ALBERT

Description: A medical grade nitrous oxide (N2O) and gaseous oxygen (GOX) “Nytrox” blend is investigated as a volumetrically-efficient replacement for GOX in SmallSat-scale hybrid propulsion systems. Combined with 3-D printed acrylonitrile butadiene styrene (ABS), the propellants represent a significantly safer, but superior performing, alternative to environmentally-unsustainable spacecraft propellants like hydrazine. In a manner analogous to the creation of soda-water using dissolved carbon dioxide, Nytrox is created by bubbling GOX under pressure into N2O until the solution reaches saturation. Oxygen in the ullage dilutes N2O vapor and increases the required decomposition energy barrier by several orders of magnitude. Thus, risks associated with inadvertent thermal or catalytic N2O decomposition are virtually eliminated. Preliminary results of a test-and-evaluation campaign are reported. A small spacecraft thruster is first tested using gaseous oxygen and 3-D printed ABS as the baseline propellants. Tests were then repeated using Nytrox as a “drop-in” replacement for GOX. Parameters compared include ignition reliability, latency, initiation energy, thrust coefficient, characteristic velocity, specific impulse, combustion efficiency, and fuel regression rate. Tests demonstrate Nytrox as an effective replacement for GOX, exhibiting a slightly reduced specific impulse, but with significantly higher volumetric efficiency. Vacuum specific impulse exceeding 300 s is reported. Future research topics are recommended.

Description: Decabrominated diphenyl ether (BDE-209) is a primary component of the brominated flame retardants used in a variety of industrial and domestic applications. BDE-209 bioaccumulates in aquatic organisms and has been identified as an emerging contaminant that threatens human and ecosystem health. Sequential photolysis-microbial biodegradation processes were utilized here to treat BDE-209 in clay- or soil-water slurries. The removal efficiency of BDE-209 in the clay-water slurries was high; i.e., 96.5%, while that in the soil-water slurries was minimal. In the clay-water slurries the first order rate constants for the UV photolysis and biodegradation of BDE-209 were 0.017 1/day and 0.026 1/day, respectively. UV wavelength and intensity strongly influenced the BDE-209 photolysis and the subsequent biodegradation of photolytic products. Facultative chemotrophic bacteria, including Acidovorax spp., Pseudomonas spp., Novosphingobium spp. and Sphingomonas spp., were the dominant members of the bacterial community (about 71%) at the beginning of the biodegradation; many of these organisms have previously been shown to biodegrade BDE-209 and other polybrominated diphenyl ether (PBDE) congeners. The Achromobacter sp. that were isolated (NH-2; NH-4; NH-6) were especially effective during the BDE-209 degradation. These results indicated the effectiveness of the sequential UV photolysis and biodegradation for treating certain BDE-209-contaminated solids; e.g., clays; in bioreactors containing such solids as aqueous slurries. Achieving a similar treatment effectiveness for more heterogeneous solids containing natural organic matter, e.g., surface solids, appears to be significantly more difficult. Further investigations are needed in order to understand the great difference between the clay-water or soil-water slurries.

Description: High levels of storage iron may increase malaria susceptibility. This risk has not been investigated in semi-immune adolescents. We investigated whether baseline iron status of non-pregnant adolescent girls living in a high malaria transmission area in Burkina Faso affected malaria risk during the following rainy season. For this prospective study, we analysed data from an interim safety survey, conducted six months into a randomised iron supplementation trial. We used logistic regression to model the risk of P. falciparum infection prevalence by microscopy, the pre-specified interim safety outcome, in relation to iron status, nutritional indicators and menarche assessed at recruitment. The interim survey was attended by 1223 (82%) of 1486 eligible participants, 1084 (89%) of whom were

Description: Ergot, fungal genus Claviceps, are worldwide distributed grass pathogens known for their production of toxic ergot alkaloids (EAs) and the great agricultural impact they have on both cereal crop and farm animal production. EAs are traditionally considered as the only factor responsible for ergot toxicity. Using broad sampling covering 13 ergot species infecting wild or agricultural grasses (including cereals) across Europe, USA, New Zealand, and South Africa we showed that the content of ergochrome pigments were comparable to the content of EAs in sclerotia. While secalonic acids A–C (SAs), the main ergot ergochromes (ECs), are well known toxins, our study is the first to address the question about their contribution to overall ergot toxicity. Based on our and published data, the importance of SAs in acute intoxication seems to be negligible, but the effect of chronic exposure needs to be evaluated. Nevertheless, they have biological activities at doses corresponding to quantities found in natural conditions. Our study highlights the need for a re-evaluation of ergot toxicity mechanisms and further studies of SAs’ impact on livestock production and food safety.

Description: Mounting evidence suggests that dietary oligosaccharides promote brain development. This study assessed the capacity of oligofructose (OF) alone or in combination with 2′-fucosyllactose (2′-FL) to alter recognition memory, structural brain development, and hippocampal gene expression. Beginning on postnatal day (PND) 2, male pigs received one of three milk replacers formulated to contain OF, OF + 2′-FL, or no oligosaccharides (CON). Pigs were tested on the novel object recognition task using delays of 1 or 48 h at PND 22. At PND 32–33, magnetic resonance imaging (MRI) procedures were used to assess structural brain development and hippocampal tissue was collected for analysis of mRNA expression. Pigs that consumed the OF diet demonstrated increased recognition memory after a 1 h delay, whereas those consuming diets containing OF + 2′-FL displayed increased recognition memory after a 48 h delay. Pigs fed OF or OF + 2′-FL exhibited a larger relative volume of the olfactory bulbs compared with CON pigs. Provision of OF or OF + 2′-FL altered gene expression related to dopaminergic, GABAergic, cholinergic, cell adhesion, and chromatin remodeling processes. Collectively, these data indicate that dietary OF and OF + 2′-FL differentially improve cognitive performance and affect olfactory bulb structural development and hippocampal gene expression.

Description: 5-Fluorouracil remains a foundational component of chemotherapy for solid tumour malignancies. While considered a generally safe and effective chemotherapeutic, 5-fluorouracil has demonstrated severe adverse event rates of up to 30%. Understanding the pharmacokinetics of 5-fluorouracil can improve the precision medicine approaches to this therapy. A single enzyme, dihydropyrimidine dehydrogenase (DPD), mediates 80% of 5-fluorouracil elimination, through hepatic metabolism. Importantly, it has been known for over 30-years that adverse events during 5-fluorouracil therapy are linked to high systemic exposure, and to those patients who exhibit DPD deficiency. To date, pre-treatment screening for DPD deficiency in patients with planned 5-fluorouracil-based therapy is not a standard of care. Here we provide a focused review of 5-fluorouracil metabolism, and the efforts to improve predictive dosing through screening for DPD deficiency. We also outline the history of key discoveries relating to DPD deficiency and include relevant information on the potential benefit of therapeutic drug monitoring of 5-fluorouracil. Finally, we present a brief case report that highlights a limitation of pharmacogenetics, where we carried out therapeutic drug monitoring of 5-fluorouracil in an orthotopic liver transplant recipient. This case supports the development of robust multimodality precision medicine services, capable of accommodating complex clinical dilemmas.

Description: Increasing rifampicin (RIF) dosages could significantly reduce tuberculosis (TB) treatment durations. Understanding the pharmacokinetic-pharmacodynamics (PK–PD) of increasing RIF dosages could inform clinical regimen selection. We used intracellular PD modelling (PDi) to predict clinical outcomes, primarily time to culture conversion, of increasing RIF dosages. PDi modelling utilizes in vitro-derived measurements of intracellular (macrophage) and extracellular Mycobacterium tuberculosis sterilization rates to predict the clinical outcomes of RIF at increasing doses. We evaluated PDi simulations against recent clinical data from a high dose (35 mg/kg per day) RIF phase II clinical trial. PDi-based simulations closely predicted the observed time-to-patient culture conversion status at eight weeks (hazard ratio: 2.04 (predicted) vs. 2.06 (observed)) for high dose RIF-based treatments. However, PDi modelling was less predictive of culture conversion status at 26 weeks for high-dosage RIF (99% predicted vs. 81% observed). PDi-based simulations indicate that increasing RIF beyond 35 mg/kg/day is unlikely to significantly improve culture conversion rates, however, improvements to other clinical outcomes (e.g., relapse rates) cannot be ruled out. This study supports the value of translational PDi-based modelling in predicting culture conversion rates for antitubercular therapies and highlights the potential value of this platform for the improved design of future clinical trials.

Description: Pseudomonas aeruginosa is an opportunistic pathogen that causes pneumonia in immunocompromised and intensive care unit (ICU) patients. During host infection, P. aeruginosa upregulates the type III secretion system (T3SS), which is used to intoxicate host cells with exoenzyme (Exo) virulence factors. Of the four known Exo virulence factors (U, S, T and Y), ExoU has been shown in prior studies to associate with high mortality rates. Preclinical studies have shown that ExoY is an important edema factor in lung infection caused by P. aeruginosa, although its importance in clinical isolates of P. aeruginosa is unknown. We hypothesized that expression of ExoY would be highly prevalent in clinical isolates and would significantly contribute to patient morbidity secondary to P. aeruginosa pneumonia. A single-center, prospective observational study was conducted at the University of Alabama at Birmingham Hospital. Mechanically ventilated ICU patients with a bronchoalveolar lavage fluid culture positive for P. aeruginosa were included. Enrolled patients were followed from ICU admission to discharge and clinical P. aeruginosa isolates were genotyped for the presence of exoenzyme genes. Ninety-nine patients were enrolled in the study. ExoY was present in 93% of P. aeruginosa clinical isolates. Moreover, ExoY alone (ExoY+/ExoU−) was present in 75% of P. aeruginosa isolates, compared to 2% ExoU alone (ExoY−/ExoU+). We found that bacteria isolated from human samples expressed active ExoY and ExoU, and the presence of ExoY in clinical isolates was associated with end-organ dysfunction. This is the first study we are aware of that demonstrates that ExoY is important in clinical outcomes secondary to nosocomial pneumonia.

Description: Treatment for osteosarcoma (OS) has been largely unchanged for several decades, with typical therapies being a mixture of chemotherapy and surgery. Although therapeutic targets and products against cancer are being continually developed, only a limited number have proved therapeutically active in OS. Thus, the understanding of the OS microenvironment and its interactions are becoming more important in developing new therapies. Three-dimensional (3D) models are important tools in increasing our understanding of complex mechanisms and interactions, such as in OS. In this review, in vivo animal models, in vitro 3D models and in ovo chorioallantoic membrane (CAM) models, are evaluated and discussed as to their contribution in understanding the progressive nature of OS, and cancer research. We aim to provide insight and prospective future directions into the potential translation of 3D models in OS.

Description: The cornerstone of molecular magnetism is a detailed understanding of the relationship between structure and magnetic behaviour, i.e., the development of magneto-structural correlations. Traditionally, the synthetic chemist approaches this challenge by making multiple compounds that share a similar magnetic core but differ in peripheral ligation. Changes in the ligand framework induce changes in the bond angles and distances around the metal ions, which are manifested in changes to magnetic susceptibility and magnetisation data. This approach requires the synthesis of a series of different ligands and assumes that the chemical/electronic nature of the ligands and their coordination to the metal, the nature and number of counter ions and how they are positioned in the crystal lattice, and the molecular and crystallographic symmetry have no effect on the measured magnetic properties. In short, the assumption is that everything outwith the magnetic core is inconsequential, which is a huge oversimplification. The ideal scenario would be to have the same complex available in multiple structural conformations, and this is something that can be achieved through the application of external hydrostatic pressure, correlating structural changes observed through high-pressure single crystal X-ray crystallography with changes observed in high-pressure magnetometry, in tandem with high-pressure inelastic neutron scattering (INS), high-pressure electron paramagnetic resonance (EPR) spectroscopy, and high-pressure absorption/emission/Raman spectroscopy. In this review, which summarises our work in this area over the last 15 years, we show that the application of pressure to molecule-based magnets can (reversibly) (1) lead to changes in bond angles, distances, and Jahn–Teller orientations; (2) break and form bonds; (3) induce polymerisation/depolymerisation; (4) enforce multiple phase transitions; (5) instigate piezochromism; (6) change the magnitude and sign of pairwise exchange interactions and magnetic anisotropy, and (7) lead to significant increases in magnetic ordering temperatures.