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To achieve complete elimination of anthropogenic micropollutants in aquatic environments, advanced oxidation processes are intensively researched as remedies and potential advanced purification stages in wastewater treatment facilities. Persalts, like persulfates, percarbonates and periodates, have been investigated as potential accelerators or enhancers of these processes. This short review provides an overview of the efficiency of the persalts demonstrated for the degradation of the seven most frequently occurring pharmaceuticals in the aquatic environment: carbamazepine, ciprofloxacin, diclofenac, ibuprofen, metoprolol, paracetamol and sulfamethoxazole. While persulfates were the most commonly used, all persalts increase the effectiveness of the degradation of the pharmaceutical contaminants by increasing the formation of hydroxyl radicals, especially in the case of sodium percarbonate. Persalts are efficiently activated through UVC irradiation. The generated hydroxyl radicals are the main factor for product formation and hence dominate the chemical structures of the transformation products. From the ecotoxicological perspective, the use of persalts causes little or no hazard, if the conditions are such that acidification can be neglected. While they are transformed to stable anions on reaction, the resulting transformation products of the anthropogenic micropollutants were predicted by quantitative structure activity relation analysis to possess lower ecotoxicity than the initial drugs.

Cancer-associated, loss-of-function mutations in genes encoding subunits of the BRG1/BRM-associated factor (BAF) chromatin-remodeling complexes 1 – 8 often cause drastic chromatin accessibility changes, especially in important regulatory regions 9 – 19 . However, it remains unknown how these changes are established over time (for example, immediate consequences or long-term adaptations), and whether they are causative for intracomplex synthetic lethalities, abrogating the formation or activity of BAF complexes 9 , 20 – 24 . In the present study, we use the dTAG system to induce acute degradation of BAF subunits and show that chromatin alterations are established faster than the duration of one cell cycle. Using a pharmacological inhibitor and a chemical degrader of the BAF complex ATPase subunits 25 , 26 , we show that maintaining genome accessibility requires constant ATP-dependent remodeling. Completely abolishing BAF complex function by acute degradation of a synthetic lethal subunit in a paralog-deficient background results in an almost complete loss of chromatin accessibility at BAF-controlled sites, especially also at superenhancers, providing a mechanism for intracomplex synthetic lethalities. Acute degradation of the BAF subunit SMARCA4 shows rapid chromatin accessibility changes, thus suggesting that maintenance of genome accessibility requires constant ATP-dependent remodeling.

The Mediator complex directs signals from DNA-binding transcription factors to RNA polymerase II (Pol II). Despite this pivotal position, mechanistic understanding of Mediator in human cells remains incomplete. Here we quantified Mediator-controlled Pol II kinetics by coupling rapid subunit degradation with orthogonal experimental readouts. In agreement with a model of condensate-driven transcription initiation, large clusters of hypophosphorylated Pol II rapidly disassembled upon Mediator degradation. This was accompanied by a selective and pronounced disruption of cell-type-specifying transcriptional circuits, whose constituent genes featured exceptionally high rates of Pol II turnover. Notably, the transcriptional output of most other genes was largely unaffected by acute Mediator ablation. Maintenance of transcriptional activity at these genes was linked to an unexpected CDK9-dependent compensatory feedback loop that elevated Pol II pause release rates across the genome. Collectively, our work positions human Mediator as a globally acting coactivator that selectively safeguards the functionality of cell-type-specifying transcriptional networks. Analysis with alleles encoding pharmacologically degradable Mediator subunits shows that Mediator acts as a global coactivator that facilitates transcription globally but is acutely required for cell-type-specific gene regulatory circuits.

BACKGROUNDInduction of innate immune memory, also termed trained immunity, by the antituberculosis vaccine bacillus Calmette-Guérin (BCG) contributes to protection against heterologous infections. However, the overall impact of BCG vaccination on the inflammatory status of an individual is not known; while induction of trained immunity may suggest increased inflammation, BCG vaccination has been epidemiologically associated with a reduced incidence of inflammatory and allergic diseases.METHODSWe investigated the impact of BCG (BCG-Bulgaria, InterVax) vaccination on systemic inflammation in a cohort of 303 healthy volunteers, as well as the effect of the inflammatory status on the response to vaccination. A targeted proteome platform was used to measure circulating inflammatory proteins before and after BCG vaccination, while ex vivo Mycobacterium tuberculosis- and Staphylococcus aureus-induced cytokine responses in peripheral blood mononuclear cells were used to assess trained immunity.RESULTSWhile BCG vaccination enhanced cytokine responses to restimulation, it reduced systemic inflammation. This effect was validated in 3 smaller cohorts, and was much stronger in men than in women. In addition, baseline circulating inflammatory markers were associated with ex vivo cytokine responses (trained immunity) after BCG vaccination.CONCLUSIONThe capacity of BCG to enhance microbial responsiveness while dampening systemic inflammation should be further explored for potential therapeutic applications.FUNDINGNetherlands Organization for Scientific Research, European Research Council, and the Danish National Research Foundation.

Vulvovaginal candidiasis (VVC) is a widespread vaginal infection primarily caused by Candida albicans. VVC affects up to 75% of women of childbearing age once in their life, and up to 9% of women in different populations experience more than three episodes per year, which is defined as recurrent vulvovaginal candidiasis (RVVC). RVVC results in diminished quality of life as well as increased associated healthcare costs. For a long time, VVC has been considered the outcome of inadequate host defenses against Candida colonization, as in the case of primary immunodeficiencies associated with persistent fungal infections and insufficient clearance. Intensive research in recent decades has led to a new hypothesis that points toward a local mucosal overreaction of the immune system rather than a defective host response to Candida colonization. This review provides an overview of the current understanding of the host immune response in VVC pathogenesis and suggests that a tightly regulated fungus–host–microbiota interplay might exert a protective role against recurrent Candida infections.

The gut microbiome is an ecosystem that involves complex interactions. Currently, our knowledge about the role of the gut microbiome in health and disease relies mainly on differential microbial abundance, and little is known about the role of microbial interactions in the context of human disease. Here, we construct and compare microbial co-abundance networks using 2,379 metagenomes from four human cohorts: an inflammatory bowel disease (IBD) cohort, an obese cohort and two population-based cohorts. We find that the strengths of 38.6% of species co-abundances and 64.3% of pathway co-abundances vary significantly between cohorts, with 113 species and 1,050 pathway co-abundances showing IBD-specific effects and 281 pathway co-abundances showing obesity-specific effects. We can also replicate these IBD microbial co-abundances in longitudinal data from the IBD cohort of the integrative human microbiome (iHMP-IBD) project. Our study identifies several key species and pathways in IBD and obesity and provides evidence that altered microbial abundances in disease can influence their co-abundance relationship, which expands our current knowledge regarding microbial dysbiosis in disease. Gut microbiome alterations have been linked to inflammatory bowel disease (IBD) and obesity. Here, the authors characterize the metagenomes of four large human cohorts and perform co-abundance network analysis showing that dysbiosis in disease is marked by the altered co-abundance relationships, suggesting that pathway coabundance networks are more heterogeneous than species network.

Pharmaceuticals are found in waterbodies worldwide. Conventional sewage treatment plants are often not able to eliminate these micropollutants. Hence, Advanced Oxidation Processes (AOPs) have been heavily investigated. Here, metoprolol is exposed to UV irradiation, hydrogen peroxide, and ozonation. Degradation was analyzed using chemical kinetics both for initial and secondary products. Photo-induced irradiation enhanced by hydrogen peroxide addition accelerated degradation more than ozonation, leading to complete elimination. Degradation and transformation products were identified by high-performance liquid-chromatography coupled to high-resolution higher-order mass spectrometry. The proposed structures allowed to apply Quantitative Structure-Activity Relationship (QSAR) analysis to predict ecotoxicity. Degradation products were generally associated with a lower ecotoxicological hazard to the aquatic environment according to OECD QSAR toolbox and VEGA. Comparison of potential structural isomers suggested forecasts may become more reliable with larger databases in the future.

Virtual Reality (VR) construction safety training modules have reached a level of maturity which renders them as a serious alternative to traditional safety training modules. The purpose of this study is to investigate the usability of a particular safety training module related to “Working at heights” for blue-collar construction workers in Kuwait. A mixed study approach was applied based on a semi-quasi experimental research design, utilizing a control group/experimental group with pre-/post-test measurements, supplemented by observations. The findings indicate a statistically insignificant higher learning effectiveness of the workers exposed to the VR approach. Observations confirmed that trainees require an extended time of preparation to become familiar with moving within the virtual environment and using the related hardware. Furthermore, younger users with less work experience reported a higher usability than older users with more work experience. VR content developers are encouraged to investigate the possibilities of simplifying the virtual environment to make it more relevant for blue-collar workers, reduce the complexity of the hardware, and intensify the feeling of the consequences resulting from users’ choices. Construction companies and educational institutions training construction blue-collar workers can benefit from the VR approach to safety training if they allow sufficient time for familiarization with the virtual training module.

The lack of standardization in the methods of DNA extraction from fecal samples represents the major source of experimental variation in the microbiome research field. In this study, we aimed to compare the metagenomic profiles and microbiome–phenotype associations obtained by applying two commercially available DNA extraction kits: the AllPrep DNA/RNA Mini Kit (APK) and the QIAamp Fast DNA Stool Mini Kit (FSK). Using metagenomic sequencing data available from 745 paired fecal samples from two independent population cohorts, Lifelines-DEEP (LLD, n = 292) and the 500 Functional Genomics project (500FG, n = 453), we confirmed significant differences in DNA yield and the recovered microbial communities between protocols, with the APK method resulting in a higher DNA concentration and microbial diversity. Further, we observed a massive difference in bacterial relative abundances at species-level between the APK and the FSK protocols, with > 75% of species differentially abundant between protocols in both cohorts. Specifically, comparison with a standard mock community revealed that the APK method provided higher accuracy in the recovery of microbial relative abundances, with the absence of a bead-beating step in the FSK protocol causing an underrepresentation of gram-positive bacteria. This heterogeneity in the recovered microbial composition led to remarkable differences in the association with anthropometric and lifestyle phenotypes. The results of this study further reinforce that the choice of DNA extraction method impacts the metagenomic profile of human gut microbiota and highlight the importance of harmonizing protocols in microbiome studies.

Introduction Tyrosine kinase inhibitors, including lenvatinib approved for advanced non-medullary thyroid cancer (TC), affect the immune system. As tumor-related inflammation contributes to TC pathogenesis, this study assesses the immunomodulatory effects of lenvatinib, focusing on myeloid cells. Methods Peripheral blood was collected from 16 lenvatinib-treated and 15 untreated TC patients (cross-sectional cohort), and from eight patients before and after > 1 month of lenvatinib (longitudinal cohort). Immune profiling included cell subset counts, proteomic analyses, and ex vivo cytokine assays in peripheral blood mononuclear cells (PBMCs) and monocytes. Monocytes from healthy donors were used to evaluate metabolic activity, reactive oxygen species (ROS) production, and phagocytosis. Tumor-intrinsic effects of lenvatinib were studied by proteomics and immunophenotyping of the TPC-1 cell line. Results Lenvatinib increased lymphocytes and reduced neutrophils. In both cohorts, lenvatinib modulated the inflammatory proteome with elevated VEGFA, CCL11, MMP-10, and TRAIL. Monocytes exposed ex vivo to lenvatinib showed reduced production of IL-1β, IL-6, IL-8, and IL-10. In patients treated with lenvatinib, monocytes displayed increased IL-1Ra and TNF, while PBMCs exhibited enhanced IFN-γ production. Monocytes from healthy donors displayed reduced glycolysis and increased ROS after lenvatinib exposure. In TPC-1 cells, lenvatinib altered the secretome and upregulated MHC class I, PD-L1, and CD40. Conclusions Lenvatinib treatment has broad immunomodulatory effects in patients with TC, including shifts in immune cell populations, changes in the proteome, and reprogramming of cytokine responses. Lenvatinib also impacts monocyte metabolism and tumor cell phenotype. These findings provide insight into the multifaceted immunological activities of lenvatinib and highlight opportunities for treatment strategies. Trial registration Not applicable, this is a noninterventional trial.