Alternative bait trials in the Barents Sea snow crab fishery

Commercial harvesting of snow crab (Chionoecetes opilio) in the Barents Sea started in 2012 by Norwegian fishing vessels. This new fishery has significant bait requirements, representing an emerging conservation challenge. In this study, we evaluate the performance of five alternative (natural) baits manufactured from the waste stream of existing and sustainably managed harp seal (Pagophilus groenlandicus) and minke whale (Balaenoptera acutorostrata) capture. Five different types of new bait were evaluated, including seal fat (SF), seal fat with skin (SFS), seal meat with bone (SMB), whale fat with skin (WFS), and whale meat with fat (WMF). A comparative fishing experiment was conducted onboard a commercial snow crab fishing vessel in the Barents Sea (May–June, 2016) to evaluate the performance of traditional bait (squid, Illexs spp.) and alternative baits at catching snow crabs. Performance of the different baits were compared on the basis of the number of commercial crab caught per trap haul catch per unit effort (CPUE) and carapace width (CW). Our results showed that SF and SFS performed equally well to traditional bait, with no statistical difference in CPUE (p-value = 0.325 and 0.069, respectively). All of the other experimental baits significantly decreased CPUE, when compared to squid. No significant effect of bait treatment on CW was detected and the cumulative distribution of CW was the same between control traps and each of the bait treatments. Overall the results indicated that SF and SFS represent a viable alternative to replace traditional bait, addressing a key conservation challenge in this bait intensive snow crab fishery

A novel derivative of thioridazine shows low toxicity and efficient activity against gram‐positive pathogens

Thioridazine hydrochloride (HCl) has been suggested as a promising antimicrobial helper compound for the treatment of infections with antimicrobial-resistant bacteria. Unfortunately, the therapeutic concentration of thioridazine HCl is generally higher than what can be tolerated clinically, in part due to its toxic side effects on the central nervous system. Therefore, we aimed to synthesize a less toxic thioridazine derivative that would still retain its properties as a helper compound. This resulted in a compound designated 1-methyl-2-(2-(2-(methylthio)-10H-phenothiazin-10-yl)ethyl)-1-pentylpiperidin-1-ium bromide (abbreviated T5), which exhibited low blood–brain barrier permeability. The lowest minimal inhibitory concentration (MIC) against Staphylococcus aureus exposed to the novel compound was reduced 32-fold compared to thioridazine HCl (from 32 µg/mL to 1 µg/mL). The MIC values for T5 against five Gram-positive pathogens ranged from 1 µg/mL to 8 µg/mL. In contrast to thioridazine HCl, T5 does not act synergistically with oxacillin. In silico predictive structure analysis of T5 suggests that an acceptably low toxicity and lack of induced cytotoxicity was demonstrated by a lactate dehydrogenase assay. Conclusively, T5 is suggested as a novel antimicrobial agent against Gram-positive bacteria. However, future pharmacokinetic and pharmacodynamic studies are needed to clarify the clinical potential of this novel discovery

Development of a multifunctional benzophenone linker for peptide stapling and photoaffinity labeling

Photoaffinity labelling is a useful method for studying how proteins interact with ligands and biomolecules, and can help identify and characterise new targets for the development of new therapeutics. We present the design and synthesis of a novel multifunctional benzophenone linker, which serves as both a photocrosslinking motif and a peptide stapling reagent. Using a double-click stapling methodology, we attach the benzophenone to the peptide via the staple linker, rather than modifying the peptide sequence with a photocrosslinking amino acid. Applied to a p53-derived peptide, the resulting photoreactive stapled peptide is able to preferentially crosslink with MDM2 in the presence of competing protein. This multifunctional linker also features an extra alkyne handle for downstream applications such as pull-down assays, and can be used to investigate the target selectivity of stapled peptides.This work was supported by the EPSRC, BBSRC, MRC, Wellcome Trust and ERC (FP7/2007-2013; 279337/DOS). We thank Dr. Clemens Mayer for access to the UV crosslinker (University Chemical Laboratory, University of Cambridge), Weiyan Chen and Fran Kundel (University Chemical Laboratory, University of Cambridge) for assistance with the Typhoon imager and Dr. Laura Itzhaki and Wenshu Xu (Department of Pharmacology, University of Cambridge) for assistance with SDS-PAGE.This is the final version of the article. It first appeared from Wiley via https://doi.org/10.1002/cbic.20150064

Insight Into the Anti-staphylococcal Activity of JBC 1847 at Sub-Inhibitory Concentration

Multidrug-resistant pathogens constitute a serious global issue and, therefore, novel antimicrobials with new modes of action are urgently needed. Here, we investigated the effect of a phenothiazine derivative (JBC 1847) with high antimicrobial activity on Staphylococcus aureus, using a wide range of in vitro assays, flow cytometry, and RNA transcriptomics. The flow cytometry results showed that JBC 1847 rapidly caused depolarization of the cell membrane, while the macromolecule synthesis inhibition assay showed that the synthesis rates of DNA, RNA, cell wall, and proteins, respectively, were strongly decreased. Transcriptome analysis of S. aureus exposed to sub-inhibitory concentrations of JBC 1847 identified a total of 78 downregulated genes, whereas not a single gene was found to be significantly upregulated. Most importantly, there was downregulation of genes involved in adenosintrifosfat (ATP)-dependent pathways, including histidine biosynthesis, which is likely to correlate with the observed lower level of intracellular ATP in JBC 1847–treated cells. Furthermore, we showed that JBC 1847 is bactericidal against both exponentially growing cells and cells in a stationary growth phase. In conclusion, our results showed that the antimicrobial properties of JBC 1847 were primarily caused by depolarization of the cell membrane resulting in dissipation of the proton motive force (PMF), whereby many essential bacterial processes are affected. JBC 1847 resulted in lowered intracellular levels of ATP followed by decreased macromolecule synthesis rate and downregulation of genes essential for the amino acid metabolism in S. aureus. Bacterial compensatory mechanisms for this proposed multi-target activity of JBC 1847 seem to be limited based on the observed very low frequency of resistance toward the compound

Development of a Multifunctional Benzophenone Linker for Peptide Stapling and Photoaffinity Labelling.

Photoaffinity labelling is a useful method for studying how proteins interact with ligands and biomolecules, and can help identify and characterise new targets for the development of new therapeutics. We present the design and synthesis of a novel multifunctional benzophenone linker that serves as both a photo-crosslinking motif and a peptide stapling reagent. Using double-click stapling, we attached the benzophenone to the peptide via the staple linker, rather than by modifying the peptide sequence with a photo-crosslinking amino acid. When applied to a p53-derived peptide, the resulting photoreactive stapled peptide was able to preferentially crosslink with MDM2 in the presence of competing protein. This multifunctional linker also features an extra alkyne handle for downstream applications such as pull-down assays, and can be used to investigate the target selectivity of stapled peptides.This work was supported by the EPSRC, BBSRC, MRC, Wellcome Trust and ERC (FP7/2007-2013; 279337/DOS). We thank Dr. Clemens Mayer for access to the UV crosslinker (University Chemical Laboratory, University of Cambridge), Weiyan Chen and Fran Kundel (University Chemical Laboratory, University of Cambridge) for assistance with the Typhoon imager and Dr. Laura Itzhaki and Wenshu Xu (Department of Pharmacology, University of Cambridge) for assistance with SDS-PAGE.This is the final version of the article. It first appeared from Wiley via https://doi.org/10.1002/cbic.20150064

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Cross-sectional analysis of students and school workers reveals a high number of asymptomatic SARS-CoV-2 infections during school reopening in Brazilian cities

Brazil experienced one of the most prolonged periods of school closures, and reopening could have exposed students to high rates of SARS-CoV-2 infection. However, the infection status of students and school workers at the time of the reopening of schools located in Brazilian cities is unknown. Here we evaluated viral carriage by RT-PCR and seroprevalence of anti-SARS-CoV-2 antibodies (IgM and IgG) by immunochromatography in 2259 individuals (1139 students and 1120 school workers) from 28 schools in 28 Brazilian cities. We collected the samples within 30 days after public schools reopened and before the start of vaccination campaigns. Most students (n = 421) and school workers (n = 446) had active (qRT-PCR + IgM− IgG− or qRT-PCR + IgM + IgG−/+) SARS-CoV-2 infection. Regression analysis indicated a strong association between the infection status of students and school workers. Furthermore, while 45% (n = 515) of the students and 37% (n = 415) of the school workers were neither antigen nor antibody positive in laboratory tests, 16% of the participants (169 students and 193 school workers) were oligosymptomatic, including those reinfected. These individuals presented mild symptoms such as headache, sore throat, and cough. Notably, most of the individuals were asymptomatic (83.9%). These results indicate that many SARS-CoV-2 infections in Brazilian cities during school reopening were asymptomatic. Thus, our study highlights the need to promote a coordinated public health effort to guarantee a safe educational environment while avoiding exacerbating pre-existent social inequalities in Brazil, reducing social, mental, and economic losses for students, school workers, and their families