Enablement by single-use technology of production of two billion vaccine doses of adenovirus-vectored vaccine in under a year

Manufacturing of the simian adenovirus-vectored vaccine ChAdOx1 nCoV-19 (AZD1222, Vaxzevria) has played an important role in control of the COVID-19 pandemic. More than two billion doses have been produced, with the majority both made and used in low and middle income countries. This has been enabled by a programme of early technology transfer to multiple drug substance production sites, occurring in parallel with process development. The University of Oxford was transferring technology to five sites by March 2020, and AstraZeneca subsequently extended the drug substance manufacturing network to 12 countries. This innovative approach was possible only as a result of single-use technology (SUT), and the presentation will provide a case study of the application of such technology to pandemic response. Pre-pandemic research in the Jenner Institute had developed a potentially scalable adenovirus manufacturing process, prioritising simplicity and end-to-end single-use product contact materials to facilitate future technology transfer. From February 2020, this was aggressively scaled up, reaching 200L by April and 1000L by June. In most respects the process scaled linearly, with small-scale work largely predictive of parameters which were successful at large scale. In parallel, process optimisations targeted further simplification. This simple SUT-based process has been the critical factor enabling distributed manufacturing of a novel product type in existing facilities. Several of the facilities contributing to the production (including those in LMICs and the one which has contributed most to global output) had no previous experience of viral vector manufacture, yet were able to rapidly and effectively on-board the process and. Use of shared SUT has also assisted product comparability across the network. SUT has thus played a pivotal role in both scale-up and scale-out, allowing manufacturing to reach a scale we believe to be unprecedented for any viral vector, and making a major contribution to equity of access to COVID-19 vaccines

Control of coordinatively unsaturated Zr sites in ZrO2 for efficient C–H bond activation

Due to the complexity of heterogeneous catalysts, identification of active sites and the ways for their experimental design are not inherently straightforward but important for tailored catalyst preparation. The present study reveals the active sites for efficient C–H bond activation in C1–C4 alkanes over ZrO2 free of any metals or metal oxides usually catalysing this reaction. Quantum chemical calculations suggest that two Zr cations located at an oxygen vacancy are responsible for the homolytic C–H bond dissociation. This pathway differs from that reported for other metal oxides used for alkane activation, where metal cation and neighbouring lattice oxygen form the active site. The concentration of anion vacancies in ZrO2 can be controlled through adjusting the crystallite size. Accordingly designed ZrO2 shows industrially relevant activity and durability in non-oxidative propane dehydrogenation and performs superior to state-of-the-art catalysts possessing Pt, CrOx, GaOx or VOx species

Variations of sedimentary environment under cyclical aridification and impacts on eodiagenesis of tight sandstones from the late Middle Jurassic Shaximiao Formation in Central Sichuan Basin

Understanding eodiagenesis is essential to decoding the diagenetic pathways of tight sandstones that act as excellent unconventional oil & gas reservoirs. Great paleoclimate change is capable of influencing eodiagenetic processes of tight sandstones through variations of sedimentary environment. However, it is less noted how climate gradients between the greenhouse and the hothouse conditions impact the eodiagenesis of tight sandstones. We examined eodiagenetic processes that has been operated in the Shaximiao Formation sandstones using petrographic observation, scanning electron microscopy, geochemistry, and XRD analysis to reveal impacts of the transitional climate changes on the differential eodiagenesis and implications for the diagenesis-porosity evolution. Based on sequence stratigraphy, the Shaximiao Formation is divided into four sub-members SXM1, SXM2, SXM3, and SXM4, respectively. Dark sandstones and mudstones mainly occurred in the SXM1 and the SXM2. Grey-green clastic rocks are dominant in the SXM3, whereas red mudstones frequently appear in the SXM4. Paleoclimate indices denote that a cyclical aridification from the warm-humid to hot-semiarid conditions took place from the SXM1 to the SXM4. It could have been caused by the megamonsoon effect and the paleogeographic shift along with the breakup of the Pangaea supercontinent. Combined with the migration of depocenters, the paleoclimate change resulted in transformation of sediment provenances from mafic igneous rocks to quartzose sedimentary rock along with the decreasing textural maturity. Therefore, sedimentary environments varied from the high-saline to low-saline and from low-oxygen to high-oxygen conditions respectively, which had a crucial impact on eodiagenetic cements which were formed in the Shaximiao Formation. Chlorite and laumontite cement precipitation was promoted by high-saline alkaline fluids. Chlorite proportions show an arched trend from the SXM1 to the SXM4, compatible with those of primary and secondary porosities. In contrast, laumontite proportions exhibit a decreasing variation from the SXM1 to the SXM4. High percentages of early cements are favorable to improving resistance to the compaction and preservation of primary pores. However, high chlorite (>5%) and laumontite (>10%) proportions are destructive for the reservoir quality. Large quantities of laumontite cements occupy primary pores and impede diagenetic fluids flowing and are not favorable to the dissolution. By contrast, an excess of chlorite cements can be dissolved to produce secondary pores during the organic acid release. Thus, the SXM2 is potential as a reservoir for oil & gas. Therefore, those eodiagenetic cements can control the late diagenetic evolution and the reservoir quality. Observations made here have implications for understanding tight sandstone reservoirs elsewhere in the world

Scintigraphic assessment of bone status at one year following hip resurfacing : comparison of two surgical approaches using SPECT-CT scan

Objectives: To study the vascularity and bone metabolism of the femoral head/neck following hip resurfacing arthroplasty, and to use these results to compare the posterior and the trochanteric-flip approaches. Methods: In our previous work, we reported changes to intra-operative blood flow during hip resurfacing arthroplasty comparing two surgical approaches. In this study, we report the vascularity and the metabolic bone function in the proximal femur in these same patients at one year after the surgery. Vascularity and bone function was assessed using scintigraphic techniques. Of the 13 patients who agreed to take part, eight had their arthroplasty through a posterior approach and five through a trochanteric-flip approach. Results: One year after surgery, we found no difference in the vascularity (vascular phase) and metabolic bone function (delayed phase) at the junction of the femoral head/neck between the two groups of patients. Higher radiopharmaceutical uptake was found in the region of the greater trochanter in the trochanteric-flip group, related to the healing osteotomy. Conclusions: Our findings using scintigraphic techniques suggest that the greater intra-operative reduction in blood flow to the junction of the femoral head/neck, which is seen with the posterior approach compared with trochanteric flip, does not result in any difference in vascularity or metabolic bone function one year after surgery

Helicity Analysis of Semileptonic Hyperon Decays Including Lepton Mass Effects

Using the helicity method we derive complete formulas for the joint angular decay distributions occurring in semileptonic hyperon decays including lepton mass and polarization effects. Compared to the traditional covariant calculation the helicity method allows one to organize the calculation of the angular decay distributions in a very compact and efficient way. In the helicity method the angular analysis is of cascade type, i.e. each decay in the decay chain is analyzed in the respective rest system of that particle. Such an approach is ideally suited as input for a Monte Carlo event generation program. As a specific example we take the decay $\Xi^0 \to \Sigma^+ + l^- + \bar{\nu}_l$ ($l^-=e^-, \mu^-$) followed by the nonleptonic decay $\Sigma^+ \to p + \pi^0$ for which we show a few examples of decay distributions which are generated from a Monte Carlo program based on the formulas presented in this paper. All the results of this paper are also applicable to the semileptonic and nonleptonic decays of ground state charm and bottom baryons, and to the decays of the top quark.Comment: Published version. 40 pages, 11 figures included in the text. Typos corrected, comments added, references added and update

Characteristic Evolution and Matching

I review the development of numerical evolution codes for general relativity based upon the characteristic initial value problem. Progress in characteristic evolution is traced from the early stage of 1D feasibility studies to 2D axisymmetric codes that accurately simulate the oscillations and gravitational collapse of relativistic stars and to current 3D codes that provide pieces of a binary black hole spacetime. Cauchy codes have now been successful at simulating all aspects of the binary black hole problem inside an artificially constructed outer boundary. A prime application of characteristic evolution is to extend such simulations to null infinity where the waveform from the binary inspiral and merger can be unambiguously computed. This has now been accomplished by Cauchy-characteristic extraction, where data for the characteristic evolution is supplied by Cauchy data on an extraction worldtube inside the artificial outer boundary. The ultimate application of characteristic evolution is to eliminate the role of this outer boundary by constructing a global solution via Cauchy-characteristic matching. Progress in this direction is discussed.Comment: New version to appear in Living Reviews 2012. arXiv admin note: updated version of arXiv:gr-qc/050809

Proteomics of tissue factor silencing in cardiomyocytic cells reveals a new role for this coagulation factor in splicing machinery control

YesIt has long been known that Tissue Factor (TF) plays a role in blood coagulation and has a direct thrombotic action that is closely related to cardiovascular risk, but it is becoming increasingly clear that it has a much wider range of biological functions that range from inflammation to immunity. It is also involved in maintaining heart haemostasis and structure, and the observation that it is down-regulated in the myocardium of patients with dilated cardiomyopathy suggests that it influences cell-to-cell contact stability and contractility, and thus contributes to cardiac dysfunction. However, the molecular mechanisms underlying these coagulation-independent functions have not yet been fully elucidated. In order to analyse the influence of TF on the cardiomyocitic proteome, we used functional biochemical approaches incorporating label-free quantitative proteomics and gene silencing, and found that this provided a powerful means of identifying a new role for TF in regulating splicing machinery together with the expression of several proteins of the spliceosome, and mRNA metabolism with a considerable impact on cell viability