استكشف المجموعة الواسعة من العناوين المتاحة.

In 1957 Abbott and Ballantine described a highly toxic activity from a dinoflagellate isolated from the English Channel in 1949 by Mary Park. From a culture maintained at Plymouth Laboratory since 1950, we have been able to isolate two toxic molecules (abbotoxin and 59-E-Chloro-abbotoxin), determine the planar structures by analysis of HRMS and 1D and 2D NMR spectra, and found them to be karlotoxin (KmTx) congeners. Both toxins kill larval zebrafish with symptoms identical to those described by Abbot and Ballantine for gobies ( Gobius virescens ). Using surface plasma resonance the sterol binding specificity of karlotoxins is shown to require desmethyl sterols. Our results with black lipid membranes indicate that karlotoxin forms large-conductance channels in the lipid membrane, which are characterized by large ionic conductance, poor ionic selectivity, and a complex gating behavior that exhibits strong voltage dependence and multiple gating patterns. In addition, we show that KmTx 2 pore formation is a highly targeted mechanism involving sterol-specificity. This is the first report of the functional properties of the membrane pores formed by karlotoxins and is consistent with the initial observations of Abbott and Ballantine from 1957.

Marine microbes are capable of producing secondary metabolites for defense and competition. Factors exerting an impact on secondary metabolite production of microbial communities included bioactive natural products and co-culturing. These external influences may have practical applications such as increased yields or the generation of new metabolites from otherwise silent genes in addition to reducing or limiting the production of undesirable metabolites. In this paper, we discuss the metabolic profiles of a marine Pseudomonas aeruginosa in the presence of a number of potential chemical epigenetic regulators, adjusting carbon sources and co-culturing with other microbes to induce a competitive response. As a result of these stressors certain groups of antibiotics or antimalarial agents were increased most notably when treating P. aeruginosa with sceptrin and co-culturing with another Pseudomonas sp. An interesting cross-talking event between these two Pseudomonas species when cultured together and exposed to sceptrin was observed.

Marine sources have long been known for their potential to produce unique skeletons and various biological activities. Fractionation of the ethanol extracts of an undescribed species of Monanchora Carter, 1883 and a specimen closely comparable to Monanchora pulchra (Lambe, 1895) (Class Demospongiae, Order Poecilosclerida, Family Crambeidae), yielded a known compound, monanchocidin A. Monanchocidin A, a secondary metabolite, showed potent selective activity for the melanoma panel in the NCI cancer cell screening panel.

Sponges have generated significant interest as a source of bioactive and elaborate secondary metabolites that hold promise for the development of novel therapeutics for the control of an array of human diseases. However, research and development of marine natural products can often be hampered by the difficulty associated with obtaining a stable and sustainable production source. Herein we report the first successful characterization and utilization of the microbiome of a marine invertebrate to identify a sustainable production source for an important natural product scaffold. Through molecular-microbial community analysis, optimization of fermentation conditions and MALDI-MS imaging, we provide the first report of a sponge-associated bacterium ( sp.) that produces the manzamine class of antimalarials from the Indo-Pacific sponge (Thiele, 1899) (Class Demospongiae, Order Haplosclerida, Family Petrosiidae). These findings suggest that a general strategy of analysis of the macroorganism's microbiome could significantly transform the field of natural products drug discovery by gaining access to not only novel drug leads, but the potential for sustainable production sources and biosynthetic genes at the same time.

This work features natural products isolated from both the marine and microbial environments. Part I focuses on the elucidation of toxins from harmful algal blooms (HAB). The HAB dinoflagellate Karlodinium veneficum produces a harmful suite of molecules identified as the karlotoxins (KmTx) that have been implicated in massive fish kills pan-globally. Nine new karlotoxin congeners were isolated from various Karlodinium blooms around the world and utilizing the structure of KmTx2 were characterized using overlaid 2D NMR techniques. Due to the contrasting conformational differences between KmTx and the closely related amphidinols, the absolute configuration of KmTx was further evaluated by extensive computational analysis of the J-based coupling constants (JBCA) and chemical shifts (CS) of the 1H and 13C NMR data. In addition, the total synthesis of one congener is being attempted to obtain additional material for biological studies and further structure activity relationship (SAR) studies. The expanded SAR of the class is being explored for new insights for agents for the treatment of cancer and as angiogenesis inhibitors. Part II focuses on the isolation and characterization of novel lactone lipids, scoriosin and its methyl ester, isolated from Scorias spongiosa, a fungus that is commonly referred to as sooty mold and can be found growing on both Fagus sylvaticus and Fagus grandifolia, better known as the European and American beech trees. Using a combination of calculated and experimental electronic circular dichroism (ECD) and CS analysis, the absolute configuration of the molecules was established. Both compounds displayed antimicrobial and antifungal activity with IC50 values in the low μM to high nM range for Cryptococcus neoformans, Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA). The second project in Part II focuses on using matrix assisted laser desorption ionization- mass spectrometry (MALDI-MS) imaging to confirm production of key pharmaceutical precursor secondary metabolites from marine associated bacteria. Through microbial community analysis, optimization of fermentation conditions and MALDI-MS imaging, the first report of a sponge-associated bacterium (Micromonospora sp. M42) from the Indo-Pacific sponge Acanthostrongylophora ingens (Thiele, 1899) that produces the manzamine class of antimalarials is presented.

Background Physical activity is important for healthy ageing, however most older adults are inactive. Numerous reviews with a range of inclusion criteria have been conducted on digital interventions to promote physical activity in older adults, and a synthesis of these is needed. Therefore, the objective of this study is to conduct an umbrella review and meta-meta-analysis on the effectiveness of digital interventions to promote physical activity in older adults. Methods Nine databases were searched from January 2010 to December 2023. Systematic reviews and meta-analyses of primary studies using digital physical activity interventions to target healthy older adults or clinical populations of older adults with a self-reported or device measured physical activity outcome were eligible for inclusion. Results In total, 22 systematic reviews and meta-analyses covering 185 primary research papers were eligible for inclusion. The total number of participants across all primary studies was 28,198. Most (21, 95%) reviews and meta-analyses were rated as having a low or critically low AMSTAR-2 confidence rating. Of the 22 included systematic reviews, 13 (59%) conducted a meta-analysis and 10 (45%) conducted a narrative synthesis. Most systematic reviews with a narrative synthesis found strong evidence for a positive effect or moderate evidence for a positive effect for physical activity outcomes (7/9, 78%) and steps (3/3, 100%). The meta-meta-analysis of primary papers included in meta-analyses demonstrated a significant moderate effect for steps and a significant small effect for total PA and MVPA. The strength of effect did not vary by intervention components (activity tracker, app-based, SMS/phone, web-based, and face-to-face), population (primary or secondary prevention), control group (none, other digital intervention, or non-digital intervention), or outcome measurement (self-reported or device measured). Only 3 (14%) reviews included longer term follow up outcomes after the end of the intervention, with mixed results. Conclusions Evidence from 22 reviews and meta-analyses suggests that digital physical activity interventions are effective at increasing physical activity in older adults. Further primary research is needed in adults 65 years and over exclusively, and with longer-term follow up of physical activity outcomes. Future reviews should include a published protocol and interpret results according to risk-of-bias.

Cultivated oat ( Avena sativa L.) is an allohexaploid (AACCDD, 2 n  = 6 x  = 42) thought to have been domesticated more than 3,000 years ago while growing as a weed in wheat, emmer and barley fields in Anatolia 1 , 2 . Oat has a low carbon footprint, substantial health benefits and the potential to replace animal-based food products. However, the lack of a fully annotated reference genome has hampered efforts to deconvolute its complex evolutionary history and functional gene dynamics. Here we present a high-quality reference genome of A . sativa and close relatives of its diploid ( Avena longiglumis , AA, 2 n  = 14) and tetraploid ( Avena insularis , CCDD, 2 n  = 4 x  = 28) progenitors. We reveal the mosaic structure of the oat genome, trace large-scale genomic reorganizations in the polyploidization history of oat and illustrate a breeding barrier associated with the genome architecture of oat. We showcase detailed analyses of gene families implicated in human health and nutrition, which adds to the evidence supporting oat safety in gluten-free diets, and we perform mapping-by-sequencing of an agronomic trait related to water-use efficiency. This resource for the Avena genus will help to leverage knowledge from other cereal genomes, improve understanding of basic oat biology and accelerate genomics-assisted breeding and reanalysis of quantitative trait studies. Assembly of the hexaploid oat genome and its diploid and tetraploid relatives clarifies the evolutionary history of oat and allows mapping of genes for agronomic traits.

Gene regulatory elements are central drivers of phenotypic variation and thus of critical importance towards understanding the genetics of complex traits. The Functional Annotation of Animal Genomes consortium was formed to collaboratively annotate the functional elements in animal genomes, starting with domesticated animals. Here we present an expansive collection of datasets from eight diverse tissues in three important agricultural species: chicken ( Gallus gallus ), pig ( Sus scrofa ), and cattle ( Bos taurus ). Comparative analysis of these datasets and those from the human and mouse Encyclopedia of DNA Elements projects reveal that a core set of regulatory elements are functionally conserved independent of divergence between species, and that tissue-specific transcription factor occupancy at regulatory elements and their predicted target genes are also conserved. These datasets represent a unique opportunity for the emerging field of comparative epigenomics, as well as the agricultural research community, including species that are globally important food resources. In order to interpret non-coding variants, information about regulatory elements in the genome is essential. Here, the authors annotate regulatory elements in chicken, pig and cattle, and characterize conservation of these elements between species.

Trimethylation of histone H3 Lys-27 (H3K27me3) plays a critical role in regulating gene expression during plant and animal development. We characterized the genome-wide distribution of H3K27me3 in five developmentally distinct tissues in maize (Zea mays) plants of two genetic backgrounds, B73 and Mo17. There were more substantial differences in the genome-wide profile of H3K27me3 between different tissues than between the two genotypes. The tissue-specific patterns of H3K27me3 were often associated with differences in gene expression among the tissues and most of the imprinted genes that are expressed solely from the paternal allele in endosperm are targets of H3K27me3. A comparison of the H3K27me3 targets in rice (Oryza sativa), maize, and Arabidopsis thaliana provided evidence for conservation of the H3K27me3 targets among plant species. However, there was limited evidence for conserved targeting of H3K27me3 in the two maize subgenomes derived from whole-genome duplication, suggesting the potential for subfunctionalization of chromatin regulation of paralogs. Genomic profiling of H3K27me3 in loss-of-function mutant lines for Maize Enhancer of zeste-like2 (Mez2) and Mez3, two of the three putative H3K27me3 methyltransferases present in the maize genome, suggested partial redundancy of this gene family for maintaining H3K27me3 patterns. Only a portion of the targets of H3K27me3 required Mez2 and/or Mez3, and there was limited evidence for functional consequences of H3K27me3 at these targets.

DNA methylation is a chromatin modification that is frequently associated with epigenetic regulation in plants and mammals. However, genetic changes such as transposon insertions can also lead to changes in DNA methylation. Genome-wide profiles of DNA methylation for 20 maize (Zea mays) inbred lines were used to discover differentially methylated regions (DMRs). The methylation level for each of these DMRs was also assayed in 31 additional maize or teosinte genotypes, resulting in the discovery of 1966 common DMRs and 1754 rare DMRs. Analysis of recombinant inbred lines provides evidence that the majority of DMRs are heritable. A local association scan found that nearly half of the DMRs with common variation are significantly associated with single nucleotide polymorphisms found within or near the DMR. Many of the DMRs that are significantly associated with local genetic variation are found near transposable elements that may contribute to the variation in DNA methylation. Analysis of gene expression in the same samples used for DNA methylation profiling identified over 300 genes with expression patterns that are significantly associated with DNA methylation variation. Collectively, our results suggest that DNA methylation variation is influenced by genetic and epigenetic changes that are often stably inherited and can influence the expression of nearby genes.