Joint Multipoint Linkage Analysis of Multivariate Qualitative and Quantitative Traits. II. Alcoholism and Event-Related Potentials

The availability of robust quantitative biological markers that are correlated with qualitative psychiatric phenotypes can potentially improve the power of linkage methods to detect quantitative-trait loci influencing psychiatric disorders. We apply a variance-component method for joint multipoint linkage analysis of multivariate discrete and continuous traits to the extended pedigree data from the Collaborative Study on the Genetics of Alcoholism, in a bivariate analysis of qualitative alcoholism phenotypes and quantitative event-related potentials. Joint consideration of the DSM-IV diagnosis of alcoholism and the amplitude of the P300 component of the Cz event-related potential significantly increases the evidence for linkage of these traits to a chromosome 4 region near the class I alcohol dehydrogenase locus ADH3. A likelihood-ratio test for complete pleiotropy is significant, suggesting that the same quantitative-trait locus influences both risk of alcoholism and the amplitude of the P300 component.     

Seedling performance in a trioecious cactus,Pachycereus pringlei: Effects of maternity and paternity

We studied seed germination and the growth and survivorship of seedlings of females and hermaphrodites ofPachycereus pringlei (cardon), a Mexican columnar cactus whose geographically variable breeding system includes trioecy and gynodioecy. Results of a two-year field experiment conducted near Bahia Kino, Sonora, Mexico and a ten-month laboratory experiment were similar and did not support the hypothesis that seedlings of females outperform those of hermaphrodites. In the field, percent seed germination and 2-yr seedling survivorship averaged 66% and 95%, respectively and did not differ among six treatment classes. Seedlings of hermaphrodites generally were larger than those of females at the end of both experiments. Selfed seedlings of hermaphrodites did not grow more slowly than outcrossed seedlings of hermaphrodites or females. Hermaphrodite seedlings performed best when pollinated with hermaphrodite pollen; female seedlings performed best with male pollen. We conclude that superior seedling performance cannot explain why females are able to coexist with hermaphrodites in populations of this cactus. Instead, we postulate that greater annual seed production, which averaged 1.6 times higher in females than in hermaphrodites in two years, may be sufficient to allow females to co-occur with hermaphrodites in this large, longlived plant, especially if sex determination involves cytoplasmic-nuclear inheritance.     

Ecological correlates of anuran exercise physiology

Summary Studies of exercise physiology of anuran amphibians have led to the suggestion that there is a dichotomy between species that depend upon movement to escape from predators and species that utilize static defenses. This generalization has been based upon a limited taxonomic survey and it contrasts with morphological, ecological, and behavioral studies that have revealed diverse and complex interrelationships among these features of anuran biology. We tested the hypothesis of a dichotomy of physiological types among anurans by measuring aerobic and anaerobic metabolism during maximum exercise for 17 species representing seven families and a variety of ecological types and locomotor modes. All degrees of dependence upon aerobic and anaerobic power input were found among the 17 species and the variation did not follow phylogenetic divisions. No single, simple prediction of the predominant source of power utilized for activity by the anurans we studied is possible. Predator avoidance behavior was not significantly correlated with the metabolic pattern. Predatory mode (active versus passive searchers) and mode of locomotion (non-jumpers versus jumpers) were correlated with dependence upon aerobic energy production and with each other. Reproductive behavior is probably another associated factor. The diversity of modes of power input among anurans is great and is intimately linked with numerous features of a species' biology. Single-factor explanations of this physiological characteristic are not appropriate.     

Changes in the associations of race and rurality with SARS-CoV-2 infection,mortality, and case fatality in the United States from February 2020 to March 2021: A population-based cohort study

BackgroundWe examined whether key sociodemographic and clinical risk factors for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and mortality changed over time in a population-based cohort study.Methods and findingsIn a cohort of 9,127,673 persons enrolled in the United States Veterans Affairs (VA) healthcare system, we evaluated the independent associations of sociodemographic and clinical characteristics with SARS-CoV-2 infection (n = 216,046), SARS-CoV-2–related mortality (n = 10,230), and case fatality at monthly intervals between February 1, 2020 and March 31, 2021. VA enrollees had a mean age of 61 years (SD 17.7) and were predominantly male (90.9%) and White (64.5%), with 14.6% of Black race and 6.3% of Hispanic ethnicity. Black (versus White) race was strongly associated with SARS-CoV-2 infection (adjusted odds ratio [AOR] 5.10, [95% CI 4.65 to 5.59], p-value <0.001), mortality (AOR 3.85 [95% CI 3.30 to 4.50], p-value < 0.001), and case fatality (AOR 2.56, 95% CI 2.23 to 2.93, p-value < 0.001) in February to March 2020, but these associations were attenuated and not statistically significant by November 2020 for infection (AOR 1.03 [95% CI 1.00 to 1.07] p-value = 0.05) and mortality (AOR 1.08 [95% CI 0.96 to 1.20], p-value = 0.21) and were reversed for case fatality (AOR 0.86, 95% CI 0.78 to 0.95, p-value = 0.005). American Indian/Alaska Native (AI/AN versus White) race was associated with higher risk of SARS-CoV-2 infection in April and May 2020; this association declined over time and reversed by March 2021 (AOR 0.66 [95% CI 0.51 to 0.85] p-value = 0.004). Hispanic (versus non-Hispanic) ethnicity was associated with higher risk of SARS-CoV-2 infection and mortality during almost every time period, with no evidence of attenuation over time. Urban (versus rural) residence was associated with higher risk of infection (AOR 2.02, [95% CI 1.83 to 2.22], p-value < 0.001), mortality (AOR 2.48 [95% CI 2.08 to 2.96], p-value < 0.001), and case fatality (AOR 2.24, 95% CI 1.93 to 2.60, p-value < 0.001) in February to April 2020, but these associations attenuated over time and reversed by September 2020 (AOR 0.85, 95% CI 0.81 to 0.89, p-value < 0.001 for infection, AOR 0.72, 95% CI 0.62 to 0.83, p-value < 0.001 for mortality and AOR 0.81, 95% CI 0.71 to 0.93, p-value = 0.006 for case fatality). Throughout the observation period, high comorbidity burden, younger age, and obesity were consistently associated with infection, while high comorbidity burden, older age, and male sex were consistently associated with mortality. Limitations of the study include that changes over time in the associations of some risk factors may be affected by changes in the likelihood of testing for SARS-CoV-2 according to those risk factors; also, study results apply directly to VA enrollees who are predominantly male and have comprehensive healthcare and need to be confirmed in other populations.ConclusionsIn this study, we found that strongly positive associations of Black and AI/AN (versus White) race and urban (versus rural) residence with SARS-CoV-2 infection, mortality, and case fatality observed early in the pandemic were ameliorated or reversed by March 2021.

George Ioannou and co-workers study the distribution of SARS-CoV-2 infections and outcomes among the United States population.     

Neurovascular coupling and oximetry during epileptic events

Epilepsy is an abnormal brain state in which a large population of neurons is synchronously active, causing an enormous increase in metabolic demand. Recent investigations using high-resolution imaging techniques, such as optical recording of intrinsic signals and voltagesensitive dyes, as well as measurements with oxygen-sensitive electrodes have elucidated the spatiotemporal relationship between neuronal activity, cerebral blood volume, and oximetry in vivo. A focal decrease in tissue oxygenation and a focal increase in deoxygenated hemoglobin occurs following both interictal and ictal events. This “epileptic dip” in oxygenation can persist for the duration of an ictal event, suggesting that cerebral blood flow is inadequate to meet metabolic demand. A rapid focal increase in cerebral blood flow and cerebral blood volume also accompanies epileptic events; however, this increase in perfusion soon (>2 s) spreads to a larger area of the cortex than the excitatory change in membrane potential. Investigations in humans during neurosurgical operations have confirmed the laboratory data derived from animal studies. These data not only have clinical implications for the interpretation of noninvasive imaging studies such as positron emission tomography, single-photon emission tomography, and functional magnetic resonance imaging but also provide a mechanism for the cognitive decline in patients with chronic epilepsy.     

Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative

We conducted genomewide linkage analyses on 1,152 individuals from 250 families segregating for bipolar disorder and related affective illnesses. These pedigrees were ascertained at 10 sites in the United States, through a proband with bipolar I affective disorder and a sibling with bipolar I or schizoaffective disorder, bipolar type. Uniform methods of ascertainment and assessment were used at all sites. A 9-cM screen was performed by use of 391 markers, with an average heterozygosity of 0.76. Multipoint, nonparametric linkage analyses were conducted in affected relative pairs. Additionally, simulation analyses were performed to determine genomewide significance levels for this study. Three hierarchical models of affection were analyzed. Significant evidence for linkage (genomewide P<.05) was found on chromosome 17q, with a peak maximum LOD score of 3.63, at the marker D17S928, and on chromosome 6q, with a peak maximum LOD score of 3.61, near the marker D6S1021. These loci met both standard and simulation-based criteria for genomewide significance. Suggestive evidence of linkage was observed in three other regions (genomewide P<.10), on chromosomes 2p, 3q, and 8q. This study, which is based on the largest linkage sample for bipolar disorder analyzed to date, indicates that several genes contribute to bipolar disorder.     

An Accessory Agonist Binding Site Promotes Activation of α4β2* Nicotinic Acetylcholine Receptors

Neuronal nicotinic acetylcholine receptors containing α4, β2, and sometimes other subunits (α4β2* nAChRs) regulate addictive and other behavioral effects of nicotine. These nAChRs exist in several stoichiometries, typically with two high affinity acetylcholine (ACh) binding sites at the interface of α4 and β2 subunits and a fifth accessory subunit. A third low affinity ACh binding site is formed when this accessory subunit is α4 but not if it is β2. Agonists selective for the accessory ACh site, such as 3-[3-(3-pyridyl)-1,2,4-oxadiazol-5-yl]benzonitrile (NS9283), cannot alone activate a nAChR but can facilitate more efficient activation in combination with agonists at the canonical α4β2 sites. We therefore suggest categorizing agonists according to their site selectivity. NS9283 binds to the accessory ACh binding site; thus it is termed an accessory site-selective agonist. We expressed (α4β2)₂ concatamers in Xenopus oocytes with free accessory subunits to obtain defined nAChR stoichiometries and α4/accessory subunit interfaces. We show that α2, α3, α4, and α6 accessory subunits can form binding sites for ACh and NS9283 at interfaces with α4 subunits, but β2 and β4 accessory subunits cannot. To permit selective blockage of the accessory site, α4 threonine 126 located on the minus side of α4 that contributes to the accessory site, but not the α4β2 sites, was mutated to cysteine. Alkylation of this cysteine with a thioreactive reagent blocked activity of ACh and NS9283 at the accessory site. Accessory agonist binding sites are promising drug targets.