The total burden of rare,non-synonymous exome genetic variants is not associated with childhood or late-life cognitive ability

Human cognitive ability shows consistent, positive associations with fitness components across the life-course. Underlying genetic variation should therefore be depleted by selection, which is not observed. Genetic variation in general cognitive ability (intelligence) could be maintained by a mutation–selection balance, with rare variants contributing to its genetic architecture. This study examines the association between the total number of rare stop-gain/loss, splice and missense exonic variants and cognitive ability in childhood and old age in the same individuals. Exome array data were obtained in the Lothian Birth Cohorts of 1921 and 1936 (combined N = 1596). General cognitive ability was assessed at age 11 years and in late life (79 and 70 years, respectively) and was modelled against the total number of stop-gain/loss, splice, and missense exonic variants, with minor allele frequency less than or equal to 0.01, using linear regression adjusted for age and sex. In both cohorts and in both the childhood and late-life models, there were no significant associations between rare variant burden in the exome and cognitive ability that survived correction for multiple testing. Contrary to our a priori hypothesis, we observed no evidence for an association between the total number of rare exonic variants and either childhood cognitive ability or late-life cognitive ability.     

Banning Fisheries Discards Abruptly Has a Negative Impact on the Population Dynamics of Charismatic Marine Megafauna

Food subsidies have the potential to modify ecosystems and affect the provision of goods and services. Predictable Anthropogenic Food Subsidies (PAFS) modify ecosystems by altering ecological processes and food webs. The global concern over the effects of PAFS in ecosystems has led to development of environmental policies aimed at curbing the production or ultimately banning of PAFS. However, the effects of reducing or banning PAFS are not known. We explore the consequences of PAFS removal in a marine ecosystem under two scenarios: 1) gradual reduction, or 2) an abrupt ban, using a mass balance model to test these hypotheses–The reduction or loss of PAFS will: i) modify trophic levels and food webs through effects on foraging by opportunistic species, ii) increase the resilience of opportunistic species to food shortages, and iii) modify predator–prey interactions through shifts in prey consumption. We found that PAFS lower the trophic levels of opportunistic scavengers and increase their food pathways. Scavengers are able to switch prey when PAFS are reduced gradually but they decline when PAFS are abruptly banned. PAFS reduction to a certain minimal level causes a drop in the ecosystem’s stability. We recommend gradual reduction of PAFS to a minimal level that would maintain the ecosystem’s stability and allow species exploiting PAFS to habituate to the food subsidy reduction.     

Oligomeric State and Thermal Stability of Apo- and Holo- Human Ornithine δ-Aminotransferase

Human ornithine δ-aminotransferase (hOAT) (EC 2.6.1.13) is a mitochondrial pyridoxal 5′-phosphate (PLP)-dependent aminotransferase whose deficit is associated with gyrate atrophy, a rare autosomal recessive disorder causing progressive blindness and chorioretinal degeneration. Here, both the apo- and holo-form of recombinant hOAT were characterized by means of spectroscopic, kinetic, chromatographic and computational techniques. The results indicate that apo and holo-hOAT (a) show a similar tertiary structure, even if apo displays a more pronounced exposure of hydrophobic patches, (b) exhibit a tetrameric structure with a tetramer-dimer equilibrium dissociation constant about fivefold higher for the apoform with respect to the holoform, and (c) have apparent T_m values of 46 and 67?°C, respectively. Moreover, unlike holo-hOAT, apo-hOAT is prone to unfolding and aggregation under physiological conditions. We also identified Arg217 as an important hot-spot at the dimer–dimer interface of hOAT and demonstrated that the artificial dimeric variant R217A exhibits spectroscopic properties, T_m values and catalytic features similar to those of the tetrameric species. This finding indicates that the catalytic unit of hOAT is the dimer. However, under physiological conditions the apo-tetramer is slightly less prone to unfolding and aggregation than the apo-dimer. The possible implications of the data for the intracellular stability and regulation of hOAT are discussed.     

Intrinsic vs. extrinsic influences on life history expression: metabolism and parentally induced temperature influences on embryo development rate

Intrinsic processes are assumed to underlie life history expression and trade‐offs, but extrinsic inputs are theorised to shift trait expression and mask trade‐offs within species. Here, we explore application of this theory across species. We do this based on parentally induced embryo temperature as an extrinsic input, and mass‐specific embryo metabolism as an intrinsic process, underlying embryonic development rate. We found that embryonic metabolism followed intrinsic allometry rules among 49 songbird species from temperate and tropical sites. Extrinsic inputs via parentally induced temperatures explained the majority of variation in development rates and masked a relationship with metabolism; metabolism explained a minor proportion of the variation in development rates among species, and only after accounting for temperature effects. We discuss evidence that temperature further obscures the expected interspecific trade‐off between development rate and offspring quality. These results demonstrate the importance of considering extrinsic inputs to trait expression and trade‐offs across species.     

Altered Intracellular Localization of SOD1 in Leukocytes from Patients with Sporadic Amyotrophic Lateral Sclerosis

Several lines of evidence support the hypothesis of a toxic role played by wild type SOD1 (WT-SOD1) in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS). In this study we investigated both distribution and expression profile of WT-SOD1 in leukocytes from 19 SALS patients and 17 healthy individuals. Immunofluorescence experiments by confocal microscopy showed that SOD1 accumulates in the nuclear compartment in a group of SALS subjects. These results were also confirmed by western blot carried out on soluble nuclear and cytoplasmic fractions, with increased nuclear SOD1 level (p<0.05). In addition, we observed the presence of cytoplasmic SOD1 aggregates in agreement with an increased amount of the protein recovered by the insoluble fraction. A further confirmation of the overall increased level of SOD1 has been obtained from single cells analysis using flow cytometry as cells from SALS patients showed an higher SOD1 protein content (p<0.05). These findings add further evidence to the hypothesis of an altered WT-SOD1 expression profile in peripheral blood mononuclear cells (PBMCs) from patients with ALS suggesting that WT-SOD1 species with different degrees of solubility could be involved in the pathogenesis of the disease.     

Voltage-dependent activation and inactivation of calcium channels in PC12 cells. Correlation with neurotransmitter release

The existence and mechanisms of inactivation of voltage-gated Ca2+ channels are important, but still debatable, physiological problems. By using the Ca2+ indicators quin2 and fura-2, we demonstrate that in PC12 cells voltage-gated Ca2+ channels undergo inactivation dependent on both voltage and [Ca2+]i. Inactivation, however, is never complete and a small number of channels remains open during prolonged depolarization, explaining the steady state elevation of [Ca2+]i observed in cells depolarized with high KCl. A close parallel exists between Ca2+ channel inactivation and the transient nature of neurotransmitter release: secretion is rapidly stimulated during the first 30 s of depolarization, when a transient overshoot in [Ca2+]i can be demonstrated, while it is negligible during the following period, despite the persistence of an elevated [Ca2+]i; predepolarization in Ca2+-free medium and subsequent addition of Ca2+ (a condition which allows the development of the voltage inactivation) abolishes the fast phase of secretion, while not modifying the steady state [Ca2+]i eventually attained; and increases in the intracellular Ca2+ buffering decreases the amplitude of the fast secretion phase induced by KCl without altering the steady state [Ca2+]i. We suggest that localized [Ca2+]i gradients form close to the plasma membrane shortly after depolarization and that the [Ca2+]i reached in these regions is the relevant parameter in the regulation of secretion.     

Localization of Usher syndrome type II to chromosome 1q

Usher syndrome is characterized by congenital hearing loss, progressive visual impairment due to retinitis pigmentosa, and variable vestibular problems. The two subtypes of Usher syndrome, types I and II, can be distinguished by the degree of hearing loss and by the presence or absence of vestibular dysfunction. Type I is characterized by a profound hearing loss and totally absent vestibular responses, while type II has a milder hearing loss and normal vestibular function. Fifty-five members of eight type II Usher syndrome families were typed for three DNA markers in the distal region of chromosome 1q: D1S65 (pEKH7.4), REN (pHRnES1.9), and D1S81 (pTHH33). Statistically significant linkage was observed for Usher syndrome type II with a maximum multipoint lod score of 6.37 at the position of the marker THH33, thus localizing the Usher type II (USH2) gene to 1q. Nine families with type I Usher syndrome failed to show linkage to the same three markers. The statistical test for heterogeneity of linkage between Usher syndrome types I and II was highly significant, thus demonstrating that they are due to mutations at different genetic loci.     

Metabolism of semisynthetic single-chain GM1 derivatives in cerebellar granule cells in culture

Semisynthetic single-chain GM1 derivatives containing N-acetyl-sphingosine (LIGA4) or N-dichloroacetyl-sphingosine (LIGA20) were recently reported to exert strong protection against glutamate-induced neuronal death in primary cultures of cerebellar granule cells. Elucidation of the molecular mechanism underlying the evoked effect requires knowledge of the metabolic fate of such molecules in the same cultured cells. For this, LIGA4 and LIGA20 were made radioactive on the long chain base moiety and added to cerebellar granule cells in culture in parallel with GM1 ganglioside. The metabolic fate was then investigated. It was found that both these molecules were easily taken up by the cells and promptly metabolized in a fashion qualitatively similar to that of control GM1. The highest amount processed was attributed to the different aggregation properties of LIGAs in solution. Among metabolites, higher accumulation of the single-chain ceramide residues was found after LIGA administration. Interestingly, sphingomyelin was generated, regardless the added compound, suggesting a recycling of the free long chain base.     

Electrical characteristics of ascidian egg fragments

Fragments of ascidian eggs, but at random in any plane and ranging in size from 10 to 90% of the total egg volume, displayed the electrical characteristics of the intact egg, having a resting potential of -86 mV and giving rise to an action potential upon stimulation by electrical current injection. Following insemination, the fragments generated fertilization potentials, comparable to those of intact eggs, although the repolarization phase was shorter. Our data show that there are sufficient ion channels throughout the egg surface to generate action potentials and fertilization potentials in excised egg fragments, irrespective of their global origin. Furthermore, the fertilizing spermatozoon is capable of activating fertilization channels in areas of the egg plasma membrane not destined for sperm entry.