POSTNATAL BRAIN DYSMORPHOLOGY INDUCED BY PRENATAL ALCOHOL EXPOSURE: A PRECLINICAL MRI STUDY

poster abstractBrain dysmorphology is one of the most critical features of Fetal Alcohol Spectrum Disorders (FASD). This study was designed to use high resolution preclinical MRI system to compare the brain structures between alcohol exposed C57BL/6 mice with control. The objective is to examine how alcohol affects a dose- and timing-dependent brain dysmorphology during development comparable to that of human FASD. Three treated groups, ALC (pre- and pregnancy alcohol with 4.2 % (v/v) alcohol liquid), PF (pre alcohol and a calorically matched liquid pregnancy diet), and CHOW (ad lib chow/water), were examined. Mouse heads were imaged using 9.4T preclinical MRI system with 3D gradient echo (GRE) sequence to acquire volumetric images with voxel size as low as 40 microns. Whole brain, olfactory bulbs, cortex, hypothalamus, and cerebellum were segmented and the volumes were calculated. Data was examined by ANOVA followed with paired comparison between treatment groups to test the effect of prenatal alcohol exposure. ALC group had shown consistently smaller mean volumes of difference brain regions than the other two groups. Volume of total brain, olfactory bulbs and cerebellum were observed to be significantly different for ALC compared to PF pups. This indicated that prenatal alcohol exposure caused retarded fetal brain development. Comparing PF with CHOW pups, only cerebellum volume was observed to be significantly different. For cortex volume, no significant difference was shown for any pairwise comparison. These results suggest that alcohol effect contribute to brain dysmorphology, and match with our previous craniofacial dysmorphology study. This could be important to assist in the understanding of clinical variants of human FASD patients in brain dysmorphology

Statistics and Universality in Simplified Models of Planetary Formation

In this paper, we modify Laskar's simplified model of planetary evolution and accretion [J. Laskar, Phys. Rev. Lett, vol 84, p 3240 (2000)] to account for the full conservation of the total angular momentum of the system, and extend it to incorporate an accretion probability that depends on the mass and relative velocity of the colliding particles. We present statistical results for the mass and eccentricity of the planets formed, in terms of their semi-major axes, for a large number of realisations of different versions of the model. In particular, we find that by combining the mass-dependent accretion probability and the velocity-selection mechanism, the planets formed display a systematic occurrence at specific locations. By introducing properly scaled variables, our results are universal with respect to the total angular momentum of the system, the mass of the planetesimal disc, and the mass of the central star.Comment: 13 pages, 21 figures, some in colour. Accepted in MNRA

A common contrast pooling rule for suppression within and between the eyes

Recent work has revealed multiple pathways for cross-orientation suppression in cat and human vision. In particular, ipsiocular and interocular pathways appear to assert their influence before binocular summation in human but have different (1) spatial tuning, (2) temporal dependencies, and (3) adaptation after-effects. Here we use mask components that fall outside the excitatory passband of the detecting mechanism to investigate the rules for pooling multiple mask components within these pathways. We measured psychophysical contrast masking functions for vertical 1 cycle/deg sine-wave gratings in the presence of left or right oblique (645 deg) 3 cycles/deg mask gratings with contrast C%, or a plaid made from their sum, where each component (i) had contrast 0.5Ci%. Masks and targets were presented to two eyes (binocular), one eye (monoptic), or different eyes (dichoptic). Binocular-masking functions superimposed when plotted against C, but in the monoptic and dichoptic conditions, the grating produced slightly more suppression than the plaid when Ci $ 16%. We tested contrast gain control models involving two types of contrast combination on the denominator: (1) spatial pooling of the mask after a local nonlinearity (to calculate either root mean square contrast or energy) and (2) "linear suppression" (Holmes & Meese, 2004, Journal of Vision 4, 1080–1089), involving the linear sum of the mask component contrasts. Monoptic and dichoptic masking were typically better fit by the spatial pooling models, but binocular masking was not: it demanded strict linear summation of the Michelson contrast across mask orientation. Another scheme, in which suppressive pooling followed compressive contrast responses to the mask components (e.g., oriented cortical cells), was ruled out by all of our data. We conclude that the different processes that underlie monoptic and dichoptic masking use the same type of contrast pooling within their respective suppressive fields, but the effects do not sum to predict the binocular case

Sibling comparisons elucidate the associations between educational attainment polygenic scores and alcohol, nicotine and cannabis.

Background and aimsThe associations between low educational attainment and substance use disorders (SUDs) may be related to a common genetic vulnerability. We aimed to elucidate the associations between polygenic scores for educational attainment and clinical criterion counts for three SUDs (alcohol, nicotine and cannabis).DesignPolygenic association and sibling comparison methods. The latter strengthens inferences in observational research by controlling for confounding factors that differ between families.SettingSix sites in the United States.ParticipantsEuropean ancestry participants aged 25 years and older from the Collaborative Study on the Genetics of Alcoholism (COGA). Polygenic association analyses included 5582 (54% female) participants. Sibling comparisons included 3098 (52% female) participants from 1226 sibling groups nested within the overall sample.MeasurementsOutcomes included criterion counts for DSM-5 alcohol use disorder (AUDSX), Fagerström nicotine dependence (NDSX) and DSM-5 cannabis use disorder (CUDSX). We derived polygenic scores for educational attainment (EduYears-GPS) using summary statistics from a large (> 1 million) genome-wide association study of educational attainment.FindingsIn polygenic association analyses, higher EduYears-GPS predicted lower AUDSX, NDSX and CUDSX [P < 0.01, effect sizes (R2 ) ranging from 0.30 to 1.84%]. These effects were robust in sibling comparisons, where sibling differences in EduYears-GPS predicted all three SUDs (P < 0.05, R2 0.13-0.20%).ConclusionsIndividuals who carry more alleles associated with educational attainment tend to meet fewer clinical criteria for alcohol, nicotine and cannabis use disorders, and these effects are robust to rigorous controls for potentially confounding factors that differ between families (e.g. socio-economic status, urban-rural residency and parental education)

A Clash of Old and New Scientific Concepts in Toxicity, with Important Implications for Public Health

Background A core assumption of current toxicologic procedures used to establish health standards for chemical exposures is that testing the safety of chemicals at high doses can be used to predict the effects of low-dose exposures, such as those common in the general population. This assumption is based on the precept that “the dose makes the poison”: higher doses will cause greater effects. Objectives We challenge the validity of assuming that high-dose testing can be used to predict low-dose effects for contaminants that behave like hormones. We review data from endocrinology and toxicology that falsify this assumption and summarize current mechanistic understanding of how low doses can lead to effects unpredictable from high-dose experiments. Discussion Falsification of this assumption raises profound issues for regulatory toxicology. Many exposure standards are based on this assumption. Rejecting the assumption will require that these standards be reevaluated and that procedures employed to set health standards be changed. The consequences of these changes may be significant for public health because of the range of health conditions now plausibly linked to exposure to endocrine-disrupting contaminants. Conclusions We recommend that procedures to establish acceptable exposure levels for endocrine-disrupting compounds incorporate the inability for high-dose tests to predict low-dose results. Setting acceptable levels of exposure must include testing for health consequences at prevalent levels of human exposure, not extrapolations from the effects observed in high-dose experiments. Scientists trained in endocrinology must be engaged systematically in standard setting for endocrine-disrupting compounds

Collisional evolution of eccentric planetesimal swarms

Models for the steady state collisional evolution of low eccentricity planetesimal belts identify debris disks with hot dust at 1AU, like eta Corvi and HD69830, as anomalous since collisional processing should have removed most of the planetesimal mass over their >1 Gyr lifetimes. This paper looks at the effect of large planetesimal eccentricities (e>>0.3) on their collisional lifetime and the amount of mass that can remain at late times M_{late}. For an axisymmetric planetesimal disk with common pericentres and eccentricities e, we find that M_{late} \propto e^{-5/3}(1+e)^{4/3}(1-e)^{-3}. For a scattered disk-like population (i.e., common pericentres), in the absence of dynamical evolution, the mass evolution at late times would be as if only planetesimals with the largest eccentricity were present. Despite the increased remaining mass, higher eccentricities do not increase the hot emission from the collisional cascade until e>0.99, partly because most collisions occur near pericentre thus increasing the dust blow-out diameter. However, at high eccentricities (e>0.97) the blow-out population extending out from pericentre may be detectable above the collisional cascade; higher eccentricities also increase the probability of witnessing a recent collision. All of the imaging and spectroscopic constraints for eta Corvi can be explained with a single planetesimal population with pericentre at 0.75AU, apocentre at 150AU, and mass 5M_\oplus; however, the origin of such a high eccentricity population remains challenging. The mid-IR excess to HD69830 can be explained by the ongoing destruction of a debris belt produced in a recent collision in an eccentric planetesimal belt, but the lack of far-IR emission requires small bound grains to be absent from the parent planetesimal belt, possibly due to sublimation.Comment: MNRAS in pres

Genome-wide survival analysis of age at onset of alcohol dependence in extended high-risk COGA families.

BackgroundThe age at onset of alcohol dependence (AD) is a critical moderator of genetic associations for alcohol dependence. The present study evaluated whether single nucleotide polymorphisms (SNPs) can influence the age at onset of AD in large high-risk families from the Collaborative Study on the Genetics of Alcoholism (COGA).MethodsGenomewide SNP genotyping was performed in 1788 regular drinkers from 118 large European American families densely affected with alcoholism. We used a genome-wide Cox proportional hazards regression model to test for association between age at onset of AD and SNPs.ResultsThis family-based analysis identified an intergenic SNP, rs2168784 on chromosome 3 that showed strong evidence of association (P=5×10(-9)) with age at onset of AD among regular drinkers. Carriers of the minor allele of rs2168784 had 1.5 times the hazard of AD onset as compared with those homozygous for the major allele. By the age of 20 years, nearly 30% of subjects homozygous for the minor allele were alcohol dependent while only 19% of those homozygous for the major allele were. We also identified intronic SNPs in the ADP-ribosylation factor like 15 (ARL15) gene on chromosome 5 (P=1.11×10(-8)) and the UTP20 small subunit (UTP20) gene on chromosome 12 (P=4.32×10(-8)) that were associated with age at onset of AD.ConclusionsThis extended family based genome-wide cox-proportional hazards analysis identified several loci that might be associated with age at onset of AD

The formation of Kuiper-belt Binaries through Exchange Reactions

Recent observations have revealed an unexpectedly high binary fraction among the Trans-Neptunian Objects (TNOs) that populate the Kuiper-belt. The discovered binaries have four characteristics they comprise a few percent of the TNOs, the mass ratio of their components is close to unity, their internal orbits are highly eccentric, and the orbits are more than 100 times wider than the primary's radius. In contrast, theories of binary asteroid formation tend to produce close, circular binaries. Therefore, a new approach is required to explain the unique characteristics of the TNO binaries. Two models have been proposed. Both, however, require extreme assumptions on the size distribution of TNOs. Here we show a mechanism which is guaranteed to produces binaries of the required type during the early TNO growth phase, based on only one plausible assumption, namely that initially TNOs were formed through gravitational instabilities of the protoplanetary dust layer.Comment: 12pages, 4 figure

Combined Face-Brain Morphology and Associated Neurocognitive Correlates in Fetal Alcohol Spectrum Disorders

BACKGROUND: Since the 1970s, a range of facial, neurostructural, and neurocognitive adverse effects have been shown to be associated with prenatal alcohol exposure. Typically, these effects are studied individually and not in combination. Our objective is to improve the understanding of the teratogenic effects of prenatal alcohol exposure by simultaneously considering face-brain morphology and neurocognitive measures. METHODS: Participants were categorized as control (n = 47), fetal alcohol syndrome (FAS, n = 22), or heavily exposed (HE) prenatally, but not eligible for a FAS diagnosis (HE, n = 50). Structural brain MRI images and high-resolution 3D facial images were analyzed using dense surface models of features of the face and surface shape of the corpus callosum (CC) and caudate nucleus (CN). Asymmetry of the CN was evaluated for correlations with neurocognitive measures. RESULTS: (i) Facial growth delineations for FAS, HE, and controls are replicated for the CN and the CC. (ii) Concordance of clinical diagnosis and face-based control-FAS discrimination improves when the latter is combined with specific brain regions. In particular, midline facial regions discriminate better when combined with a midsagittal profile of the CC. (iii) A subset of HE individuals was identified with FAS-like CN dysmorphism. The average of this HE subset was FAS-like in its facial dysmorphism. (iv) Right-left asymmetry found in the CNs of controls is not apparent for FAS, is diminished for HE, and correlates with neurocognitive measures in the combined FAS and HE population. CONCLUSIONS: Shape analysis which combines facial regions with the CN, and with the CC, better identify those with FAS. CN asymmetry was reduced for FAS compared to controls and is strongly associated with general cognitive ability, verbal learning, and recall in those with prenatal alcohol exposure. This study further extends the brain-behavior relationships known to be vulnerable to alcohol teratogenesis