Search

This study describes how the application of evolutionary algorithms (EAs) can be used to study motor function in humans with Parkinson’s disease (PD) and in animal models of PD. Human data is obtained using commercially available sensors via a range of non-invasive procedures that follow conventional clinical practice. EAs can then be used to classify human data for a range of uses, including diagnosis and disease monitoring. New results are presented that demonstrate how EAs can also be used to classify fruit flies with and without genetic mutations that cause Parkinson’s by using measurements of the proboscis extension reflex. The case is made for a computational approach that can be applied across human and animal studies of PD and lays the way for evaluation of existing and new drug therapies in a truly objective way.

For too long ‘queer’ has been understood as the antithesis of the domestic, insofar as the domestic is taken to represent the strict heteronormative gender roles that queer seeks to challenge. On t...

This article addresses the important topic of how we discuss the history of the African population in Britain in our public historical spaces. In recent decades historians have established that the African presence in Britain is long-standing and we have also accepted the importance of discussing the impact of the system of Atlantic slavery in our national history. In consequence, information about British involvement in the transatlantic slaving economy has entered school curricula, public historical spaces and public debate. This article suggests that we might want to revisit the presentation of this history as we gain more information about the African presence away from London and the major ports. It suggests that the story of Africans in the provinces is, perhaps, not best explained using the histories of large metropolitan centres and ports deeply entangled with slavery. It argues that the information from Norfolk indicates that we should explore an idea that different regions might have responded to the arrival of Africans in different ways and we might be best served by assuming that there was no such thing as a ‘model’ of British responses to this process. It suggests that we consider a presentation of the history of Norfolk's African population that emphasizes integration, personal agency and the lack of antipathy towards Africans, and does not start from a default assumption of enslavement.

Genetic studies have established that heparan sulphate proteoglycans (HSPGs) are required for signalling by key developmental regulators, including Hedgehog, Wnt/Wg, FGF, and BMP/Dpp. Post-synthetic remodelling of heparan sulphate (HS) by Sulf1 has been shown to modulate these same signalling pathways. Sulf1 codes for an N-acetylglucosamine 6-O-endosulfatase, an enzyme that specifically removes the 6-O sulphate group from glucosamine in highly sulfated regions of HS chains. One striking aspect of Sulf1 expression in all vertebrates is its co-localisation with that of Sonic hedgehog in the floor plate of the neural tube. We show here that Sulf1 is required for normal specification of neural progenitors in the ventral neural tube, a process known to require a gradient of Shh activity. We use single-cell injection of mRNA coding for GFP-tagged Shh in early Xenopus embryos and find that Sulf1 restricts ligand diffusion. Moreover, we find that the endogenous distribution of Shh protein in Sulf1 knockdown embryos is altered, where a less steep ventral to dorsal gradient forms in the absence of Sulf1, resulting in more a diffuse distribution of Shh. These data point to an important role for Sulf1 in the ventral neural tube, and suggests a mechanism whereby Sulf1 activity shapes the Shh morphogen gradient by promoting ventral accumulation of high levels of Shh protein.

Highlights • Dermatofibrosarcoma Protuberans is an uncommon tumour, making up less than 0.1% of all malignancies. • We present a case of a 42 year old man referred by his GP with a lump on the right parietal region of the scalp. • Excision biopsy was performed and on review of the pathology it was noted that the lesion was a Dermatofibrosarcoma Protuberans. • The expected residual scalp defect would be difficult to close with local flaps, so facilitate closure tissue expansion was undertaken for 6 weeks prior to definitive surgery. • With regards to tumours of the head and neck, use of a tissue expander has been recommended to improve cosmetic outcomes following respective surgery with wide margins., Introduction Dermatofibrosarcoma Protuberans is an uncommon tumour, making up less than 0.1% of all malignancies. With regards to soft tissue tumours; this pathology is thought to make up less than 2% of the sum total. Traditionally treatment has been wide local excision, with or without adjuvant radiotherapy. Presentation of case We present a case of a 42 year old man referred by his GP with a lump on the right parietal region of the scalp. An USS done by his GP revealed a complex hypoechoic cystic mass, some 2 cm × 1 cm × 2 cm. Excision biopsy was performed and on review of the pathology it was noted that the lesion was a Dermatofibrosarcoma Protuberans. Due to the relatively low grade of this sarcoma, it was decided to treat with wide local excision with 2–4 cm margins. The expected residual scalp defect would be difficult to close with local flaps. To facilitate closure tissue expansion was undertaken for 6 weeks prior to definitive surgery. Discussion With regards to tumours of the head and neck, use of a tissue expander has been recommended to improve cosmetic outcomes following respective surgery with wide margins. Ultimately the timing of tissue expansion i.e. before/after resection of the tumour, must weight the risk of delayed resective surgery on prognosis against the benefits of this reconstructive technique. Conclusion Head and neck tumours requiring careful reconstruction may benefit from tissue expansion to provide adequate volumes of matching soft tissue, as shown in this case.

Highlights • Cystadenoma of apocrine origin is a tumour of the sweat gland that is benign in nature. • Classification of this pathology is based upon histological characteristics plus histochemical analysis. • Prevalence of cystadenoma has been suggested to be quite rare, in the region of 1 in 1000 of subcutaneous biopsies observed. • Previous classification of cystadenoma via histological and immunohistochemical method; has revealed only two distinct entities and the term hydrocystoma was often used in place of cystadenoma. • More recent studies have suggested that a third type can be identified via immunohistochemical analysis., Introduction Cystadenoma of apocrine origin is a tumour of the sweat gland that is benign in nature. Classification of this pathology is based upon histological characteristics plus histochemical analysis. Prevalence of cystadenoma has been suggested to be quite rare, in the region of 1 in 1000 of subcutaneous biopsies observed. Presentation of case We present a case of a 40 year old man referred by his GP with a suboccipital lump, present for some years. On examination the lump was approximately 4–5 cm in diameter and an unusual punctum was present. The patient proceeded to an excision of the lesion and the gross specimen showed characteristics of a multiloculated cyst, measuring some 5 cm × 3.5 cm. Histopathology of the tumour revealed an apocrine cystadenoma; there were no features suggestive of malignancy. Discussion Previous classification of cystadenoma via histological and immunohistochemical method; has revealed only two distinct entities and the term hydrocystoma was often used in place of cystadenoma. More recent studies have suggested that a third type can be identified via immunohistochemical analysis. This third type; apocrine hydrocystoma, reveals that those previously defined as eccrine in origin may also be related to the apocrine ducts. Conclusion Apocrine cystadenoma remains a benign pathology and treatment should be focussed on excision, without need for further intervention. Apocrine cystadenoma remains a relatively rare pathology, though one which should not recur if adequate treatment is given.

Supplemental Digital Content is available in the text., Rationale: Blood flow–induced shear stress controls endothelial cell (EC) physiology during atherosclerosis via transcriptional mechanisms that are incompletely understood. The mechanosensitive transcription factor TWIST is expressed during embryogenesis, but its role in EC responses to shear stress and focal atherosclerosis is unknown. Objective: To investigate whether TWIST regulates endothelial responses to shear stress during vascular dysfunction and atherosclerosis and compare TWIST function in vascular development and disease. Methods and Results: The expression and function of TWIST1 was studied in EC in both developing vasculature and during the initiation of atherosclerosis. In zebrafish, twist was expressed in early embryonic vasculature where it promoted angiogenesis by inducing EC proliferation and migration. In adult porcine and murine arteries, TWIST1 was expressed preferentially at low shear stress regions as evidenced by quantitative polymerase chain reaction and en face staining. Moreover, studies of experimental murine carotid arteries and cultured EC revealed that TWIST1 was induced by low shear stress via a GATA4-dependent transcriptional mechanism. Gene silencing in cultured EC and EC-specific genetic deletion in mice demonstrated that TWIST1 promoted atherosclerosis by inducing inflammation and enhancing EC proliferation associated with vascular leakiness. Conclusions: TWIST expression promotes developmental angiogenesis by inducing EC proliferation and migration. In addition to its role in development, TWIST is expressed preferentially at low shear stress regions of adult arteries where it promotes atherosclerosis by inducing EC proliferation and inflammation. Thus, pleiotropic functions of TWIST control vascular disease and development.

This article explores British ‘nuclear culture’ by examining how individuals and groups within British government tried to comprehend nuclear weapons after the advent of the hydrogen bomb in 1952. It argues that thinking about nuclear weaponry was not uniform, and there was no monolithic ‘nuclear culture’ in government. Instead, political and social habits interacted with Cold War experience to create views of the nuclear weapon – nuclear cultures – that varied across government to create a diverse, and shifting, set of ideas – nuclear cultures – about what the nuclear weapon meant in British hands, and the role it played in providing military power and political influence.

In order to identify early transcriptional targets of MyoD prior to skeletal muscle differentiation, we have undertaken a transcriptomic analysis on gastrula stage Xenopus embryos in which MyoD has been knocked-down. Our validated list of genes transcriptionally regulated by MyoD includes Esr1 and Esr2, which are known targets of Notch signalling, and Tbx6, mesogenin, and FoxC1; these genes are all are known to be essential for normal somitogenesis but are expressed surprisingly early in the mesoderm. In addition we found that MyoD is required for the expression of myf5 in the early mesoderm, in contrast to the reverse relationship of these two regulators in amniote somites. These data highlight a role for MyoD in the early mesoderm in regulating a set of genes that are essential for both myogenesis and somitogenesis.

The government of the United Kingdom has participated in the development and deployment of nuclear weapons for over 60 years, an involvement beginning during the Second World War, when Winston Chur...

This special issue of the Journal of Genocide Research on nuclear weapons is published in the shadow of the untimely death of a scholar who was extremely keen to play a part in the project from the...

This protocol describes a method to visualise ligands distributed across a field of cells. The ease of expressing exogenous proteins, together with the large size of their cells in early embryos, make Xenopus laevis a useful model for visualising GFP-tagged ligands. Synthetic mRNAs are efficiently translated after injection into early stage Xenopus embryos, and injections can be targeted to a single cell. When combined with a lineage tracer such as membrane tethered RFP, the injected cell (and its descendants) that are producing the overexpressed protein can easily be followed. This protocol describes a method for the production of fluorescently tagged Wnt and Shh ligands from injected mRNA. The methods involve the micro dissection of ectodermal explants (animal caps) and the analysis of ligand diffusion in multiple samples. By using confocal imaging, information about ligand secretion and diffusion over a field of cells can be obtained. Statistical analyses of confocal images provide quantitative data on the shape of ligand gradients. These methods may be useful to researchers who want to test the effects of factors that may regulate the shape of morphogen gradients.

Introduction and objectivesThe zinc-finger transcription factor Krϋppel-like factor 2 (KLF2) transduces blood flow into molecular signals responsible for a wide range of responses within the vasculature. KLF2 maintains a healthy, quiescent endothelial phenotype. Previous studies report a range of phenotypes following morpholino antisense oligonucleotide-induced klf2a knockdown in zebrafish. Targeted genome editing is an increasingly applied method for functional assessment of candidate genes. We therefore generated a stable klf2a mutant zebrafish and characterised its cardiovascular and haematopoietic development.Methods and resultsUsing Transcription Activator-Like Effector Nucleases (TALEN) we generated a klf2a mutant (klf2ash317) with a 14bp deletion leading to a premature stop codon in exon 2. Western blotting confirmed loss of wild type Klf2a protein and the presence of a truncated protein in klf2ash317 mutants. Homozygous klf2ash317 mutants exhibit no defects in vascular patterning, survive to adulthood and are fertile, without displaying previously described morphant phenotypes such as high-output cardiac failure, reduced haematopoetic stem cell (HSC) development or impaired formation of the 5th accessory aortic arch. Homozygous klf2ash317 mutation did not reduce angiogenesis in zebrafish with homozygous mutations in von Hippel Lindau (vhl), a form of angiogenesis that is dependent on blood flow. We examined expression of three klf family members in wildtype and klf2ash317 zebrafish. We detected vascular expression of klf2b (but not klf4a or biklf/klf4b/klf17) in wildtypes but found no differences in expression that might account for the lack of phenotype in klf2ash317 mutants. klf2b morpholino knockdown did not affect heart rate or impair formation of the 5th accessory aortic arch in either wildtypes or klf2ash317 mutants.ConclusionsThe klf2ash317 mutation produces a truncated Klf2a protein but, unlike morpholino induced klf2a knockdown, does not affect cardiovascular development.

The last 30 years have seen an increasing acceptance of an apparently ubiquitous link between the state and the use of force, with violence now seen as a defining attribute of the state. Few have questioned this approach, but it constitutes a significant shift that contrasts with that of previous eras, where violence was a symptom of failure. This unquestioned link would appear to be deepening our problems in considering the difficulties facing liberal democracies at the beginning of the twenty-first century. Resume: Les trente dernieres annees ont vu le renforcement du lien entre l'etat et l'usage de la force et la violence comme un attribut essentiel de l'etat. On a peu conteste cette approche bien qu'elle soit en contradiction avec des interpretations precedentes qui considerait la violence comme l'admission d'un echec. Remettre en question ce lien entre etat et violence permet de reconsiderer les difficultes des democraties liberales au debut du vingt et unieme siecle.

Until the late 1960s most interpretations of Red Friday presented a government wishing to defeat organised labour but caught unprepared and forced to retreat. Recent years have seen growing agreement that the government sought to avoid confrontation, reflecting consensual views of Baldwin's variety of one-nation Conservatism. One important component underpinning this view has been a notion that the government's emergency apparatus was capable of defeating any industrial action, and therefore, that the government chose to avoid conflict. However, examination of government activity reveals that the emergency apparatus was not ready and ministers were concerned about this situation. This information suggests that a reassessment of current interpretations of these events, and of Baldwinian Conservatism more generally, may be productive.

Lin28 family proteins share a unique structure, with both zinc knuckle and cold shock RNA-binding domains, and were originally identified as regulators of developmental timing in Caenorhabditis elegans. They have since been implicated as regulators of pluripotency in mammalian stem cells in culture. Using Xenopus tropicalis, we have undertaken the first analysis of the effects on the early development of a vertebrate embryo resulting from global inhibition of the Lin28 family. The Xenopus genome contains two Lin28-related genes, lin28a and lin28b. lin28a is expressed zygotically, whereas lin28b is expressed both zygotically and maternally. Both lin28a and lin28b are expressed in pluripotent cells of the Xenopus embryo and are enriched in cells that respond to mesoderm-inducing signals. The development of axial and paraxial mesoderm is severely abnormal in lin28 knockdown (morphant) embryos. In culture, the ability of pluripotent cells from the embryo to respond to the FGF and activin/nodal-like mesoderm-inducing pathways is compromised following inhibition of lin28 function. Furthermore, there are complex effects on the temporal regulation of, and the responses to, mesoderm-inducing signals in lin28 morphant embryos. We provide evidence that Xenopus lin28 proteins play a key role in choreographing the responses of pluripotent cells in the early embryo to the signals that regulate germ layer specification, and that this early function is probably independent of the recognised role of Lin28 proteins in negatively regulating let-7 miRNA biogenesis.

The modern infantry soldier is expected to operate across a wide spectrum of operational scenarios from war fighting to humanitarian aid. Deployments can be National, International Single/Joint Services or as part of a coalition with other international services. Key to success in any military operation is the ability for personnel at the combat level to manage and control their environment and to directly influence their situation. This needs to be done in real-time, through decisive actions base on sound and safe situational awareness information. An integrated digital soldier system has recently been designed and developed, which allows combat units to monitor and react to the 'chaos of battle'. This digital mapping, navigation and communication capability has a recognised relationship to the safe operation of combat capability and as such requires an explicit safety argument with associated evidence to demonstrate that residual risk is as low as reasonably practicable. This paper presents the real example of how the risk evaluation and preliminary safety case development was actually done for this new equipment. It was an expression of wish that the safety case would be in electronic format using graphical notations. In this way, the case for safety could be demonstrated remotely and used as programme submission evidence as part of key gateways early in the military procurement cycle. This paper will present the key stages that the programme team went through in developing the preliminary safety case, from hazard identification through to graphical argument construction and on to publication. During this relatively short project it has also been possible to record the resource effort used through this component of the programme, so this is also presented as rich evidence for future programmes. (6 pages)

The duty holder for corporate risk has the responsibility to manage the corporate residual risk portfolio based on the operational profile of the corporate entity. When a new operational requirement is placed on the company, a risk assessment is required to make the risk profile of the new operation explicit to the duty holder. The completeness and accuracy of the information to support his operational decision and the corporate risk exposure is critical to the duty holder.This paper presents a real example of how the risk evaluation was actually done for a new operational requirement to carry out a series of sea-based trials using a small rigid inflatable vessel to evaluate prototype communication equipment. It proposes that corporate benefit balance was improved, since capability was extended with minimum potential for harm. Rather than a hypothetical example, this paper will discuss a real operational requirement, with rich meta-information and will follow through from trial specification, hazard identification to presentation of residual risk profile and operational recommendations. (5 pages)

On 31 July 1925, or ‘Red Friday’ as it came to be known, Stanley Baldwin’s Conservative government intervened in an industrial dispute in the British coalfields, offering to provide an extremely costly subsidy to the coal industry while a Royal Commission examined its economic circumstances. This step averted a national lockout of miners by colliery owners, which would have led to widespread sympathetic industrial action by the members of other British trade unions. Nine months later the failure to find a mutually acceptable solution to the difficulties in the coal industry resulted in the General Strike. At the time, the Red Friday decision was fiercely attacked by many. Yet, the dominant interpretation of this action in recent years has been to see it in the context of what Philip Williamson calls Baldwin’s ‘appeal for industrial peace’: a final attempt at mediation in which, after ‘unsuccessful attempts during July 1925 to reconcile coal owners’ and miners’ leaders, and in the face of threatened strikes by transport unions in support of miners, he [Baldwin] took the large political risk of offering a temporary Government subsidy and a Royal Commission of Inquiry’.1 This reading of Red Friday sits comfortably with the dominant conception of British governance in this and other eras, which emphasises a culture of minimal force, consensus and dialogue.

Since the early 1990s ring-substituted derivatives of amphetamine have been abused widely in the Republic of Ireland. The main ring-substituted amphetamines being abused include methylenedioxyamphetamine (MDA), methylenedioxymethamphetamine (MDMA) and methylenedioxyethamphetamine (MDEA). A newer illicit synthetic analogue, which has been seized to a lesser extent by Irish police, is N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB). The work presented here involved the determination of the type of ring-substituted amphetamines being abused by a group of recovering opiate abusers participating in a methadone maintenance programme in a Dublin Drug Rehabilitation Centre. Urine samples which tested positive for amphetamines and ring-substituted amphetamines via EMIT immunoassay were subjected to further analysis using GC-MS with MBTFA flash derivatization. It was found that the methylenedioxypropanamines were being abused, as was amphetamine itself. However, no abuse of methylenedioxybutanamines or thioamphetamines was observed.