D(-)-Mandelate Dehydrogenase of the Yeast Rhodotorula graminis

1. The yeast Rhodotorula graminis strain KGX 39 can grow on D(--)- or L(+)-mandelate as a sole source of carbon and energy. The first step in the dissimilation of mandelate involves stereospecific oxidation to phenylgiyoxylate, and this is then degraded via benzaldehyde to benzoate. Preliminary evidence had indicated the presence of a dye-linked L(+)-mandelate dehydrogenase and an NAD+-dependent D(--)-mandelate dehydrogenase in this organism. This thesis is concerned with the purification and characterization of the NAD+-dependent D(--)-mandelate dehydrogenase

Invasive alien species in the food chain : advancing risk assessment models to address climate change, economics and uncertainty

Economic globalization depends on the movement of people and goods between countries. As these exchanges increase, so does the potential for translocation of harmful pests, weeds, and pathogens capable of impacting our crops, livestock and natural resources (Hulme 2009), with concomitant impacts on global food security (Cook et al. 2011)

Development of a networked photonic‐enabled staring radar testbed for urban surveillance

Urban surveillance of slow-moving small targets such as drones and birds in low to medium airspace using radar presents significant challenges. Detecting, locating and identifying such low observable targets in strong clutter requires both innovation in radar hardware design and optimisation of processing algorithms. To this end, the University of Birmingham (UoB) has set-up a testbed of two L-band staring radars to support performance benchmarking using datasets of target and clutter from realistic urban environment. This testbed is also providing the vehicle to understand how novel radar architectures can enhance radar capabilities. Some of the challenges in installing the radar at the UoB campus are highlighted. Detailed benchmarking results are provided from urban monostatic and bistatic field trials that form the basis for performance comparison against future hardware modification. The solution to the challenge of interfacing the radar to the external oscillators is described and stand-alone bench tests with the candidate oscillators are reported. The testbed provides a valuable capability to undertake detailed analysis of performance of Quantum photonic-enabled radar and allows for its comparison with conventional oscillator technology for surveillance of low observable targets in the presence of urban clutter

Site-specific ubiquitination exposes a linear motif to promote interferon-α receptor endocytosis

Ligand-induced endocytosis and lysosomal degradation of cognate receptors regulate the extent of cell signaling. Along with linear endocytic motifs that recruit the adaptin protein complex 2 (AP2)–clathrin molecules, monoubiquitination of receptors has emerged as a major endocytic signal. By investigating ubiquitin-dependent lysosomal degradation of the interferon (IFN)-α/β receptor 1 (IFNAR1) subunit of the type I IFN receptor, we reveal that IFNAR1 is polyubiquitinated via both Lys48- and Lys63-linked chains. The SCFβTrcp (Skp1–Cullin1–F-box complex) E3 ubiquitin ligase that mediates IFNAR1 ubiquitination and degradation in cells can conjugate both types of chains in vitro. Although either polyubiquitin linkage suffices for postinternalization sorting, both types of chains are necessary but not sufficient for robust IFNAR1 turnover and internalization. These processes also depend on the proximity of ubiquitin-acceptor lysines to a linear endocytic motif and on its integrity. Furthermore, ubiquitination of IFNAR1 promotes its interaction with the AP2 adaptin complex that is required for the robust internalization of IFNAR1, implicating cooperation between site-specific ubiquitination and the linear endocytic motif in regulating this process

Scalable 3D Printed Molds for Human Tissue Engineered Skeletal Muscle

Tissue engineered skeletal muscle allows investigation of the cellular and molecular mechanisms that regulate skeletal muscle pathology. The fabricated model must resemble characteristics of in vivo tissue and incorporate cost-effective and high content primary human tissue. Current models are limited by low throughput due to the complexities associated with recruiting tissue donors, donor specific variations, as well as cellular senescence associated with passaging. This research presents a method using fused deposition modeling (FDM) and laser sintering (LS) 3D printing to generate reproducible and scalable tissue engineered primary human muscle, possessing aligned mature myotubes reminiscent of in vivo tissue. Many existing models are bespoke causing variability when translated between laboratories. To this end, a scalable model has been developed (25–500 μL construct volumes) allowing fabrication of mature primary human skeletal muscle. This research provides a strategy to overcome limited biopsy cell numbers, enabling high throughput screening of functional human tissue

A heart failure self-management program for patients of all literacy levels: A randomized, controlled trial [ISRCTN11535170]

BACKGROUND: Self-management programs for patients with heart failure can reduce hospitalizations and mortality. However, no programs have analyzed their usefulness for patients with low literacy. We compared the efficacy of a heart failure self-management program designed for patients with low literacy versus usual care. METHODS: We performed a 12-month randomized controlled trial. From November 2001 to April 2003, we enrolled participants aged 30–80, who had heart failure and took furosemide. Intervention patients received education on self-care emphasizing daily weight measurement, diuretic dose self-adjustment, and symptom recognition and response. Picture-based educational materials, a digital scale, and scheduled telephone follow-up were provided to reinforce adherence. Control patients received a generic heart failure brochure and usual care. Primary outcomes were combined hospitalization or death, and heart failure-related quality of life. RESULTS: 123 patients (64 control, 59 intervention) participated; 41% had inadequate literacy. Patients in the intervention group had a lower rate of hospitalization or death (crude incidence rate ratio (IRR) = 0.69; CI 0.4, 1.2; adjusted IRR = 0.53; CI 0.32, 0.89). This difference was larger for patients with low literacy (IRR = 0.39; CI 0.16, 0.91) than for higher literacy (IRR = 0.56; CI 0.3, 1.04), but the interaction was not statistically significant. At 12 months, more patients in the intervention group reported monitoring weights daily (79% vs. 29%, p < 0.0001). After adjusting for baseline demographic and treatment differences, we found no difference in heart failure-related quality of life at 12 months (difference = -2; CI -5, +9). CONCLUSION: A primary care-based heart failure self-management program designed for patients with low literacy reduces the risk of hospitalizations or death

NF-kappa B p65 serine 467 phosphorylation sensitizes mice to weight gain and TNF alpha-or diet-induced inflammation

The NF-kappa B family of transcription factors is essential for an effective immune response, but also controls cell metabolism, proliferation and apoptosis. Its broad relevance and the high connectivity to diverse signaling pathways require a tight control of NF-kappa B activity. To investigate the control of NF-kappa B activity by phosphorylation of the NF-kappa B p65 subunit, we generated a knock-in mouse model in which serine 467 (the mouse homolog of human p65 serine 468) was replaced with a non-phosphorylatable alanine (S467A). This substitution caused reduced p65 protein synthesis and diminished TNF alpha-induced expression of a selected group of NF-kappa B dependent genes. Intriguingly, high-fat fed S467A mice displayed increased locomotor activity and energy expenditure, which coincided with a reduced body weight gain. Although glucose metabolism or insulin sensitivity was not improved, diet-induced liver inflammation was diminished in S467A mice. Altogether, this study demonstrates that phosphorylation of p65 serine 467 augment NF-kappa B activity and exacerbates various deleterious effects of overnutrition in mice.</p

Confirmed 6-Month Disability Improvement and Worsening Correlate with Long-term Disability Outcomes in Alemtuzumab-Treated Patients with Multiple Sclerosis: Post Hoc Analysis of the CARE-MS Studies.

INTRODUCTION In the 2-year CARE-MS trials (NCT00530348; NCT00548405) in patients with relapsing-remitting multiple sclerosis, alemtuzumab showed superior efficacy versus subcutaneous interferon beta-1a. Efficacy was maintained in two consecutive extensions (NCT00930553; NCT02255656). This post hoc analysis compared disability outcomes over 9 years among alemtuzumab-treated patients according to whether they experienced confirmed disability improvement (CDI) or worsening (CDW) or neither CDI nor CDW. METHODS CARE-MS patients were randomized to receive two alemtuzumab courses (12 mg/day; 5 days at baseline; 3 days at 12 months), with additional as-needed 3-day courses in the extensions. CDI or CDW were defined as ≥ 1.0-point decrease or increase, respectively, in Expanded Disability Status Scale (EDSS) score from core study baseline confirmed over 6 months, assessed in patients with baseline EDSS score ≥ 2.0. Improved or stable EDSS scores were defined as ≥ 1-point decrease or ≤ 0.5-point change (either direction), respectively, from core study baseline. Functional systems (FS) scores were also assessed. RESULTS Of 511 eligible patients, 43% experienced CDI and 34% experienced CDW at any time through year 9 (patients experiencing both CDI and CDW were counted in each individual group); 29% experienced neither CDI nor CDW. At year 9, patients with CDI had a -0.58-point mean EDSS score change from baseline; 88% had stable or improved EDSS scores. Improvements occurred across all FS, primarily in sensory, pyramidal, and cerebellar domains. Patients with CDW had a +1.71-point mean EDSS score change; 16% had stable or improved EDSS scores. Patients with neither CDI nor CDW had a -0.10-point mean EDSS score change; 98% had stable or improved EDSS scores. CONCLUSION CDI achievement at any point during the CARE-MS studies was associated with improved disability at year 9, highlighting the potential of alemtuzumab to change the multiple sclerosis course. Conversely, CDW at any point was associated with worsened disability at year 9