Scarring Effects on Tunneling in Chaotic Double-Well Potentials

The connection between scarring and tunneling in chaotic double-well potentials is studied in detail through the distribution of level splittings. The mean level splitting is found to have oscillations as a function of energy, as expected if scarring plays a role in determining the size of the splittings, and the spacing between peaks is observed to be periodic of period {$2\pi\hbar$} in action. Moreover, the size of the oscillations is directly correlated with the strength of scarring. These results are interpreted within the theoretical framework of Creagh and Whelan. The semiclassical limit and finite-{$\hbar$} effects are discussed, and connections are made with reaction rates and resonance widths in metastable wells.Comment: 22 pages, including 11 figure

Assessment of a polygenic hazard score for the onset of pre-clinical Alzheimer’s disease

Background: With a growing number of loci associated with late-onset (sporadic) Alzheimer’s disease (AD), the polygenic contribution to AD is now well established. The development of polygenic risk score approaches have shown promising results for identifying individuals at higher risk of developing AD, thereby facilitating the development of preventative and therapeutic strategies. A polygenic hazard score (PHS) has been proposed to quantify age-specific genetic risk for AD. In this study, we assessed the predictive power and transferability of this PHS in an independent cohort, to support its clinical utility. Results: Using genotype and imaging data from 780 individuals enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, we investigated associations between the PHS and several AD-related traits, including 1) cross-sectional Aβ-amyloid (Aβ) deposition, 2) longitudinal brain atrophy, 3) longitudinal cognitive decline, 4) age of onset. Except in the cognitive domain, we obtained results that were consistent with previously published findings. The PHS was associated with increased Aβ burden, faster regional brain atrophy and an earlier age of onset. Conclusion: Overall, the results support the predictive power of a PHS, however, with only marginal improvement compared to apolipoprotein E alone

Predictive Modeling Techniques in Prostate Cancer

A number of new predictive modeling techniques have emerged in the past several years. These methods can be used independently or in combination with traditional modeling techniques to produce useful tools for the management of prostate cancer. Investigators should be aware of these techniques and avail themselves of their potentially useful properties. This review outlines selected predictive methods that can be used to develop models that may be useful to patients and clinicians for prostate cancer management.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63147/1/10915360152745812.pd

Validation of a priori candidate Alzheimer’s disease SNPs with brain amyloid-beta deposition

The accumulation of brain amyloid β (Aβ) is one of the main pathological hallmarks of Alzheimer’s disease (AD). However, the role of brain amyloid deposition in the development of AD and the genetic variants associated with this process remain unclear. In this study, we sought to identify associations between Aβ deposition and an a priori evidence based set of 1610 genetic markers, genotyped from 505 unrelated individuals (258 Aβ+ and 247 Aβ−) enrolled in the Australian Imaging, Biomarker & Lifestyle (AIBL) study. We found statistically significant associations for 6 markers located within intronic regions of 6 genes, including AC103796.1-BDNF, PPP3R1, NGFR, KL, ABCA7 & CALHM1. Although functional studies are required to elucidate the role of these genes in the accumulation of Aβ and their potential implication in AD pathophysiology, our findings are consistent with results obtained in previous GWAS efforts

Thinking like a man? The cultures of science

Culture includes science and science includes culture, but conflicts between the two traditions persist, often seen as clashes between interpretation and knowledge. One way of highlighting this false polarity has been to explore the gendered symbolism of science. Feminism has contributed to science studies and the critical interrogation of knowledge, aware that practical knowledge and scientific understanding have never been synonymous. Persisting notions of an underlying unity to scientific endeavour have often impeded rather than fostered the useful application of knowledge. This has been particularly evident in the recent rise of molecular biology, with its delusory dream of the total conquest of disease. It is equally prominent in evolutionary psychology, with its renewed attempts to depict the fundamental basis of sex differences. Wars over science have continued to intensify over the last decade, even as our knowledge of the political, economic and ideological significance of science funding and research has become ever more apparent

Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus

Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 (PRDM5) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus (P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to date

The Chagos Islands cases: the empire strikes back

Good governance requires the accommodation of multiple interests in the cause of decision making. However, undue regard for particular sectional interests can take their toll upon public faith in government administration. Historically, broad conceptions of the good of the commonwealth were employed to outweigh the interests of groups that resisted colonisation. In the decision making of the British Empire, the standard approach for justifying the marginalisation of the interests of colonised groups was that they were uncivilised and that particular hardships were the price to be paid for bringing to them the imperial dividend of industrial society. It is widely assumed that with the dismantling of the British Empire, such impulses and their accompanying jurisprudence became a thing of the past. Even as decolonisation proceeded apace after the Second World War, however, the United Kingdom maintained control of strategically important islands with a view towards sustaining its global role. In an infamous example from this twilight period of empire, in the 1960s imperial interests were used to justify the expulsion of the Chagos islanders from the British Indian Ocean Territory (BIOT). Into the twenty-first century, this forced elision of the UK’s interests with the imperial “common good” continues to take centre stage in courtroom battles over the islanders’ rights, being cited before domestic and international tribunals in order to maintain the Chagossians’ exclusion from their homeland. This article considers the new jurisprudence of imperialism which has emerged in a string of decisions which have continued to marginalise the Chagossians’ interests

Plasma cholesterol levels and brain development in preterm newborns.

BackgroundTo assess whether postnatal plasma cholesterol levels are associated with microstructural and macrostructural regional brain development in preterm newborns.MethodsSixty preterm newborns (born 24-32 weeks gestational age) were assessed using MRI studies soon after birth and again at term-equivalent age. Blood samples were obtained within 7 days of each MRI scan to analyze for plasma cholesterol and lathosterol (a marker of endogenous cholesterol synthesis) levels. Outcomes were assessed at 3 years using the Bayley Scales of Infant Development, Third Edition.ResultsEarly plasma lathosterol levels were associated with increased axial and radial diffusivities and increased volume of the subcortical white matter. Early plasma cholesterol levels were associated with increased volume of the cerebellum. Early plasma lathosterol levels were associated with a 2-point decrease in motor scores at 3 years.ConclusionsHigher early endogenous cholesterol synthesis is associated with worse microstructural measures and larger volumes in the subcortical white matter that may signify regional edema and worse motor outcomes. Higher early cholesterol is associated with improved cerebellar volumes. Further work is needed to better understand how the balance of cholesterol supply and endogenous synthesis impacts preterm brain development, especially if these may be modifiable factors to improve outcomes

Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus

Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 (PRDM5) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus (P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to dat

Using imputation to provide harmonized longitudinal measures of cognition across AIBL and ADNI

To improve understanding of Alzheimer’s disease, large observational studies are needed to increase power for more nuanced analyses. Combining data across existing observational studies represents one solution. However, the disparity of such datasets makes this a non-trivial task. Here, a machine learning approach was applied to impute longitudinal neuropsychological test scores across two observational studies, namely the Australian Imaging, Biomarkers and Lifestyle Study (AIBL) and the Alzheimer\u27s Disease Neuroimaging Initiative (ADNI) providing an overall harmonised dataset. MissForest, a machine learning algorithm, capitalises on the underlying structure and relationships of data to impute test scores not measured in one study aligning it to the other study. Results demonstrated that simulated missing values from one dataset could be accurately imputed, and that imputation of actual missing data in one dataset showed comparable discrimination (p \u3c 0.001) for clinical classification to measured data in the other dataset. Further, the increased power of the overall harmonised dataset was demonstrated by observing a significant association between CVLT-II test scores (imputed for ADNI) with PET Amyloid-β in MCI APOE-ε4 homozygotes in the imputed data (N = 65) but not for the original AIBL dataset (N = 11). These results suggest that MissForest can provide a practical solution for data harmonization using imputation across studies to improve power for more nuanced analyses