Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: Increased susceptibility of females

Apolipoprotein E (apoE) mediates the redistribution of lipids among cells and is expressed at highest levels in brain and liver. Human apoE exists in three major isoforms encoded by distinct alleles (ɛ2, ɛ3, and ɛ4). Compared with APOE ɛ2 and ɛ3, APOE ɛ4 increases the risk of cognitive impairments, lowers the age of onset of Alzheimer’s disease (AD), and decreases the response to AD treatments. Besides age, inheritance of the APOE ɛ4 allele is the most important known risk factor for the development of sporadic AD, the most common form of this illness. Although numerous hypotheses have been advanced, it remains unclear how APOE ɛ4 might affect cognition and increase AD risk. To assess the effects of distinct human apoE isoforms on the brain, we have used the neuron-specific enolase (NSE) promoter to express human apoE3 or apoE4 at similar levels in neurons of transgenic mice lacking endogenous mouse apoE. Compared with NSE-apoE3 mice and wild-type controls, NSE-apoE4 mice showed impairments in learning a water maze task and in vertical exploratory behavior that increased with age and were seen primarily in females. These findings demonstrate that human apoE isoforms have differential effects on brain function in vivo and that the susceptibility to apoE4-induced deficits is critically influenced by age and gender. These results could be pertinent to cognitive impairments observed in human APOE ɛ4 carriers. NSE-apoE mice and similar models may facilitate the preclinical assessment of treatments for apoE-related cognitive deficits.

Biogeographic range expansion into South America by Coccidioides immitis mirrors New World patterns of human migration

Long-distance population dispersal leaves its characteristic signature in genomes, namely, reduced diversity and increased linkage between genetic markers. This signature enables historical patterns of range expansion to be traced. Herein, we use microsatellite loci from the human pathogen Coccidioides immitis to show that genetic diversity in this fungus is geographically partitioned throughout North America. In contrast, analyses of South American C. immitis show that this population is genetically depauperate and was founded from a single North American population centered in Texas. Variances of allele distributions show that South American C. immitis have undergone rapid population growth, consistent with an epidemic increase in postcolonization population size. Herein, we estimate the introduction into South America to have occurred within the last 9,000–140,000 years. This range increase parallels that of Homo sapiens. Because of known associations between Amerindians and this fungus, we suggest that the colonization of South America by C. immitis represents a relatively recent and rapid codispersal of a host and its pathogen.

Flower color variation: A model for the experimental study of evolution

We review the study of flower color polymorphisms in the morning glory as a model for the analysis of adaptation. The pathway involved in the determination of flower color phenotype is traced from the molecular and genetic levels to the phenotypic level. Many of the genes that determine the enzymatic components of flavonoid biosynthesis are redundant, but, despite this complexity, it is possible to associate discrete floral phenotypes with individual genes. An important finding is that almost all of the mutations that determine phenotypic differences are the result of transposon insertions. Thus, the flower color diversity seized on by early human domesticators of this plant is a consequence of the rich variety of mobile elements that reside in the morning glory genome. We then consider a long history of research aimed at uncovering the ecological fate of these various flower phenotypes in the southeastern U.S. A large body of work has shown that insect pollinators discriminate against white phenotypes when white flowers are rare in populations. Because the plant is self-compatible, pollinator bias causes an increase in self-fertilization in white maternal plants, which should lead to an increase in the frequency of white genes, according to modifier gene theory. Studies of geographical distributions indicate other, as yet undiscovered, disadvantages associated with the white phenotype. The ultimate goal of connecting ecology to molecular genetics through the medium of phenotype is yet to be attained, but this approach may represent a model for analyzing the translation between these two levels of biological organization.

A polygenic mouse model of psoriasiform skin disease in CD18-deficient mice.

Previously, a hypomorphic mutation in CD18 was generated by gene targeting, with homozygous mice displaying increased circulating neutrophil counts, defects in the response to chemically induced peritonitis, and delays in transplantation rejection. When this mutation was backcrossed onto the PL/J inbred strain, virtually all homozygous mice developed a chronic inflammatory skin disease with a mean age of onset of 11 weeks after birth. The disease was characterized by erythema, hair loss, and the development of scales and crusts. The histopathology revealed hyperplasia of the epidermis, subcorneal microabscesses, orthohyperkeratosis, parakeratosis, and lymphocyte exocytosis, which are features in common with human psoriasis and other hyperproliferative inflammatory skin disorders. Repetitive cultures failed to demonstrate bacterial or fungal organisms potentially involved in the pathogenesis of this disease, and the dermatitis resolved rapidly after subcutaneous administration of dexamethasone. Homozygous mutant mice on a (PL/J x C57BL/6J)F1 background did not develop the disease and backcross experiments suggest that a small number of genes (perhaps as few as one), in addition to CD18, determine susceptibility to the disorder. This phenotype provides a model for inflammatory skin disorders, may have general relevance to polygenic human inflammatory diseases, and should help to identify genes that interact with the beta2 integrins in inflammatory processes.

Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease.

Apolipoprotein E (apoE) is critical in the modulation of cholesterol and phospholipid transport between cells of different types. Human apoE is a polymorphic protein with three common alleles, APO epsilon 2, APO epsilon 3, and APO epsilon 4. ApoE4 is associated with sporadic and late-onset familial Alzheimer disease (AD). Gene dose was shown to have an effect on risk of developing AD, age of onset, accumulation of senile plaques in the brain, and reduction of choline acetyltransferase (ChAT) activity in the hippocampus of AD subjects. To characterize the possible impact of the apoE4 allele on cholinergic markers in AD, we examined the effect of apoE4 allele copy number on pre- and postsynaptic markers of cholinergic activity. ApoE4 allele copy number showed an inverse relationship with residual brain ChAT activity and nicotinic receptor binding sites in both the hippocampal formation and the temporal cortex of AD subjects. AD cases lacking the apoE4 allele showed ChAT activities close or within age-matched normal control values. The effect of the apoE4 allele on cholinomimetic drug responsiveness was assessed next in a group (n = 40) of AD patients who completed a double-blind, 30-week clinical trial of the cholinesterase inhibitor tacrine. Results showed that > 80% of apoE4-negative AD patients showed marked improvement after 30 weeks as measured by the AD assessment scale (ADAS), whereas 60% of apoE4 carriers had ADAS scores that were worse compared to baseline. These results strongly support the concept that apoE4 plays a crucial role in the cholinergic dysfunction associated with AD and may be a prognostic indicator of poor response to therapy with acetylcholinesterase inhibitors in AD patients.

Genetic dissection of Alzheimer disease, a heterogeneous disorder.

The genetics of Alzheimer disease (AD) are complex and not completely understood. Mutations in the amyloid precursor protein gene (APP) can cause early-onset autosomal dominant AD. In vitro studies indicate that cells expressing mutant APPs overproduce pathogenic forms of the A beta peptide, the major component of AD amyloid. However, mutations in the APP gene are responsible for 5% or less of all early-onset familial AD. A locus on chromosome 14 is responsible for AD in other early-onset AD families and represents the most severe form of the disease in terms of age of onset and rate of decline. Attempts to identify the AD3 gene by positional cloning methods are underway. At least one additional early-onset AD locus remains to be located. In late-onset AD, the apolipoprotein E gene allele epsilon 4 is a risk factor for AD. This allele appears to act as a dose-dependent age-of-onset modifier. The epsilon 2 allele of this gene may be protective. Other late-onset susceptibility factors remain to be identified.

Gaia-ESO Survey: Analysis of pre-main sequence stellar spectra

Context. The Gaia-ESO Public Spectroscopic Survey is obtaining high-quality spectroscopy of some 100 000 Milky Way stars using the FLAMES spectrograph at the VLT, down to V = 19 mag, systematically covering all the main components of the Milky Way and providing the first homogeneous overview of the distributions of kinematics and chemical element abundances in the Galaxy. Observations of young open clusters, in particular, are giving new insights into their initial structure, kinematics, and their subsequent evolution. Aims. This paper describes the analysis of UVES and GIRAFFE spectra acquired in the fields of young clusters whose population includes pre-main sequence (PMS) stars. The analysis is applied to all stars in such fields, regardless of any prior information on membership, and provides fundamental stellar atmospheric parameters, elemental abundances, and PMS-specific parameters such as veiling, accretion, and chromospheric activity. Methods. When feasible, different methods were used to derive raw parameters (e.g. line equivalent widths) fundamental atmospheric parameters and derived parameters (e.g. abundances). To derive some of these parameters, we used methods that have been extensively used in the past and new ones developed in the context of the Gaia-ESO survey enterprise. The internal precision of these quantities was estimated by inter-comparing the results obtained by these different methods, while the accuracy was estimated by comparison with independent external data, such as effective temperature and surface gravity derived from angular diameter measurements, on a sample of benchmarks stars. A validation procedure based on these comparisons was applied to discard spurious or doubtful results and produce recommended parameters. Specific strategies were implemented to resolve problems of fast rotation, accretion signatures, chromospheric activity, and veiling. Results. The analysis carried out on spectra acquired in young cluster fields during the first 18 months of observations, up to June 2013, is presented in preparation of the first release of advanced data products. These include targets in the fields of the ρ Oph, Cha I, NGC 2264, γ Vel, and NGC 2547 clusters. Stellar parameters obtained with the higher resolution and larger wavelength coverage from UVES are reproduced with comparable accuracy and precision using the smaller wavelength range and lower resolution of the GIRAFFE setup adopted for young stars, which allows us to provide stellar parameters with confidence for the much larger GIRAFFE sample. Precisions are estimated to be ≈120 K rms in Teff, ≈0.3 dex rms in log g, and ≈0.15 dex rms in [Fe/H] for the UVES and GIRAFFE setups.

Population synthesis of isolated neutron stars with magneto-rotational evolution – II. From radio-pulsars to magnetars

Population synthesis studies constitute a powerful method to reconstruct the birth distribution of periods and magnetic fields of the pulsar population. When this method is applied to populations in different wavelengths, it can break the degeneracy in the inferred properties of initial distributions that arises from single-band studies. In this context, we extend previous works to include X-ray thermal emitting pulsars within the same evolutionary model as radio-pulsars. We find that the cumulative distribution of the number of X-ray pulsars can be well reproduced by several models that, simultaneously, reproduce the characteristics of the radio-pulsar distribution. However, even considering the most favourable magneto-thermal evolution models with fast field decay, lognormal distributions of the initial magnetic field overpredict the number of visible sources with periods longer than 12 s. We then show that the problem can be solved with different distributions of magnetic field, such as a truncated lognormal distribution, or a binormal distribution with two distinct populations. We use the observational lack of isolated neutron stars (NSs) with spin periods P > 12 s to establish an upper limit to the fraction of magnetars born with B > 1015 G (less than 1 per cent). As future detections keep increasing the magnetar and high-B pulsar statistics, our approach can be used to establish a severe constraint on the maximum magnetic field at birth of NSs.

(Table 1) Concentration and geological parameters of n-alkanes and n-alkenes in surface sediments from the Gulf of Gabes, Tunisia

Abstract Hydrocarbons in surface sediments were studied quantitatively and qualitatively in 18 stations along the coastline of Gabes Gulf in Tunisia. The results show that the total hydrocarbon levels vary along a wide range from 90 to 1,800 ppm. The GC-MS profiles of aliphatic hydrocarbons vary according to the stations and show that the hydrocarbons were derived from various sources. A special feature prevalent in several stations was identified: aliphatic hydrocarbons with distinctive chemical features. This includes a high abundance of even-numbered n-alkanes (n-C14 - n-C26, maximizing at n-C18, n-C20 and n-C22) and n-alk-1-enes (n-C14:1 - n-C24:1, maximizing at n-C16:1, n-C18:1, n-C20:1 and n-C22:1). This unusual predominance of even-numbered n-alkanes/alkenes is reported for the first time in the Gulf of Gabes and it thus contributes to the information on the rare occurrence of such distributions in the geosphere.

Stable oxygen isotope ratios of benthic and planktonic foraminifera from early Miocene sediments of DSDP Site 90-593 on the Challenger Plateau, Pacific Ocean (Table 1)

Oxygen isotope data are compared with relative abundances of selected planktic foraminifera through a ca. 15 m interval at DSDP Site 593 (Tasman Sea, southwest Pacific, 40°S) in which there are prominent changes in population sizes, as well as several evolutionary events. We focus on the relation between faunal and climatic histories. The base of early Miocene oxygen isotope Zone Mi1b (uppermost planktic foraminiferal Zone N.6) is identified from closesampled (c. 14 kyr) isotope records of Globigerina woodi and Cibicides kullenbergi. Chronostratigraphic interpolations, using the first occurrences of Globorotalia praescitula, G. mimea and Praeorbulina curva give an age estimate of ca. 18.4 Ma (cf. 18.1 -18.3 Ma for the base of the zone at DSDP Site 608 (type level, north Atlantic, 43°N) ). Another significant benthic delta18O enrichment event, informally designated as the base of zone "Mi1c", is identified 10 m higher in the sequence at ca. 17.8 Ma. Populations of Globoquadriau dehiscens and Globigerinoides trilobus (inferred to be near the southern margin of their distributions) either reduced considerably or withdrew, particularly in the vicinity of zone "Mi1c". A bioseries linking Globorotalia incognita with G. zealandica developed following the benthic delta18O enrichment spike at the base of Zone Mi1b; the latter species became extinct (at least regionally) just above the base of zone "Mi1c". In contrast, the apparently opportunistic Globorotlia praescitula increased dramatically in abundance at this time; there were also transformations in its architecture, leading to the evolutionary appearance of G. miozea. While planktic foraminifera abundances often do not closely covary with the detailed isotope records and tend to be more stable through time, the near coincidence of evolutionary and biogeographic events with isotopic events suggests at least indirect adaptive responses to climatic changes. Early Miocene middle-latitude planktic foraminiferal evolution, biogeography, and biostratigraphy, may be intimately connected with climatic history.

Alkenon concentrations of Creatcesous sediments of DSDP Hole 76-534A (Table 1)

We here report the discovery of unusual distributions of long-chain alkenones (C37-C42) in two Cretaceous black shales from the Blake-Bahama Basin, western North Atlantic. These sediments are Cenomanian (c. 95 Ma) and mid-Albian (c. 105 Ma) in age, thus significantly extending the geological range of these compounds. The precise source of these lipids is, as yet, unknown, although they may derive from an ancient ancestor of Emiliania huxleyi.

Petrology, geochemistry and K-Ar Age determination of De Gerlache Seamount basalts

The De Gerlache Seamounts are two topographic highs in the Bellingshausen Sea, southeastern Pacific. Petrological and geochemical studies together with K-Ar age determinations were carried out on four dredged basalt samples collected during a RV Polarstern expedition (ANT-XII/4) in 1995. Minor and trace element composition suggest alkaline basalt compositions. Compared to alkaline basalts of adjacent West Antarctica (the Jones Mountains) and of Peter I Island, the samples have lower mg-numbers, lower Ni and Cr contents and lower high field-strength elements (HFSE)/Nb and large-ion lithophile elements (LILE)/HFSE ratios. Three of the four samples have low K, Rb, and Cs concentrations relative to alkaline basalts. The K-depletion and other elemental concentrations may be explained by 1.1% melting of amphibole bearing mantle material. Additionally, low Rb and Ba values suggest low concentrations of these elements in the mantle source. K-Ar age determinations yield Miocene ages (20-23 Ma) that are similar in age to other alkaline basalts of West Antarctica (Thurston Island, the Jones Mountains, Antarctic Peninsula) and the suggested timing of onset of Peter I Island volcanism (~10-20 Ma). The occurrence of the DGS and Peter I Island volcanism along an older but reactivated tectonic lineation suggests that the extrusions exploited a zone of pre-existing lithospheric weakness. The alkaline nature and age of the DGS basalts support the assumption of plume activity in the Bellingshausen Sea.

An analysis of clinical characteristics in genetically linked migraine-affected pedigrees

Migraine is a common complex disorder characterized by severe recurrent headache and usually accompanied by nausea and vomiting. Previous studies in our laboratory have utilized three large multigenerational Australian pedigrees affected with migraine to indicate that the disease is genetically heterogeneous, with linkage results implicating genomic susceptibility regions on both chromosomes 19p and Xq. The present study explores the possibility of a correlation between genetic and clinical heterogeneity in these affected pedigrees. Specifically, the clinical characteristics of migraine including subtype, age of onset, frequency, duration, and disease symptoms were compared between the migraine pedigrees, and gender differences were also assessed. Our exploratory analyses revealed no significant differences in any of the clinical characteristics tested between the chromosome 19-linked family and the two X-linked families. Also, we did not detect any differences in male vs. female clinical features for these pedigrees. In conclusion, migraine is considered to be a clinically and genetically heterogeneous disorder; however, our study provided no conclusive evidence that variation in genomic susceptibility region is related to heterogeneity at the clinical level in these migraine-affected pedigrees.

Australian microhylid frogs (Cophixalus and Austrochaperina): phylogeny, taxonomy, calls, distributions and breeding biology

Despite a considerable surge in herpetological research in Australia over the last couple of decades the Australian microhylid frogs (Cophixalus and Austrochaperina) remain relatively poorly known. Herein I present the results of extensive fieldwork and molecular, morphological and call analysis with the aim of resolving taxonomy, call variation and distributions, and increasing our understanding of breeding biology. Analysis of 943 base pairs of mitochondrial 16S rRNA and 12S rRNA provides a well supported phylogeny that is largely consistent with current taxonomy. Levels of divergence between species are substantial and significant phylogeographic structuring is evident in C. ornatus, C. neglectus and C. aenigma, sp. nov. The description of C. concinnus was based on a mixed collection of two species from Thornton Peak and a new species is described to resolve this. C. aenigma, sp. nov., is described from high-elevation (>750 m) rainforest across the Carbine, Thornton, Finnigan and Bakers Blue Mountain uplands, north-east Queensland. C. concinnus is redescribed as a highly distinct species restricted to rainforest and boulder fields at the summit of Thornton Peak (>1100 m). Despite protection in Daintree National Park in the Wet Tropics World Heritage Area, predictions of the impact of global warming suggest C. concinnus to be of very high conservation concern ( Critically Endangered, IUCN criteria). The mating call of two species ( C. mcdonaldi and C. exiguus) is described for the first time and high levels of call variation within C. ornatus, C. neglectus, C. hosmeri, C. aenigma and Austrochaperina fryi are presented. Such variation is often attributable to genetically divergent lineages, altitudinal variation and courtship; however, in some instances ( particularly within C. hosmeri) the source or function of highly distinct calls at a site remains obscure. Molecular, morphological and call analyses allow the clarification of species distributions, especially in the northern mountains of the Wet Tropics. Notes are presented on the breeding biology of C. aenigma, C. bombiens, C. concinnus, C. exiguus, C. infacetus, C. mcdonaldi, C. monticola, C. neglectus, C. ornatus and C. saxatilis, which are largely consistent with previous accounts: small terrestrial clutches usually attended by a male. Courtship behaviour in C. ornatus is described and the first records of multiple clutching in Australian microhylids are presented (for C. ornatus and C. infacetus).

Three putative types of El Nino revealed by spatial variability in impact on Australian wheat yield

The El Nino-Southern Oscillation (ENSO) phenomenon significantly impacts rainfall and ensuing crop yields in many parts of the world. In Australia, El Nino events are often associated with severe drought conditions. However, El Nino events differ spatially and temporally in their manifestations and impacts, reducing the relevance of ENSO-based seasonal forecasts. In this analysis, three putative types of El Nino are identified among the 24 occurrences since the beginning of the twentieth century. The three types are based on coherent spatial patterns (footprints) found in the El Nino impact on Australian wheat yield. This bioindicator reveals aligned spatial patterns in rainfall anomalies, indicating linkage to atmospheric drivers. Analysis of the associated ocean-atmosphere dynamics identifies three types of El Nino differing in the timing of onset and location of major ocean temperature and atmospheric pressure anomalies. Potential causal mechanisms associated with these differences in anomaly patterns need to be investigated further using the increasing capabilities of general circulation models. Any improved predictability would be extremely valuable in forecasting effects of individual El Nino events on agricultural systems.