Mode Of Action Research Articles

Prevalence and risk factors of self-reported hearing loss, tinnitus, and dizziness in a population-based sample from rural northeastern Germany

A close anatomical and physiological relationship is known between the senses of hearing and balance, while an additional pathophysiological interaction is supposed. The mechanisms underlying this association are not yet fully understood, especially in individuals without a known specific otologic disorder. In particular, only scarce information on the combined occurrence of audiovestibular sensory impairment is available so far. Therefore, this study aims to provide further insight into the prevalence and co-prevalence of the audiovestibular symptoms hearing loss, tinnitus and dizziness. Additionally, the influence of potential risk factors from lifestyle habits as well as cardiovascular and metabolic conditions on the development of those symptoms is studied. Data was analyzed from 8134 individuals from the population-based Study of Health in Pomerania (SHIP). SHIP pursues a broad and comprehensive examination program in chronologically separated cohorts with longitudinal follow-up. Cohorts are sampled from Western Pomerania, a rural region of north-eastern Germany. The study population represents a cross-sectional analysis from the cohorts SHIP-START (recruited 1997–2001) and SHIP-TREND (recruited 2008–2012), sampled for baseline investigations (SHIP-START-0 and SHIP-TREND-0) at the age of 20–79 years. Audiovestibular symptoms as outcome variables were assessed by structured questionnaires. Additionally, individuals were comprehensively characterized regarding modifiable lifestyle factors as well as cardiovascular and metabolic disorders, allowing the assessment of their role as exposure variables. We calculated a weighted prevalence of 14.2% for hearing loss, 9.7% for tinnitus, and 13.5% for dizziness in the population. Prevalence increased with age and differed among the sexes. A considerable share of 28.0% of the investigated individuals reported more than one symptom at once. The prevalence of hearing loss as well as tinnitus increased between the two cohorts. A moderate positive correlation was found between the occurrence of hearing loss and tinnitus (phi-coefficient 0.318). In multivariable regression analyses, education was identified as a significant protective factor while only smoking was significantly associated with all three symptoms. Furthermore, several cardiovascular risk factors contributed to both hearing loss and dizziness. In conclusion, audiovestibular symptoms are highly prevalent in the investigated population. A considerable but complex influence of risk factors points towards a relation with neuronal as well as cardiovascular disease processes. To clarify the underlying mechanisms, the interaction between the senses of hearing and balance as well as the mode of action of the risk factors should be evaluated in more detail in the future.

Nutraceuticals: An alternative to pharmaceuticals

The study is aimed to highlights the different aspects of nutraceuticals including market trends, difficulties, and the processing methods used to harness natural resources. A very broad "nutraceutical" rise has been caused by the nutraceuticals' reach for healthcare management of chronic disorders. The majority of settings had a negligible impact on inadequate eating and lifestyle choices. Research on nutraceuticals is very important and reasonably priced. The healthcare and pharmaceutical industries are facing difficulties as a result of its financial system. It has been found that nutraceuticals contribute to the prevention of infection and cancer and have a positive effect on immune system and cardiovascular health. Based on their composition and mode of action, nutraceuticals are categorized into classes. The many kinds of nutraceuticals and their potential therapeutic effects in illness, such as their anti-inflammatory, anti-cancer, antioxidant, and anti-lipid properties, will be discussed in this review. Additionally Over the last fifty years, lifestyles have been significantly impacted by urbanization, the rate of industrialization, and rapid change. which resulted in the formation of a junk food eating habit.The ability to eat healthily is impacted by these practices, which gradually reduce the quantity and quality of nutrients consumed. Dementia, starvation, and degenerative diseases are becoming more common as a result of the population’s changed eating habits. In recent years, people’s worries about their health and ability to receive healthcare have grown. Nutraceuticals are essential for boosting immunity without compromising the body’s natural defenses. Nutraceuticals are present in active foods, designer meals, medical diets, dietary supplements, and other diet regimens that offer additional health benefits. Nutrient-rich foods help with a number of bodily functions, including the prevention and treatment of diseases. The medicinal plant offers a range of phytochemical qualities to address different medical issues.

Metabolomic insights into plant-derived cyclolinopeptides as natural therapeutics for management of paroxysmal hypertension: an in-silico approach

Paroxysmal hypertension is a type of response exerted by the body towards external stimulus like physical, mental, or emotional stress which leads to chemical changes in the body that accelerates the physiological parameters like stress hyper-glycemia, obesity, stress cardiomyopathy, hemorrhagic stroke etc. Due to ill effects of chemical drugs administered by the clinicians, there is need of natural anti-depressant products which may serve as an alternative medicine. Compounds like cyclolinopeptides, cyclosporin A, and curcacyclines have exhibited potential immunosuppressive activity. With objective of drug discovery, this study investigates the role of sub-types of cyclolinopeptides as potential drugs against paroxysmal hypertension and predict their mode of action in biochemical pathways and their role in mitigation of stress induced hyper response.

A review on multifarious medicinal potential of green synthesized silver nanoparticles

Momentous advancement in nanotechnology has greatly participated in bringing transformations in various challenges of society like energy production, information technology, health and environment. Out of all the challenges society is currently facing, health is the major issue. Cancer, Bacterial, Fungal and other numerous diseases are there which we need to encounter with the best possible methods. Nanoparticles owing to their better size to area ratio act as good drug delivery agents. Synthesis of nanoparticles (NPs) has already travelled a long pathway and researchers are looking for green synthesis of NPs which is non-toxic and non-hazardous pathway of NPs synthesis. Green synthesis of NPs can be performed using bacteria, fungi, algae, virus, plant extracts etc. Green synthesis is preferable because of its cost-effectiveness, energy-efficient nature, bio-compatibility and being therapeutically significant. Biological media tend to have antioxidant properties preferably plant resources which when incorporated with metal, transport same property to such nanoparticles synthesized. Since ancient times, it has been read and well-researched that silver accounts various health benefits. Therefore, silver NPs (AgNPs) are looked upon for their novel use in therapies and treatment against numerous diseases as anticancer, anti-fungal, antibacterial. This review commentates on therapeutic activity of green synthesized AgNPs, their mode of action, and potential medicinal use against many diseases as well as their antioxidant potential.

PFOS impairs cardiac function and energy metabolism under high-fat diet: Insights into role of circulating macrophage emphasized by exposure distribution

Per- and polyfluoroalkyl substances (PFAS), widely utilized in consumer products, have been linked to an increased risk of cardiovascular disease (CVD). With the increasing prevalence of high-fat diet, a common risk factor for CVD, the PFAS exposed populations who consume a high-fat diet will inevitably grow and may have a higher CVD risk. However, the potential toxic effect and mode of action remain elusive. We constructed a mouse model orally exposed to perfluorooctane sulfonate (PFOS), a prototypical PFAS, and fed a high-fat diet. PFOS exposure induced cardiomyopathy and structural abnormalities in the mice heart. Moreover, a characteristic of energy metabolism remodeling from aerobic to anaerobic process was observed. Interestingly, PFOS was rarely detected in heart but showed high level in serum, suggesting an indirect route of action for PFOS-caused cardiac toxicity. We further demonstrated that PFOS-caused circulating inflammation promoted metabolic remodeling and contractile dysfunction in cardiomyocytes. Wherein, PFOS stimulated the release of IL-1β from circulating proinflammatory macrophages mediated by NF-κB and caspase-1. This study provides valuable data on PFAS-induced cardiac risks associated with exposed populations with increasing high-fat diet consumption, highlighting the significance of indirect pathways in PFOS's impact on the heart, based on the distribution of internal exposure.

Circular RNAs mediate the regulation of maternal placental nutrient transport and fetal development by sugar-sweetened beverages

Epidemiological and experimental studies have demonstrated a strong association between maternal diet and fetal birth weight, obesity, and metabolic syndrome. We investigated the pathways and modes of action of circular RNAs (circRNAs) that mediate the regulation of maternal reproductive performance and fetal development by sugar-sweetened beverages (20 % sucrose water, SSBs) using C57BL/6J mice as a model. Results showed that SSBs significantly increased the reproductive performance (P<0.05), body weight (P<0.01), fetal birth weight (P<0.05), placental weight (P<0.01), and the expression of nutrient transporter genes in the placenta and fetal liver (P<0.05), mainly by accelerating the maternal energy metabolism during pregnancy. However, maternal serum biochemical indices, antioxidant indices, and pathological damage to the liver and placenta predicted that the mother would be at greater health risks during this period. Moreover, transcriptomics results indicated that the differentially expressed (DE) circRNAs in the placenta regulate the maternal multiple metabolic pathways and the placental nutrient transport efficiency by sponging miRNAs and forming growth factors and proteins, ultimately improving the maternal reproductive performance. In addition, we verified the reliability of the sequencing results using reverse transcription polymerase chain reaction and identified the possibility of DE circRNAs binding to nutrient transporter genes using targeting relationship prediction. Finally, we constructed a correlation network that regulates maternal placental nutrient transport based on DE circRNAs, targeted miRNAs and nutrient transport-related genes. This study will provide scientific dietary guidance for pregnant women and new research ideas for preventing and treating pregnancy complications.

Structure-based screening, optimization and biological evaluation of novel chrysin-based derivatives as selective PPARγ modulators for the treatment of T2DM and hepatic steatosis

In consideration of several serious side effects induced by the classical AF-2 involved “lock” mechanism, recently disclosed PPARγ-Ser273 phosphorylation mode of action has become an alternative and mainstream mechanism for currently PPARγ-based drug discovery and development with an improved therapeutic index. In this study, by virtue of structure-based virtual high throughput screening (SB-VHTS), structurally chemical optimization by targeting the inhibition of the PPARγ-Ser273 phosphorylation as well as in vitro biological evaluation, which led to the final identification of a chrysin-based potential hit (YGT-31) as a novel selective PPARγ modulator with potent binding affinity and partial agonism. Further in vivo evaluation demonstrated that YGT-31 possessed potent glucose-lowering and relieved hepatic steatosis effects without involving the TZD-associated side effects. Mechanistically, YGT-31 presented such desired therapeutic index, mainly because it effectively inhibited the CDK5-mediated PPARγ-Ser273 phosphorylation, selectively elevated the level of insulin sensitivity-related Glut4 and adiponectin but decreased the expression of insulin-resistance-associated genes PTP1B and SOCS3 as well as inflammation-linked genes IL-6, IL-1β and TNFα. Finally, the molecular docking study was also conducted to uncover an interesting hydrogen-bonding network of YGT-31 with PPARγ-Ser273 phosphorylation-related key residues Ser342 and Glu343, which not only gave a clear verification for our targeting modification but also provided a proof of concept for the abovementioned molecular mechanism.

Deciphering the Intracellular Action of the Antimicrobial Peptide A11 via an In-Depth Analysis of Its Effect on the Global Proteome of Acinetobacter baumannii.

The potential antimicrobial activity and low propensity to induce the development of bacterial resistance have rendered antimicrobial peptides (AMPs) as novel and ideal candidate therapeutic agents for the treatment of infections caused by drug-resistant pathogenic bacteria. The targeting of bacterial membranes by AMPs has been typically considered their sole mode of action; however, increasing evidence supports the existence of multiple and complementary functions of AMPs that result in bacterial death. An in-depth characterization of their mechanism of action could facilitate further research and development of AMPs with higher potency. The current study employs biophysics and proteomics approaches to unveil the mechanisms underlying the antibacterial activity of A11, a potential candidate AMP, against Acinetobacter baumannii, a leading cause of hospital-acquired infections (HAIs) and consequently, a serious global threat. A11 peptide was found to induce membrane depolarization to a high extent, as revealed by flow cytometry and electron microscopy analyses. The prompt intracellular penetration of A11 peptide, observed using confocal microscopy, was found to occur concomitantly with a very low degree of membrane lysis, suggesting that its mode of action predominantly involves a nonlytic killing mechanism. Quantitative proteomics analysis employed for obtaining insights into the mechanisms underlying the antimicrobial activity of A11 peptide revealed that it disrupted energy metabolism, interfered with protein homeostasis, and inhibited fatty acid synthesis that is essential for cell membrane integrity; all these impacted the cellular functions of A. baumannii. A11 treatment also impacted signal transduction associated with the regulation of biofilm formation, hindered the stress response, and influenced DNA repair processes; these are all crucial survival mechanisms of A. baumannii. Additionally, robust antibacterial activity was exhibited by A11 peptide against multidrug-resistant (MDR) and extensively drug-resistant (XDR) clinical isolates of A. baumannii; moreover, A11 peptide exhibited synergy with levofloxacin and minocycline as well as low propensity for inducing resistance. Taken together, the findings emphasize the therapeutic potential of A11 peptide as an antibacterial agent against drug-resistant A. baumannii and underscore the need for further investigation.

Peptide lipidation and shortening optimises antibacterial, antibiofilm and membranolytic actions of an amphiphilic polylysine-polyphenyalanine octapeptide

The demand for broad-spectrum antibacterial agents continues with increasing rates of resistance of microbial pathogens to traditional antibiotics. Peptides and lipopeptides are gaining traction as promising novel, class-reference antibiotics for tackling difficult-to-treat infections caused by multi-drug resistant bacteria. To identify novel candidates and expand treatment options in clinical settings, we explored the in vitro antibacterial potential and mode of action of a short octapeptide combining a cationic block of four lysines and a highly hydrophobic segment of four phenylalanines (K4F4), and two K4F4-inspired lipopeptides (Palmitoyl-K4F4 and K4-NH-Palmitoyl). Preliminary AI-based screening had revealed the antimicrobial potential of the K4F4 peptide coupled with limited haemolytic activity. Broth dilution and haemolytic assays have confirmed these in silico predictions. Overall, our lipidated peptides were more active at lower MIC values compared to non-lipidated species, indicating the beneficial impact of tailing lipidation on design of peptide-based antimicrobials. An integrated view of the membrane-active mechanism of these novel therapeutic templates was obtained using a combination of flow cytometry, fluorescence microscopy and dye-based permeabilization assays. K4F4 and its lipidated derivatives act via a fast-disrupting mechanism without inducing bacterial resistance mechanisms in a long-term exposure assay. A K4F4-inspired lipopeptide together with its shorter version (K4-NH-Palmitoyl), were more stable in environments closer emulating physiological conditions, showing a higher antibacterial response in physiological salts and serum than their parent peptide. Our findings reveal the antibacterial and antibiofilm potential of a novel polylysine-polyphenyalanine peptide and highlight the significant contribution of lipidation and shortening as molecular engineering strategies to improve and guide the future design of next-generation membrane-targeting antibiotics.

AOP-based framework for predicting the joint action mode of di-(2-ethylhexyl) phthalate and bisphenol A co-exposure on autism spectrum disorder

Autism spectrum disorder (ASD), also known as autism, is a common, highly hereditary and heterogeneous neurodevelopmental disorder. The global prevalence of ASD among children continues to rise significantly, which is partially attributed to environmental pollution. It has been reported that pre- or post-natal exposure to di-(2-ethylhexyl) phthalate (DEHP) or bisphenol A (BPA), two prevalent environmental endocrine disruptors, increases the risk of ASD in offspring. Yet, the joint action mode linking DEHP and BPA with ASD is incompletely understood. This study aims to unravel the joint action mode of DEHP and BPA co-exposure on the development of ASD. An adverse outcome pathway (AOP) framework was employed to integrate data from multiple public database and construct chemical-gene-phenotype-disease networks (CGPDN) for DEHP- and BPA-related ASD. Topological analysis and comprehensive literature exploration of the CGPDN were performed to build the AOP. By analysis of shared key events (KEs) or phenotypes within the AOP or the CGPDN, we uncovered two AOPs, decreased N-methyl-D-aspartate receptor (NMDAR) and estrogen antagonism that were likely linked to ASD, both with moderate confidence. Our analysis further predicted that the joint action mode of DEHP and BPA related ASD was possibly an additive or synergistic action. Thus, we propose that the co-exposure to BPA and DEHP perhaps additively or synergistically increases the risk of ASD.

A Synergistic Indole-3-Acetic Acid-Producing Synthetic Bacterial Consortium Benefits Walnut Seedling Growth

Synthetic microbial communities (SynComs) have been shown to be an ecofriendly alternative for promoting plant growth. However, the mechanisms by which SynCom inoculants drive plant growth promotion in rhizosphere soil are still not fully explored. Herein, we designed a three-strain consortium based on the biocompatibility among strains and indole-3-acetic acid (IAA) production. The consortium containing Bacillus safensis 5-49, Bacillus stratosphericus 5-54, and Bacillus halotolerans 6-30 possessed a synergistic effect on IAA production and biofilm formation. Genetic analysis suggested that IAA was synthesized through tryptophan-dependent pathways in the strains. The consortium outperformed the plant growth-promoting effect observed with single strains, showing an increase in walnut (Juglans regia) seedling dry weight by 92.3% over the non-inoculated plants after 60 days of cultivation. This effect was underpinned by the synergistic interactions of the consortium, which was evidenced by the significantly increased relative abundance of Bacillus and tryptophan metabolism-associated genes in the rhizosphere of consortium-inoculated plants. Meanwhile, the consortium increased the relative abundance of indigenous Pseudomonas in rhizosphere soil, providing a synergistic effect on improving soil enzyme activities and thus available nutrients. The available N, P, and K contents in the consortium-inoculated plant rhizosphere were 3.77–28.4% higher than those in non-inoculated samples. This work provided an efficient bacterial consortium and proposed the mode of action by which this consortium improved plant growth and soil fertility.

Screening of the global health priority BoxⓇ reveals potential new disinfectants against the emerging multidrug-resistant pathogen Candida auris

BackgroundCandida auris has been identified by the World Health Organization as a critical pathogen due to its invasive nature, resistance to multiple drugs, and high mortality rates in hospital outbreaks. This fungus can persist on surfaces and human skin for extended periods, complicating infection control efforts. The need for effective disinfection strategies is urgent, as current disinfectants are often ineffective against C. auris biofilms. ObjectiveThe study aimed to identify potential disinfectants from a collection of 240 compounds in the Global Health Priority Box® that are effective against C. auris, particularly strains resistant to existing options. MethodsThe research employed a screening protocol using a fluconazole-resistant strain of C. auris (149/23). Antifungal activity was assessed using the microdilution method to determine Minimum Inhibitory Concentrations (MICs) and Minimum Fungicidal Concentrations (MFCs). Additional assays were conducted to evaluate biofilm inhibition, biofilm eradication, cell membrane integrity, nucleotide leakage, sorbitol protection assay, efflux pump inhibition, and hemolysis assay. ResultsTwo compounds, Hydramethylnon (MMV1577471) and Flufenerim (MMV1794206), demonstrated significant inhibitory effects against C. auris. Hydramethylnon exhibited potent antifungal activity, inhibiting up to 93 % of fungal growth with an MFC of 16 μg/mL. Flufenerim inhibited up to 58 % of fungal growth, showing fungistatic action with an MFC greater than 4 μg/mL. Biofilm inhibition tests showed that both compounds significantly inhibited biofilm formation, with increased efficacy at higher concentrations. Both compounds showed eradication rates in both stages. Furthermore, Hydramethylnon and Flufenerim did not affect cell membrane integrity or nucleotide leakage, suggesting a mode of action not reliant on disrupting these cellular components. The sorbitol protection assay revealed that neither compound caused cell wall damage. In the efflux pump inhibition assay, Hydramethylnon did not activate efflux pumps, while Flufenerim activated efflux pumps, reducing its effectiveness. Hemocompatibility assay showed safety. ConclusionThe study highlights Hydramethylnon and Flufenerim as promising candidates for further development as disinfectants, offering potential solutions to the urgent need for effective disinfection agents against C. auris. The findings underscore the value of screening compound collections to identify novel antifungal agents and understand their mechanisms of action, thereby contributing to the advancement of new disinfection strategies in healthcare settings.

Polyphyllin II Induces Apoptosis in Fibrosarcoma Cells via Activating Pyruvate Kinase M2.

Aerobic glycolysis is a metabolic reprogramming of tumor cells that is essential for sustaining their phenotype of fast multiplication by continuously supplying energy and mass. Pyruvate kinase M2 (PKM2) has a vital role in this process, which has given it high interest as a target for anticancer drug development. With potent toxicity to many types of cancer cells, polyphyllin II (PP2), a steroidal saponin isolated from the herbaceous plant Rhizoma paridis, brought to our attention that it might interfere with the PKM2 activity. In this study, we discovered that PP2 was a novel agonist of PKM2. PP2 activated recombinant PKM2 and changed the protein's oligomeric state to activate intracellular PKM2. At the same time, PP2 suppressed its protein kinase function by decreasing the content of nuclear PKM2. The mRNA levels of its downstream genes, such as Glut1, LDHA, and MYC, were inhibited. In addition, PP2 induced oxidative stress by downregulating the expression and activity of antioxidant proteins such as NQO1, TrxR, and Trx in HT-1080 cells, which in turn led to mitochondrial dysfunction and ultimately induced apoptosis. Moreover, PP2 reduced the proliferation and migration of HT-1080 cells. Thus, targeting the glycolysis pathway offers an unprecedented mode of action for comprehending PP2's pharmacological impacts and advances PP2's further development in fibrosarcoma therapy.

Investigating the mechanisms of action of thyroid disruptors: A multimodal approach that integrates in vitro and metabolomic analysis

The thyroid gland, a vital component of the endocrine system, plays a pivotal role in regulating metabolic processes, growth, and development. To better characterize thyroid system disrupting chemicals (TSDC), we followed the next-generation risk assessment approach, which further considers the mechanistic profile of xenobiotics. We combined targeted in vitro testing with untargeted metabolomics. Four known TSDC, propyl-thiouracil (PTU), sodium perchlorate, triclosan, and 5-pregnen-3β-ol-20-one-16α‑carbonitrile (PCN) were investigated using rat in vitro models, including primary hepatocytes, PCCL3 cells, thyroid microsomes, and three-dimensional thyroid follicles. We confirmed each compound's mode of action, PTU inhibited thyroperoxidase activity and thyroid hormones secretion in thyroid cells model, sodium perchlorate induced a NIS-mediated iodide uptake decrease as triclosan to a lesser extent, and PCN activated expression and activity of hepatic enzymes (CYPs and UGTs) involved in thyroid hormones metabolism. In parallel, we characterized intracellular metabolites of interest. We identified disrupted basal metabolic pathways, but also metabolites directly linked to the compound's mode of action as tyrosine derivates for sodium perchlorate and triclosan, bile acids involved in beta-oxidation, and precursors of cytochrome P450 synthesis for PCN. This pilot study has provided metabolomic fingerprinting of dedicated TSDC exposures, which could be used to screen and differentiate specific modes of action.

Pyrolysis and flammability of phosphorus based flame retardant pressure sensitive adhesives and adhesive tapes

Pressure-sensitive adhesive tapes are used in a variety of applications such as construction, aircrafts, railway vehicles, and ships, where flame retardancy is essential. Especially in these applications, phosphorus-based flame retardants are often chosen over halogenated ones due to their advantages in terms of toxicity. Although there are pressure-sensitive adhesives with phosphorus flame retardants available on the market, their flame-retardant modes of action and mechanisms are not entirely understood. This research article provides fundamental pyrolysis research of three phosphorus-based flame retardants that exhibit different mechanisms in a pressure-sensitive adhesive matrix. The flame-retardants modes of action and mechanisms of a 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO) derivate, an aryl phosphate, and a self-synthesized, covalently bonded DOPO derivate (copolymerized) are investigated. The blended DOPO derivate is volatilized at rather low temperatures while the covalently bonded DOPO derivate decomposes together with the polymer matrix at the same temperature. Both DOPO derivates release PO radicals which are known for their flame inhibition. The aryl phosphate decomposes at higher temperatures, releases small amounts of aryl phosphates into the gas phase, and acts predominantly the condensed phase. The aryl phosphate acts as precursor for phosphoric acid and improves the charring of the pressure sensitive adhesive matrix. All flame retardants enhance the flammability of the adhesives depending on their individual mode of action while the covalently bonded flame retardant additionally improves the mechanical properties at elevated temperatures making it a promising future technology for pressure-sensitive adhesives.

A Novel Method for the Assessment of Feeding Rate as a Phenotypic Endpoint for the Impact of Pollutants in Daphnids.

Traditional approaches for monitoring aquatic pollution primarily rely on chemical analysis and the detection of pollutants in the aqueous environments. However, these methods lack realism and mechanistic insight and, thus, are increasingly supported by effect-based methods, which offer sensitive endpoints. In this context, daphnids, a freshwater species used extensively in molecular ecotoxicology, offer fast and noninvasive approaches to assess the impact of pollutants. Among the phenotypic endpoints used, feeding rate is a highly sensitive approach because it provides evidence of physiological alterations even in sublethal concentrations. However, there has been no standardized method for measuring feeding rate in daphnids, and several approaches follow different protocols. There is a diversity among tests employing large volumes, extensive incubation times, and high animal densities, which in turn utilize measurements of algae via fluorescence, radiolabeling, or counting ingested cells. These tests are challenging and laborious and sometimes require cumbersome instrumentation. In the present study, we optimized the conditions of a miniaturized fast, sensitive, and high-throughput assay to assess the feeding rate based on the ingestion of fluorescent microparticles. The protocol was optimized in neonates in relation to the concentration of microplastic and the number of animals to increase reproducibility. Daphnids, following exposures to nonlethal concentrations, were incubated with microplastics; and, as filter feeders, they ingest microparticles. The new approach revealed differences in the physiology of daphnids in concentrations below the toxicity limits for a range of pollutants of different modes of action, thus proving feeding to be a more sensitive and noninvasive endpoint in pollution assessment. Environ Toxicol Chem 2024;00:1-11. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Design, Synthesis, and Biological Activity of Silicon-Containing Carboxamide Fungicides.

Bioisosteric silicon replacement has proven to be a valuable strategy in the design of bioactive molecules for crop protection and drug development. Twenty-one novel carboxamides possessing a silicon-containing biphenyl moiety were synthesized and tested for their antifungal activity and succinate dehydrogenase (SDH) enzymatic inhibitory activity. Among these novel succinate dehydrogenase inhibitors (SDHIs), compounds 3a, 3e, 4l, and 4o possessing appropriate clog P and topological polar surface area values showed excellent inhibitory effects against Rhizoctonia solani, Sclerotinia sclerotiorum, Botrytis cinerea, and Fusarium graminearum at 10 mg/L in vitro, and the EC50 values of 4l and 4o were 0.52 and 0.16 mg/L against R. solani and 0.066 and 0.054 mg/L against S. sclerotiorum, respectively, which were superior to those of Boscalid. Moreover, compound 3a demonstrated superior SDH enzymatic inhibitory activity (IC50 = 8.70 mg/L), exhibiting 2.54-fold the potency of Boscalid (IC50 = 22.09 mg/L). Docking results and scanning electron microscope experiments revealed similar mode of action between compound 3a and Boscalid. The new silicon-containing carboxamide 3a is a promising SDHI candidate that deserves further investigation.

Toxic eburicol accumulation drives the antifungal activity of azoles against Aspergillus fumigatus

Azole antifungals inhibit the sterol C14-demethylase (CYP51/Erg11) of the ergosterol biosynthesis pathway. Here we show that the azole-induced synthesis of fungicidal cell wall carbohydrate patches in the pathogenic mold Aspergillus fumigatus strictly correlates with the accumulation of the CYP51 substrate eburicol. A lack of other essential ergosterol biosynthesis enzymes, such as sterol C24-methyltransferase (Erg6A), squalene synthase (Erg9) or squalene epoxidase (Erg1) does not trigger comparable cell wall alterations. Partial repression of Erg6A, which converts lanosterol into eburicol, increases azole resistance. The sterol C5-desaturase (ERG3)-dependent conversion of eburicol into 14-methylergosta-8,24(28)-dien-3β,6α-diol, the “toxic diol” responsible for the fungistatic activity against yeasts, is not required for the fungicidal effects in A. fumigatus. While ERG3-lacking yeasts are azole resistant, ERG3-lacking A. fumigatus becomes more susceptible. Mutants lacking mitochondrial complex III functionality, which are much less effectively killed, but strongly inhibited in growth by azoles, convert eburicol more efficiently into the supposedly “toxic diol”. We propose that the mode of action of azoles against A. fumigatus relies on accumulation of eburicol which exerts fungicidal effects by triggering cell wall carbohydrate patch formation.

How are nature-based interventions defined in mild cognitive impairment and dementia studies? A conceptual systematic review and novel taxonomy.

To systematically review research testing nature-based interventions for people living with mild cognitive impairment or dementia, and to report how authors have defined their interventions by presenting a taxonomy of the nature-based interventions. A conceptual systematic review of research published between 2008 and 2024 investigating nature-based interventions for people living with mild cognitive impairment or dementia was conducted. Three reviewers contributed independently. Exclusion criteria: not specifying if participants had mild cognitive impairment or dementia, only recruiting caregivers, no primary data, study protocols, abstracts, reviews, not peer-reviewed journal articles and any other grey literature. Intervention descriptions within the papers were thematically analysed. Fifty-two articles reporting fifty-one studies were included. The most common interventions were nature virtual reality (VR technology) and gardening. From the definition data, we produced a taxonomy with overarching domains of: (a) Other terms used; (b) Characteristics; (c) Activities. Subdomains included: development or approach, modes of action, location, physical features, and activities. Some interventions could be grouped. Structure and standardisation of the interventions varied, with a lack of clear reporting. This taxonomy provides conceptualisations of nature-based interventions that can be used by future researchers to guide the development, evaluation and reporting of robust interventions in this area.

Local adaptation, recombination, and the fate of neopolyploids.

Polyploidy is widely recognized as an important speciation mechanism because it isolates tetraploids from their diploid progenitors. Polyploidy also provides new genetic material that may facilitate adaptive evolution. However, new mutations are more likely to arise after a neopolyploid already has successfully invaded a population. Thus, the role of adaptive forces in establishing a polyploid remains unclear. One solution to this apparent paradox may lie in the capacity of polyploids to suppress recombination among preexisting locally adapted alleles. The local adaptation mechanism requires that spatially heterogeneous selection acts on multiple loci and that gene flow introduces maladapted alleles to the population where the polyploid forms. The mechanism requires neither strong genetic drift nor any intrinsic benefit of genome doubling and can accommodate any mode of gene action. A unique prediction of the mechanism is that adaptive alleles should predate polyploidization, a pattern consistent with observations from a few well-studied polyploids. The mechanism is also consistent with the coexistence of both diploid and tetraploid cytotypes, fitness heterogeneity among independently derived polyploids, and the prevalence of outcrossing among older polyploids. The local adaptation mechanism also makes novel predictions about circumstances favoring polyploid invasions that can be tested using molecular genetic or comparative approaches.