Directed growth of early cortical axons is influenced by a chemoattractant released from an intermediate target

Projection neurons throughout the mature mammalian neocortex extend efferent axons either through the ventrolaterally positioned internal capsule to subcortical targets or through the dorsally located midline corpus callosum to the contralateral cortex. In rats, the internal capsule is pioneered on E14, but the corpus callosum is not pioneered until E17, even though these two types of projection neurons are generated at the same time. Here we use axonal markers to demonstrate that early cortical axon growth is directed toward the nascent internal capsule, which could account for the timing difference in the development of the two efferent pathways, This directed axon growth may be due to a chemoattractant and/or a chemorepellent secreted by intermediate targets of corlical efferent axons, the nascent internal capsule, or the medial wall of the dorsal telencephalon (MDT), respectively, To test for these soluble activities, explants of E15 rat neocortex and intermediate targets were cocultured in collagen gels. Cortical axon outgrowth was directed toward the internal capsule, but outgrowth was nondirected and suppressed when cocultured with MDT, suggesting that the internal capsule releases a chemoattractant for cortical axons, whereas the MDT releases a chemosuppressant. Because the chemoattractant Netrin-1 is expressed in the internal capsule, we cocultured cortical explants with E13 rat floor plate, which expresses Netrin-1, or with Netrin-1-transfected or control-transfected 293T cells. Cortical axon growth was directed toward both floor plate and Netrin-1-transfected 293T cells, as it had been toward the internal capsule, but not toward control-transfected 293T cells. These findings suggest that early events in cortical axon pathfinding may be controlled by a soluble activity which attracts initial axon growth toward the internal capsule and that this activity may be due to Netrin-1

Numerics of boundary-domain integral and integro-differential equations for BVP with variable coefficient in 3D

This is the post-print version of the article. The official published version can be accessed from the links below - Copyright @ 2013 Springer-VerlagA numerical implementation of the direct boundary-domain integral and integro-differential equations, BDIDEs, for treatment of the Dirichlet problem for a scalar elliptic PDE with variable coefficient in a three-dimensional domain is discussed. The mesh-based discretisation of the BDIEs with tetrahedron domain elements in conjunction with collocation method leads to a system of linear algebraic equations (discretised BDIE). The involved fully populated matrices are approximated by means of the H-Matrix/adaptive cross approximation technique. Convergence of the method is investigated.This study is partially supported by the EPSRC grant EP/H020497/1:"Mathematical Analysis of Localised-Boundary-Domain Integral Equations for Variable-Coefficients Boundary Value Problems"

Increased toxin expression in a Clostridium difficile mfd mutant

BACKGROUND: The symptoms of Clostridium difficile infection are mediated primarily by two toxins, TcdA and TcdB, the expression of which is governed by a multitude of factors including nutrient availability, growth phase and cell stress. Several global regulators have been implicated in the regulation of toxin expression, such as CcpA and CodY. RESULTS: During attempts to insertionally inactivate a putative secondary cell wall polysaccharide synthesis gene, we obtained several mutants containing off-target insertions. One mutant displayed an unusual branched colony morphology and was investigated further. Marker recovery revealed an insertion in mfd, a gene encoding a transcription-coupled repair factor. The mfd mutant exhibited pleiotropic effects, in particular increased expression of both toxin A and B (TcdA and TcdB) compared to the parental strain. Western blotting and cellular cytotoxicity assays revealed increased expression across all time points over a 24 h period, with inactivation of mfd resulting in at least a 10 fold increase in cell cytotoxicity. qRT-PCR demonstrated the upregulation of both toxins occurred on a transcriptional level. All effects of the mfd mutation were complemented by a plasmid-encoded copy of mfd, showing the effects are not due to polar effects of the intron insertion or to second site mutations. CONCLUSIONS: This study adds Mfd to the repertoire of factors involved in regulation of toxin expression in Clostridium difficile. Mfd is known to remove RNA polymerase molecules from transcriptional sites where it has stalled due to repressor action, preventing transcriptional read through. The consistently high levels of toxin in the C. difficile mfd mutant indicate this process is inefficient leading to transcriptional de-repression

Remotely acting SMCHD1 gene regulatory elements: in silico prediction and identification of potential regulatory variants in patients with FSHD

Background: Facioscapulohumeral dystrophy (FSHD) is commonly associated with contraction of the D4Z4 macro-satellite repeat on chromosome 4q35 (FSHD1) or mutations in the SMCHD1 gene (FSHD2). Recent studies have shown that the clinical manifestation of FSHD1 can be modified by mutations in the SMCHD1 gene within a given family. The absence of either D4Z4 contraction or SMCHD1 mutations in a small cohort of patients suggests that the disease could also be due to disruption of gene regulation. In this study, we postulated that mutations responsible for exerting a modifier effect on FSHD might reside within remotely acting regulatory elements that have the potential to interact at a distance with their cognate gene promoter via chromatin looping. To explore this postulate, genome-wide Hi-C data were used to identify genomic fragments displaying the strongest interaction with the SMCHD1 gene. These fragments were then narrowed down to shorter regions using ENCODE and FANTOM data on transcription factor binding sites and epigenetic marks characteristic of promoters, enhancers and silencers

Questioning Classic Patient Classification Techniques in Gait Rehabilitation: Insights from Wearable Haptic Technology

Classifying stroke survivors based on their walking abilities is an important part of the gait rehabilitation process. It can act as powerful indicator of function and prognosis in both the early days after a stroke and long after a survivor receives rehabilitation. This classification often relies solely on walking speed; a quick and easy measure, with only a stopwatch needed. However, walking speed may not be the most accurate way of judging individual’s walking ability. Advances in technology mean we are now in a position where ubiquitous and wearable technologies can be used to elicit much richer measures to characterise gait. In this paper we present a case study from one of our studies, where within a homogenous group of stroke survivors (based on walking speed classification) important differences in individual results and the way they responded to rhythmic haptic cueing were identified during the piloting of a novel gait rehabilitation technique

Effects of storage temperature on the change in size of Calliphora vicina larvae during preservation in 80% ethanol

The size of immature blowflies is a common measure to estimate the minimum time between death and the discovery of a corpse, also known as the minimum post-mortem interval. This paper investigates the effects of preservation, in 80% ethanol, on the length and weight of first instar, second instar, feeding third instar, and post-feeding third instar Calliphora vicina larvae, at three different storage temperatures. For each larval stage, the length of larvae was recorded after 0 h, 3 h, 6 h, 9 h, 12 h, 24 h, 72 h, 7 days, 14 days, 30 days, 91 days, 182 days, 273 days, and 365 days of storage in 80% ethanol, at −25°C, 6°C and 24°C. Storage temperature had no statistically significant effect on the change in larval length and weight for all larval stages, but larval length and weight were significantly affected by the duration of preservation for first, second, and feeding third instar larvae, but not for post-feeding larvae. Generally, first and second instar larvae reduced in size over time, while feeding third instar larvae increased slightly in size, and post-feeding larvae did not change in size over time. The length of blowfly larvae preserved in 80% ethanol is not affected by constant storage temperatures between −25°C and +24°C, but we recommend that forensic entomologists should use the models provided to correct for changes in larval length that do become apparent over time.Open Access This article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Elective Modernism and the Politics of (Bio) Ethical Expertise

In this essay I consider whether the political perspective of third wave science studies – ‘elective modernism’ – offers a suitable framework for understanding the policy-making contributions that (bio)ethical experts might make. The question arises as a consequence of the fact that I have taken inspiration from the third wave in order to develop an account of (bio)ethical expertise. I offer a précis of this work and a brief summary of elective modernism before considering their relation. The view I set out suggests that elective modernism is a political philosophy and that although its use in relation to the use of scientific expertise in political and policy-making process has implications for the role of (bio)ethical expertise it does not, in the final analysis, provide an account that is appropriate for this latter form of specialist expertise. Nevertheless, it is an informative perspective, and one that can help us make sense of the political uses of (bio)ethical expertise

Field evidence for the upwind velocity shift at the crest of low dunes

Wind topographically forced by hills and sand dunes accelerates on the upwind (stoss) slopes and reduces on the downwind (lee) slopes. This secondary wind regime, however, possesses a subtle effect, reported here for the first time from field measurements of near-surface wind velocity over a low dune: the wind velocity close to the surface reaches its maximum upwind of the crest. Our field-measured data show that this upwind phase shift of velocity with respect to topography is found to be in quantitative agreement with the prediction of hydrodynamical linear analysis for turbulent flows with first order closures. This effect, together with sand transport spatial relaxation, is at the origin of the mechanisms of dune initiation, instability and growth.Comment: 13 pages, 6 figures. Version accepted for publication in Boundary-Layer Meteorolog

Ovarian cancer symptom awareness and anticipated delayed presentation in a population sample

Background: While ovarian cancer is recognised as having identifiable early symptoms, understanding of the key determinants of symptom awareness and early presentation is limited. A population-based survey of ovarian cancer awareness and anticipated delayed presentation with symptoms was conducted as part of the International Cancer Benchmarking Partnership (ICBP). Methods: Women aged over 50 years were recruited using random probability sampling (n = 1043). Computer-assisted telephone interviews were used to administer measures including ovarian cancer symptom recognition, anticipated time to presentation with ovarian symptoms, health beliefs (perceived risk, perceived benefits/barriers to early presentation, confidence in symptom detection, ovarian cancer worry), and demographic variables. Logistic regression analysis was used to identify the contribution of independent variables to anticipated presentation (categorised as < 3 weeks or ≥ 3 weeks). Results: The most well-recognised symptoms of ovarian cancer were post-menopausal bleeding (87.4%), and persistent pelvic (79.0%) and abdominal (85.0%) pain. Symptoms associated with eating difficulties and changes in bladder/bowel habits were recognised by less than half the sample. Lower symptom awareness was significantly associated with older age (p ≤ 0.001), being single (p ≤ 0.001), lower education (p ≤ 0.01), and lack of personal experience of ovarian cancer (p ≤ 0.01). The odds of anticipating a delay in time to presentation of ≥ 3 weeks were significantly increased in women educated to degree level (OR = 2.64, 95% CI 1.61 – 4.33, p ≤ 0.001), women who reported more practical barriers (OR = 1.60, 95% CI 1.34 – 1.91, p ≤ 0.001) and more emotional barriers (OR = 1.21, 95% CI 1.06 – 1.40, p ≤ 0.01), and those less confident in symptom detection (OR = 0.56, 95% CI 0.42 – 0.73, p ≤ 0.001), but not in those who reported lower symptom awareness (OR = 0.99, 95% CI 0.91 – 1.07, p = 0.74). Conclusions: Many symptoms of ovarian cancer are not well-recognised by women in the general population. Evidence-based interventions are needed not only to improve public awareness but also to overcome the barriers to recognising and acting on ovarian symptoms, if delays in presentation are to be minimised

Visual attention and autistic behavior in infants with fragile X syndrome

Fragile X syndrome (FXS) is the leading known inherited cause of intellectual disability and the most common known biological cause of autism. Approximately 25% to 50% of males with FXS meet full diagnostic criteria for autism. Despite the high comorbidity between FXS and autism and the ability to diagnose FXS prenatally or at birth, no studies have examined indicators of autism in infants with FXS. The current study focused on indices of visual attention, one of the earliest and most robust behavioral indicators of autism in idiopathic (non-FXS) autism. Analyses revealed lower HR variability, shallower HR decelerations, and prolonged look durations in 12-month old infants with FXS that were correlated with severity of autistic behavior but not mental age