Restrictive covenants in Xanadu

Legal scholarship is naturally inclined towards explanations and justifications of contemporary law. In the case of restrictive covenants and building schemes this has led to a distorted perception of the historical record, as revealed in recorded case reports dating from the nineteenth century. It is argued that the restrictive covenant had its historical genesis not in a response to industrialisation and mass urbanisation, but in the developments of resort towns in the eighteenth and early nineteenth centuries, as a response to the needs of land developers. Furthermore, it is argued that a better historical understanding of these origins illuminates contemporary problems concerned with the adaptability of law and the potential roles of law in development

Computerised cognitive assessment in patients with traumatic brain injury: an observational study of feasibility and sensitivity relative to established clinical scales

Background: Online technology could potentially revolutionise how patients are cognitively assessed and monitored. However, it remains unclear whether assessments conducted remotely can match established pen-and-paper neuropsychological tests in terms of sensitivity and specificity. Methods: This observational study aimed to optimise an online cognitive assessment for use in traumatic brain injury (TBI) clinics. The tertiary referral clinic in which this tool has been clinically implemented typically sees patients a minimum of 6 months post-injury in the chronic phase. Between March and August 2019, we conducted a cross-group, cross-device and factor analyses at the St. Mary's Hospital TBI clinic and major trauma wards at Imperial College NHS trust and St. George's Hospital in London (UK), to identify a battery of tasks that assess aspects of cognition affected by TBI. Between September 2019 and February 2020, we evaluated the online battery against standard face-to-face neuropsychological tests at the Imperial College London research centre. Canonical Correlation Analysis (CCA) determined the shared variance between the online battery and standard neuropsychological tests. Finally, between October 2020 and December 2021, the tests were integrated into a framework that automatically generates a results report where patients’ performance is compared to a large normative dataset. We piloted this as a practical tool to be used under supervised and unsupervised conditions at the St. Mary's Hospital TBI clinic in London (UK). Findings: The online assessment discriminated processing-speed, visual-attention, working-memory, and executive-function deficits in TBI. CCA identified two significant modes indicating shared variance with standard neuropsychological tests (r = 0.86, p < 0.001 and r = 0.81, p = 0.02). Sensitivity to cognitive deficits after TBI was evident in the TBI clinic setting under supervised and unsupervised conditions (F (15,555) = 3.99; p < 0.001). Interpretation: Online cognitive assessment of TBI patients is feasible, sensitive, and efficient. When combined with normative sociodemographic models and autogenerated reports, it has the potential to transform cognitive assessment in the healthcare setting. Funding: This work was funded by a National Institute for Health Research (NIHR) Invention for Innovation (i4i) grant awarded to DJS and AH ( II-LB-0715-20006)

The Oogenic Germline Starvation Response in C. elegans

Many animals alter their reproductive strategies in response to environmental stress. Here we have investigated how L4 hermaphrodites of Caenorhabditis elegans respond to starvation. To induce starvation, we removed food at 2 h intervals from very early- to very late-stage L4 animals. The starved L4s molted into adulthood, initiated oogenesis, and began producing embryos; however, all three processes were severely delayed, and embryo viability was reduced. Most animals died via ‘bagging,’ because egg-laying was inhibited, and embryos hatched in utero, consuming their parent hermaphrodites from within. Some animals, however, avoided bagging and survived long term. Long-term survival did not rely on embryonic arrest but instead upon the failure of some animals to produce viable progeny during starvation. Regardless of the bagging fate, starved animals showed two major changes in germline morphology: All oogenic germlines were dramatically reduced in size, and these germlines formed only a single oocyte at a time, separated from the remainder of the germline by a tight constriction. Both changes in germline morphology were reversible: Upon re-feeding, the shrunken germlines regenerated, and multiple oocytes formed concurrently. The capacity for germline regeneration upon re-feeding was not limited to the small subset of animals that normally survive starvation: When bagging was prevented ectopically by par-2 RNAi, virtually all germlines still regenerated. In addition, germline shrinkage strongly correlated with oogenesis, suggesting that during starvation, germline shrinkage may provide material for oocyte production. Finally, germline shrinkage and regeneration did not depend upon crowding. Our study confirms previous findings that starvation uncouples germ cell proliferation from germline stem cell maintenance. Our study also suggests that when nutrients are limited, hermaphrodites scavenge material from their germlines to reproduce. We discuss our findings in light of the recently proposed state of dormancy, termed Adult Reproductive Diapause

Regulation of signal duration and the statistical dynamics of kinase activation by scaffold proteins

Scaffolding proteins that direct the assembly of multiple kinases into a spatially localized signaling complex are often essential for the maintenance of an appropriate biological response. Although scaffolds are widely believed to have dramatic effects on the dynamics of signal propagation, the mechanisms that underlie these consequences are not well understood. Here, Monte Carlo simulations of a model kinase cascade are used to investigate how the temporal characteristics of signaling cascades can be influenced by the presence of scaffold proteins. Specifically, we examine the effects of spatially localizing kinase components on a scaffold on signaling dynamics. The simulations indicate that a major effect that scaffolds exert on the dynamics of cell signaling is to control how the activation of protein kinases is distributed over time. Scaffolds can influence the timing of kinase activation by allowing for kinases to become activated over a broad range of times, thus allowing for signaling at both early and late times. Scaffold concentrations that result in optimal signal amplitude also result in the broadest distributions of times over which kinases are activated. These calculations provide insights into one mechanism that describes how the duration of a signal can potentially be regulated in a scaffold mediated protein kinase cascade. Our results illustrate another complexity in the broad array of control properties that emerge from the physical effects of spatially localizing components of kinase cascades on scaffold proteins.Comment: 12 pages, 6 figure

Investigating the complex genetic architecture of ankle-brachial index, a measure of peripheral arterial disease, in non-Hispanic whites

<p>Abstract</p> <p>Background</p> <p>Atherosclerotic peripheral arterial disease (PAD) affects 8–10 million people in the United States and is associated with a marked impairment in quality of life and an increased risk of cardiovascular events. Noninvasive assessment of PAD is performed by measuring the ankle-brachial index (ABI). Complex traits, such as ABI, are influenced by a large array of genetic and environmental factors and their interactions. We attempted to characterize the genetic architecture of ABI by examining the main and interactive effects of individual single nucleotide polymorphisms (SNPs) and conventional risk factors.</p> <p>Methods</p> <p>We applied linear regression analysis to investigate the association of 435 SNPs in 112 positional and biological candidate genes with ABI and related physiological and biochemical traits in 1046 non-Hispanic white, hypertensive participants from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. The main effects of each SNP, as well as SNP-covariate and SNP-SNP interactions, were assessed to investigate how they contribute to the inter-individual variation in ABI. Multivariable linear regression models were then used to assess the joint contributions of the top SNP associations and interactions to ABI after adjustment for covariates. We reduced the chance of false positives by 1) correcting for multiple testing using the false discovery rate, 2) internal replication, and 3) four-fold cross-validation.</p> <p>Results</p> <p>When the results from these three procedures were combined, only two SNP main effects in <it>NOS3</it>, three SNP-covariate interactions (<it>ADRB2 </it>Gly 16 – lipoprotein(a) and <it>SLC4A5 </it>– diabetes interactions), and 25 SNP-SNP interactions (involving SNPs from 29 different genes) were significant, replicated, and cross-validated. Combining the top SNPs, risk factors, and their interactions into a model explained nearly 18% of variation in ABI in the sample. SNPs in six genes (<it>ADD2, ATP6V1B1, PRKAR2B, SLC17A2, SLC22A3, and TGFB3</it>) were also influencing triglycerides, C-reactive protein, homocysteine, and lipoprotein(a) levels.</p> <p>Conclusion</p> <p>We found that candidate gene SNP main effects, SNP-covariate and SNP-SNP interactions contribute to the inter-individual variation in ABI, a marker of PAD. Our findings underscore the importance of conducting systematic investigations that consider context-dependent frameworks for developing a deeper understanding of the multidimensional genetic and environmental factors that contribute to complex diseases.</p

Current trends in leather science

Abstract In preparing the second edition of ‘Tanning Chemistry. The Science of Leather.’, the literature was updated and the content was revised and reviewed. Here, the new findings are presented and discussed. Notable developments include the necessary rethinking of the mechanism of sulfide unhairing because of new understanding of the aqueous chemistry of sulfide species. Revision upwards of the value of the second pKa for sulfide species ionisation means that S2− cannot exist in an aqueous medium, so the unhairing species in hair burn reactions is HS−. Although the technology remains the same, this means the mechanisms of associated reactions such as immunisation must be revised. Rawstock preservation has benefitted from studies of the potential role of materials from plants which accumulate salt, but which also contribute terpene compounds. There is also further discussion on the continuing issue of chromium (VI) in the leather industry. The application to processing of new solvents, ionic liquids and deep eutectics, is the coming technology, which offers transforming options for new chemistries and products. Renewed interest in vegetable tanning and methods of wet white processing are current trends. Also, within the topic of reagent delivery is processing in a solid medium of plastic beads. Graphical abstrac

National and firm-level drivers of the devolution of HRM decision making to line managers

Multinational companies must understand the influences on responsibility for managing people so that they can manage talent consistently thus ensuring that it is transferable across locations. We examine the impact of firm and national level characteristics on the devolution of HRM decision making to line managers. Our analysis draws on data from 2335 indigenous organizations in 21 countries. At the firm level, we found that where the HR function has higher power, devolution is less likely. At the national level, devolution of decision making to line management is more likely in societies with more stringent employment laws and lower power distance

Telomeric Trans-Silencing in Drosophila melanogaster: Tissue Specificity, Development and Functional Interactions between Non-Homologous Telomeres

BACKGROUND: The study of P element repression in Drosophila melanogaster led to the discovery of the telomeric Trans-Silencing Effect (TSE), a homology-dependent repression mechanism by which a P-transgene inserted in subtelomeric heterochromatin (Telomeric Associated Sequences, "TAS") has the capacity to repress in trans, in the female germline, a homologous P-lacZ transgene located in euchromatin. TSE can show variegation in ovaries, displays a maternal effect as well as an epigenetic transmission through meiosis and involves heterochromatin and RNA silencing pathways. PRINCIPAL FINDINGS: Here, we analyze phenotypic and genetic properties of TSE. We report that TSE does not occur in the soma at the adult stage, but appears restricted to the female germline. It is detectable during development at the third instar larvae where it presents the same tissue specificity and maternal effect as in adults. Transgenes located in TAS at the telomeres of the main chromosomes can be silencers which in each case show the maternal effect. Silencers located at non-homologous telomeres functionally interact since they stimulate each other via the maternally-transmitted component. All germinally-expressed euchromatic transgenes tested, located on all major chromosomes, were found to be repressed by a telomeric silencer: thus we detected no TSE escaper. The presence of the euchromatic target transgene is not necessary to establish the maternal inheritance of TSE, responsible for its epigenetic behavior. A single telomeric silencer locus can simultaneously repress two P-lacZ targets located on different chromosomal arms. CONCLUSIONS AND SIGNIFICANCE: Therefore TSE appears to be a widespread phenomenon which can involve different telomeres and work across the genome. It can explain the P cytotype establishment by telomeric P elements in natural Drosophila populations

Openness in participation, assessment, and policy making upon issues of environment and environmental health: a review of literature and recent project results

Issues of environment and environmental health involve multiple interests regarding e.g. political, societal, economical, and public concerns represented by different kinds of organizations and individuals. Not surprisingly, stakeholder and public participation has become a major issue in environmental and environmental health policy and assessment. The need for participation has been discussed and reasoned by many, including environmental legislators around the world. In principle, participation is generally considered as desirable and the focus of most scholars and practitioners is on carrying out participation, and making participation more effective. In practice also doubts regarding the effectiveness and importance of participation exist among policy makers, assessors, and public, leading even to undermining participatory practices in policy making and assessment