“The Dashing Subaltern”: Sir Richard Turner in Retrospect

When war came to Canada in August 1914, thousands rallied to the call to arms. Colonel Sam Huges the charismatic and controversial Minister of Militia and Defence scrapped his department’s meticulous plans for mobilizing the nation’s militia and assumed control with amazing, almost fortuitous, results. By September, 33,000 recruits were training at a hastily constructed Camp Valcartier, Quebec. A month later the first contingent of the legendary Canadian Expeditionary Force (CEF) sailed for England (the largest military force ever to cross the Atlantic up to that time)

The human adenovirus 5 L4 promoter is activated by cellular stress response protein p53

During adenovirus infection, the emphasis of gene expression switches from early genes to late genes in a highly regulated manner. Two gene products, L4-22K and L4-33K, contribute to this switch by activating the Major Late Transcription Unit (MLTU) and regulating the splicing of its transcript. L4-22K and L4-33K expression is driven initially by a recently described L4 promoter (L4P) embedded within the MLTU that is activated by early and intermediate viral factors: E1A, E4 Orf3 and IVa2. Here we show that this promoter is also significantly activated by the cellular stress response regulator, p53. Exogenous expression of p53 activated L4P in reporter assays whilst depletion of endogenous p53 inhibited the induction of L4P by viral activators. Chromatin immunoprecipitation studies showed that p53 associates with L4P and that during adenovirus type 5 (Ad5) infection this association peaks at 12 h.p.i., coinciding with the phase of the infectious cycle when L4P is active, and is then lost as MLP activation commences. P53 activation of L4P is significant during Ad5 infection since depletion of p53 prior to infection of either immortalised or normal cells led to severely reduced late gene expression. The association of p53 with L4P is transient due to the action of products of L4P activity (L4-22K/33K), which establish a negative feedback loop that ensures the transient activity of L4P at the start of the late phase and contributes to an efficient switch from early to late phase virus gene expression

Biochemical and immunological studies of the cellular tumour antigen

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Adenovirus serotype 5 L4-22K and L4-33K proteins have distinct functions in regulating late gene expression

Adenoviruses express up to 20 distinct mRNAs from five major late transcription unit (MLTU) regions, L1 to L5, by differential splicing and polyadenylation of the primary transcript. MLTU expression is regulated at transcriptional and posttranscriptional levels. The L4-33K protein acts as a splicing factor to upregulate several MLTU splice acceptor sites as the late phase progresses. The L4 region also expresses a 22K protein whose sequence is related to the sequence of L4-33K. L4-22K is shown here also to have an important role in regulating the pattern of MLTU gene expression. An adenovirus genome containing a stop codon in the L4-22K open reading frame expressed low levels of both structural and nonstructural late proteins compared to the wild-type (wt) adenovirus genome; a decrease in intermediate proteins, IVa2 and IX, was also observed. However, early protein synthesis and replication were unaffected by the absence of L4-22K. Intermediate and late protein expression was restored to wt levels by L4-22K expressed in trans but not by L4-33K. Increased MLTU promoter activity, resulting from stabilization of the transcriptional activator IVa2 by L4-22K, made a small contribution to this restoration of late gene expression. However, the principal effect of L4-22K was on the processing of MLTU RNA into specific cytoplasmic mRNA. L4-22K selectively increased expression of penton mRNA and protein, whereas splicing to create penton mRNA is known not to be increased by L4-33K. These results indicate that L4-22K plays a key role in the early-late switch in MLTU expression, additional to and distinct from the role of L4-33K

The biophysical effects of Neolithic island colonization: general dynamics and sociocultural implications

Does anthropogenic environmental change constrain long-term sociopolitical outcomes? It is clear that human colonization of islands radically alters their biological and physical systems. Despite considerable contextual variability in the local specificities of this alteration, in this paper I argue that these processes are to some extent regular, predictable, and have socio-political implications. Reviewing the data for post-colonization ecodynamics, I show that Neolithic colonization of previously insulated habitats drives biotic homogenization. I argue that we should expect such homogenization to promote regular types of change in biophysical systems, types of change that can be described in sum as environmentally convergent. Such convergence should have significant implications for human social organization over the long term, and general dynamics of this sort are relevant in the context of understanding remarkably similar social evolutionary trajectories towards wealth-inequality not only islands, but also more generally.This research was undertaken while holding a Renfrew Fellowship in the McDonald Institute for Archaeological Research and Homerton College, University of Cambridge, for which support I am grateful and I acknowledge

TOWARD A MORE JUST AND TRULY INTERNATIONAL EDUCATION

International schools have proliferated in the last 20 years. Although one might expect students who attend such schools to represent a heterogenous, diverse population, in reality, many schools have selective admissions practices, and their education has a strong western influence derived from the few Anglophone countries from which the majority of their teachers come. The problem of practice addressed is a lack of alignment between one school’s mission and values and school practices and curricula that inadvertently continue to promote exclusion and privilege. This organizational improvement plan proposes (a) creating an admissions policy and structure that ensures that the school can include and equitably serve neurodiverse learners; (b) developing an antiracist curriculum that calls on students (and teachers) to reflect on their own privilege and learn to stand up rather than stand by; and (c) reviewing curricula, texts, and library holdings to ensure materials reflect the diversity of the student body. The ultimate goal is to help the organization become more diverse, equitable, and inclusive. Foundational to this work are transformative and transformational leadership approaches, which rely on critique of current practices combined with idealized influence and modelling for the teachers leading the change. The proposed change plan relies on a collaborative approach characterized by empathy for challenges to change; the change plan also attends to the emotional impact of the change process, offers a model for beginning and sustaining change collaboratively, offers a monitoring and evaluation framework, and provides an intentional communication plan

Generation of cell lines to complement Adenovirus vectors using recombination-mediated cassette exchange

Background Adenovirus serotype 5 (Ad5) has many favourable characteristics for development as a gene therapy vector. However, the utility of current Ad5 vectors is limited by transient transgene expression, toxicity and immunogenicity. The most promising form of vector is the high capacity type, which is deleted for all viral genes. However, these vectors can only be produced to relatively low titres and with the aid of helper virus. Therefore a continuing challenge is the generation of more effective Ad5 vectors that can still be grown to high titres. Our approach is to generate complementing cell lines to support the growth of Ad5 vectors with novel late gene deficiencies. Results We have used LoxP/Cre recombination mediated cassette exchange (RMCE) to generate cell lines expressing Ad5 proteins encoded by the L4 region of the genome, the products of which play a pivotal role in the expression of Ad5 structural proteins. A panel of LoxP parent 293 cell lines was generated, each containing a GFP expression cassette under the control of a tetracycline-regulated promoter inserted at a random genome location; the cassette also contained a LoxP site between the promoter and GFP sequence. Clones displayed a variety of patterns of regulation, stability and level of GFP expression. Clone A1 was identified as a suitable parent for creation of inducible cell lines because of the tight inducibility and stability of its GFP expression. Using LoxP-targeted, Cre recombinase-mediated insertion of an L4 cassette to displace GFP from the regulated promoter in this parent clone, cell line A1-L4 was generated. This cell line expressed L4 100K, 22K and 33K proteins at levels sufficient to complement L4-33K mutant and L4-deleted viruses. Conclusions RMCE provides a method for rapid generation of Ad5 complementing cell lines from a pre-selected parental cell line, chosen for its desirable transgene expression characteristics. Parent cell lines can be selected for high or low gene expression, and for tight regulation, allowing viral protein expression to mirror that found during infection. Cell lines derived from a single parent will allow the growth of different vectors to be assessed without the complication of varying complementing protein expression

Arbitration - Sure, but Only on Our Terms: Escape Clauses in Uninsured Motorist Policies - Schaefer v. Allstate Ins. Co.

Historically, the insurance industry has widely used arbitration to resolve disputes.2 Insurance companies have increasingly included escape clauses in their policies.\u27 These clauses allow an insurance company to ignore an arbitrator\u27s award and have a claim directly heard in a trial court if the award exceeds a pre-determined amount.\u27 The Ohio Supreme Court in Schaefer v. Allstate Insurance Co. addressed this issue and decided that the escape clause was unenforceable due to public policy.\u2