Polycaprolactone-based scaffold plus recombinant human bone morphogenic protein rhBMP-2) in a sheep thoracic spine fusion model

Adolescent idiopathic scoliosis is a complex three dimensional deformity affecting 2-3% of the general population. The resulting spinal deformity consists of coronal curvature, hypokyphosis of the thoracic spine and vertebral rotation in the axial plane with posterior elements turned into the curve concavity. The potential for curve progression is heightened during the adolescent growth spurt. Success of scoliosis deformity correction depends on solid bony fusion between adjacent vertebrae after the intervertebral (IV) discs have been surgically cleared and the disc spaces filled with graft material. Recently a bioactive and resorbable scaffold fabricated from medical grade polycaprolactone has been developed for bone regeneration at load bearing sites. Combined with rhBMP-2, this has been shown to be successful in acting as a bone graft substitute in a porcine lumbar interbody fusion model when compared to autologous bone graft alone. The study aimed to establish a large animal thoracic spine interbody fusion model, develop spine biodegradable scaffolds (PCL) in combination with biologics (rhBMP-2) and to establish a platform for research into spine tissue engineering constructs. Preliminary results demonstrate higher grades of radiologically evident bony fusion across all levels when comparing fusion scores between the 3 and 6 month postop groups at the PCL CaP coated scaffold level, which is observed to be a similar grade to autograft, while no fusion is seen at the scaffold only level. Results to date suggest that the combination of rhBMP-2 and scaffold engineering actively promotes bone formation, laying the basis of a viable tissue engineered constructs.

I sang Amazing Grace for about 3 hours that day : understanding Indigenous Australians’ experience of seclusion

Research shows that Indigenous Australians suspicion and fear of being ‘locked up’ may influence mental health service avoidance. Given this, the aim of this study was to explore, by qualitative analysis of in depth interviews (N = 3), how three Indigenous people experienced the controversial practice of seclusion Hans-Georg Gadamer’s phenomenology guided analysis of the material, and allowed narrated experiences to be understood within their cultural and historical context. Participants viewed seclusion negatively: police involvement in psychiatric care; perceptions of being punished and powerless; occasions of extreme use of force; and lack of care were prominent themes throughout the interviews. While power imbalances inherent in seclusion are problematic for all mental health clients, the distinguishing factor in the Indigenous clients’ experience is that seclusion is continuous with the discriminatory and degrading treatment by governments, police and health services that many Indigenous people have experienced since colonisation. The participants’ experiences echoed Goffman’s (1961) findings that institutional practices act to degrade and dehumanise clients whose resulting conformity eases the work of nursing staff. While some nurses perceive that seclusion reduces clients’ agitation (Meehan, Bergen & Fjeldsoe, 2004; Wynaden et al., 2001), one must ask at what cost to clients’ dignity, humanity and basic human rights.

Structure and assembly of immature HIV

The major structural components of HIV are synthesized as a 55-kDa polyprotein, Gag. Particle formation is driven by the self-assembly of Gag into a curved hexameric lattice, the structure of which is poorly understood. We used cryoelectron tomography and contrast-transfer-function corrected subtomogram averaging to study the structure of the assembled immature Gag lattice to approximate to 17-angstrom resolution. Gag is arranged in the immature virus as a single, continuous, but incomplete hexameric lattice whose curvature is mediated without a requirement for pentameric defects. The resolution of the structure allows positioning of individual protein domains. High-resolution crystal structures were fitted into the reconstruction to locate protein-protein interfaces involved in Gag assembly, and to identify the structural transformations associated with virus maturation. The results of this study suggest a concept for the formation of nonsymmetrical enveloped viruses of variable sizes.

Three-dimensional analysis of budding sites and released virus suggests a revised model for HIV-1 morphogenesis

Current models of HIV-1 morphogenesis hold that newly synthesized viral Gag polyproteins traffic to and assemble at the cell membrane into spherical protein shells. The resulting late-budding structure is thought to be released by the cellular ESCRT machinery severing the membrane tether connecting it to the producer cell. Using electron tomography and scanning transmission electron microscopy, we find that virions have a morphology and composition distinct from late-budding sites. Gag is arranged as a continuous but incomplete sphere in the released virion. In contrast, late-budding sites lacking functional ESCRT exhibited a nearly closed Gag sphere. The results lead us to propose that budding is initiated by Gag assembly, but is completed in an ESCRT-dependent manner before the Gag sphere is complete. This suggests that ESCRT functions early in HIV-1 release-akin to its role in vesicle formation-and is not restricted to severing the thin membrane tether.

Structural analysis of the roles of influenza A virus membrane-associated proteins in assembly and morphology

The assembly of influenza A virus at the plasma membrane of infected cells leads to release of enveloped virions that are typically round in tissue culture-adapted strains but filamentous in strains isolated from patients. The viral proteins hemagglutinin (HA), neuraminidase (NA), matrix protein 1 (M1), and M2 ion channel all contribute to virus assembly. When expressed individually or in combination in cells, they can all, under certain conditions, mediate release of membrane-enveloped particles, but their relative roles in virus assembly, release, and morphology remain unclear. To investigate these roles, we produced membrane-enveloped particles by plasmid-derived expression of combinations of HA, NA, and M proteins (M1 and M2) or by infection with influenza A virus. We monitored particle release, particle morphology, and plasma membrane morphology by using biochemical methods, electron microscopy, electron tomography, and cryo-electron tomography. Our data suggest that HA, NA, or HANA (HA plus NA) expression leads to particle release through nonspecific induction of membrane curvature. In contrast, coexpression with the M proteins clusters the glycoproteins into filamentous membrane protrusions, which can be released as particles by formation of a constricted neck at the base. HA and NA are preferentially distributed to differently curved membranes within these particles. Both the budding intermediates and the released particles are morphologically similar to those produced during infection with influenza A virus. Together, our data provide new insights into influenza virus assembly and show that the M segment together with either of the glycoproteins is the minimal requirement to assemble and release membrane-enveloped particles that are truly virus-like.

Georg Calixtus and the Humanist tradition

Georg Calixtus (1586–1656) was a Lutheran theologian, prominent in the German lands during the first half of the seventeenth century. Existing research focuses on Calixtus‘ contributions to religious and theological debates, particularly in regard to his role in the Syncretistic Controversy of the latter half of the seventeenth century, and in regard to his unique position as a Lutheran who aspired to reunion between the different Christian confessions. This thesis problematises this focus on Calixtus by theologians and ecclesiastical historians, and argues that the genesis and transmission of his ideas cannot be fully appreciated without considering his relationship with the broader intellectual milieu of early modern Europe. It does this by exploring Calixtus‘ interaction with the humanist tradition, in particular by reconsidering his relationship with Isaac Casaubon (1559–1614), and by exploring his work in light of intellectual movements that were taking place outside the Christian church. In so doing, this thesis argues that Calixtus made contributions to early modern thought that have been overlooked in the existing literature. It also becomes apparent that much research remains to be done to gain a more accurate picture of his place in the early modern intellectual landscape, and of his legacy to later generations of scholars.

Georg Calixtus, Isaac Casaubon, and the Consensus of Antiquity

This article explores the relationship between Georg Calixtus (1586-1656) and Isaac Casaubon (1559-1614). It does this in order to highlight an oversight in the existing literature concerning Calixtus, and to encourage scholars to revisit the work of Early Modern figures who have previously been considered only from modern disciplinary perspectives. By emphasizing the relationship between Calixtus and Casaubon, this article argues that Calixtus was potentially exposed to much broader circles of intellectual debate than has previously been considered, and that a reevaluation of his work in light of these debates is therefore in order.

Scientia temporum & rerum : History or Antiquarianism? The collection of examples in Georg Calixtus' De studio historiarum oratio (1629)

This paper explores an early modern application of the Stoic principle of similitudo temporum to the study of history. In so doing, it highlights the tension between historiography and antiquarianism, suggesting that the collection of remains – whether material or immaterial – was understood in at least some early modern circles as an integral part of the historiographic process. It also emphasises the evolving meaning of “history” during this time, drawing attention to the perceived novelty of such antiquarian approaches to the study of the past, and briefly exploring subtle differences between the example at hand and the work and activities of better-known figures such as Nicolas-Claude Fabri de Peiresc and Justus Lipsius. As such, this paper makes a contribution to our evolving understanding of early modern scholarship, and draws attention to the variegated approaches of its practitioners to contemporary issues.

A new life of Hans Christian Andersen : a study of the ‘peculiar nature’ of an author’s life

A review of "Hans Christian Andersen : European Witness" by Paul Binding (Yale UP, 2014). How a writer bears witness to his age is necessarily the expression of many things, not least the possibly quite peculiar nature of an author’s life. Literary works often emerge from complex upbringings, from periods of youthful isolation spent reading and writing. More still seem to have been written as a result of the fraught relationships that befall authors, perhaps because authors so often view their relationships with a degree of creative and critical distance. And yet, if a writer’s output evidences an unusual life, it also witnesses broader questions being asked by a community as a whole. At some level, even the most remarkable figures are typical of their age, and reflections of it. By the close of Paul Binding’s study of the life and works of Hans Christian Andersen (1805–75), we are reminded that extraordinary feats of originality and imagination are often the result of how unique minds enter wider discourses...

New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10−8). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Directional dominance on stature and cognition in diverse human populations

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3, 4. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10−300, 2.1 × 10−6, 2.5 × 10−10 and 1.8 × 10−10, respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months’ less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5, 6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.