A window to the first stars: An investigation of chemically near-pristine environments.

The first stars in the Universe are an elusive stellar population that we know relatively little about. They are the only stellar population to necessarily form in the absence of metals. Thus, they are in principle easy to identify. However, we are yet to detect a metal-free star in the local Universe. The fusion of metals in the cores of these first stars marks the onset of complex chemical evolution. The eventual collapse of massive (>10M_sun) metal-free stars released the first instances of metals into the surrounding environment. From simulations of stellar evolution, we know that stars with different properties produce different chemical patterns. Thus, to study these stars, we can search for environments that have retained the chemical fingerprint of the first supernovae. It is the environments that have experienced minimal processing through stars that are likely to showcase the chemistry of the first stellar population. These `windows to the first stars' can be identified through their lack of metals. This thesis presents a novel stochastic chemical enrichment model that uses the chemistry of relic environments to investigate the properties of the enriching stellar population. This model, along with nucleosynthetic yield calculations, allows us to investigate the number of massive stars that have chemically contributed to an environment, the mass distribution of the enriching population, the typical explosion energy of their supernovae, and the degree of mixing between the stellar layers. The utility of this model is shown by searching for the chemical fingerprint of the first stars in both the most metal-poor damped Lyman-alpha systems (DLAs) and the most metal-poor stars in the halo of the Milky Way. We also present and analyse new observational data of near-pristine DLAs. This includes the first bound on the carbon isotope ratio of a chemically near-pristine DLA. This isotope ratio can be used to investigate enrichment from low mass ( ~1M_sun) metal-free stars. The full complement of chemistry available for this DLA suggests that it may have experienced a hiatus in star formation following the epoch of reionisation. Finally, we present the precise [O/Fe] abundance determinations of two near-pristine DLAs. This investigation aims to establish whether [O/Fe] is elevated amongst the most metal-poor DLAs. The ultimate goal of this thesis is to investigate the properties of the first stars through their surviving chemistry and establish the most useful metals to utilise to this end. There is a focus on the most metal-poor DLAs and their role in early chemical enrichment and galaxy evolution

Weighing harms, benefits, and alternatives for a young man with a recent flare of ulcerative colitis

A critical appraisal and clinical application of Sandborn WJ, Su C, Sands B, et al. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2017 May 4;376(18):1723-1736. doi: 10.1056/NEJMoa160691

Not too big, not too small:blood pressure cuff size matters

[No abstract

Chronicles of Oklahoma

Article describes the history of Seminole origins, leadership, warfare, treaties with the United States government, and complex pattern of being uprooted and transplanted through droughts and battles

Towards ultra metal-poor DLAs: linking the chemistry of the most metal-poor DLA to the first stars

We present new Keck/HIRES data of the most metal-poor damped Lyman-alpha (DLA) system currently known. By targeting the strongest accessible Fe II features, we have improved the upper limit of the [Fe/H] abundance determination by ~1 dex, finding [Fe/H]<-3.66 (2 sigma). We also provide the first upper limit on the relative abundance of an odd-atomic number element for this system [Al/H]<-3.82 (2 sigma). Our analysis thus confirms that this z_abs=3.07 DLA is not only the most metal-poor DLA but also the most iron-poor DLA currently known. We use the chemistry of this DLA, combined with a stochastic chemical enrichment model, to probe its enrichment history. We find that this DLA is best modelled by the yields of an individual Population III progenitor rather than multiple Population III stars. We then draw comparisons with other relic environments and, particularly, the stars within nearby ultra-faint dwarf galaxies. We identify a star within Bootes I, with a similar chemistry to that of the DLA presented here, suggesting that it may have been born in a gas cloud that had similar properties. The extremely metal-poor DLA at redshift z_abs=3.07 (i.e. ~2 Gyrs after the Big Bang) may reside in one of the least polluted environments in the early Universe.Comment: 15 pages, 12 figures, accepted for publication in Monthly Notices of the Royal Astronomical Societ

Continuous integrated biologics manufacturing

Biosimilars and patent expiry are forcing the biopharma industry to find new ways to maintain competitiveness by ensuring affordability, quality, and delivery performance. Despite great improvements in upstream processing (USP) efficiency, higher titres create downstream processing (DSP) bottlenecks and facility fit issues: Equipment reaches its physical and capacity limits thereby increasing processing time, material consumption and overall cost. Continuous processes have been proposed as a solution to many of these issues as they offer higher productivity while reducing cycle times, buffer/resin usage and required footprint. A consortium of UK based biopharmaceutical companies, suppliers and not for profit research organisations, funded by an Innovate UK grant, has been created and will investigate how such an integrated, continuous downstream process system can be realised. The system has been constructed and is currently operating at the Centre for Process Innovation at Darlington, UK. The project combines and condenses multiple DSP unit operations to function as one uninterrupted system with integrated analytics and overarching automated control. The aim is to create an operationally-efficient, multi-product platform which replicates the functionality of a larger plant processing 100 L feedstock per day (independent of product titre). The integrated unit will be tested on several biologic processes demonstrating the system’s potential to enable product changeover, increased facility flexibility and productivity. Significant focus will be given to process validation procedures and the use of low level control to achieve process stability (steady state) and maintain acceptable product quality. This work will lay the foundation for real-time release strategies and replace drug substance release testing. This presentation will provide an overview of the project and show recently-acquired data from the automated purification of industry-relevant monoclonal antibodies. In doing so, this will highlight the applicability and demonstrate the real-world potential for integrated continuous processing to advance the manufacturing of biopharmaceuticals

Primordial Helium-3 Redux: The Helium Isotope Ratio of the Orion Nebula*

We report the first direct measurement of the helium isotope ratio, 3He/4He, outside of the Local Interstellar Cloud, as part of science-verification observations with the upgraded CRyogenic InfraRed Echelle Spectrograph. Our determination of 3He/4He is based on metastable He i* absorption along the line of sight toward Θ2A Ori in the Orion Nebula. We measure a value 3He/4He = (1.77 ± 0.13) × 10−4, which is just ∼40% above the primordial relative abundance of these isotopes, assuming the Standard Model of particle physics and cosmology, (3He/4He)p = (1.257 ± 0.017) × 10−4. We calculate a suite of galactic chemical evolution simulations to study the Galactic build up of these isotopes, using the yields from Limongi & Chieffi for stars in the mass range M = 8–100 M⊙ and Lagarde et al. for M = 0.8–8 M⊙. We find that these simulations simultaneously reproduce the Orion and protosolar 3He/4He values if the calculations are initialized with a primordial ratio ${\left({}^{3}\mathrm{He}{/}^{4}\mathrm{He}\right)}_{{\rm{p}}}=(1.043\pm 0.089)\times {10}^{-4}$. Even though the quoted error does not include the model uncertainty, this determination agrees with the Standard Model value to within ∼2σ. We also use the present-day Galactic abundance of deuterium (D/H), helium (He/H), and 3He/4He to infer an empirical limit on the primordial 3He abundance, ${\left({}^{3}\mathrm{He}/{\rm{H}}\right)}_{{\rm{p}}}\leqslant (1.09\pm 0.18)\times {10}^{-5}$, which also agrees with the Standard Model value. We point out that it is becoming increasingly difficult to explain the discrepant primordial 7Li/H abundance with nonstandard physics, without breaking the remarkable simultaneous agreement of three primordial element ratios (D/H, 4He/H, and 3He/4He) with the Standard Model values

Developing a flexible automated continuous downstream processing system for research to clinical supply

Continuous manufacturing has gained a lot of attention over the last 10-15 years for numerous reasons such as the potential for higher efficiencies, reduced cost of goods, and improved product quality. However, the adoption of these technologies has been slow due to concerns over operating these processes in a GMP manufacturing environment. Some of these concerns relate to the operation of multiple continuous unit operations in an integrated process sequence. This presentation will highlight these concerns and show how these issues were addressed by developing an overarching automated and modular platform which can be easily adapted for processing most products. The developed automation platform is the result of a project funded by Innovate UK that brings together a number of biopharmaceutical companies including Allergan, AstraZeneca, Fujifilm Diosynth Biotechnologies and GSK to identify and address these issues. One objective of the project is to develop a flexible automated biologics downstream process consisting of multiple unit operations that can be rapidly reconfigured for manufacturing different products. To that end the process has been design with modularity in mind with each module having common inputs and outputs. The automation software has also been developed in a way that most typical downstream processes can be implemented in the system with little to no software updates. The ability to rapidly reconfigure the process has been demonstrated by using the system to produce two products with different process sequences. Another issue that inhibits the adoption of continuous technologies is the concern over simultaneously operating multiple unit operations. This presentation will detail how the automation software was developed to control both the key unit operations such as chromatography and filtration steps but also intermediate operations such as feed conditioning and viral inactivation steps. The automated system reduces the complexity of downstream processes, which can have in excess of eleven unit operations, to a single user-friendly interface. Implementing this control platform enables a single operator to control the entire process. This presentation will also detail how the automation strategy has been developed to enable a single operator to deal with start-up/shutdown, perturbations in the process and mid-process equipment turnover. It will highlight the challenges that have been faced when developing this system and how these have been overcome. The aim of this project was to improve efficiency by reducing processing time when compared to the current batch process and this was demonstrated by testing the system with two different products (a MAb and a MAb fusion protein). Furthermore, this presentation with show data from the production of these two products that demonstrates comparability between the continuous process and the original batch processes

The complex interplay between kidney injury and inflammation

Abstract Acute kidney injury (AKI) has gained significant attention following patient safety alerts about the increased risk of harm to patients, including increased mortality and hospitalization. Common causes of AKI include hypovolaemia, nephrotoxic medications, ischaemia and acute glomerulonephritis, although in reality it may be undetermined or multifactorial. A period of inflammation either as a contributor to the kidney injury or resulting from the injury is almost universally seen. This article was compiled following a workshop exploring the interplay between injury and inflammation. AKI is characterized by some degree of renal cell death through either apoptosis or necrosis, together with a strong inflammatory response. Studies interrogating the resolution of renal inflammation identify a whole range of molecules that are upregulated and confirm that the kidneys are able to intrinsically regenerate after an episode of AKI, provided the threshold of damage is not too high. Kidneys are unable to generate new nephrons, and dysfunctional or repeated episodes will lead to further nephron loss that is ultimately associated with the development of renal fibrosis and chronic kidney disease (CKD). The AKI to CKD transition is a complex process mainly facilitated by maladaptive repair mechanisms. Early biomarkers mapping out this process would allow a personalized approach to identifying patients with AKI who are at high risk of developing fibrosis and subsequent CKD. This review article highlights this process and explains how laboratory models of renal inflammation and injury assist with understanding the underlying disease process and allow interrogation of medications aimed at targeting the mechanistic interplay.</jats:p

Cell Senescence-Independent Changes of Human Skin Fibroblasts with Age

Skin ageing is defined, in part, by collagen depletion and fragmentation that leads to a loss of mechanical tension. This is currently believed to reflect, in part, the accumulation of senescent cells. We compared the expression of genes and proteins for components of the extracellular matrix (ECM) as well as their regulators and found that in vitro senescent cells produced more matrix metalloproteinases (MMPs) than proliferating cells from adult and neonatal donors. This was consistent with previous reports of senescent cells contributing to increased matrix degradation with age; however, cells from adult donors proved significantly less capable of producing new collagen than neonatal or senescent cells, and they showed significantly lower myofibroblast activation as determined by the marker α-SMA. Functionally, adult cells also showed slower migration than neonatal cells. We concluded that the increased collagen degradation of aged fibroblasts might reflect senescence, the reduced collagen production likely reflects senescence-independent processes