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Background Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by mutations within the dystrophin gene. DMD is characterized by progressive skeletal muscle degeneration and atrophy and progressive cardiomyopathy. It has been observed the severity of cardiomyopathy varies in patients with DMD. Methods and Results A cohort of male patients with DMD and female DMD carriers underwent whole exome sequencing. Potential risk factor variants were identified according to their functional annotations and frequencies. Cardiac function of 15 male patients with DMD was assessed by cardiac magnetic resonance imaging, and various cardiac magnetic resonance imaging parameters and circulating biomarkers were compared between genotype groups. Five subjects carrying potential risk factor variants in the cystic fibrosis transmembrane regulator gene demonstrated lower left ventricular ejection fraction, larger left ventricular end-diastolic volume, and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels compared with 10 subjects who did not carry the potential risk factor variants (P=0.023, 0.019 and 0.028, respectively). Conclusions This study revealed heterozygous cystic fibrosis transmembrane regulator gene missense variants were associated with worse cardiac function in patients with DMD. The cystic fibrosis transmembrane regulator gene may serve as a genetic modifier that accounts for more severe cardiomyopathy in patients with DMD, who would require more aggressive management of the cardiomyopathy.

Single-cell ATAC-seq (scATAC-seq) profiles the chromatin accessibility landscape at single cell level, thus revealing cell-to-cell variability in gene regulation. However, the high dimensionality and sparsity of scATAC-seq data often complicate the analysis. Here, we introduce a method for analyzing scATAC-seq data, called Single-Cell ATAC-seq analysis via Latent feature Extraction (SCALE). SCALE combines a deep generative framework and a probabilistic Gaussian Mixture Model to learn latent features that accurately characterize scATAC-seq data. We validate SCALE on datasets generated on different platforms with different protocols, and having different overall data qualities. SCALE substantially outperforms the other tools in all aspects of scATAC-seq data analysis, including visualization, clustering, and denoising and imputation. Importantly, SCALE also generates interpretable features that directly link to cell populations, and can potentially reveal batch effects in scATAC-seq experiments.

Multiple genetic loci have been reported for progeroid syndromes. However, the molecular defects in some extremely rare forms of progeria have yet to be elucidated. Here, we report a 21-year-old man of Chinese ancestry who has an autosomal recessive form of progeria, characterized by severe dwarfism, mandibular hypoplasia, hyperopia, and partial lipodystrophy. Analyses of exome sequencing data from the entire family revealed only 1 rare homozygous missense variant (c.86C>T; p.Pro29Leu) in TOMM7 in the proband, while the parents and 2 unaffected siblings were heterozygous for the variant. TOMM7, a nuclear gene, encodes a translocase in the outer mitochondrial membrane. The TOMM complex makes up the outer membrane pore, which is responsible for importing many preproteins into the mitochondria. A proteomic comparison of mitochondria from control and proband-derived cultured fibroblasts revealed an increase in abundance of several proteins involved in oxidative phosphorylation, as well as a reduction in abundance of proteins involved in phospholipid metabolism. We also observed elevated basal and maximal oxygen consumption rates in the fibroblasts from the proband as compared with control fibroblasts. We concluded that altered mitochondrial protein import due to biallelic loss-of-function TOMM7 can cause severe growth retardation and progeroid features., Introduction In the last 2 decades, considerable progress has been made in identifying the molecular genetic basis of several progeroid syndromes, including mandibuloacral dysplasia (MAD), mandibular hypoplasia, deafness and progeroid [...]

TRIM33 is a chromatin reader required for mammalian mesendoderm differentiation after activation of Nodal signaling, while its role in mESCs is still elusive. Here, we report that TRIM33 co‐localizes with promyelocytic leukemia nuclear bodies (PML‐NBs) specifically in mESCs, to mediate Nodal signaling‐directed transcription of Lefty1/2. We show that TRIM33 puncta formation in mESCs depends on PML and on specific assembly of PML‐NBs. Moreover, TRIM33 and PML co‐regulate Lefty1/2 expression in mESCs, with both PML protein and formation of mESCs‐specific PML‐NBs being required for TRIM33 recruitment to these loci, and PML‐NBs directly associating with the Lefty1/2 loci. Finally, a TurboID proximity‐labeling experiment confirmed that TRIM33 is highly enriched only in mESCs‐specific PML‐NBs. Thus, our study supports a model in which TRIM33 condensates regulate Nodal signaling‐directed transcription in mESCs and shows that PML‐NBs can recruit distinct sets of client proteins in a cell‐context‐dependent manner. Synopsis: The chromatin reader TRIM33 is involved in cell fate decisions under different cell contexts, but the molecular details are still elusive. Here, TRIM33 is found to co‐condense with PML nuclear bodies (PML‐NBs) in mESCs to transcriptionally regulate Lefty1/2 expression upon Nodal signaling. TRIM33 is recruited into PML‐NBs selectively in mESCs, but not in differentiated cells.PML‐NB client protein composition differs between mESCs, oxidative stress‐treated mESCs, and differentiated cells.PML‐NBs regulate expression of gene clusters, including Lefty1/2 loci in mESCs.PML‐NBs form a regulatory hub for TRIM33 control of Lefty1/2 expression upon Nodal signaling. [ABSTRACT FROM AUTHOR]

In this study, a type of alkaline solid polyelectrolyte (ASPE) membrane was developed via the introduction of microcrystalline cellulose (MCC) and its modified product (QMCC) into the polyvinyl alcohol (PVA) matrix. In this process, green NaOH/urea-based solvent was used to achieve a good dispersion of MCC in the PVA matrix; meanwhile, the OH− groups in the NaOH/urea-based solvent provided an alkaline environment for good ion conductivity. Compared to the MCC-incorporated ASPE, further improved conductivity was achieved when the MCC was modified with quantitative quaternary ammonium salt. TGA showed that the addition of QMCC improved the water retention of the matrix, which was beneficial to the OH− conduction in the system. Compared to the control (50 mS cm−1), a maximum conductivity of 238 mS cm−1 was obtained after the incorporation of QMCC in the PVA matrix. Moreover, the tensile strength of the polymer electrolyte were also significantly increased with the addition of QMCC. Finally, this developed ASPE membrane was used in assembling a flexible Zn–air battery and showed a promising potential in the development of flexible electronic devices. [ABSTRACT FROM AUTHOR]