Bullet impacts and built heritage damage 1640–1939

© 2018, The Author(s). Conflict damage to heritage has been thrust into the global spotlight during recent conflict in the Middle East. While the use of social media has heightened and enhanced public awareness of this ‘cultural terrorism’, the occurrence of this type of vandalism is not new. In fact, as this study demonstrates, evidence of the active targeting of sites, as well as collateral damage when heritage is caught in crossfire, is widely visible around Europe and further afield. Using a variety of case studies ranging from the 1640s to the 1930s, we illustrate and quantify the changing impact of ballistics on heritage buildings as weaponry and ammunition have increased in both energy and energy density potential. In the first instance, this study highlights the increasing threats to heritage in conflict areas. Second, it argues for the pressing need to quantify and map damage to the stonework in order to respond to these challenges

Biomechanics and the thermotolerance of development

Successful completion of development requires coordination of patterning events with morphogenetic movements. Environmental variability challenges this coordination. For example, developing organisms encounter varying environmental temperatures that can strongly influence developmental rates. We hypothesized that the mechanics of morphogenesis would have to be finely adjusted to allow for normal morphogenesis across a wide range of developmental rates. We formulated our hypothesis as a simple model incorporating time-dependent application of force to a viscoelastic tissue. This model suggested that the capacity to maintain normal morphogenesis across a range of temperatures would depend on how both tissue viscoelasticity and the forces that drive deformation vary with temperature. To test this model we investigated how the mechanical behavior of embryonic tissue (Xenopus laevis) changed with temperature; we used a combination of micropipette aspiration to measure viscoelasticity, electrically induced contractions to measure cellular force generation, and confocal microscopy to measure endogenous contractility. Contrary to expectations, the viscoelasticity of the tissues and peak contractile tension proved invariant with temperature even as rates of force generation and gastrulation movements varied three-fold. Furthermore, the relative rates of different gastrulation movements varied with temperature: the speed of blastopore closure increased more slowly with temperature than the speed of the dorsal-to-ventral progression of involution. The changes in the relative rates of different tissue movements can be explained by the viscoelastic deformation model given observed viscoelastic properties, but only if morphogenetic forces increase slowly rather than all at once. © 2014 von Dassow et al

The Multicultural Classroom as a Comparative Law Site: A United Kingdom Perspective

This chapter studies the impact of the recent multicultural approach to comparative legal studies on comparative law teaching, with a focus on British debates and literature. I will argue that the multicultural turn of (comparative) legal teaching, reflected for example in a greater diversity of teaching techniques, a greater emphasis on minority issues and law &… disciplines, responds to a multiplicity of motivations. Pedagogically, it is a response to the increasingly diverse backgrounds of students and their differing intellectual starting-points. Pragmatically, it is a means to boost students’ employability and intellectual versality in a job market that now values “cultural awareness skills”. Finally, conceptually, it is a tool designed to unravel the pluralistic nature of law. From these diverse drivers to the multicultural turn in (comparative) legal teaching, it is possible to identify similarities with other recent trends of globalisation and internationalisation of legal education. However, this article will submit that differences remain. Having analysed these differences, I will go on to argue and reveal that in them lie the core features of a multicultural approach to legal teaching and its intrinsic connections to comparative law, as the multicultural classroom itself becomes a comparative law site

Deficient Signaling via Alk2 (Acvr1) Leads to Bicuspid Aortic Valve Development

Bicuspid aortic valve (BAV) is the most common congenital cardiac anomaly in humans. Despite recent advances, the molecular basis of BAV development is poorly understood. Previously it has been shown that mutations in the Notch1 gene lead to BAV and valve calcification both in human and mice, and mice deficient in Gata5 or its downstream target Nos3 have been shown to display BAVs. Here we show that tissue-specific deletion of the gene encoding Activin Receptor Type I (Alk2 or Acvr1) in the cushion mesenchyme results in formation of aortic valve defects including BAV. These defects are largely due to a failure of normal development of the embryonic aortic valve leaflet precursor cushions in the outflow tract resulting in either a fused right- and non-coronary leaflet, or the presence of only a very small, rudimentary non-coronary leaflet. The surviving adult mutant mice display aortic stenosis with high frequency and occasional aortic valve insufficiency. The thickened aortic valve leaflets in such animals do not show changes in Bmp signaling activity, while Map kinase pathways are activated. Although dysfunction correlated with some pro-osteogenic differences in gene expression, neither calcification nor inflammation were detected in aortic valves of Alk2 mutants with stenosis. We conclude that signaling via Alk2 is required for appropriate aortic valve development in utero, and that defects in this process lead to indirect secondary complications later in life

Surprisingly Simple Mechanical Behavior of a Complex Embryonic Tissue

Background: Previous studies suggest that mechanical feedback could coordinate morphogenetic events in embryos. Furthermore, embryonic tissues have complex structure and composition and undergo large deformations during morphogenesis. Hence we expect highly non-linear and loading-rate dependent tissue mechanical properties in embryos. Methodology/Principal Findings: We used micro-aspiration to test whether a simple linear viscoelastic model was sufficient to describe the mechanical behavior of gastrula stage Xenopus laevis embryonic tissue in vivo. We tested whether these embryonic tissues change their mechanical properties in response to mechanical stimuli but found no evidence of changes in the viscoelastic properties of the tissue in response to stress or stress application rate. We used this model to test hypotheses about the pattern of force generation during electrically induced tissue contractions. The dependence of contractions on suction pressure was most consistent with apical tension, and was inconsistent with isotropic contraction. Finally, stiffer clutches generated stronger contractions, suggesting that force generation and stiffness may be coupled in the embryo. Conclusions/Significance: The mechanical behavior of a complex, active embryonic tissue can be surprisingly well described by a simple linear viscoelastic model with power law creep compliance, even at high deformations. We found no evidence of mechanical feedback in this system. Together these results show that very simple mechanical models can be useful in describing embryo mechanics. © 2010 von Dassow et al

Heart Valve Tissue Engineering: Concepts, Approaches, Progress, and Challenges

Potential applications of tissue engineering in regenerative medicine range from structural tissues to organs with complex function. This review focuses on the engineering of heart valve tissue, a goal which involves a unique combination of biological, engineering, and technological hurdles. We emphasize basic concepts, approaches and methods, progress made, and remaining challenges. To provide a framework for understanding the enabling scientific principles, we first examine the elements and features of normal heart valve functional structure, biomechanics, development, maturation, remodeling, and response to injury. Following a discussion of the fundamental principles of tissue engineering applicable to heart valves, we examine three approaches to achieving the goal of an engineered tissue heart valve: (1) cell seeding of biodegradable synthetic scaffolds, (2) cell seeding of processed tissue scaffolds, and (3) in-vivo repopulation by circulating endogenous cells of implanted substrates without prior in-vitro cell seeding. Lastly, we analyze challenges to the field and suggest future directions for both preclinical and translational (clinical) studies that will be needed to address key regulatory issues for safety and efficacy of the application of tissue engineering and regenerative approaches to heart valves. Although modest progress has been made toward the goal of a clinically useful tissue engineered heart valve, further success and ultimate human benefit will be dependent upon advances in biodegradable polymers and other scaffolds, cellular manipulation, strategies for rebuilding the extracellular matrix, and techniques to characterize and potentially non-invasively assess the speed and quality of tissue healing and remodeling

Altered versican cleavage in ADAMTS5 deficient mice : a novel etiology of myxomatous valve disease

AbstractIn fetal valve maturation the mechanisms by which the relatively homogeneous proteoglycan-rich extracellular matrix (ECM) of endocardial cushions is replaced by a specialized and stratified ECM found in mature valves are not understood. Therefore, we reasoned that uncovering proteases critical for ‘remodeling’ the proteoglycan rich (extracellular matrix) ECM may elucidate novel mechanisms of valve development. We have determined that mice deficient in ADAMTS5, (A Disintegrin-like And Metalloprotease domain with ThromboSpondin-type 1 motifs) which we demonstrated is expressed predominantly by valvular endocardium during cardiac valve maturation, exhibited enlarged valves. ADAMTS5 deficient valves displayed a reduction in cleavage of its substrate versican, a critical cardiac proteoglycan. In vivo reduction of versican, in Adamts5−/− mice, achieved through Vcan heterozygosity, substantially rescued the valve anomalies. An increase in BMP2 immunolocalization, Sox9 expression and mesenchymal cell proliferation were observed in Adamts5−/− valve mesenchyme and correlated with expansion of the spongiosa (proteoglycan-rich) region in Adamts5−/− valve cusps. Furthermore, these data suggest that ECM remodeling via ADAMTS5 is required for endocardial to mesenchymal signaling in late fetal valve development. Although adult Adamts5−/− mice are viable they do not recover from developmental valve anomalies and have myxomatous cardiac valves with 100% penetrance. Since the accumulation of proteoglycans is a hallmark of myxomatous valve disease, based on these data we hypothesize that a lack of versican cleavage during fetal valve development may be a potential etiology of adult myxomatous valve disease

An Expanded Set of Amino Acid Analogs for the Ribosomal Translation of Unnatural Peptides

BACKGROUND: The application of in vitro translation to the synthesis of unnatural peptides may allow the production of extremely large libraries of highly modified peptides, which are a potential source of lead compounds in the search for new pharmaceutical agents. The specificity of the translation apparatus, however, limits the diversity of unnatural amino acids that can be incorporated into peptides by ribosomal translation. We have previously shown that over 90 unnatural amino acids can be enzymatically loaded onto tRNA. METHODOLOGY/PRINCIPAL FINDINGS: We have now used a competition assay to assess the efficiency of tRNA-aminoacylation of these analogs. We have also used a series of peptide translation assays to measure the efficiency with which these analogs are incorporated into peptides. The translation apparatus tolerates most side chain derivatives, a few alpha,alpha disubstituted, N-methyl and alpha-hydroxy derivatives, but no beta-amino acids. We show that over 50 unnatural amino acids can be incorporated into peptides by ribosomal translation. Using a set of analogs that are efficiently charged and translated we were able to prepare individual peptides containing up to 13 different unnatural amino acids. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that a diverse array of unnatural building blocks can be translationally incorporated into peptides. These building blocks provide new opportunities for in vitro selections with highly modified drug-like peptides

Transcriptomic analysis of the temporal host response to skin infestation with the ectoparasitic mite Psoroptes ovis

<p>Abstract</p> <p>Background</p> <p>Infestation of ovine skin with the ectoparasitic mite <it>Psoroptes ovis </it>results in a rapid cutaneous immune response, leading to the crusted skin lesions characteristic of sheep scab. Little is known regarding the mechanisms by which such a profound inflammatory response is instigated and to identify novel vaccine and drug targets a better understanding of the host-parasite relationship is essential. The main objective of this study was to perform a combined network and pathway analysis of the <it>in vivo </it>skin response to infestation with <it>P. ovis </it>to gain a clearer understanding of the mechanisms and signalling pathways involved.</p> <p>Results</p> <p>Infestation with <it>P. </it>ovis resulted in differential expression of 1,552 genes over a 24 hour time course. Clustering by peak gene expression enabled classification of genes into temporally related groupings. Network and pathway analysis of clusters identified key signalling pathways involved in the host response to infestation. The analysis implicated a number of genes with roles in allergy and inflammation, including pro-inflammatory cytokines (<it>IL1A, IL1B, IL6, IL8 </it>and <it>TNF</it>) and factors involved in immune cell activation and recruitment (<it>SELE, SELL, SELP, ICAM1, CSF2, CSF3, CCL2 </it>and <it>CXCL2</it>). The analysis also highlighted the influence of the transcription factors NF-kB and AP-1 in the early pro-inflammatory response, and demonstrated a bias towards a Th2 type immune response.</p> <p>Conclusions</p> <p>This study has provided novel insights into the signalling mechanisms leading to the development of a pro-inflammatory response in sheep scab, whilst providing crucial information regarding the nature of mite factors that may trigger this response. It has enabled the elucidation of the temporal patterns by which the immune system is regulated following exposure to <it>P. ovis</it>, providing novel insights into the mechanisms underlying lesion development. This study has improved our existing knowledge of the host response to <it>P. ovis</it>, including the identification of key parallels between sheep scab and other inflammatory skin disorders and the identification of potential targets for disease control.</p