Magnetic Structure-Dependent Spin Texture Lattice in Hexagonal MnFeCoGe Magnets.

Topological spin textures are of great significance in magnetic information storage and spintronics due to their high storage density and low drive current. In this work, the transformation of magnetic configuration from chaotic labyrinth domains to uniform stripe domains was observed in MnFe1-xCoxGe magnets. This change occurs due to the noncollinear magnetic structure switching to a uniaxial ferromagnetic structure with increasing Co content, as identified by neutron diffraction results and Lorentz transmission electron microscopy (L-TEM). Of utmost importance, a hexagonal lattice of high-density robust type-II magnetic bubble lattice was established for x = 0.8 through out-of-plane magnetic field stimulation and field-cooling. The dimensions of the type-II magnetic bubbles were found to be tuned by the sample thickness. Therefore, the stabilization of complex magnetic spin textures, associated with enhanced uniaxial ferromagnetic interaction and magnetic dipole-dipole interaction in MnFe1-xCoxGe through magnetic structure manipulation, as further confirmed by the micromagnetic simulations, will provide a convenient and efficient strategy for designing topological spin textures with potential applications in spintronic devices.

Transcriptome Dynamics and Cell Dialogs Between Oocytes and Granulosa Cells in Mouse Follicle Development.

The development and maturation of follicles is a sophisticated and multistage process. The dynamic gene expression of oocytes and their surrounding somatic cells and the dialogs between these cells are critical to this process. In this study, we accurately classified the oocyte and follicle development into nine stages and profiled the gene expression of mouse oocytes and their surrounding granulosa cells and cumulus cells. The clustering of the transcriptomes showed the trajectories of two distinct development courses of oocytes and their surrounding somatic cells. Gene expression changes precipitously increased at Type 4 stage and drastically dropped afterward within both oocytes and granulosa cells. Moreover, the number of differentially expressed genes between oocytes and granulosa cells dramatically increased at Type 4 stage, most of which persistently passed on to the later stages. Strikingly, cell communications within and between oocytes and granulosa cells became active from Type 4 stage onward. Cell dialogs connected oocytes and granulosa cells in both unidirectional and bidirectional manners. TGFB2/3, TGFBR2/3, INHBA/B, and ACVR1/1B/2B of TGF-ß signaling pathway functioned in the follicle development. NOTCH signaling pathway regulated the development of granulosa cells. Additionally, many maternally DNA methylation- or H3K27me3-imprinted genes remained active in granulosa cells but silent in oocytes during oogenesis. Collectively, Type 4 stage is the key turning point when significant transcription changes diverge the fate of oocytes and granulosa cells, and the cell dialogs become active to assure follicle development. These findings shed new insights on the transcriptome dynamics and cell dialogs facilitating the development and maturation of oocytes and follicles.

Prediction of a Novel Electromechanical Response in Polar Polymers with Rigid Backbones: Contrasting Furan-Derived Nanothreads to Poly(Vinylidene Fluoride).

Syn furan nanothreads have all oxygen atoms arranged on one side of the thread backbone; these polar threads present intriguing opportunities in electromechanical response owing to their rigid ladder-like backbone. We retrained a C/H/O reactive force field to simulate their response to external electric field for both end-anchored individual threads and bulk nanothread crystals, contrasting the results to those for poly(vinylidene fluoride) (PVDF) polymer. Whereas the field induces a length-independent torque in PVDF through backbone rotation about σ bonds, furan-derived nanothreads generate a length-dependent torque by progressively twisting their rigid backbone. This mode of response couples the rotational history of the electric field to axial tension in the anchored thread. In simulations of densely packed syn furan nanothread crystals without anchors, the crystals pole in a field (∼3 GV/m at 300 K) similar to that seen in simulations of PVDF, suggesting that crystals of polar nanothreads can be ferroelectric.

Single-cell and spatial multiomic inference of gene regulatory networks using SCRIPro.

MOTIVATION: The burgeoning generation of single-cell or spatial multiomic data allows for the characterization of gene regulation networks (GRNs) at an unprecedented resolution. However, the accurate reconstruction of GRNs from sparse and noisy single-cell or spatial multiomic data remains challenging. RESULTS: Here, we present SCRIPro, a comprehensive computational framework that robustly infers GRNs for both single-cell and spatial multi-omics data. SCRIPro first improves sample coverage through a density clustering approach based on multiomic and spatial similarities. Additionally, SCRIPro scans transcriptional regulator (TR) importance by performing chromatin reconstruction and in silico deletion analyses using a comprehensive reference covering 1,292 human and 994 mouse TRs. Finally, SCRIPro combines TR-target importance scores derived from multiomic data with TR-target expression levels to ensure precise GRN reconstruction. We benchmarked SCRIPro on various datasets, including single-cell multiomic data from human B-cell lymphoma, mouse hair follicle development, Stereo-seq of mouse embryos, and Spatial-ATAC-RNA from mouse brain. SCRIPro outperforms existing motif-based methods and accurately reconstructs cell type-specific, stage-specific, and region-specific GRNs. Overall, SCRIPro emerges as a streamlined and fast method capable of reconstructing TR activities and GRNs for both single-cell and spatial multi-omic data. AVAILABILITY: SCRIPro is available at https://github.com/wanglabtongji/SCRIPro. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Mycobacterium tuberculosis inhibits METTL14-mediated m6A methylation of Nox2 mRNA and suppresses anti-TB immunity.

Internal N6-methyladenosine (m6A) modifications are among the most abundant modifications of messenger RNA, playing a critical role in diverse biological and pathological processes. However, the functional role and regulatory mechanism of m6A modifications in the immune response to Mycobacterium tuberculosis infection remains unknown. Here, we report that methyltransferase-like 14 (METTL14)-dependent m6A methylation of NAPDH oxidase 2 (Nox2) mRNA was crucial for the host immune defense against M. tuberculosis infection and that M. tuberculosis-secreted antigen EsxB (Rv3874) inhibited METTL14-dependent m6A methylation of Nox2 mRNA. Mechanistically, EsxB interacted with p38 MAP kinase and disrupted the association of TAB1 with p38, thus inhibiting the TAB1-mediated autophosphorylation of p38. Interaction of EsxB with p38 also impeded the binding of p38 with METTL14, thereby inhibiting the p38-mediated phosphorylation of METTL14 at Thr72. Inhibition of p38 by EsxB restrained liquid-liquid phase separation (LLPS) of METTL14 and its subsequent interaction with METTL3, preventing the m6A modification of Nox2 mRNA and its association with the m6A-binding protein IGF2BP1 to destabilize Nox2 mRNA, reduce ROS levels, and increase intracellular survival of M. tuberculosis. Moreover, deletion or mutation of the phosphorylation site on METTL14 impaired the inhibition of ROS level by EsxB and increased bacterial burden or histological damage in the lungs during infection in mice. These findings identify a previously unknown mechanism that M. tuberculosis employs to suppress host immunity, providing insights that may empower the development of effective immunomodulators that target M. tuberculosis.

ADNP modulates SINE B2-derived CTCF-binding sites during blastocyst formation in mice.

CTCF is crucial for chromatin structure and transcription regulation in early embryonic development. However, the kinetics of CTCF chromatin occupation in preimplantation embryos have remained unclear. In this study, we used CUT&RUN technology to investigate CTCF occupancy in mouse preimplantation development. Our findings revealed that CTCF begins binding to the genome prior to zygotic genome activation (ZGA), with a preference for CTCF-anchored chromatin loops. Although the majority of CTCF occupancy is consistently maintained, we identified a specific set of binding sites enriched in the mouse-specific short interspersed element (SINE) family B2 that are restricted to the cleavage stages. Notably, we discovered that the neuroprotective protein ADNP counteracts the stable association of CTCF at SINE B2-derived CTCF-binding sites. Knockout of Adnp in the zygote led to impaired CTCF binding signal recovery, failed deposition of H3K9me3, and transcriptional derepression of SINE B2 during the morula-to-blastocyst transition, which further led to unfaithful cell differentiation in embryos around implantation. Our analysis highlights an ADNP-dependent restriction of CTCF binding during cell differentiation in preimplantation embryos. Furthermore, our findings shed light on the functional importance of transposable elements (TEs) in promoting genetic innovation and actively shaping the early embryo developmental process specific to mammals.

Amplifying Nanoparticle Reinforcement through Low Volume Topologically Controlled Chemical Coupling.

We present a streamlined method to covalently bond hydroxylated carbon nanotubes (CNOH) within a polyphenol matrix, all achieved through a direct, solvent-free process. Employing an extremely small concentration of CNOH (0.01% w/w) along with topologically contrasting linkers led to a maximum of 5-fold increase in modulus and a 25% enhancement in tensile strength compared to the unaltered matrix, an order of magnitude greater reinforcement (w/w) compared to state-of-the-art melt-processed nanocomposites. Through dynamic mechanical analysis, low field solid-state nuclear magnetic resonance spectroscopy, and molecular dynamics simulations, we uncovered the profound influence of linker's conformational degrees of freedom on the segmental dynamics and therefore the material's properties.

ISR inhibition reverses pancreatic ß-cell failure in Wolfram syndrome models.

Pancreatic ß-cell failure by WFS1 deficiency is manifested in individuals with wolfram syndrome (WS). The lack of a suitable human model in WS has impeded progress in the development of new treatments. Here, human pluripotent stem cell derived pancreatic islets (SC-islets) harboring WFS1 deficiency and mouse model of ß cell specific Wfs1 knockout were applied to model ß-cell failure in WS. We charted a high-resolution roadmap with single-cell RNA-seq (scRNA-seq) to investigate pathogenesis for WS ß-cell failure, revealing two distinct cellular fates along pseudotime trajectory: maturation and stress branches. WFS1 deficiency disrupted ß-cell fate trajectory toward maturation and directed it towards stress trajectory, ultimately leading to ß-cell failure. Notably, further investigation of the stress trajectory identified activated integrated stress response (ISR) as a crucial mechanism underlying WS ß-cell failure, characterized by aberrant eIF2 signaling in WFS1-deficient SC-islets, along with elevated expression of genes in regulating stress granule formation. Significantly, we demonstrated that ISRIB, an ISR inhibitor, efficiently reversed ß-cell failure in WFS1-deficient SC-islets. We further validated therapeutic efficacy in vivo with ß-cell specific Wfs1 knockout mice. Altogether, our study provides novel insights into WS pathogenesis and offers a strategy targeting ISR to treat WS diabetes.