Intramolecular Acylal Cyclisation (IAC) as an Efficient Synthetic Strategy towards the Total Synthesis of Erythrina Alkaloid Derivatives

Compounds that comprise the erythrina alkaloid class of natural products are based on a tetracyclic spiroamine framework and exhibit a range of biological activities on the central nervous system. Herein, we report a new and efficient total synthesis of this multiple-ring system based on an intramolecular acylal cyclisation (IAC) approach. Using this methodology, the tetracyclic core was rapidly assembled over a two-step domino process catalysed by a Lewis acid. The effect of heteroatoms, substituents and ring size on the IAC has also been investigated, and the broad application of this procedure is demonstrated by the synthesis of a library of derivatives in good yields with excellent regioselectivity

Disrupted working memory circuitry and psychotic symptoms in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is a recurrent genetic mutation that is highly penetrant for psychosis. Behavioral research suggests that 22q11DS patients exhibit a characteristic neurocognitive phenotype that includes differential impairment in spatial working memory (WM). Notably, spatial WM has also been proposed as an endophenotype for idiopathic psychotic disorder, yet little is known about the neurobiological substrates of WM in 22q11DS. In order to investigate the neural systems engaged during spatial WM in 22q11DS patients, we collected functional magnetic resonance imaging (fMRI) data while 41 participants (16 22q11DS patients, 25 demographically matched controls) performed a spatial capacity WM task that included manipulations of delay length and load level. Relative to controls, 22q11DS patients showed reduced neural activation during task performance in the intraparietal sulcus (IPS) and superior frontal sulcus (SFS). In addition, the typical increases in neural activity within spatial WM-relevant regions with greater memory load were not observed in 22q11DS. We further investigated whether neural dysfunction during WM was associated with behavioral WM performance, assessed via the University of Maryland letter-number sequencing (LNS) task, and positive psychotic symptoms, assessed via the Structured Interview for Prodromal Syndromes (SIPS), in 22q11DS patients. WM load activity within IPS and SFS was positively correlated with LNS task performance; moreover, WM load activity within IPS was inversely correlated with the severity of unusual thought content and delusional ideas, indicating that decreased recruitment of working memory-associated neural circuitry is associated with more severe positive symptoms. These results suggest that 22q11DS patients show reduced neural recruitment of brain regions critical for spatial WM function, which may be related to characteristic behavioral manifestations of the disorder

Clarifying misconceptions of extinction risk assessment with the IUCN Red List

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.The identification of species at risk of extinction is a central goal of conservation. As the use of data compiled for IUCN Red List assessments expands, a number of misconceptions regarding the purpose, application and use of the IUCN Red List categories and criteria have arisen. We outline five such classes of misconception; the most consequential drive proposals for adapted versions of the criteria, rendering assessments among species incomparable. A key challenge for the future will be to recognize the point where understanding has developed so markedly that it is time for the next generation of the Red List criteria. We do not believe we are there yet but, recognizing the need for scrutiny and continued development of Red Listing, conclude by suggesting areas where additional research could be valuable in improving the understanding of extinction risk among species

Modelling the potential non-breeding distribution of Spoon-billed Sandpiper Calidris pygmaea

SummaryThe Spoon-billed Sandpiper Calidris pygmaea is a ‘Critically Endangered’ migratory shorebird. The species faces an array of threats in its non-breeding range, making conservation intervention essential. However, conservation efforts are reliant on identifying the species’ key stopover and wintering sites. Using Maximum Entropy models, we predicted Spoon-billed Sandpiper distribution across the non-breeding range, using data from recent field surveys and satellite tracking. Model outputs suggest only a limited number of stopover sites are suitable for migrating birds, with sites in the Yellow Sea and on the Jiangsu coast in China highlighted as particularly important. All the previously known core wintering sites were identified by the model including the Ganges-Brahmaputra Delta, Nan Thar Island and the Gulf of Mottama. In addition, the model highlighted sites subsequently found to be occupied, and pinpointed potential new sites meriting investigation, notably on Borneo and Sulawesi, and in parts of India and the Philippines. A comparison between the areas identified as most likely to be occupied and protected areas showed that very few locations are covered by conservation designations. Known sites must be managed for conservation as a priority, and potential new sites should be surveyed as soon as is feasible to assess occupancy status. Site protection should take place in concert with conservation interventions including habitat management, discouraging hunting, and fostering alternative livelihoods.Field surveys in Russian non-breeding grounds were supported by RSPB, MHS and NABU. Field surveys in Gulf of Mottama partly supported by BBC Wildlife Fund. Satellite tagging data collection partly supported by The Biodiversity Investigation, Observation and Assessment Program (2019 - 2023) of the Ministry of Ecology and Environment of China, RSPB and a private donor. Bangladesh Spoon-billed Sandpiper Conservation Project’s fieldwork in Meghna Estuary (2015 - 2016) supported by RSPB. Data collection by EL partly supported by Basic research program (budgetary funds), projects number АААА-А19-119022190168-8 and АААА-А19-119021990093-8). PT supported by Moscow State University Grant for Leading Scientific Schools "Depository of the Living Systems" in the MSU Development Program framework. TBL was funded by the Natural Environment Research Council UK, and the IAPETUS Doctoral Training Partnership

Improving the psychological evaluation of exercise referral: psychometric properties of the Exercise Referral Quality of Life Scale

There is a growing need to assess the psychological outcomes of exercise referral and the National Institute of Health and Care Excellence has called for the routine assessment of life-quality. However, a quality of life scale specific to the requirements of exercise referral is currently unavailable. Therefore, the aim of this study was to produce a quality of life measure for this purpose. The Exercise Referral Quality of Life Scale is a 22-item measure comprising three domains: mental and physical health, injury pain and illness and physical activity facilitators. Exploratory factor analysis determined the initial factor structure and was subsequently confirmed by confirmatory factor analysis. Additional scale properties were also assessed. The scale contributes to the global need for improved consistent psychological outcome assessment of exercise referral

Antenna-coupled TES bolometers for the SPIDER experiment

SPIDER is a proposed balloon-borne experiment designed to search for the imprints of gravity waves on the polarization of the cosmic microwave background radiation. The required wide frequency coverage, large number of sensitive detectors, and the stringent power constraints on a balloon are made possible by antenna-coupled TES bolometers. Several prototype devices have been fabricated and optically characterized. Their spectral and angular responses agree well with the theoretical expectations

A nationwide survey to measure practice variation of catheterisation management in patients undergoing vaginal prolapse surgery

Urinary catheterisation following vaginal prolapse surgery causes inconvenience for patients, risk of urinary tract infections and potentially longer hospitalisation. Possibly, practice variation exists concerning diagnosis and management of abnormal postvoid residual (PVR) volume implying suboptimal treatment for certain subgroups. Nationwide questionnaire-based survey. Post-operatively, 77% performed transurethral indwelling catheterisation, 12% suprapubic catheterisation and 11% intermittent catheterisation. Catheterisation was applied 3 days (1-7 days) following anterior repair and 1 day (1-3 days) following all other procedures. The median cut-off point for abnormal PVR was 150 mL (range 50-250 mL). Treatment of abnormal PVR consisted mostly of prolonging transurethral indwelling catheterisation for 2 days (range 1-5 days; 57%), 29% by intermittent and 12% by suprapubic catheterisation. Antibiotics were administered by 21% either routinely or based on symptoms only. Due to insufficient evidence and suboptimal implementation of available evidence, practice variation in catheterisation regimens is hig

Axl/Gas6/NFκB signalling in schwannoma pathological proliferation, adhesion and survival.

TAM family receptor tyrosine kinases comprising Tyro3 (Sky), Axl, and Mer are overexpressed in some cancers, correlate with multidrug resistance and contribute to tumourigenesis by regulating invasion, angiogenesis, cell survival and tumour growth. Mutations in the gene coding for a tumour suppressor merlin cause development of multiple tumours of the nervous system such as schwannomas, meningiomas and ependymomas occurring spontaneously or as part of a hereditary disease neurofibromatosis type 2. The benign character of merlin-deficient tumours makes them less responsive to chemotherapy. We previously showed that, amongst other growth factor receptors, TAM family receptors (Tyro3, Axl and Mer) are significantly overexpressed in schwannoma tissues. As Axl is negatively regulated by merlin and positively regulated by E3 ubiquitin ligase CRL4DCAF1, previously shown to be a key regulator in schwannoma growth we hypothesized that Axl is a good target to study in merlin-deficient tumours. Moreover, Axl positively regulates the oncogene Yes-associated protein, which is known to be under merlin regulation in schwannoma and is involved in increased proliferation of merlin-deficient meningioma and mesothelioma. Here, we demonstrated strong overexpression and activation of Axl receptor as well as its ligand Gas6 in human schwannoma primary cells compared to normal Schwann cells. We show that Gas6 is mitogenic and increases schwannoma cell-matrix adhesion and survival acting via Axl in schwannoma cells. Stimulation of the Gas6/Axl signalling pathway recruits Src, focal adhesion kinase (FAK) and NFκB. We showed that NFκB mediates Gas6/Axl-mediated overexpression of survivin, cyclin D1 and FAK, leading to enhanced survival, cell-matrix adhesion and proliferation of schwannoma. We conclude that Axl/FAK/Src/NFκB pathway is relevant in merlin-deficient tumours and is a potential therapeutic target for schwannoma and other merlin-deficient tumours

A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis

<p>Abstract</p> <p>Background</p> <p>Long-term immunosuppression is often required in myasthenia gravis (MG). There are no published trials using methotrexate (MTX) in MG. The steroid-sparing efficacy of azathioprine (AZA) has been demonstrated after 18-months of starting therapy. However, AZA is considered expensive in Africa. We evaluated the steroid-sparing efficacy of MTX (17.5 mg weekly) compared with AZA (2.5 mg/kg daily) in subjects recently diagnosed with generalized MG by assessing their average monthly prednisone requirements.</p> <p>Methods</p> <p>The primary outcome was the average daily prednisone requirement by month between the two groups. Prednisone was given at the lowest dose to manage MG symptoms and adjusted as required according to protocol. Single-blinded assessments were performed 3-monthly for 2-years to determine the quantitative MG score and the MG activities of daily living score in order to determine those with minimal manifestations of MG.</p> <p>Results</p> <p>Thirty-one subjects (AZA n = 15; MTX n = 16) satisfied the inclusion criteria but only 24 were randomized. Baseline characteristics were similar. There was no difference between the AZA- and MTX-groups in respect of prednisone dosing (apart from months 10 and 12), in quantitative MG Score improvement, proportions in sustained remission, frequencies of MG relapses, or adverse reactions and/or withdrawals. The MTX-group received lower prednisone doses between month 10 (p = 0.047) and month 12 (p = 0.039). At month 12 the prednisone dose per kilogram bodyweight in the MTX-group (0.15 mg/kg) was half that of the AZA-group (0.31 mg/kg)(p = 0.019).</p> <p>Conclusions</p> <p>This study provides evidence that in patients with generalized MG methotrexate is an effective steroid-sparing agent 10 months after treatment initiation. Our data suggests that in generalized MG methotrexate has similar efficacy and tolerability to azathioprine and may be the drug of choice in financially constrained health systems.</p> <p>Trial registration</p> <p>SANCTR:DOH-27-0411-2436</p