the IL-6 gene locus and BMD of the spine or hip in either Caucasians or African Americans.

Analysis of heritability of hormonal responses to alcohol in twins: beta-endorphin as a potential biomarker of genetic risk for alcoholism.

BACKGROUND: Hormonal responses to alcohol have been reported to differ in subjects with and without a family history of alcoholism which suggests that alcohol-induced hormonal changes might be used to identify individuals who are at elevated genetic risk for developing alcoholism. However, before a biological response can be used as a marker of genetic risk for disease, it must first be demonstrated that the response is, in fact, heritable. The present study was designed to determine whether hormonal responses to alcohol are heritable. METHODS: The adrenocorticotropic hormone (ACTH), beta-endorphin (beta-E), cortisol (CORT), and prolactin (PRL) responses to alcohol were examined in male and female identical (monozygotic or MZ) and fraternal (dizygotic or DZ) twin pairs. Male subjects consumed 0.35 g ethanol/kg body weight (BW) and females consumed 0.325 g ethanol/kg BW in each of two alcohol drinking sessions administered 1 hr apart (total dose of 0.7 g/kg BW in males and 0.65 g/kg BW in females). Plasma hormone content was analyzed in samples collected before (resting conditions) and at 15, 60, 75, 120, 180, and 240 min after onset of drinking. Hormonal responses to alcohol were examined with twin analyses using the TWINAN90 program. A separate analysis was performed for each of the four hormones. A subset of subjects from each zygosity was seen on two separate occasions to establish retest reliability. Heritability of hormonal responses to alcohol was estimated using the intraclass correlation approach before and after removing the contribution of covariates that have the potential of influencing the plasma levels of these hormones. RESULTS: Resting plasma levels of all four hormones were within the expected range, and the beta-E, ACTH, and PRL responses to the alcohol challenge evidenced good test-retest reliability. Of the four hormones examined, the only one that showed significant heritability after alcohol drinking was beta-E. Heritability estimates were not altered for any of the four hormones after removal of the variance contributed by covariates, such as gender and age. CONCLUSIONS: Taken together with other recent findings, the results suggest that the beta-E response to alcohol may represent a new biomarker that can be used to identify individuals who are at elevated genetic risk for developing alcoholism.

Sibling pair linkage and association studies between bone mineral density and the insulin-like growth factor I gene locus.

A major determinant of the risk for osteoporosis in later life is bone mineral density (BMD) attained during early adulthood. BMD is a complex trait that presumably is influenced by multiple genes. Insulin-like growth factor I (IGF-I) is an attractive candidate gene for osteoporosis susceptibility, because IGF-I has marked effects on bone cells and has been implicated in the pathogenesis of osteoporosis. The IGF-I gene contains a microsatellite repeat polymorphism approximately 1 kb upstream from the IGF-I gene transcription start site, and previous investigators have found a higher prevalence of the 192/192 genotype of this polymorphism among men with idiopathic osteoporosis compared to controls. In this study we used this IGF-I polymorphism to test for an association between this polymorphism and BMD in our large population of premenopausal women (1 sister randomly chosen from 292 Caucasian and 71 African-American families). We also used this polymorphism to detect linkage to BMD elsewhere in the IGF-I gene or in a nearby gene using sibling pair linkage analysis in healthy premenopausal sister pairs (542 sibling pairs: 418 Caucasian and 124 African-American). Neither test provided any evidence of linkage or association between the IGF-I gene locus and spine or femoral neck BMD in Caucasians or African-Americans.

Longitudinal cognitive and motor changes among presymptomatic Huntington disease gene carriers.

OBJECTIVE: To determine whether longitudinal changes in cognitive and motor function can be detected among clinically presymptomatic individuals carrying the Huntington disease (HD) allele. DESIGN: A longitudinal, case-control, double-blind study comparing presymptomatic gene carriers and non-gene carriers at risk for HD examined an average of 3.7 years apart. SETTING: The Department of Medical and Molecular Genetics at a general clinic research center in Indianapolis, Ind. PARTICIPANTS: A sample of 43 at-risk individuals consisting of presymptomatic gene carriers (n = 12) and non-gene carriers (n = 31). MEASURES: Huntington disease gene status was determined by molecular testing of the HD gene. Subscales from the Wechsler Adult Intelligence Scale-Revised and a quantified neurologic rating scale were administered. RESULTS: Scores on the digit symbol subscale of the Wechsler Adult Intelligence Scale-Revised (P<.05) and 2 neurologic variables-optokinetic nystagmus (P<.01) and rapid alternating movements (P<.005)-declined more rapidly among presymptomatic gene carriers than among non-gene carriers. At follow-up examination, compared with nongene carriers, presymptomatic gene carriers had significantly lower scores on the digit symbol subscale (P = .02) and for 4 neurologic variables-rapid alternating movements (P<.005), optokinetic nystagmus (P<.001), overall ocular movements (P<.02), and chorea of the trunk (P<.02). CONCLUSIONS: Psychomotor speed, optokinetic nystagmus, and rapid alternating movements demonstrated significant decline early in the pathological process of HD. These results suggest that subtle worsening of psychomotor, oculomotor, and motor functions occurs before the onset of signs sufficient to make a clinical diagnosis in individuals who have inherited the HD allele.

The effect of apolipoprotein E epsilon4 in the relationships of smoking and drinking to cognitive function.

OBJECTIVES: To investigate the joint effect of the apolipoprotein E epsilon4 (APOE epsilon4), smoking and drinking on cognitive performance in a population-based longitudinal study of elderly men. DESIGN AND SETTING: The NHLBI Twin Study, a longitudinal cardiovascular study of World War II, white, male veterans. PARTICIPANTS: A total of 589 male participants in the third cardiovascular examination of this panel and aged 59-69 when assessed for cognitive function. OUTCOME MEASURES: Cognitive function assessed by the Mini-Mental State Examination, the Digit Symbol Substitution Test, the Benton Visual Retention Test, APOE epsilon4 allele frequency and cardiovascular disease (CVD) health status. RESULTS: For the sample as a whole, after adjustment for age, education and CVD, smoking was significantly associated with poor cognitive function (odds ratio (OR) = 2.0, 95% confidence interval (CI) 1.2-3.2, in current smokers compared with never smokers), whereas light drinking (one or fewer drinks per day) showed a protective effect (OR = 0.6, 95% CI 0.4-0.9 compared with abstainers). Stratification by APOE epsilon4 indicated that the protective effect of light drinking was stronger and the harmful effect of smoking was weaker among APOE epsilon4 carriers than among noncarriers. CONCLUSIONS: These data suggest a possible mediating effect of the APOE epsilon4 allele in the relation of smoking and drinking to cognitive function in the elderly.

A twin study of genetic influences on the acute adaptation of the EEG to alcohol.

A two-dose alcohol challenge protocol was used to study genetic influences on the acute adaptation of the EEG to alcohol in 53 monozygotic and 38 same-sex dizygotic Caucasian twin pairs averaging 30 years of age. Equal doses of alcohol were administered at 10:00 and 11:00 AM, yielding mean peak breath alcohol concentrations of 0.057% and 0.099%, respectively. Eyes-closed, resting EEG was recorded four times: at baseline; on the ascending limb of the overall experiment at a breath alcohol concentration (BrAC) near 0.06%; on the descending limb at a BrAC near the value when the subject's EEG was obtained on the ascending limb; and, finally, when the BrAC fell to 0.02%. Genetic analyses of log-transformed values of total spectral power (L10TSP) and spectral band power (L10SBP) were performed on EEG spectra averaged across all 17 scalp lead locations. After adjusting for body weight, a significant fraction of population variance in L10TSP was attributable to genetic influence: H2 values for TSP were 0.73, 0.72, and 0.73 at the three postalcohol EEG recordings, respectively. Similar findings pertained to each L10SBP at each postalcohol recording, except forthe delta band. The change in postethanol EEG power was examined for evidence that genes influence acute adaptations in brain function. Descending-minus-ascending limb L10TSP was normalized by the individual's ascending limb L10TSP to minimize nonalcohol-related effects that can influence both measurements. Earlier analyses of the same sample's initial EEG response to alcohol noted a substantial increase in the ascending limb EEG power, compared with baseline. Thus, positive values of the postethanol change denote a progression away from baseline attributable to acute sensitization to alcohol; negative values signify a return toward baseline values suggesting acute tolerance to alcohol. Genetic analysis of the normalized difference in L10TSP had a highly significant H2 value of 0.70, indicating that both acute tolerance and acute sensitization to alcohol may represent adaptations reflecting substantial heritable influence. Slightly smaller, but significant values of H2 for the normalized difference in L10SPB were observed for delta, alpha-slow and beta-slow frequency bands. In contrast, H2 for the differences between the final and ascending limb EEG power were not significant, except for the theta band. Thus, heritable drowsiness may have contributed to detection of genetic influences on acute adaptation, but represent a potential confound only in the theta band.

Linkage of a QTL contributing to normal variation in bone mineral density to chromosome 11q12-13.

Osteoporosis is a leading public health problem that is responsible for substantial morbidity and mortality. A major determinant of the risk for osteoporosis in later life is bone mineral density (BMD) attained during early adulthood. BMD is a complex trait that presumably is influenced by multiple genes. Recent linkage of three Mendelian BMD-related phenotypes, autosomal dominant high bone mass, autosomal recessive osteoporosis-pseudoglioma, and autosomal recessive osteopetrosis to chromosome 11q12-13 led us to evaluate this region to determine if the underlying gene(s) could also contribute to variation in BMD in the normal population. We performed a linkage study in a sample of 835 premenopausal Caucasian and African-American sisters to identify genes underlying BMD variation. A maximum multipoint LOD score of 3.50 with femoral neck BMD was obtained near the marker D11S987, in the same chromosomal region as the three Mendelian traits mentioned above. Our results suggest that the gene(s) underlying these Mendelian phenotypes also play a role in determining peak BMD in the normal population and are the first using linkage methods to establish a chromosomal location for a gene important in determining peak BMD. These findings support the hypothesis that a gene responsible for one or more of the rare Mendelian BMD traits linked to chromosome 11q12-13 has an important role in osteoporosis in the general population.

Influences of chorion type on saccadic eye movements in twins.

PURPOSE: The influence of genetic and prenatal environmental factors on characteristics of saccadic performance were evaluated in young monozygotic (MZ) twins (8-19 years old) of known chorion type. METHODS: Saccadic eye movements were recorded using an infrared system. Saccadic latency, accuracy, and parameters of amplitude-peak velocity exponential equation (main sequence) were quantified. RESULTS: Intraclass correlations of saccadic parameters differed significantly from zero for monochorionic and dichorionic MZ twins. The within-pair mean squares were significantly less, and intraclass correlations were significantly higher in monochorionic than in dichorionic twins for latency and were similar for other saccadic parameters (accuracy, slope of main sequence, and peak velocity for 15 degrees saccades). CONCLUSIONS: These findings confirmed previous reports that saccadic parameters of MZ twins are significantly correlated and indicated that similarity of these parameters seen in MZ twins may be driven both by genetic and by prenatal environmental factors.

Smooth pursuit in twins before and after alcohol ingestion.

PURPOSE: The influence of genetic factors on characteristics of smooth pursuit were evaluated in young adult monozygotic (MZ) and dizygotic (DZ) twins before and after the administration of a single dose of ethanol. METHODS: Sinusoidal pursuit was recorded using a scleral search coil at frequencies of 0.25 and 0.5 Hz before and after alcohol consumption. Pursuit gain, interval between saccades, saccadic accuracy, and saccadic amplitude were quantified. RESULTS: Alcohol consumption reduced pursuit gain and saccadic accuracy and increased the rate and amplitude of saccades. Before and after alcohol consumption, the intraclass correlations for MZ twins (rMZ) were highly significant for pursuit gain, interval between saccades, and saccade amplitude. Corresponding correlations for DZ twins (rDZ) were not significant. Heritability values were similar before and after alcohol ingestion. CONCLUSIONS: The disparity between rMZ and rDZ suggests either multiple gene interactions or common environmental influences for MZ twins, greater than those for DZ twins.