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The safety and efficacy of kratom (Mitragyna speciosa ) for treatment of pain is highly controversial. Kratom produces more than 40 structurally related alkaloids, but most studies have focused on just two of these, mitragynine and 7-hydroxymitragynine. Here, we profiled 53 commercial kratom products using untargeted LC–MS metabolomics, revealing two distinct chemotypes that contain different levels of the alkaloid speciofoline. Both chemotypes were confirmed with DNA barcoding to be M. speciosa. To evaluate the biological relevance of variable speciofoline levels in kratom, we compared the opioid receptor binding activity of speciofoline, mitragynine, and 7-hydroxymitragynine. Mitragynine and 7-hydroxymitragynine function as partial agonists of the human µ-opioid receptor, while speciofoline does not exhibit measurable binding affinity at the µ-, δ- or ƙ-opioid receptors. Importantly, mitragynine and 7-hydroxymitragynine demonstrate functional selectivity for G-protein signaling, with no measurable recruitment of β-arrestin. Overall, the study demonstrates the unique binding and functional profiles of the kratom alkaloids, suggesting potential utility for managing pain, but further studies are needed to follow up on these in vitro findings. All three kratom alkaloids tested inhibited select cytochrome P450 enzymes, suggesting a potential risk for adverse interactions when kratom is co-consumed with drugs metabolized by these enzymes.

Background Prone positioning in combination with the application of low tidal volume and adequate positive end-expiratory pressure (PEEP) improves survival in patients with moderate to severe acute respiratory distress syndrome (ARDS). However, the effects of PEEP on end-expiratory transpulmonary pressure (Ptp exp ) during prone positioning require clarification. For this purpose, the effects of three different PEEP titration strategies on Ptp exp , respiratory mechanics, mechanical power, gas exchange, and hemodynamics were evaluated comparing supine and prone positioning. Methods In forty consecutive patients with moderate to severe ARDS protective ventilation with PEEP titrated according to three different titration strategies was evaluated during supine and prone positioning: (A) ARDS Network recommendations (PEEP ARDSNetwork ), (B) the lowest static elastance of the respiratory system (PEEP Estat,RS ), and (C) targeting a positive Ptp exp (PEEP Ptpexp ). The primary endpoint was to analyze whether Ptp exp differed significantly according to PEEP titration strategy during supine and prone positioning. Results Ptp exp increased progressively with prone positioning compared with supine positioning as well as with PEEP Estat,RS and PEEP Ptpexp compared with PEEP ARDSNetwork (positioning effect p  < 0.001, PEEP strategy effect p  < 0.001). PEEP was lower during prone positioning with PEEP Estat,RS and PEEP Ptpexp (positioning effect p  < 0.001, PEEP strategy effect p  < 0.001). During supine positioning, mechanical power increased progressively with PEEP Estat,RS and PEEP Ptpexp compared with PEEP ARDSNetwork , and prone positioning attenuated this effect (positioning effect p  < 0.001, PEEP strategy effect p  < 0.001). Prone compared with supine positioning significantly improved oxygenation (positioning effect p  < 0.001, PEEP strategy effect p  < 0.001) while hemodynamics remained stable in both positions. Conclusions Prone positioning increased transpulmonary pressures while improving oxygenation and hemodynamics in patients with moderate to severe ARDS when PEEP was titrated according to the ARDS Network lower PEEP table. This PEEP titration strategy minimized parameters associated with ventilator-induced lung injury induction, such as transpulmonary driving pressure and mechanical power. We propose that a lower PEEP strategy (PEEP ARDSNetwork ) in combination with prone positioning may be part of a lung protective ventilation strategy in patients with moderate to severe ARDS. Trial registration German Clinical Trials Register ( DRKS00017449 ). Registered June 27, 2019. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00017449

The influence of the laser fluence on the quality of percussion-drilled holes was investigated both experimentally and by an analytical model. The study reveals that the edge quality of the drilled microholes depends on the laser fluence reaching the rear exit of the hole and changes with the number of pulses applied after breakthrough. The minimum fluence that must reach the hole’s exit in order to obtain high-quality microholes in stainless steel was experimentally found to be 2.8 times the ablation threshold.

During pulmonary mucormycosis, inhaled sporangiospores adhere to, germinate, and invade airway epithelial cells to establish infection. We provide evidence that HIF1α plays dual roles in airway epithelial cells during Mucorales infection. We observed an increase in HIF1α protein accumulation and increased expression of many known HIF1α-responsive genes during in vitro infection, indicating that HIF1α signaling is activated by Mucorales infection. Inhibition of HIF1α signaling led to a substantial decrease in the ability of R. delemar to invade cultured airway epithelial cells. Transcriptome analysis revealed that R. delemar infection induces the expression of many pro-inflammatory genes whose expression was significantly reduced by HIF1α inhibition. Importantly, pharmacological inhibition of HIF1α increased survival in a mouse model of pulmonary mucormycosis without reducing fungal burden. These results suggest that HIF1α plays two opposing roles during mucormycosis: one that facilitates the ability of Mucorales to invade the host cells and one that facilitates the ability of the host to mount an innate immune response. Mucorales fungi are the cause of deadly pulmonary infections. Here, Kavaliauskas et al show that fungal spores activate hypoxia-inducible factor 1-alpha signalling to promote invasion into airway epithelial cells.

A model-based data analysis of the depth measurements performed during percussion drilling in stainless steel reveals the occurrence of microstructures by observed deviations from model expectations. For the data analysis, an adaptive correction factor c A was introduced into an analytical drilling model to account for changes in the absorptance caused by the microstructures. The analysis of the temporal evolution of c A during drilling shows that the presence of microstructures coincides with an increased absorption, while the formation of a single borehole tip is associated with a reduced absorption.

Kratom (Mitragyna speciosa) contains over 50 alkaloids, yet the pharmacological activity of most remains poorly defined, limiting our understanding of its therapeutic potential and safety profile. We conducted a comprehensive evaluation of both indole and oxindole alkaloids at human mu-, kappa-, and delta-opioid receptors (hMOR, hKOR, hDOR), integrating radioligand binding, cAMP inhibition, β-arrestin2 recruitment, [35S]GTPƔS assays, and molecular docking. While the activity of major alkaloids like mitragynine and 7-hydroxymitragynine is well documented, we report detailed functional and structural characterization of lesser-known kratom alkaloids, including epiallo-isopaynantheine, isopaynantheine, mitraciliatine, and isospeciofoline. These compounds exhibited diverse receptor selectivity and functional profiles, ranging from G protein-biased agonism to mixed MOR antagonism/KOR agonism. Notably, speciophylline demonstrated positive allosteric modulation at hMOR without direct orthosteric binding - a mechanism not previously demonstrated experimentally for kratom alkaloids at human opioid receptors. Several oxindole alkaloids showed potent hMOR agonism with minimal β-arrestin2 recruitment, representing an extreme G-protein signaling bias that distinguishes them from classical opioids. Structure-activity analysis identified conserved pharmacophoric elements at C15 and C20 that govern receptor affinity and functional profile across both indole and oxindole scaffolds. This systematic characterization at human opioid receptors reveals a pharmacologically diverse and structurally tunable class of natural products with potential as templates for developing opioid analgesics with improved therapeutic profiles.

Luminophore stained micro- and nanobeads made from organic polymers like polystyrene (PS) are broadly used in the life and material sciences as luminescent reporters, for bead-based assays, sensor arrays, printable barcodes, security inks, and the calibration of fluorescence microscopes and flow cytometers. Initially mostly prepared with organic dyes, meanwhile luminescent core/shell nanoparticles (NPs) like spherical semiconductor quantum dots (QDs) are increasingly employed for bead encoding. This is related to their narrower emission spectra, tuneability of emission color, broad wavelength excitability, and better photostability. However, correlations between particle architecture, morphology, and photoluminescence (PL) of the luminescent nanocrystals used for encoding and the optical properties of the NP-stained beads have been rarely explored. This encouraged us to perform a screening study on the incorporation of different types of luminescent core/shell semiconductor nanocrystals into polymer microparticles (PMPs) by a radical-induced polymerization reaction. Nanocrystals explored include CdSe/CdS QDs of varying CdS shell thickness, a CdSe/ZnS core/shell QD, CdSe/CdS quantum rods (QRs), and CdSe/CdS nanoplatelets (NPLs). Thereby, we focused on the applicability of these NPs for the polymerization synthesis approach used and quantified the preservation of the initial NP luminescence. The spectroscopic characterization of the resulting PMPs revealed the successful staining of the PMPs with luminescent CdSe/CdS QDs and CdSe/CdS NPLs. In contrast, usage of CdSe/CdS QRs and CdSe QDs with a ZnS shell did not yield luminescent PMPs. The results of this study provide new insights into structure–property relationships between NP stained PMPs and the initial luminescent NPs applied for staining and underline the importance of such studies for the performance optimization of NP-stained beads.

Aspergillus fumigatus is the major airborne fungal pathogen that affects humans. In order to cause an invasive infection, inhaled spores must avoid killing by innate immune cells that are recruited to the site of infection. Aspergillus fumigatus is an environmental fungus that can cause life-threatening pulmonary disease. Infections initiate when conidia are inhaled and land deep inside the small airways and alveoli of the lungs, where they interact with epithelial cells. These cells provide a physical barrier and secrete chemokines to attract innate immune cells to the site of infection. Melanin, a key constituent of the conidial cell wall, is required for the establishment of invasive infection due to its ability to inhibit the function of innate immune cells recruited to clear the infection. Here, we provide evidence for an additional mechanism by which A. fumigatus can alter host innate immune responses. In vitro infection of a normal human small airway epithelial cell line (HSAEC1-KT) caused a decrease in extracellular protein levels of CXCL10 and CCL20, two proinflammatory chemokines that are required for the host defense against aspergillosis, despite a dramatic increase in the levels of each mRNA. A. fumigatus depleted recombinant human CXCL10 and CCL20 from medium in the absence of host cells, suggesting that the block in accumulation is downstream of protein translation and secretion. Melanin is both necessary and sufficient for this chemokine-depleting activity because a dihydroxynaphthalene (DHN)-melanin-deficient strain of A. fumigatus is defective in depleting chemokines and purified melanin ghosts retain potent depletion activity. We propose that A. fumigatus , through the action of melanin, depletes important chemokines, thereby dampening the innate immune response to promote infection. IMPORTANCE Aspergillus fumigatus is the major airborne fungal pathogen that affects humans. In order to cause an invasive infection, inhaled spores must avoid killing by innate immune cells that are recruited to the site of infection. Understanding how A. fumigatus achieves immune evasion is important for the development of novel therapeutics. We provide evidence that melanin, a pigment contained in the spore cell wall, can remove certain chemokines from the extracellular space to suppress the host inflammatory response that is responsible for clearing fungal infection.

Pluvial floods in urban areas are caused by local, fast storm events with very high rainfall rates, which lead to inundation of streets and buildings before the storm water reaches a watercourse. An increase in frequency and intensity of heavy rainfall events and an ongoing urbanization may further increase the risk of pluvial flooding in many urban areas. Currently, warnings for pluvial floods are mostly limited to information on rainfall intensities and durations over larger areas, which is often not detailed enough to effectively protect people and goods. We present a proof‐of‐concept for an impact‐based forecasting system for pluvial floods. Using a model chain consisting of a rainfall forecast, an inundation, a contaminant transport and a damage model, we are able to provide predictions for the expected rainfall, the inundated areas, spreading of potential contamination and the expected damage to residential buildings. We use a neural network‐based inundation model, which significantly reduces the computation time of the model chain. To demonstrate the feasibility, we perform a hindcast of a recent pluvial flood event in an urban area in Germany. The required spatio‐temporal accuracy of rainfall forecasts is still a major challenge, but our results show that reliable impact‐based warnings can be forecasts are available up to 5 min before the peak of an extreme rainfall event. Based on our results, we discuss how the outputs of the impact‐based forecast could be used to disseminate impact‐based early warnings. Plain Language Summary Pluvial floods are caused by local rain storms with extreme rainfall rates, which leads to immediate flooding of streets and buildings in urban areas. These events are expected to increase in the future due to climate change and growing urban areas. Pluvial floods are directly caused by a rainstorm, which gives citizens and emergency responders usually only a few minutes to act. Existing forecasting systems for pluvial floods are limited to rainfall forecasts that neither provide information about where a flood might occur nor how severe the impacts will be. Here, the main challenge is that current computer models that predict inundation take too long to run to release flood forecasts early enough. We present a new inundation model that can predict inundation for an upcoming flood event in a fraction of the time of existing models. We combine this model with models that predict the spreading of contamination (e.g., from a car accident) and the damage to residential buildings. For a real flood event we can show that this information can be released up to 5 min before the rainfall peak, which gives citizens and emergency responders the opportunities to safe lives and protect important valuables. Key Points First impact‐based forecasting for pluvial foods Artificial neural network inundation model significantly cuts calculation time to 0.1% of a physically based model with comparable accuracy Forecast with estimates for inundated areas, spreading of contaminants and expected damage could be released 5 min before peak rainfall

Mucormycosis is a life-threatening, invasive fungal infection that is caused by various species belonging to the order Mucorales. Rhizopus species are the most common cause of the disease, responsible for approximately 70% of all cases of mucormycosis. During pulmonary mucormycosis, inhaled Rhizopus spores must adhere to and invade airway epithelial cells in order to establish infection. The molecular mechanisms that govern this interaction are poorly understood. We performed an unbiased survey of the host transcriptional response during early stages of Rhizopus arrhizus var. delemar ( R. delemar ) infection in a murine model of pulmonary mucormycosis using transcriptome sequencing (RNA-seq). Network analysis revealed activation of the host’s epidermal growth factor receptor (EGFR) signaling. Consistent with the RNA-seq results, EGFR became phosphorylated upon in vitro infection of human alveolar epithelial cells with several members of the Mucorales, and this phosphorylated, activated form of EGFR colocalized with R. delemar spores. Inhibition of EGFR signaling with cetuximab or gefitinib, specific FDA-approved inhibitors of EGFR, significantly reduced the ability of R. delemar to invade and damage airway epithelial cells. Furthermore, gefitinib treatment significantly prolonged survival of mice with pulmonary mucormycosis, reduced tissue fungal burden, and attenuated the activation of EGFR in response to pulmonary mucormycosis. These results indicate EGFR represents a novel host target to block invasion of alveolar epithelial cells by R. delemar , and inhibition of EGFR signaling provides a novel approach for treating mucormycosis by repurposing an FDA-approved drug. IMPORTANCE Mucormycosis is an increasingly common, highly lethal fungal infection with very limited treatment options. Using a combination of in vivo animal models, transcriptomics, cell biology, and pharmacological approaches, we have demonstrated that Mucorales fungi activate EGFR signaling to induce fungal uptake into airway epithelial cells. Inhibition of EGFR signaling with existing FDA-approved drugs significantly increased survival following R. arrhizus var. delemar infection in mice. This study enhances our understanding of how Mucorales fungi invade host cells during the establishment of pulmonary mucormycosis and provides a proof-of-concept for the repurposing of FDA-approved drugs that target EGFR function. Mucormycosis is an increasingly common, highly lethal fungal infection with very limited treatment options. Using a combination of in vivo animal models, transcriptomics, cell biology, and pharmacological approaches, we have demonstrated that Mucorales fungi activate EGFR signaling to induce fungal uptake into airway epithelial cells. Inhibition of EGFR signaling with existing FDA-approved drugs significantly increased survival following R. arrhizus var. delemar infection in mice. This study enhances our understanding of how Mucorales fungi invade host cells during the establishment of pulmonary mucormycosis and provides a proof-of-concept for the repurposing of FDA-approved drugs that target EGFR function.