'Education, education, education' : legal, moral and clinical

This article brings together Professor Donald Nicolson's intellectual interest in professional legal ethics and his long-standing involvement with law clinics both as an advisor at the University of Cape Town and Director of the University of Bristol Law Clinic and the University of Strathclyde Law Clinic. In this article he looks at how legal education may help start this process of character development, arguing that the best means is through student involvement in voluntary law clinics. And here he builds upon his recent article which argues for voluntary, community service oriented law clinics over those which emphasise the education of students

Topological Methods for Exploring Low-density States in Biomolecular Folding Pathways

Characterization of transient intermediate or transition states is crucial for the description of biomolecular folding pathways, which is however difficult in both experiments and computer simulations. Such transient states are typically of low population in simulation samples. Even for simple systems such as RNA hairpins, recently there are mounting debates over the existence of multiple intermediate states. In this paper, we develop a computational approach to explore the relatively low populated transition or intermediate states in biomolecular folding pathways, based on a topological data analysis tool, Mapper, with simulation data from large-scale distributed computing. The method is inspired by the classical Morse theory in mathematics which characterizes the topology of high dimensional shapes via some functional level sets. In this paper we exploit a conditional density filter which enables us to focus on the structures on pathways, followed by clustering analysis on its level sets, which helps separate low populated intermediates from high populated uninteresting structures. A successful application of this method is given on a motivating example, a RNA hairpin with GCAA tetraloop, where we are able to provide structural evidence from computer simulations on the multiple intermediate states and exhibit different pictures about unfolding and refolding pathways. The method is effective in dealing with high degree of heterogeneity in distribution, capturing structural features in multiple pathways, and being less sensitive to the distance metric than nonlinear dimensionality reduction or geometric embedding methods. It provides us a systematic tool to explore the low density intermediate states in complex biomolecular folding systems.Comment: 23 pages, 6 figure

A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease

While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics). The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance) predisposed to a complex disease (Parkinson disease [PD]). We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs) that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 × 10−38), survival free of PD (hazards ratio = 19.0, p = 5.43 × 10−48), and PD age at onset (R2 = 0.68, p = 1.68 × 10−51). By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers

Neither Replication nor Simulation Supports a Role for the Axon Guidance Pathway in the Genetics of Parkinson's Disease

Susceptibility to sporadic Parkinson's disease (PD) is thought to be influenced by both genetic and environmental factors and their interaction with each other. Statistical models including multiple variants in axon guidance pathway genes have recently been purported to be capable of predicting PD risk, survival free of the disease and age at disease onset; however the specific models have not undergone independent validation. Here we tested the best proposed risk panel of 23 single nucleotide polymorphisms (SNPs) in two PD sample sets, with a total of 525 cases and 518 controls. By single marker analysis, only one marker was significantly associated with PD risk in one of our sample sets (rs6692804: P = 0.03). Multi-marker analysis using the reported model found a mild association in one sample set (two sided P = 0.049, odds ratio for each score change = 1.07) but no significance in the other (two sided P = 0.98, odds ratio = 1), a stark contrast to the reported strong association with PD risk (P = 4.64×10−38, odds ratio as high as 90.8). Following a procedure similar to that used to build the reported model, simulated multi-marker models containing SNPs from randomly chosen genes in a genome wide PD dataset produced P-values that were highly significant and indistinguishable from similar models where disease status was permuted (3.13×10−23 to 4.90×10−64), demonstrating the potential for overfitting in the model building process. Together, these results challenge the robustness of the reported panel of genetic markers to predict PD risk in particular and a role of the axon guidance pathway in PD genetics in general

Frequency and topography of cerebral microbleeds in dementia with Lewy bodies compared to Alzheimer's disease

AbstractAimTo determine the frequency and topographic distribution of cerebral microbleeds (CMBs) in dementia with Lewy bodies (DLB) in comparison to CMBs in Alzheimer disease dementia (AD).MethodsConsecutive probable DLB (n = 23) patients who underwent 3-T T2* weighted gradient-recalled-echo MRI, and age and gender matched probable Alzheimer's disease patients (n = 46) were compared for the frequency and location of CMBs.ResultsThe frequency of one or more CMBs was similar among patients with DLB (30%) and AD (24%). Highest densities of CMBs were found in the occipital lobes of patients with both DLB and AD. Patients with AD had greater densities of CMBs in the parietal, temporal lobes and infratentorial regions compared to DLB (p < 0.05).ConclusionCMBs are as common in patients with DLB as in patients with AD, with highest densities observed in the occipital lobes, suggesting common pathophysiologic mechanisms underlying CMBs in both diseases

Predominant expression of Alzheimer’s disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts

BIN1 is not expressed in human brain microglial cells. (A) Immunohistochemical staining of adjacent sections of normal human brain cortex with antibodies against BIN1 or Iba1 reveals that BIN1 immunoreactive cells that are morphologically distinct from microglia. The boxed region is shown at a higher magnification on the right. (B) Single and two-color immunostaining of the human brain using antibodies against BIN1 and CD45 reveals that perivenular CD45-positive cells of the hematopoietic lineage do not express BIN1. (TIFF 4392 kb

Success for All in England: Results From the Third Year of a National Evaluation

This article reports the third-year findings of a longitudinal evaluation in England of Success for All (SFA), a comprehensive literacy program. Eighteen SFA schools across England and 18 control schools, matched on prior achievement and demographics, were included in this quasi-experimental study. The results of hierarchical linear modeling analysis reveal a statistically significant positive school-level effect for SFA schools compared with control schools on standardized reading measures of word-level and decoding skills, and there were directionally positive but nonsignificant school-level effects on measures of comprehension and fluency. Practical and policy implications of these findings are discussed, particularly as they relate to recent English government policies encouraging schools to implement research-proven approaches

Pre-neoplastic alterations define CLL DNA methylome and persist through disease progression and therapy

Most human cancers converge to a deregulated methylome with reduced global levels and elevated methylation at select CpG islands. To investigate the emergence and dynamics of the cancer methylome, we characterized genome-wide DNA methylation in preneoplastic monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), including serial samples collected across disease course. We detected the aberrant tumor-associated methylation landscape at CLL diagnosis and found no significant differentially methylated regions in the high-count MBL-to-CLL transition. Patient methylomes showed remarkable stability with natural disease and posttherapy progression. Single CLL cells were consistently aberrantly methylated, indicating a homogeneous transition to the altered epigenetic state and a distinct expression profile together with MBL cells compared with normal B cells. Our longitudinal analysis reveals the cancer methylome to emerge early, which may provide a platform for subsequent genetically driven growth dynamics, and, together with its persistent presence, suggests a central role in disease onset. SigNifiCANCe: DNA methylation data from a large cohort of patients with MBL and CLL show that epigenetic transformation emerges early and persists throughout disease stages with limited subsequent changes. Our results indicate an early role for this aberrant landscape in the normal-to-preneoplastic transition that may reflect a pan-cancer mechanism