Integration of host strain bioengineering and bioprocess development using ultra-scale down studies to select the optimum combination: An antibody fragment primary recovery case study.

An ultra scale-down primary recovery sequence was established for a platform E. coli Fab production process. It was used to evaluate the process robustness of various bioengineered strains. Centrifugal discharge in the initial dewatering stage was determined to be the major cause of cell breakage. The ability of cells to resist breakage was dependant on a combination of factors including host strain, vector, and fermentation strategy. Periplasmic extraction studies were conducted in shake flasks and it was demonstrated that key performance parameters such as Fab titre and nucleic acid concentrations were mimicked. The shake flask system also captured particle aggregation effects seen in a large scale stirred vessel, reproducing the fine particle size distribution that impacts the final centrifugal clarification stage. The use of scale-down primary recovery process sequences can be used to screen a larger number of engineered strains. This can lead to closer integration with and better feedback between strain development, fermentation development and primary recovery studies. Biotechnol. Bioeng. © 2014 Wiley Periodicals, Inc

The empirical basis for modelling glacial erosion rates

Glaciers are highly effective agents of erosion that have profoundly shaped Earth’s surface, but there is uncertainty about how glacial erosion should be parameterised in landscape evolution models. Glacial erosion rate is usually modelled as a function of glacier sliding velocity, but the empirical basis for this relationship is weak. In turn, climate is assumed to control sliding velocity and hence erosion, but this too lacks empirical scrutiny. Here, we present statistically robust relationships between erosion rates, sliding velocities, and climate from a global compilation of 38 glaciers. We show that sliding is positively and significantly correlated with erosion, and derive a relationship for use in erosion models. Our dataset further demonstrates that the most rapid erosion is achieved at temperate glaciers with high mean annual precipitation, which serve to promote rapid sliding. Precipitation has received little attention in glacial erosion studies, but our data illustrate its importance

Conceptually driven and visually rich tasks in texts and teaching practice: the case of infinite series

The study we report here examines parts of what Chevallard calls the institutional dimension of the students’ learning experience of a relatively under-researched, yet crucial, concept in Analysis, the concept of infinite series. In particular, we examine how the concept is introduced to students in texts and in teaching practice. To this purpose, we employ Duval's Theory of Registers of Semiotic Representation towards the analysis of 22 texts used in Canada and UK post-compulsory courses. We also draw on interviews with in-service teachers and university lecturers in order to discuss briefly teaching practice and some of their teaching suggestions. Our analysis of the texts highlights that the presentation of the concept is largely a-historical, with few graphical representations, few opportunities to work across different registers (algebraic, graphical, verbal), few applications or intra-mathematical references to the concept's significance and few conceptually driven tasks that go beyond practising with the application of convergence tests and prepare students for the complex topics in which the concept of series is implicated. Our preliminary analysis of the teacher interviews suggests that pedagogical practice often reflects the tendencies in the texts. Furthermore, the interviews with the university lecturers point at the pedagogical potential of: illustrative examples and evocative visual representations in teaching; and, student engagement with systematic guesswork and writing explanatory accounts of their choices and applications of convergence tests

Strategies for the delay of surgery in the management of resectable hepatobiliary malignancies during the COVID-19 pandemic

Objective: We aimed to review data about delaying strategies for the management of hepatobiliary cancers requiring surgery during the covid-19 pandemic. Background: Given the covid-19 pandemic, many jurisdictions, to spare resources, have limited access to operating rooms for elective surgical activity, including cancer, thus forcing deferral or cancellation of cancer surgeries. Surgery for hepatobiliary cancer is high-risk and particularly resource-intensive. Surgeons must critically appraise which patients will benefit most from surgery and which ones have other therapeutic options to delay surgery. Little guidance is currently available about potential delaying strategies for hepatobiliary cancers when surgery is not possible. Methods: An international multidisciplinary panel reviewed the available literature to summarize data relating to standard-of-care surgical management and possible mitigating strategies to be used as a bridge to surgery for colorectal liver metastases, hepatocellular carcinoma, gallbladder cancer, intrahepatic cholangiocarcinoma, and hilar cholangiocarcinoma. Results: Outcomes of surgery during the covid-19 pandemic are reviewed. Resource requirements are summarized, including logistics and adverse effects profiles for hepatectomy and delaying strategies using systemic, percutaneous and radiation ablative, and liver embolic therapies. For each cancer type, the long-term oncologic outcomes of hepatectomy and the clinical tools that can be used to prognosticate for individual patients are detailed. Conclusions: There are a variety of delaying strategies to consider if availability of operating rooms decreases. This review summarizes available data to provide guidance about possible delaying strategies depending on patient, resource, institution, and systems factors. Multidisciplinary team discussions should be leveraged to consider patient- and tumour-specific information for each individual case.publishedVersio

Modelling of as manufactured geometry for prediction of impact and compression after impact behaviour of variable angle tow laminates

The development of variable angle tow technology has attracted growing attention in recent years due to its strong potential for structural tailoring. However, the full details of the failure mechanisms of variable angle tow laminates have been as yet unknown, and the design complexity also requires use of numerical analysis and novel techniques for variable angle tow composites. This paper addresses the two main problems for use of variable angle tow laminates in design. Firstly, a mathematical model is presented to build a three-dimensional variable angle tow model which exactly captures the features of as manufactured variable angle tow laminates. Secondly, impact and compression after impact models using three-dimensional detailed finite element analyses are presented to predict the failure behaviour of variable angle tow laminates including delamination evolution and crack propagation. Results obtained from the impact and compression after impact models are validated against experimental data. </jats:p

Evidence-based planning and costing palliative care services for children : novel multi-method epidemiological and economic exemplar

Background: Children’s palliative care is a relatively new clinical specialty. Its nature is multi-dimensional and its delivery necessarily multi-professional. Numerous diverse public and not-for-profit organisations typically provide services and support. Because services are not centrally coordinated, they are provided in a manner that is inconsistent and incoherent. Since the first children’s hospice opened in 1982, the epidemiology of life-limiting conditions has changed with more children living longer, and many requiring transfer to adult services. Very little is known about the number of children living within any given geographical locality, costs of care, or experiences of children with ongoing palliative care needs and their families. We integrated evidence, and undertook and used novel methodological epidemiological work to develop the first evidence-based and costed commissioning exemplar. Methods: Multi-method epidemiological and economic exemplar from a health and not-for-profit organisation perspective, to estimate numbers of children under 19 years with life-limiting conditions, cost current services, determine child/parent care preferences, and cost choice of end-of-life care at home. Results: The exemplar locality (North Wales) had important gaps in service provision and the clinical network. The estimated annual total cost of current children’s palliative care was about £5.5 million; average annual care cost per child was £22,771 using 2007 prevalence estimates and £2,437- £11,045 using new 2012/13 population-based prevalence estimates. Using population-based prevalence, we estimate 2271 children with a life-limiting condition in the general exemplar population and around 501 children per year with ongoing palliative care needs in contact with hospital services. Around 24 children with a wide range of life-limiting conditions require end-of-life care per year. Choice of end-of-life care at home was requested, which is not currently universally available. We estimated a minimum (based on 1 week of end-of-life care) additional cost of £336,000 per year to provide end-of-life support at home. Were end-of-life care to span 4 weeks, the total annual additional costs increases to £536,500 (2010/11 prices). Conclusions: Findings make a significant contribution to population-based needs assessment and commissioning methodology in children’s palliative care. Further work is needed to determine with greater precision which children in the total population require access to services and when. Half of children who died 2002-7 did not have conditions that met the globally used children's palliative care condition categories, which need revision in light of findings

Retrieving hydrological connectivity from empirical causality in karst systems

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Retrieving hydrological connectivity from empirical causality in karst systems

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Activation of XerCD-dif recombination by the FtsK DNA translocase

The FtsK translocase pumps dsDNA directionally at ∼5 kb/s and facilitates chromosome unlinking by activating XerCD site-specific recombination at dif, located in the replication terminus of the Escherichia coli chromosome. We show directly that the γ regulatory subdomain of FtsK activates XerD catalytic activity to generate Holliday junction intermediates that can then be resolved by XerC. Furthermore, we demonstrate that γ can activate XerCD-dif recombination in the absence of the translocase domain, when it is fused to XerCD, or added in isolation. In these cases the recombination products are topologically complex and would impair chromosome unlinking. We propose that FtsK translocation and activation of unlinking are normally coupled, with the translocation being essential for ensuring that the products of recombination are topologically unlinked, an essential feature of the role of FtsK in chromosome segregation

Activation of XerCD-dif recombination by the FtsK DNA translocase

The FtsK translocase pumps dsDNA directionally at ∼5 kb/s and facilitates chromosome unlinking by activating XerCD site-specific recombination at dif, located in the replication terminus of the Escherichia coli chromosome. We show directly that the γ regulatory subdomain of FtsK activates XerD catalytic activity to generate Holliday junction intermediates that can then be resolved by XerC. Furthermore, we demonstrate that γ can activate XerCD-dif recombination in the absence of the translocase domain, when it is fused to XerCD, or added in isolation. In these cases the recombination products are topologically complex and would impair chromosome unlinking. We propose that FtsK translocation and activation of unlinking are normally coupled, with the translocation being essential for ensuring that the products of recombination are topologically unlinked, an essential feature of the role of FtsK in chromosome segregation