Bacteria employed in probiotic applications help to maintain or restore a host's natural microbial floral. The ability of probiotic bacteria to successfully outcompete undesired species is often due ...to, or enhanced by, the production of potent antimicrobial toxins. The most commonly encountered of these are bacteriocins, a large and functionally diverse family of antimicrobials found in all major lineages of Bacteria. Recent studies reveal that these proteinaceous toxins play a critical role in mediating competitive dynamics between bacterial strains and closely related species. The potential use of bacteriocin-producing strains as probiotic and bioprotective agents has recently received increased attention. This review will report on recent efforts involving the use of such strains, with a particular focus on emerging probiotic therapies for humans, livestock, and aquaculture.
Organotypic models of patient-specific tumours are revolutionizing our understanding of cancer heterogeneity and its implications for personalized medicine. These advancements are, in part, ...attributed to the ability of organoid models to stably preserve genetic, proteomic, morphological and pharmacotypic features of the parent tumour in vitro, while also offering unprecedented genomic and environmental manipulation. Despite recent innovations in organoid protocols, current techniques for cancer organoid culture are inherently uncontrolled and irreproducible, owing to several non-standardized facets including cancer tissue sources and subsequent processing, medium formulations, and animal-derived three-dimensional matrices. Given the potential for cancer organoids to accurately recapitulate the intra- and intertumoral biological heterogeneity associated with patient-specific cancers, eliminating the undesirable technical variability accompanying cancer organoid culture is necessary to establish reproducible platforms that accelerate translatable insights into patient care. Here we describe the current challenges and recent multidisciplinary advancements and opportunities for standardizing next-generation cancer organoid systems.
Overfishing is the primary cause of marine defaunation, yet declines in and increasing extinction risks of individual species are difficult to measure, particularly for the largest predators found in ...the high seas
. Here we calculate two well-established indicators to track progress towards Aichi Biodiversity Targets and Sustainable Development Goals
: the Living Planet Index (a measure of changes in abundance aggregated from 57 abundance time-series datasets for 18 oceanic shark and ray species) and the Red List Index (a measure of change in extinction risk calculated for all 31 oceanic species of sharks and rays). We find that, since 1970, the global abundance of oceanic sharks and rays has declined by 71% owing to an 18-fold increase in relative fishing pressure. This depletion has increased the global extinction risk to the point at which three-quarters of the species comprising this functionally important assemblage are threatened with extinction. Strict prohibitions and precautionary science-based catch limits are urgently needed to avert population collapse
, avoid the disruption of ecological functions and promote species recovery
.
The scale and drivers of marine biodiversity loss are being revealed by the International Union for Conservation of Nature (IUCN) Red List assessment process. We present the first global reassessment ...of 1,199 species in Class Chondrichthyes—sharks, rays, and chimeras. The first global assessment (in 2014) concluded that one-quarter (24%) of species were threatened. Now, 391 (32.6%) species are threatened with extinction. When this percentage of threat is applied to Data Deficient species, more than one-third (37.5%) of chondrichthyans are estimated to be threatened, with much of this change resulting from new information. Three species are Critically Endangered (Possibly Extinct), representing possibly the first global marine fish extinctions due to overfishing. Consequently, the chondrichthyan extinction rate is potentially 25 extinctions per million species years, comparable to that of terrestrial vertebrates. Overfishing is the universal threat affecting all 391 threatened species and is the sole threat for 67.3% of species and interacts with three other threats for the remaining third: loss and degradation of habitat (31.2% of threatened species), climate change (10.2%), and pollution (6.9%). Species are disproportionately threatened in tropical and subtropical coastal waters. Science-based limits on fishing, effective marine protected areas, and approaches that reduce or eliminate fishing mortality are urgently needed to minimize mortality of threatened species and ensure sustainable catch and trade of others. Immediate action is essential to prevent further extinctions and protect the potential for food security and ecosystem functions provided by this iconic lineage of predators.
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•More than one-third of chondrichthyan fish species are threatened by overfishing•Disproportionate threat in tropics risk loss of ecosystem functions and services•Three species not seen in >80 years are Critically Endangered (Possibly Extinct)•The depletion of these species has been driven by continuing demand for human food
The IUCN Red List of Threatened Species is increasingly used to reveal the health of ocean biodiversity. Dulvy et al. assess 1,199 chondrichthyans and demonstrate the need for fishing limits on target and incidental catch and spatial protection to avoid further extinctions and allow for food security and ecosystem functions.
We present the use of functionalized gold nanoparticles (AuNPs) to combat multi-drug-resistant pathogenic bacteria. Tuning of the functional groups on the nanoparticle surface provided gold ...nanoparticles that were effective against both Gram-negative and Gram-positive uropathogens, including multi-drug-resistant pathogens. These AuNPs exhibited low toxicity to mammalian cells, and bacterial resistance was not observed after 20 generations. A strong structure–activity relationship was observed as a function of AuNP functionality, providing guidance to activity prediction and rational design of effective antimicrobial nanoparticles.
Drug resistance to approved systemic therapies in estrogen receptor-positive (ER+) breast cancer remains common. We hypothesized that factors present in the human tumor microenvironment (TME) drive ...drug resistance. Screening of a library of recombinant secreted microenvironmental proteins revealed fibroblast growth factor 2 (FGF2) as a potent mediator of resistance to anti-estrogens, mTORC1 inhibition, and phosphatidylinositol 3-kinase inhibition in ER+ breast cancer. Phosphoproteomic analyses identified ERK1/2 as a major output of FGF2 signaling via FGF receptors (FGFRs), with consequent up-regulation of Cyclin D1 and down-regulation of Bim as mediators of drug resistance. FGF2-driven drug resistance in anti-estrogen-sensitive and -resistant models, including patient-derived xenografts, was reverted by neutralizing FGF2 or FGFRs. A transcriptomic signature of FGF2 signaling in primary tumors predicted shorter recurrence-free survival independently of age, grade, stage, and FGFR amplification status. These findings delineate FGF2 signaling as a ligand-based drug resistance mechanism and highlights an underdeveloped aspect of precision oncology: characterizing and treating patients according to their TME constitution.
Target engagement assays typically detect and quantify the direct physical interaction of a protein of interest and its ligand through stability changes upon ligand binding. Commonly used target ...engagement methods detect ligand‐induced stability by subjecting samples to thermal or proteolytic stress. Here we describe a new variation to these approaches called Isothermal Ligand‐induced Resolubilization Assay (ILIRA), which utilizes lyotropic solubility stress to measure ligand binding through changes in target protein solubility. We identified distinct buffer systems and salt concentrations that compromised protein solubility for four diverse proteins: dihydrofolate reductase (DHFR), nucleoside diphosphate‐linked moiety X motif 5 (NUDT5), poly ADP‐ribose polymerase 1 (PARP1), and protein arginine N‐methyltransferase 1 (PRMT1). Ligand‐induced solubility rescue was demonstrated for these proteins, suggesting that ILIRA can be used as an additional target engagement technique. Differences in ligand‐induced protein solubility were assessed by Coomassie blue staining for SDS‐PAGE and dot blot, as well as by NanoOrange, Thioflavin T, and Proteostat fluorescence, thus offering flexibility for readout and assay throughput.
Isothermal Ligand‐Induced Resolubilization Assay (ILIRA) is a new screening method for identifying protein ligands that relies on differences in solubility between unliganded and liganded proteins under lyotropic stress conditions. In this proof‐of‐concept study, we demonstrate the application of ILIRA to different protein targets and present alternative assay modalities.
Background
New-onset substance use disorder (SUD) following bariatric surgery is a significant concern that is likely multi-factorial, although the etiologies are unclear. Previous studies have ...identified variable rates of SUD along with utilizing different methods and measures. The objective of this study is to evaluate new-onset SUD diagnoses among adults following bariatric surgery and compare these rates to those in the general population as well as those diagnosed with overweight or obesity.
Methods
Data was extracted from TriNetX Research Platform and used to build three cohorts of adults: those who had bariatric surgery (bariatric surgery cohort), those diagnosed with obesity or overweight, and a general population cohort. Rates of incident SUD were compared among these three groups. Initial encounters for all individuals were from January 1, 2018, to June 30, 2019.
Results
The incidence rate of SUD in patients with a history of bariatric surgery was 6.55% (
n
= 2523). When compared to the general population, persons who had any type of bariatric procedure had a decreased risk of new-onset SUD with an overall odds ratio (OR) 95% confidence limits (CL) of 0.89 0.86, 0.93. When compared to persons with overweight or obesity, bariatric patients were less likely to develop any form of SUD (OR: 0.65 0.62, 0.67).
Conclusion
While overall rates of new-onset SUD are lower among those who had bariatric surgery, they also vary by surgery and substance type. Efforts should still be made to address new-onset SUD in order to optimize the post-surgical care of patients.
Graphical Abstract
Arynes offer immense potential for diversification of benzenoid rings, which occur in pharmaceuticals, agrochemicals, and liquid crystals. However, accessing these high-energy intermediates requires ...synthetic precursors, which involve either harsh conditions or multistep syntheses. The development of alternative methods to access arynes using simpler substrates and milder conditions is necessary for a more streamlined approach. Here, we describe a two-step formal dehydrogenation of simple arenes to generate arynes at a remote position relative to traditionally reactive groups, e.g., halides. This approach is enabled by regioselective installation and ejection of an “onium” leaving group, and we demonstrate the compatibility of simple arenes (20 examples) and arynophiles (8 examples). Moreover, through direct comparison, we show that our formal dehydrogenation method is both more functional group tolerant and efficient in generating arynes than the current state-of-the-art aryne precursors. Finally, we show that aryne intermediates offer opportunities for regioselective C–H amination that are distinct from other methods.
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