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Mammalian SWI/SNF chromatin remodelling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF and a newly characterized non-canonical complex (ncBAF). However, their complex-specific targeting on chromatin, functions and roles in disease remain largely undefined. Here, we comprehensively mapped complex assemblies on chromatin and found that ncBAF complexes uniquely localize to CTCF sites and promoters. We identified ncBAF subunits as synthetic lethal targets specific to synovial sarcoma and malignant rhabdoid tumours, which both exhibit cBAF complex (SMARCB1 subunit) perturbation. Chemical and biological depletion of the ncBAF subunit, BRD9, rapidly attenuates synovial sarcoma and malignant rhabdoid tumour cell proliferation. Importantly, in cBAF-perturbed cancers, ncBAF complexes maintain gene expression at retained CTCF-promoter sites and function in a manner distinct from fusion oncoprotein-bound complexes. Together, these findings unmask the unique targeting and functional roles of ncBAF complexes and present new cancer-specific therapeutic targets. Michel et al. report unique localization of non-canonical BAF to CTCF sites and promoters, which confers synthetic lethality in canonical BAF-perturbed synovial sarcoma and malignant rhabdoid tumour cells.

KDM2A/FBXL11 is a Jumonji-domain containing lysine demethylase catalyzing the removal of mono- and di-methyl modifications of histone H3 lysine 36 (H3K36me1/2). While Kdm2a is required for mouse embryogenesis, its role in adult physiology has been largely unexplored. Using conditional deletion approaches, we demonstrate that Kdm2a deficiency leads to testicular atrophy and male infertility. Although spermatogonial stem cells remain unaffected, proliferating and differentiating spermatogonia exhibit delayed cell cycle progression and apoptosis. RNA-sequencing of purified spermatogonia and spermatocytes reveals Kdm2a -dependent repression of over 750 genes during spermatogonial differentiation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) demonstrates increased H3K36me2 levels at CpG-rich gene promoters in Kdm2a -deficient spermatogonia. KDM2A is required for Polycomb-mediated repression as shown by increased H3K36me2 and reduced H3K27me3 promoter occupancies and failed gene repression in Kdm2a deficient differentiating spermatogonia. Loss of Kdm2a in spermatocytes disrupts progression through meiotic prophase, as evidenced by impaired completion of chromosome synapsis and processing of meiotic double-strand breaks (DSBs), by altered chromatin states and by an impairment of X-linked gene repression. Our study thus identifies critical roles for KDM2A in coordinating gene expression programs during spermatogonial differentiation and meiosis, which are essential for male germ cell development. Here, the authors show that KDM2A regulates cell cycle progression, modulation of H3K36me2 and H3K27me3 chromatin states and gene repression which are critical for survival of differentiating spermatogonia. KDM2A regulates progression through meiosis as well.

Differentiation is accompanied by extensive epigenomic reprogramming, leading to the repression of stemness factors and the transcriptional maintenance of activated lineage-specific genes. Here we use the mammalian Hoxa cluster of developmental genes as a model system to follow changes in DNA modification patterns during retinoic acid-induced differentiation. We find the inactive cluster to be marked by defined patterns of 5-methylcytosine (5mC). Upon the induction of differentiation, the active anterior part of the cluster becomes increasingly enriched in 5-hydroxymethylcytosine (5hmC), following closely the colinear activation pattern of the gene array, which is paralleled by the reduction of 5mC. Depletion of the 5hmC generating dioxygenase Tet2 impairs the maintenance of Hoxa activity and partially restores 5mC levels. Our results indicate that gene-specific 5mC–5hmC conversion by Tet2 is crucial for the maintenance of active chromatin states at lineage-specific loci. Hox gene expression is induced upon cellular differentiation and is inhibited in pluripotent cells. Bocker and colleagues show that the maintenance of induced transcription depends on Tet2 mediated hydroxylation of 5-methylcytosine at the Hoxa gene locus, indicating that this epigenetic switch is required for an active chromatin state and gene expression.

Membrane-shaping proteins characterized by reticulon homology domains play an important part in the dynamic remodelling of the endoplasmic reticulum (ER). An example of such a protein is FAM134B, which can bind LC3 proteins and mediate the degradation of ER sheets through selective autophagy (ER-phagy) 1 . Mutations in FAM134B result in a neurodegenerative disorder in humans that mainly affects sensory and autonomic neurons 2 . Here we report that ARL6IP1, another ER-shaping protein that contains a reticulon homology domain and is associated with sensory loss 3 , interacts with FAM134B and participates in the formation of heteromeric multi-protein clusters required for ER-phagy. Moreover, ubiquitination of ARL6IP1 promotes this process. Accordingly, disruption of Arl6ip1 in mice causes an expansion of ER sheets in sensory neurons that degenerate over time. Primary cells obtained from Arl6ip1 -deficient mice or from patients display incomplete budding of ER membranes and severe impairment of ER-phagy flux. Therefore, we propose that the clustering of ubiquitinated ER-shaping proteins facilitates the dynamic remodelling of the ER during ER-phagy and is important for neuronal maintenance. The membrane-shaping protein ARL6IP1 is involved in the selective degradation of the endoplasmic reticulum, and this process depends on its ubiquitination and interaction with other membrane-shaping proteins such as FAM134B.

Current methods for structure elucidation of small molecules rely on finding similarity with spectra of known compounds, but do not predict structures de novo for unknown compound classes. We present MSNovelist, which combines fingerprint prediction with an encoder–decoder neural network to generate structures de novo solely from tandem mass spectrometry (MS 2 ) spectra. In an evaluation with 3,863 MS 2 spectra from the Global Natural Product Social Molecular Networking site, MSNovelist predicted 25% of structures correctly on first rank, retrieved 45% of structures overall and reproduced 61% of correct database annotations, without having ever seen the structure in the training phase. Similarly, for the CASMI 2016 challenge, MSNovelist correctly predicted 26% and retrieved 57% of structures, recovering 64% of correct database annotations. Finally, we illustrate the application of MSNovelist in a bryophyte MS 2 dataset, in which de novo structure prediction substantially outscored the best database candidate for seven spectra. MSNovelist is ideally suited to complement library-based annotation in the case of poorly represented analyte classes and novel compounds. MSNovelist combines fingerprint prediction with an encoder–decoder neural network for de novo structure generation of small molecules from mass spectra.

Untargeted metabolomics experiments rely on spectral libraries for structure annotation, but, typically, only a small fraction of spectra can be matched. Previous in silico methods search in structure databases but cannot distinguish between correct and incorrect annotations. Here we introduce the COSMIC workflow that combines in silico structure database generation and annotation with a confidence score consisting of kernel density P value estimation and a support vector machine with enforced directionality of features. On diverse datasets, COSMIC annotates a substantial number of hits at low false discovery rates and outperforms spectral library search. To demonstrate that COSMIC can annotate structures never reported before, we annotated 12 natural bile acids. The annotation of nine structures was confirmed by manual evaluation and two structures using synthetic standards. In human samples, we annotated and manually validated 315 molecular structures currently absent from the Human Metabolome Database. Application of COSMIC to data from 17,400 metabolomics experiments led to 1,715 high-confidence structural annotations that were absent from spectral libraries. COSMIC outperforms spectral library search for metabolite annotation and annotates previously unseen structures.

Background Sarcopenia is a growing problem, especially in nursing care. It is therefore mandatory to integrate measures such as resistance training to maintain muscle strength into nursing care. Aims The aim of this study was to investigate the acceptance and feasibility of a novel training algorithm in a nursing home environment. Furthermore, the reliability of measurements for the diagnosis of sarcopenia was tested in the nursing home setting. Methods Twenty-eight nursing home residents took part in the study, which encompassed two pre- and two post-examinations and a four-week training intervention. The training sessions were documented with regard to acceptance and feasibility as well as training motivation and intensity. Results A combined acceptance and feasibility of at least 54% was shown, quantifying adherence of the residents to the training. The operational feasibility was 91% and the exercise performance feasibility of the residents was between 88% and 94.2%. All intraclass correlation coefficients showed at least a good reliability (all ≥ 0.84). Training motivation was higher when participants trained in a group ( p  = 0.007), but training intensity was greater when they trained individually ( p  < 0.001). Discussion The main influencing factors for acceptance and feasibility were illness in general and a lack of motivation by the residents. Against the assumption, training was also possible during the weekends. Conclusions In conclusion, the study shows that our proposed training algorithm is acceptable and feasible in a nursing home environment. In future, the efficacy of the training needs to be shown. Trial registration number DRKS00030211; Date of registration: 2022-09-12.

To secure their access to water, light, and nutrients, many plant species have developed allelopathic strategies to suppress competitors. To this end, they release into the rhizosphere phytotoxic substances that inhibit the germination and growth of neighbors. Despite the importance of allelopathy in shaping natural plant communities and for agricultural production, the underlying molecular mechanisms are largely unknown. Here, we report that allelochemicals derived from the common class of cyclic hydroxamic acid root exudates directly affect the chromatin-modifying machinery in Arabidopsis thaliana. These allelochemicals inhibit histone deacetylases both in vitro and in vivo and exert their activity through locus-specific alterations of histone acetylation and associated gene expression. Our multilevel analysis collectively shows how plant-plant interactions interfere with a fundamental cellular process, histone acetylation, by targeting an evolutionarily highly conserved class of enzymes.

A glass in the system Na 2 O–SiO 2 –Al 2 O 3 –K 2 O–CaO–CaF 2 –ZnO was doped with Ce, Ag, Sn, Sb and Br. Homogeneous and transparent glass ceramics are obtained from this glass by the precipitation of CaF 2 nanoparticles. An interface-controlled crystallization mechanism hinders crystal growth after some time. By adding photosensitive agents, a tailored photoinduced CaF 2 crystallization was achieved. Structural evolution during irradiation and heat treatment was investigated by different electron microscopic techniques, e.g., scanning transmission electron microscopy (STEM) including energy-dispersive X-ray analysis (EDXS) and scanning electron microscopy (SEM) including electron backscatter diffraction (EBSD). Agglomerated structures with a size of ca. 35 nm were observed after the first thermal treatment at 530 °C. The Ag nucleation is accompanied by clustering of several components within the glass. CaF 2 particles with diameters of ca. 300 nm with a spherulitic structure are observed in the glass ceramic after the second heat treatment step at 560 °C. Calcium and fluoride are depleted from the glass matrix during crystallization, while SiO 2 is enriched. From (S)TEM micrographs, supplemented by selected area diffraction (SAD), outward growth of CaF 2 from a central point is observed. STEM–EDXS analyses show residual glass within the spherulitic structure.

Abstract Childhood exposure to green space has previously been associated with lower risk of developing schizophrenia later in life. It is unclear whether this association is mediated by genetic liability or whether the 2 risk factors work additively. Here, we investigate possible gene–environment associations with the hazard ratio (HR) of schizophrenia by combining (1) an estimate of childhood exposure to residential-level green space based on the normalized difference vegetation index (NDVI) from Landsat satellite images, with (2) genetic liability estimates based on polygenic risk scores for 19 746 genotyped individuals from the Danish iPSYCH sample. We used information from the Danish registers of health, residential address, and socioeconomic status to adjust HR estimates for established confounders, ie, parents’ socioeconomic status, and family history of mental illness. The adjusted HRs show that growing up surrounded by the highest compared to the lowest decile of NDVI was associated with a 0.52-fold (95% confidence interval [CI]: 0.40 to 0.66) lower schizophrenia risk, and children with the highest polygenic risk score had a 1.24-fold (95% CI: 1.18 to 1.30) higher schizophrenia risk. We found that NDVI explained 1.45% (95% CI: 1.07 to 1.90) of the variance on the liability scale, while polygenic risk score for schizophrenia explained 1.01% (95% CI: 0.77 to 1.46). Together they explained 2.40% (95% CI: 1.99 to 3.07) with no indication of a gene–environment interaction (P = .29). Our results suggest that risk of schizophrenia is associated additively with green space exposure and genetic liability, and provide no support for an environment-gene interaction between NDVI and schizophrenia.