Effects of single mutations on the stability of horseradish peroxidase to hydrogen peroxide

Horseradish peroxidase (HRP) is a commonly used enzyme in many biotechnological fields. Improvement of HRP stability would further increase its potential application range. In the present study, 13 single- and three double-mutants of solvent exposed, proximal lysine and glutamic acid residues were analysed for enhanced H2O2 stability. Additionally, five single- and one pentuple-consensus mutants were investigated. Most mutants displayed little or no alteration in H2O2 stability; however, three (K232N, K241F and T110V) exhibited significantly increased H2O2 tolerances of 25- (T110V), 18- (K232N), and 12-fold (K241F). This improved stability may be due to an altered enzyme-H2O2 catalysis pathway or to removal of potentially oxidisable residues

Scope sensitivity tests for preference robustness: An empirical examination of economic expectations regarding the economic valuation of politices for reducing acidity in remote mountain lakes

The paper introduces the reader to the contingent valuation method for monetary valuation of individuals preferences regarding changes to environmental goods. Approaches to the validity testing of results from such studies are discussed. These focus upon whether findings conform to prior expectations, in particular regarding whether valuations are sensitive to the size (or scope) of change being considered and whether they are invariant to changes in study design which are irrelevant from the perspective of economic theory. We apply such tests to a large sample study of two possible changes to the acidity levels of remote mountain lakes. Results suggest that robust values can be observed for a policy which would prevent further acidification of such lakes, but that values associated with measures to reduce acidity below present levels fail validity tests. Interestingly, values associated with preventing further acidification of lakes appear to be significantly lower for individuals who live further away from such lakes and there may even be a national component to this distance decay suggesting that those who live in the same country as the lakes in question hold higher values for their improvement

Astrocytic 4R tau expression drives astrocyte reactivity and dysfunction

The protein tau and its isoforms are associated with several neurodegenerative diseases, many of which are characterized by greater deposition of the 4-repeat (4R) tau isoform; however, the role of 4R tau in disease pathogenesis remains unclear. We created antisense oligonucleotides (ASOs) that alter the ratio of 3R to 4R tau to investigate the role of specific tau isoforms in disease. Preferential expression of 4R tau in human tau-expressing (hTau-expressing) mice was previously shown to increase seizure severity and phosphorylated tau deposition without neuronal or synaptic loss. In this study, we observed strong colocalization of 4R tau within reactive astrocytes and increased expression of pan-reactive and neurotoxic genes following 3R to 4R tau splicing ASO treatment in hTau mice. Increasing 4R tau levels in primary astrocytes provoked a similar response, including a neurotoxic genetic profile and diminished homeostatic function, which was replicated in human induced pluripotent stem cell-derived (iPSC-derived) astrocytes harboring a mutation that exhibits greater 4R tau. Healthy neurons cultured with 4R tau-expressing human iPSC-derived astrocytes exhibited a higher firing frequency and hypersynchrony, which could be prevented by lowering tau expression. These findings support a potentially novel pathway by which astrocytic 4R tau mediates reactivity and dysfunction and suggest that astrocyte-targeted therapeutics against 4R tau may mitigate neurodegenerative disease progression

Detection of a glitch in the pulsar J1709-4429

We report the detection of a glitch event in the pulsar J1709$-$4429 (also known as B1706$-$44) during regular monitoring observations with the Molonglo Observatory Synthesis Telescope (UTMOST). The glitch was found during timing operations, in which we regularly observe over 400 pulsars with up to daily cadence, while commensally searching for Rotating Radio Transients, pulsars, and FRBs. With a fractional size of $\Delta\nu/\nu \approx 52.4 \times10^{-9}$, the glitch reported here is by far the smallest known for this pulsar, attesting to the efficacy of glitch searches with high cadence using UTMOST.Comment: 3 pages, 1 figur

The UTMOST pulsar timing programme II:Timing noise across the pulsar population

While pulsars possess exceptional rotational stability, large scale timing studies have revealed at least two distinct types of irregularities in their rotation: red timing noise and glitches. Using modern Bayesian techniques, we investigated the timing noise properties of 300 bright southern-sky radio pulsars that have been observed over 1.0-4.8 years by the upgraded Molonglo Observatory Synthesis Telescope (MOST). We reanalysed the spin and spin-down changes associated with nine previously reported pulsar glitches, report the discovery of three new glitches and four unusual glitch-like events in the rotational evolution of PSR J1825$-$0935. We develop a refined Bayesian framework for determining how red noise strength scales with pulsar spin frequency ($\nu$) and spin-down frequency ($\dot{\nu}$), which we apply to a sample of 280 non-recycled pulsars. With this new method and a simple power-law scaling relation, we show that red noise strength scales across the non-recycled pulsar population as $\nu^{a} |\dot{\nu}|^{b}$, where $a = -0.84^{+0.47}_{-0.49}$ and $b = 0.97^{+0.16}_{-0.19}$. This method can be easily adapted to utilise more complex, astrophysically motivated red noise models. Lastly, we highlight our timing of the double neutron star PSR J0737$-$3039, and the rediscovery of a bright radio pulsar originally found during the first Molonglo pulsar surveys with an incorrectly catalogued position.Comment: Accepted by MNRAS. 28 pages, 8 figures, 8 table

The social value of a QALY : raising the bar or barring the raise?

Background: Since the inception of the National Institute for Health and Clinical Excellence (NICE) in England, there have been questions about the empirical basis for the cost-per-QALY threshold used by NICE and whether QALYs gained by different beneficiaries of health care should be weighted equally. The Social Value of a QALY (SVQ) project, reported in this paper, was commissioned to address these two questions. The results of SVQ were released during a time of considerable debate about the NICE threshold, and authors with differing perspectives have drawn on the SVQ results to support their cases. As these discussions continue, and given the selective use of results by those involved, it is important, therefore, not only to present a summary overview of SVQ, but also for those who conducted the research to contribute to the debate as to its implications for NICE. Discussion: The issue of the threshold was addressed in two ways: first, by combining, via a set of models, the current UK Value of a Prevented Fatality (used in transport policy) with data on fatality age, life expectancy and age-related quality of life; and, second, via a survey designed to test the feasibility of combining respondents’ answers to willingness to pay and health state utility questions to arrive at values of a QALY. Modelling resulted in values of £10,000-£70,000 per QALY. Via survey research, most methods of aggregating the data resulted in values of a QALY of £18,000-£40,000, although others resulted in implausibly high values. An additional survey, addressing the issue of weighting QALYs, used two methods, one indicating that QALYs should not be weighted and the other that greater weight could be given to QALYs gained by some groups. Summary: Although we conducted only a feasibility study and a modelling exercise, neither present compelling evidence for moving the NICE threshold up or down. Some preliminary evidence would indicate it could be moved up for some types of QALY and down for others. While many members of the public appear to be open to the possibility of using somewhat different QALY weights for different groups of beneficiaries, we do not yet have any secure evidence base for introducing such a system

Beyond the ostensible: an exploration of barriers to lean implementation and sustainability in healthcare

The barriers to implement lean have been well researched and have generated consistent results; this study identifies these as ostensible barriers. There is a dearth of research that focus on understanding the causes of these ostensible barriers. Thus, this study aims to empirically investigate the deeper causes that produce ostensible barriers to implement lean in emergency areas of the healthcare. To achieve this aim, the paper draws on rich, qualitative data from four different sources of data, using exploratory case studies as the main approach. Undertaking thematic analysis, six main underlying barriers emerge as the root cause of ostensible barriers. The results suggest that addressing each of the underlying barriers in healthcare is likely to support lean implementation and sustainability, by reducing the impact of restraining forces that come from stakeholders and the public healthcare system

Current Control and Future Risk in Asthma Management

Despite international and national guidelines, poor asthma control remains an issue. Asthma exacerbations are costly to both the individual, and the healthcare provider. Improvements in our understanding of the therapeutic benefit of asthma therapies suggest that, in general, while long-acting bronchodilator therapy improves asthma symptoms, the anti-inflammatory activity of inhaled corticosteroids reduces acute asthma exacerbations. Studies have explored factors which could be predictive of exacerbations. A history of previous exacerbations, poor asthma control, poor inhaler technique, a history of lower respiratory tract infections, poor adherence to medication, the presence of allergic rhinitis, gastro-oesophageal reflux disease, psychological dysfunction, smoking and obesity have all been implicated as having a predictive role in the future risk of asthma exacerbation. Here we review the current literature and discuss this in the context of primary care management of asthma