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The synthesis of a biologically relevant 2-amino- N 3-alkylamido 4-quinazolinone has been accomplished in four steps from commercially available materials using design principles from both modular and divergent synthesis. N 3-Alkylation of 2-chloro-4(3 H )-quinazolinone using methyl bromoacetate, followed by C2-amination produced a suitable scaffold for introducing molecular diversity. Optimization of alkylation conditions afforded full regioselectivity, enabling exclusive access to the N -alkylated isomer. Subsequent C2-amination using piperidine, pyrrolidine, or diethylamine, followed by amide bond formation using variously substituted phenethylamines, generated fifteen unique 4-quinazolinones bearing C2-amino and N 3-alkylamido substituents. These efforts highlight the reciprocal influence of C2 and N 3 substitution on functionalization at either position, establish an effective synthetic pathway toward 2, N 3-disubstituted 4-quinazolinones, and enable preliminary bioactivity studies while providing an experiential learning opportunity for undergraduate student researchers.

Immune checkpoint inhibitor (ICI) therapy has revolutionized oncology, but treatments are limited by immune-related adverse events, including checkpoint inhibitor colitis (irColitis). Little is understood about the pathogenic mechanisms driving irColitis, which does not readily occur in model organisms, such as mice. To define molecular drivers of irColitis, we used single-cell multi-omics to profile approximately 300,000 cells from the colon mucosa and blood of 13 patients with cancer who developed irColitis (nine on anti-PD-1 or anti-CTLA-4 monotherapy and four on dual ICI therapy; most patients had skin or lung cancer), eight controls on ICI therapy and eight healthy controls. Patients with irColitis showed expanded mucosal Tregs, ITGAE Hi CD8 tissue-resident memory T cells expressing CXCL13 and Th17 gene programs and recirculating ITGB2 Hi CD8 T cells. Cytotoxic GNLY Hi CD4 T cells, recirculating ITGB2 Hi CD8 T cells and endothelial cells expressing hypoxia gene programs were further expanded in colitis associated with anti-PD-1/CTLA-4 therapy compared to anti-PD-1 therapy. Luminal epithelial cells in patients with irColitis expressed PCSK9, PD-L1 and interferon-induced signatures associated with apoptosis, increased cell turnover and malabsorption. Together, these data suggest roles for circulating T cells and epithelial-immune crosstalk critical to PD-1/CTLA-4-dependent tolerance and barrier function and identify potential therapeutic targets for irColitis., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Control of movement is learned and uses error feedback during practice to predict actions for the next movement. We have shown that augmenting error can enhance learning, but while such findings are encouraging the methods need to be refined to accommodate a person's individual reactions to error. The current study evaluates error fields (EF) method, where the interactive robot tempers its augmentation when the error is less likely. 22 healthy participants were asked to learn moving with a visual transformation, and we enhanced the training with error fields. We found that training with error fields led to greatest reduction in error. EF training reduced error 264% more than controls who practiced without error fields, but subjects learned more slowly than our previous error magnification technique. We also found a relationship between the amount of learning and how much variability was induced by the error augmentation treatments, most likely leading to better exploration and discovery of the causes of error. These robotic training enhancements should be further explored in combination to optimally leverage error statistics to teach people how to move better., Competing Interests: Ethics Declarations Competing interests The authors declare no competing interests.

Recently, roadway releases of N , N '-substituted p -phenylenediamine (PPD) antioxidants and their transformation products (TPs) received significant attention due to the highly toxic 6PPD-quinone. However, the occurrence of PPDs and TPs in recycled tire rubber products remains uncharacterized. Here, we analyzed tire wear particles (TWPs), recycled rubber doormats, and turf-field crumb rubbers for seven PPD antioxidants, five PPD-quinones (PPDQs), and five other 6PPD TPs using liquid chromatography-tandem mass spectrometry. PPD antioxidants, PPDQs, and other TPs were present in all samples with chemical profiles dominated by 6PPD, DTPD, DPPD, and their corresponding PPDQs. Interestingly, the individual [PPDQ]/[PPD] and [TP]/[PPD] ratios significantly increased as total concentrations of the PPD-derived chemical decreased, indicating that TPs (including PPDQs) dominated the PPD-derived compounds with increased environmental weathering. Furthermore, we quantified 15 other industrial rubber additives (including bonding agents, vulcanization accelerators, benzotriazole and benzothiazole derivatives, and diphenylamine antioxidants), observing that PPD-derived chemical concentrations were 0.5-6 times higher than these often-studied additives. We also screened various other elastomeric consumer products, consistently detecting PPD-derived compounds in lab stoppers, sneaker soles, and rubber garden hose samples. These data emphasize that PPD antioxidants, PPDQs, and related TPs are important, previously overlooked contaminant classes in tire rubbers and elastomeric consumer products.

Amycolatopsis sp. MST-135876 was isolated from soil collected from the riverbank of El Pont de Suert, Catalonia, Spain. Cultivation of MST-135876 on a range of media led to the discovery of a previously unreported dichlorinated cyclic hexapeptide, suertide A (D-Ser, 5-Cl-D-Trp, 6-Cl-D-Trp, L-Ile, D-Val, D-Glu), featuring an unprecedented pair of adjacent 5/6-chlorotryptophan residues. Supplementing the growth medium with KBr resulted in production of the mono- and dibrominated analogues suertides B and C, respectively. Suertides A-C displayed selective activity against Bacillus subtilis (MIC 1.6 µg ml -1 ) and Staphylococcus aureus (MIC 3.1, 6.3, and 12.5 µg ml -1 , respectively), while suertides A and B showed appreciable activity against methicillin-resistant S. aureus (MIC 1.6 and 6.3 µg ml -1 , respectively)., (© 2022. The Author(s).)

Herbicides are vital for modern agriculture, but their utility is threatened by genetic or metabolic resistance in weeds, as well as regulatory barriers. Of the known herbicide modes of action, 7,8-dihydropterin synthase (DHPS), which is involved in folate biosynthesis, is targeted by just one commercial herbicide, asulam. A mimic of the substrate para-aminobenzoic acid, asulam is chemically similar to sulfonamide antibiotics, and although it is still in widespread use, asulam has faced regulatory scrutiny. With an entire mode of action represented by just one commercial agrochemical, we sought to improve the understanding of its plant target. Here we solve a 2.3 Å resolution crystal structure for Arabidopsis thaliana DHPS that is conjoined to 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), and we reveal a strong structural conservation with bacterial counterparts at the sulfonamide-binding pocket of DHPS. We demonstrate that asulam and the antibiotic sulfamethoxazole have herbicidal as well as antibacterial activity, and we explore the structural basis of their potency by modeling these compounds in mitochondrial HPPK/DHPS. Our findings suggest limited opportunity for the rational design of plant selectivity from asulam and indicate that pharmacokinetic or delivery differences between plants and microbes might be the best ways to safeguard this mode of action., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Studies on disrespect and abuse/mistreatment/obstetric violence during pregnancy, childbirth and puerperium have increased in recent decades. However, researchers interested in the subject face many theoretical and methodological difficulties. In this sense, this study aims to discuss and reflect on how issues related to definition and terminology, measurement, and public policies in Brazil have hindered research on this topic and the mitigation of these acts. The first problem addressed was the lack of consensus regarding the terminology and definition of this construct. This situation causes a cascading effect, impacting the use of non-validated measurement instruments and, consequently, a lack of accuracy and comparability between studies. Another issue mentioned is the lack of studies exploring the consequences of these acts on women's and newborn's health, which is one of the main gaps on the subject today. The absence of causal studies affects health decision-making, impairing the elaboration of specific public policies.