2-Benzylbenzimidazole \'nitazene\' opioids are presenting a growing threat to public health. Although various nitazenes were previously studied, systematic comparisons of the effects of different structural modifications to the 2-benzylbenzimidazole core structure on μ-opioid receptor (MOR) activity are limited. Here, we assessed in vitro structure-activity relationships of 9 previously uncharacterized nitazenes alongside known structural analogues. Specifically, we focused on MOR activation by \'ring\' substituted analogues (i.e., N-pyrrolidino and N-piperidinyl modifications), \'desnitazene\' analogues (lacking the 5-nitro group), and N-desethyl analogues. The results from two in vitro MOR activation assays (β-arrestin 2 recruitment and inhibition of cAMP accumulation) showed that \'ring\' modifications overall yield highly active drugs. With the exception of 4\'-OH analogues (which are metabolites), N-pyrrolidino substitutions were generally more favorable for MOR activation than N-piperidine substitutions. Furthermore, removal of the 5-nitro group on the benzimidazole ring consistently caused a pronounced decrease in potency. The N-desethyl modifications showed important MOR activity, and generally resulted in a slightly lowered potency than comparator nitazenes. Intriguingly, N-desethyl isotonitazene was the exception and was consistently more potent than isotonitazene. Complementing the in vitro findings and demonstrating the high harm potential associated with many of these compounds, we describe 85 forensic cases from North America and the United Kingdom involving etodesnitazene, N-desethyl etonitazene, N-desethyl isotonitazene, N-pyrrolidino metonitazene, and N-pyrrolidino protonitazene. The low-to-sub ng/mL blood concentrations observed in most cases underscore the drugs\' high potencies. Taken together, by bridging pharmacology and case data, this study may aid to increase awareness and guide legislative and public health efforts.

Chemical index components, especially those defined as quality control (QC) markers through spectrum-effect relationship approach, are commonly suggested and adopted as indicator for quality control of Traditional Chinese Medicines (TCMs). However, are chemical index components and quality control of TCMs \"never change a winning team\"? In this study, under the ponderation of the applicability of QC markers strategy, spectrum-effect relationship and OPLS-DA between GC×GC-MS fingerprint and inhibitory effect on the expression of extracellular secretory TNF-α of volatile oil from Bupleuri radix (BVO) was studied with the purpose of discovery of QC markers and establish a bioactive compounds-based QC method. 290 compounds of BVO were identified by GC×GC-MS. Besides, BVO had significant inhibitory effects on the expression of extracellular secretory TNF-α in a dose-dependent manner. The potency of different batches of BVOs could be distinguished with this bioassay-based method, which has been validated in terms of intermediate precision, repeatability, linearity, range and credibility tests. The QC markers of BVO were investigated by Spearman\'s correlation test and OPLS-DA. It is regrettable that there were no ideal QC markers of BVO could be found. In conclusion, quality control method relayed on chemical QC markers is not feasible for TCMs with complex composition but lack of ingredients that dominate in content, just like BVO. Alternatively, a bioassay-based method established in our study is suitable for quality control of BVO.

To evaluate the effects of nitrofurazone on functional processes in marine ecosystems, periphytic protozoan communities were exposed to different concentrations of the antibiotic for a 10-day duration. Species trait distributions in the tested communities were observed during exposure to five concentrations of nitrofurazone. A fuzzy coding system with seven traits and seventeen categories was used to summarize the changes in functional patterns of the test organisms. Nitrofurazone had a significant influence on the function process of the periphytic ciliate communities. Bacterivores with flattened bodies were sensitive to the toxicant whereas sessile and cylindrical raptors showed a high tolerance to nitrofurazone, invariably dominating communities exposed to high concentrations. Bootstrapped-average analysis demonstrated a significant change in functional patterns at highest nitrofurazone concentrations (8 mg l-1). Based on these findings, it is suggested that nitrofurazone may negatively influence ecosystem function in marine environments.

The slow pace of discovery of bioactive natural products can be attributed to the difficulty in rapidly identifying them in complex mixtures such as plant extracts. To overcome these hurdles, we explored the utility of two machine learning techniques, i.e., Elastic Net and Random Forests, for identifying the individual anti-inflammatory principle(s) of an extract of the inflorescences of the hops (Humulus lupulus) containing hundreds of natural products. We fractionated a hop extract by column chromatography to obtain 40 impure fractions, determined their anti-inflammatory activity using a macrophage-based bioassay that measures inhibition of iNOS-mediated formation of nitric oxide, and characterized the chemical composition of the fractions by flow-injection HRAM mass spectrometry and LC-MS/MS. Among the top 10 predictors of bioactivity were prenylated flavonoids and humulones. The top Random Forests predictor of bioactivity, xanthohumol, was tested in pure form in the same bioassay to validate the predicted result (IC50 7 µM). Other predictors of bioactivity were identified by spectral similarity with known hop natural products using the Global Natural Products Social Networking (GNPS) algorithm. Our machine learning approach demonstrated that individual bioactive natural products can be identified without the need for extensive and repetitive bioassay-guided fractionation of a plant extract.

Organic enrichment due to human impact is one of the major threats that affect benthic communities in semi-enclosed marine ecosystems, such as the Mediterranean Sea. However, many emerging sources of organic pollutants, such as those released to nature through human practices related to esthetics and cosmetics, remain underestimated, despite being an increasingly important source of organic matter input following a decade of expansion by the cosmetic industry. Therefore, an experiment was designed to explore the influence of collagen, the main component of commercialized skin anti-aging products, on a Mediterranean community of free-living marine nematodes from a beach in Rimel, northeast Tunisia. The effects of exposure for 30 days to a control treatment and three test treatments, corresponding to three levels of sedimentary enrichment with collagen (3, 6, and 12 ppm dry weight (DW)), were examined using a microcosm approach. Reductions in abundance and diversity were noted with an increase in collagen enrichment, together with a slight increase in individual weight. The presence of three species characteristic of control microcosms, Ptycholaimellus ponticus, Theristus modicus, and Kraspedonema reflectans, was clearly affected at the lowest dose; these were therefore classified as \"collagen-sensitive.\" In contrast, the numbers of \"collagen-tolerant\" species, including Sigmophoranema rufum, Lauratonema hospitum, Enoploides spiculohamatus, and Trichotheristus mirabilis, increased significantly in the treated microcosms.

Aquaculture is one of the fastest growing food producing industries in the world. This dramatic increase in growth has raised many environmental concerns. Evaluation of fish farm effluent is frequently assessed by physicochemical parameters. This approach indicates potential degradation caused by the effluent and not cumulative effects on aquatic ecosystems. This study investigated relationships between physicochemical parameters (temperature, pH, conductivity, nitrogen, phosphorus, oxygen and suspended solids), typically used to assess water quality with the Pseudokirchneriella subcapitata algal bioassay, which evaluated the potential ecotoxicological effects that freshwater fish farm effluent has on its receiving ecosystems and organisms. Influent and effluent samples were collected from a freshwater farm facility every two weeks from April 2018 to October 2018 in the Republic of Ireland. This monitoring period coincided with one of the warmest and driest periods recorded by meteorological stations in the Republic of Ireland. Physicochemical analyses were found to be similar to those in other farm studies. After exposure of algae to the effluent, stimulation of algal growth rates increased by >50%. This stimulation was observed during periods of increased temperatures which were as a result of heat wave and drought conditions experienced during monitoring. Correlation studies identified a moderately strong relationship between algal stimulation and temperature (r = -0.619). This study discovered that removal of Lemna minor (aquatic plant), impacted strongly on the freshwater farm pond-process to cope with nitrates. The constructed wetland system was unable to efficiently treat nitrates and phosphates during conditions of drought. These findings indicate that standard water quality parameters may not be applicable to inform appropriate suitability of fish farm effluent for discharge to receiving water. The research conducted in this study has suggested a potential toolbox that includes P. subcapitata may provide an early warning system for adverse effects as a result of climate change.

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BACKGROUND: Sensitive outcome measures are needed to quantify the effects of neuromodulation in mood disorders.
OBJECTIVE: This study examined the utility of a novel affective bias (AB) task in identifying transient mood changes induced by amygdala stimulation in a single rare participant.
METHODS: Localized, pulsed electrical stimulation was delivered for 8 min during measures of AB and self-reported mood. Responses were compared with those gathered without stimulation on the same day in the same setting, using paired t-tests.
RESULTS: Stimulation of the basolateral nucleus of the right amygdala at 50 Hz, 15 V, and 200 μs pulse-width produced a significant positive shift in AB (t = -2.864, df = 53, P = .006), despite equivocal findings on self-reported mood (t = -.184, df = 12, P = .857).
CONCLUSIONS: Affective bias may be more sensitive to stimulation-induced fluctuations in mood than subjective report, suggesting utility as an outcome measure in neuromodulation studies.