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Marinolides A and B, two new 24- and 26-membered bacterial macrolactones, were isolated from the marine-derived actinobacterium AJS-327 and their stereostructures initially assigned by bioinformatic data analysis. Macrolactones typically possess complex stereochemistry, the assignments of which have been one of the most difficult undertakings in natural products chemistry, and in most cases, the use of X-ray diffraction methods and total synthesis have been the major methods of assigning their absolute configurations. More recently, however, it has become apparent that the integration of bioinformatic data is growing in utility to assign absolute configurations. Genome mining and bioinformatic analysis identified the 97 kb mld biosynthetic cluster harboring seven type I polyketide synthases. A detailed bioinformatic investigation of the ketoreductase and enoylreductase domains within the multimodular polyketide synthases, coupled with NMR and X-ray diffraction data, allowed for the absolute configurations of marinolides A and B to be determined. While using bioinformatics to assign the relative and absolute configurations of natural products has high potential, this method must be coupled with full NMR-based analysis to both confirm bioinformatic assignments as well as any additional modifications that occur during biosynthesis.

Background: In electoral contexts, mental health topics have recently attracted sociopolitical relevance, influenced by policy developments, election-related psychopathology and popular discourse about individual candidates. Yet, whether this reflects generalised trends or is contingent on election-specific and contextual factors remains difficult to ascertain. Aims: This study sought to examine correlations between Google Trends (GT) data on mental health and four national elections in the US and the UK from 2008 to 2020. This was intended to yield preliminary insights into the relevance of mental health topics amongst voters and the potential impact of electoral cycles on patterns of online engagement with these issues. Methods: Monthly and daily Search Volume Indexes (SVI) were gathered from the 'Mental Health' category on GT in the US and UK from 2008 to 2023. SVI were evaluated around the past four national ballots, comparing election-year intervals and baseline data from the preceding year. Statistical tests were conducted to assess SVI and short- and long-term dynamics. Findings: The results showed heterogeneous SVI patterns related to mental health during elections in the US and the UK. In the US, there were statistically significant SVI increases proximal to the majority of elections as compared to data in the same calendar year, but these did not typically exceed baseline SVI. However, interestingly, divisive US contests showed correlations with several elevated SVI measures in the same and previous years. Conversely, there was a lack of consistent longitudinal trends in UK elections, perhaps informed by its disparate sociopolitical landscape. Conclusions: These findings underline the composite relationship between electoral politics and popular engagement with mental health topics around national votes, suggesting that this is driven more by situational factors rather than a recurrent electoral effect or signs of burgeoning engagement. Detailed research is required to understand the nuances and causality behind these dynamics and their wider implications. [ABSTRACT FROM AUTHOR]

BackgroundMutations in RPE65 cause Leber's congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited.MethodsWe performed a phase 1-2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visual function over the course of 3 years. Four participants were administered a lower dose of the vector, and 8 were administered a higher dose. In a parallel study in dogs, we investigated the relationship among vector dose, visual function, and electroretinography (ERG) findings.ResultsImprovements in retinal sensitivity were evident, to varying extents, in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining. No associated improvement in retinal function was detected by means of ERG. Three participants had intraocular inflammation, and two had clinically significant deterioration of visual acuity. The reduction in central retinal thickness varied among participants. In dogs, RPE65 gene therapy with the same vector at lower doses improved vision-guided behavior, but only higher doses resulted in improvements in retinal function that were detectable with the use of ERG.ConclusionsGene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestly and temporarily. Comparison with the results obtained in the dog model indicates that there is a species difference in the amount of RPE65 required to drive the visual cycle and that the demand for RPE65 in affected persons was not met to the extent required for a durable, robust effect. (Funded by the National Institute for Health Research and others; ClinicalTrials.gov number, NCT00643747.).

Coastal landscapes are naturally shifting mosaics of distinct ecosystems that are rapidly migrating with sea-level rise. Previous work illustrates that transitions among individual ecosystems have disproportionate impacts on the global carbon cycle, but this cannot address nonlinear interactions between multiple ecosystems that potentially cascade across the coastal landscape. Here, we synthesize carbon stocks, accumulation rates, and regional land cover data over 36 years (1984 and 2020) for a variety of ecosystems across a large portion of the rapidly transgressing mid-Atlantic coast. The coastal landscape of the Virginia Eastern Shore consists of temperate forest, salt marsh, seagrass beds, barrier islands, and coastal lagoons. We found that rapid losses and gains within individual ecosystems largely offset each other, which resulted in relatively stable areas for the different ecosystems, and a 4% (196.9 Gg C) reduction in regional carbon storage. However, new metrics of carbon replacement times indicated that it would take only ~ 7 years of carbon accumulation in surviving ecosystems to compensate this loss. Our findings reveal unique compensatory mechanisms at the scale of entire landscapes that quickly absorb losses and facilitate increased regional carbon storage in the face of historical and contemporary sea-level rise. However, the strength of these compensatory mechanisms may diminish as climate change exacerbates the magnitude of carbon losses. [ABSTRACT FROM AUTHOR]

This paper critically examines the broader implications of the recent case involving the professional football player, Ivan Toney, who was sanctioned by the English Football Association for gambling-related offences. Gambling and English professional football have many interconnections, underscored by the prominent betting culture within the sport and athletes' distinctive risk factors for pathological behaviours. Common punitive measures for betting-related offences, like complete bans from "all football-related activity", may inadvertently exacerbate extant vulnerabilities, particularly in cases where gambling disorder has been noted as a mitigating circumstance. Accordingly, this article recommends holistic approaches to such incidents, emphasising the need to balance applicable punishments with the provision of sufficient mental health support informed by current evidence. Moreover, a wider reconsideration of the potentially harmful intersections between gambling and English professional football may be necessary, involving proactive initiatives to expand prevention schemes, increase psychoeducation, and reduce mental health stigma in football. [ABSTRACT FROM AUTHOR]