Merging enzymes with chemocatalysis for amide bond synthesis

Amides are one of the most fundamental chemical bonds in nature. In addition to proteins and other metabolites, many valuable synthetic products comprise amide bonds. Despite this, there is a need for more sustainable amide synthesis. Herein, we report an integrated next generation multi-catalytic system, merging nitrile hydratase enzymes with a Cu-catalysed N-arylation reaction in a single reaction vessel, for the construction of ubiquitous amide bonds. This synergistic one-pot combination of chemo- and biocatalysis provides an amide bond disconnection to precursors, that are orthogonal to those in classical amide synthesis, obviating the need for protecting groups and delivering amides in a manner unachievable using existing catalytic regimes. Our integrated approach also affords broad scope, very high (molar) substrate loading, and has excellent functional group tolerance, telescoping routes to natural product derivatives, drug molecules, and challenging chiral amides under environmentally friendly conditions at scale

The structure of Serratia marcescens Lip, a membrane-bound component of the type VI secretion system

The high-resolution crystal structure of S. marcescens Lip reveals a new member of the transthyretin family of proteins. Lip, a core component of the type VI secretion apparatus, is localized to the outer membrane and is positioned to interact with other proteins forming this complex system

Are routinely collected NHS administrative records suitable for endpoint identification in clinical trials? Evidence from the West of Scotland coronary prevention study

Background: Routinely collected electronic patient records are already widely used in epidemiological research. In this work we investigated the potential for using them to identify endpoints in clinical trials.<p></p> Methods: The events recorded in the West of Scotland Coronary Prevention Study (WOSCOPS), a large clinical trial of pravastatin in middle-aged hypercholesterolaemic men in the 1990s, were compared with those in the record-linked deaths and hospitalisations records routinely collected in Scotland.<p></p> Results: We matched 99% of fatal study events by date. We showed excellent matching (97%) of the causes of fatal endpoint events and good matching (.80% for first events) of the causes of nonfatal endpoint events with a slightly lower rate of mismatching of record linkage than study events (19% of first study myocardial infarctions (MI) and 4% of first record linkage MIs not matched as MI). We also investigated the matching of non-endpoint events and showed a good level of matching, with .78% of first stroke/TIA events being matched as stroke/TIA. The primary reasons for mismatches were record linkage data recording readmissions for procedures or previous events, differences between the diagnoses in the routinely collected data and the conclusions of the clinical trial expert adjudication committee, events occurring outside Scotland and therefore being missed by record linkage data, miscoding of cardiac events in hospitalisations data as ‘unspecified chest pain’, some general miscoding in the record linkage data and some record linkage errors.<p></p> Conclusions: We conclude that routinely collected data could be used for recording cardiovascular endpoints in clinical trials and would give very similar results to rigorously collected clinical trial data, in countries with unified health systems such as Scotland. The endpoint types would need to be carefully thought through and an expert endpoint adjudication committee should be involved.<p></p&gt

Larger spatial footprint of wintertime total precipitation extremes in a warmer climate

The simultaneous occurrence of extremely wet winters at multiple locations in the same region can contribute to widespread flooding and associated socio-economic losses. However, the spatial extent of precipitation extremes (i.e. the area in which nearby locations experience precipitation extremes simultaneously) and its future changes are largely overlooked in climate assessments. Employing new multi-thousand-year climate model simulations, we show that under both 2.0C and 1.5C warming scenarios, wintertime total precipitation extreme extents would increase over about 80-90% of the Northern Hemisphere extratropics (i.e. the latitude band 28-78N). Stabilising at 1.5C rather than 2.0C would reduce the average magnitude of the increase by 1.7-2 times. According to the climate model, the increased extents are caused by increases in precipitation intensity rather than changes in the spatial organisation of the events. Relatively small percentage increases in precipitation intensities (e.g., by 4%) can drive disproportionately larger, by 1-2 orders of magnitude, growth in the spatial extents (by 93%)

Patterns of postmeal insulin secretion in individuals with sulfonylurea- treated KCNJ11 neonatal diabetes show predominance of non- KATP- channel pathways

Insulin secretion in sulfonylurea-treated KCNJ11 permanent neonatal diabetes mellitus (PNDM) is thought to be mediated predominantly through amplifying non-KATP-channel pathways such as incretins. Affected individuals report symptoms of postprandial hypoglycemia after eating protein/fat-rich foods. We aimed to assess the physiological response to carbohydrate and protein/fat in people with sulfonylurea-treated KCNJ11 PNDM.This article is freely available via Open Access. Click on the Publisher URL to access the full-text via the publisher's site

Organic electrode coatings for next-generation neural interfaces

Traditional neuronal interfaces utilize metallic electrodes which in recent years have reached a plateau in terms of the ability to provide safe stimulation at high resolution or rather with high densities of microelectrodes with improved spatial selectivity. To achieve higher resolution it has become clear that reducing the size of electrodes is required to enable higher electrode counts from the implant device. The limitations of interfacing electrodes including low charge injection limits, mechanical mismatch and foreign body response can be addressed through the use of organic electrode coatings which typically provide a softer, more roughened surface to enable both improved charge transfer and lower mechanical mismatch with neural tissue. Coating electrodes with conductive polymers or carbon nanotubes offers a substantial increase in charge transfer area compared to conventional platinum electrodes. These organic conductors provide safe electrical stimulation of tissue while avoiding undesirable chemical reactions and cell damage. However, the mechanical properties of conductive polymers are not ideal, as they are quite brittle. Hydrogel polymers present a versatile coating option for electrodes as they can be chemically modified to provide a soft and conductive scaffold. However, the in vivo chronic inflammatory response of these conductive hydrogels remains unknown. A more recent approach proposes tissue engineering the electrode interface through the use of encapsulated neurons within hydrogel coatings. This approach may provide a method for activating tissue at the cellular scale, however, several technological challenges must be addressed to demonstrate feasibility of this innovative idea. The review focuses on the various organic coatings which have been investigated to improve neural interface electrodes

Reality Hackers: The Next Wave of Media Revolutionaries

Just as the printing press gave rise to the nation-state, emerging technologies are reshaping collective identities and challenging our understanding of what it means to be human. Should citizens have the right to be truly anonymous on-line? Should we be concerned about the fact that so many people are choosing to migrate to virtual worlds? Are injectible microscopic radio-frequency ID chips a blessing or a curse? Is the use of cognitive enhancing nootropics a human right or an unforgivable transgression? Should genomic data about human beings be hidden away with commercial patents or open-sourced like software? Should hobbyists known as biohackers be allowed to experiment with genetic engineering in their home laboratories? The time-frame for acting on such questions is relatively short, and these decisions are too important to be left up to a small handful of scientists and policymakers. If democracy is to continue as a viable alternative to technocracy, the average citizen must become more involved in these debates. To borrow a line from the computer visionary Ted Nelson, all of us can -- and must -- understand technology now. Challenging the popular stereotype of hackers as ciminal sociopaths, reality hackers uphold the basic tenets of what Steven Levy (1984) terms the hacker ethic. These core principles include a commitment to: sharing, openness, decentralization, public access to information, and the use of new technologies to make the world a better place.https://digitalcommons.trinity.edu/mono/1000/thumbnail.jp

Adjusting for BMI in analyses of volumetric mammographic density and breast cancer risk

Abstract Background Fully automated assessment of mammographic density (MD), a biomarker of breast cancer risk, is being increasingly performed in screening settings. However, data on body mass index (BMI), a confounder of the MD–risk association, are not routinely collected at screening. We investigated whether the amount of fat in the breast, as captured by the amount of mammographic non-dense tissue seen on the mammographic image, can be used as a proxy for BMI when data on the latter are unavailable. Methods Data from a UK case control study (numbers of cases/controls: 414/685) and a Norwegian cohort study (numbers of cases/non-cases: 657/61059), both with volumetric MD measurements (dense volume (DV), non-dense volume (NDV) and percent density (%MD)) from screening-age women, were analysed. BMI (self-reported) and NDV were taken as measures of adiposity. Correlations between BMI and NDV, %MD and DV were examined after log-transformation and adjustment for age, menopausal status and parity. Logistic regression models were fitted to the UK study, and Cox regression models to the Norwegian study, to assess associations between MD and breast cancer risk, expressed as odds/hazard ratios per adjusted standard deviation (OPERA). Adjustments were first made for standard risk factors except BMI (minimally adjusted models) and then also for BMI or NDV. OPERA pooled relative risks (RRs) were estimated by fixed-effect models, and between-study heterogeneity was assessed by the I 2 statistics. Results BMI was positively correlated with NDV (adjusted r = 0.74 in the UK study and r = 0.72 in the Norwegian study) and with DV (r = 0.33 and r = 0.25, respectively). Both %MD and DV were positively associated with breast cancer risk in minimally adjusted models (pooled OPERA RR (95% confidence interval): 1.34 (1.25, 1.43) and 1.46 (1.36, 1.56), respectively; I 2 = 0%, P >0.48 for both). Further adjustment for BMI or NDV strengthened the %MD–risk association (1.51 (1.41, 1.61); I 2 = 0%, P = 0.33 and 1.51 (1.41, 1.61); I 2 = 0%, P = 0.32, respectively). Adjusting for BMI or NDV marginally affected the magnitude of the DV–risk association (1.44 (1.34, 1.54); I 2 = 0%, P = 0.87 and 1.49 (1.40, 1.60); I 2 = 0%, P = 0.36, respectively). Conclusions When volumetric MD–breast cancer risk associations are investigated, NDV can be used as a measure of adiposity when BMI data are unavailable

Medication review plus person-centred care:a feasibility study of a pharmacy-health psychology dual intervention to improve care for people living with dementia

BACKGROUND: "Behaviour that Challenges" is common in people living with dementia, resident in care homes and historically has been treated with anti-psychotics. However, such usage is associated with 1800 potentially avoidable deaths annually in the UK. This study investigated the feasibility of a full clinical trial of a specialist dementia care pharmacist medication review combined with a health psychology intervention for care staff to limit the use of psychotropics. This paper focuses on feasibility; including recruitment and retention, implementation of medication change recommendations and the experiences and expectations of care staff. METHODS: West Midlands care homes and individuals meeting the inclusion criteria (dementia diagnosis; medication for behaviour that challenges), or their personal consultee, were approached for consent. A specialist pharmacist reviewed medication. Care home staff received an educational behaviour change intervention in a three-hour session promoting person-centred care. Primary healthcare staff received a modified version of the training. The primary outcome measure was the Neuropsychiatric Inventory-Nursing Home version at 3 months. Other outcomes included quality of life, cognition, health economics and prescribed medication. A qualitative evaluation explored expectations and experiences of care staff. RESULTS: Five care homes and 34 of 108 eligible residents (31.5%) were recruited, against an original target of 45 residents across 6 care homes. Medication reviews were conducted for 29 study participants (85.3%) and the pharmacist recommended stopping or reviewing medication in 21 cases (72.4%). Of the recommendations made, 57.1% (12 of 21) were implemented, and implementation (discontinuation) took a mean of 98.4 days. In total, 164 care staff received training and 21 were interviewed. Care staff reported a positive experience of the intervention and post intervention adopting a more holistic patient-centred approach. CONCLUSIONS: The intervention contained two elements; staff training and medication review. It was feasible to implement the staff training, and the training appeared to increase the ability and confidence of care staff to manage behaviour that challenges without the need for medication. The medication review would require significant modification for full trial partly related to the relatively limited uptake of the recommendations made, and delay in implementation. TRIAL REGISTRATION: ISRCTN58330068 . Registered 15 October 2017. Retrospectively registered

Neither fair nor unchangeable but part of the natural order: orientations towards inequality in the face of criticism of the economic system

The magnitude of climate change threats to life on the planet is not matched by the level of current mitigation strategies. To contribute to our understanding of inaction in the face of climate change, the reported study draws upon the pro status quo motivations encapsulated within System Justification Theory. In an online questionnaire study, participants (N = 136) initially completed a measure of General System Justification. Participants in a “System-critical” condition were then exposed to information linking environmental problems to the current economic system; participants in a Control condition were exposed to information unrelated to either environmental problems or the economic system. A measure of Economic System Justification was subsequently administered. Regressions of Economic System Justification revealed interactions between General System Justification and Information Type: higher general system justifiers in the System-critical condition rated the economic system as less fair than did their counterparts in the Control condition. However, they also indicated inequality as more natural than did their counterparts in the Control condition. The groups did not differ in terms of beliefs about the economic system being open to change. The results are discussed in terms of how reassurance about the maintenance of the status quo may be bolstered by recourse to beliefs in a natural order