Nor-BNI Antagonism of Kappa Opioid Agonist-Induced Reinstatement of Ethanol-Seeking Behavior

Recent work suggests that the dynorphin (DYN)/kappa opioid receptor (KOR) system may be a key mediator in the behavioral effects of alcohol. The objective of the present study was to examine the ability of the KOR antagonist norbinaltorphimine (norBNI) to attenuate relapse to ethanol seeking due to priming injections of the KOR agonist U50,488 at time points consistent with KOR selectivity. Male Wistar rats were trained to self-administer a 10% ethanol solution, and then responding was extinguished. Following extinction, rats were injected with U50,488 (0.1–10 mg/kg, i.p.) or saline and were tested for the reinstatement of ethanol seeking. Next, the ability of the nonselective opioid receptor antagonist naltrexone (0 or 3.0 mg/kg, s.c.) and nor-BNI (0 or 20.0 mg/kg, i.p.) to block U50,488-induced reinstatement was examined. Priming injections U50,488 reinstated responding on the previously ethanol-associated lever. Pretreatment with naltrexone reduced the reinstatement of ethanol-seeking behavior. norBNI also attenuated KOR agonist-induced reinstatement, but to a lesser extent than naltrexone, when injected 24 hours prior to injections of U50,488, a time point that is consistent with KOR selectivity. While these results suggest that activation of KORs is a key mechanism in the regulation of ethanol-seeking behavior, U50,488-induced reinstatement may not be fully selective for KORs

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Anticonvulsant effects of cenobamate in chemically and electrically induced seizure models in rodents

Background: Cenobamate is an antiseizure medication used to treat partial-onset (focal) seizures. It is a molecule with one chiral center and a unique dual mechanism of action: enhancement of fast and slow inactivation of sodium channels with preferential inhibition of the persistent current and positive allosteric modulation of GABAA receptor-mediated ion channels. Aims/Methods: Anticonvulsant effects of cenobamate (YKP3089; R-enantiomer), YKP3090 (S-enantiomer), and YKP1983 (racemate) were evaluated in chemically and electrically induced focal and generalized seizure models in rodents. The Genetic Absence Epilepsy Rat from Strasbourg (GAERS) model examined the effect of cenobamate on spike-wave seizures. Motor coordination was assessed with rotarod tests and minimal motor impairment exams. Results: Early in development, cenobamate was found to have activity in focal and generalized seizure models in animals and was selected for continued development. Cenobamate prevented seizures in a dose-dependent manner, prevented seizure spread, and increased seizure threshold without potentiating seizure initiation or the development of tolerance to its anticonvulsant effects. In contrast, YKP3090 and YKP1983 were only effective against generalized tonic-clonic seizures. Cenobamate also protected mice from 6 Hz psychomotor-induced seizures. Cenobamate showed significant dose-dependent reductions in the number and cumulative duration of spike-and-wave discharges in the GAERS model. Discussion: Cenobamate showed efficacy or efficacy signals in all animal models of epilepsy tested with a favorable risk-versus-benefit ratio, supporting its clinical use in the treatment of partial-onset (focal) seizures in adults and warranting further clinical research in generalized seizures and absence seizures

Examining Adverse Selection in Organic Crop Insurance: Where Do We Go From Here?

Understanding when and why organic farmers use crop insurance can not only instruct the design of an equitable and financially sustainable crop insurance system but also identify production methods that decrease dependence on program-based risk management. In this article, the research team will identify factors influencing organic farmers’ decision to purchase or forgo crop insurance. Do organic farmers opt out of crop insurance because it is not cost-effective, because alternative risk management tools are preferred, due to barriers to access, or for some other reason? Understanding the drivers of and barriers to crop insurance use by organic producers can inform crop insurance designs that meet producer needs as well as illustrate alternative risk management methods that should not be lost as a result of the crop insurance safety net

Strain-Dependent Activity of Zika Virus and Exposure History in Serological Diagnostics

Zika virus (ZIKV) circulates as two separate lineages, with significant genetic variability between strains. Strain-dependent activity has been reported for dengue virus, herpes simplex virus and influenza. Strain-dependent activity of subject specimens to a virus could be an impediment to serological diagnosis and vaccine development. In order to determine whether ZIKV exhibits strain-dependent activity when exposed to antibodies, we measured the neutralizing properties of polyclonal serum and three monoclonal antibodies (ZKA185, 753(3)C10, and 4G2) against three strains of ZIKV (MR−766, PRVABC59, and R103454). Here, MR−766 was inhibited almost 60% less by ZKA185 than PRVABC59 and R103454 (p = 0.008). ZKA185 enhanced dengue 4 infection up to 50% (p = 0.0058). PRVABC59 was not inhibited by mAb 753(3)C10 while MR−766 and R103453 were inhibited up to 90% (p = 0.04 and 0.036, respectively). Patient serum, regardless of exposure history, neutralized MR−766 ~30%−40% better than PRVABC56 or R103454 (p = 0.005−0.00007). The most troubling finding was the significant neutralization of MR−766 by patients with no ZIKV exposure. We also evaluated ZIKV antibody cross reactivity with various flaviviruses and found that more patients developed cross-reactive antibodies to Japanese encephalitis virus than the dengue viruses. The data here show that serological diagnosis of ZIKV is complicated and that qualitative neutralization assays cannot discriminate between flaviviruses

Lapatinib Plasma and Tumor Concentrations and Effects on HER Receptor Phosphorylation in Tumor.

The paradigm shift in cancer treatment from cytotoxic drugs to tumor targeted therapies poses new challenges, including optimization of dose and schedule based on a biologically effective dose, rather than the historical maximum tolerated dose. Optimal dosing is currently determined using concentrations of tyrosine kinase inhibitors in plasma as a surrogate for tumor concentrations. To examine this plasma-tumor relationship, we explored the association between lapatinib levels in tumor and plasma in mice and humans, and those effects on phosphorylation of human epidermal growth factor receptors (HER) in human tumors.Mice bearing BT474 HER2+ human breast cancer xenografts were dosed once or twice daily (BID) with lapatinib. Drug concentrations were measured in blood, tumor, liver, and kidney. In a randomized phase I clinical trial, 28 treatment-naïve female patients with early stage HER2+ breast cancer received lapatinib 1000 or 1500 mg once daily (QD) or 500 mg BID before evaluating steady-state lapatinib levels in plasma and tumor.In mice, lapatinib levels were 4-fold higher in tumor than blood with a 4-fold longer half-life. Tumor concentrations exceeded the in vitro IC90 (~ 900 nM or 500 ng/mL) for inhibition of HER2 phosphorylation throughout the 12-hour dosing interval. In patients, tumor levels were 6- and 10-fold higher with QD and BID dosing, respectively, compared to plasma trough levels. The relationship between tumor and plasma concentration was complex, indicating multiple determinants. HER receptor phosphorylation varied depending upon lapatinib tumor concentrations, suggestive of changes in the repertoire of HER homo- and heterodimers.Plasma lapatinib concentrations underestimated tumor drug levels, suggesting that optimal dosing should be focused on the site of action to avoid to inappropriate dose escalation. Larger clinical trials are required to determine optimal dose and schedule to achieve tumor concentrations that maximally inhibit HER receptors.NCT00359190

The Poultry-Associated Microbiome: Network Analysis and Farm-to-Fork Characterizations

<div><p>Microbial communities associated with agricultural animals are important for animal health, food safety, and public health. Here we combine high-throughput sequencing (HTS), quantitative-PCR assays, and network analysis to profile the poultry-associated microbiome and important pathogens at various stages of commercial poultry production from the farm to the consumer. Analysis of longitudinal data following two flocks from the farm through processing showed a core microbiome containing multiple sequence types most closely related to genera known to be pathogenic for animals and/or humans, including <i>Campylobacter, Clostridium</i>, and <i>Shigella</i>. After the final stage of commercial poultry processing, taxonomic richness was ca. 2–4 times lower than the richness of fecal samples from the same flocks and <i>Campylobacter</i> abundance was significantly reduced. Interestingly, however, carcasses sampled at 48 hr after processing harboured the greatest proportion of unique taxa (those not encountered in other samples), significantly more than expected by chance. Among these were anaerobes such as <i>Prevotella</i>, <i>Veillonella</i>, <i>Leptrotrichia</i>, and multiple <i>Campylobacter</i> sequence types. Retail products were dominated by <i>Pseudomonas</i>, but also contained 27 other genera, most of which were potentially metabolically active and encountered in on-farm samples. Network analysis was focused on the foodborne pathogen <i>Campylobacter</i> and revealed a majority of sequence types with no significant interactions with other taxa, perhaps explaining the limited efficacy of previous attempts at competitive exclusion of <i>Campylobacter</i>. These data represent the first use of HTS to characterize the poultry microbiome across a series of farm-to-fork samples and demonstrate the utility of HTS in monitoring the food supply chain and identifying sources of potential zoonoses and interactions among taxa in complex communities.</p> </div

Network analysis of <i>Campylobacter</i> OTUs within poultry-associated microbiomes.

<p>A) Significant network associations for OTUs classified as <i>C. jejuni</i> and <i>C. coli</i> shown in detail, and B) in context of entire network. C) <i>C. jejuni</i> OTUs with connections only to other <i>Campylobacter</i> as shown in orange accounted for a majority of <i>Campylobacter</i> sequences. D) Two <i>Campylobacter</i> OTUs, Clstr3618 and Clstr97, shown in yellow and denoted by arrows, were connected to a much larger suite of taxa including <i>Megamonas hypermegale</i> and <i>Faecalibacterium prausnitzii</i> as discussed in the text.</p