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Abstract Extracellular matrix (ECM) in the human tissue contains vesicles, which are defined as matrix‐bound nanovesicles (MBVs). MBVs serve as one of the functional components in ECM, recapitulating part of the regulatory roles and in vivo microenvironment. In this study, extracellular vesicles from culture supernatants (SuEVs) and MBVs are isolated from the conditioned medium or ECM, respectively, of 3D human mesenchymal stem cells. Nanoparticle tracking analysis shows that MBVs are smaller than SuEVs (100–150 nm). Transmission electron microscopy captures the typical cup shape morphology for both SuEVs and MBVs. Western blot reveals that MBVs have low detection of some SuEV markers such as syntenin‐1. miRNA analysis of MBVs shows that 3D microenvironment enhances the expression of miRNAs such as miR‐19a and miR‐21. In vitro functional analysis shows that MBVs can facilitate human pluripotent stem cell‐derived forebrain organoid recovery after starvation and promote high passage fibroblast proliferation. In macrophage polarization, 2D MBVs tend to suppress the pro‐inflammatory cytokine IL‐12 β , while 3D MBVs tend to enhance the anti‐inflammatory cytokine IL‐10. This study has the significance in advancing the understanding of the bio‐interface of nanovesicles with human tissue and the design of cell‐free therapy for treating neurological disorders such as ischemic stroke.

N⁶-methyladenosine (m⁶A) methylation can be deposited on chromatin-associated RNAs (caRNAs) by the RNA methyltransferase complex (MTC) to regulate chromatin state and transcription. However, the mechanism by which MTC is recruited to distinct genomic loci remains elusive. Here we identify RBFOX2, a well-studied RNA-binding protein, as a chromatin factor that preferentially recognizes m⁶A on caRNAs. RBFOX2 can recruit RBM15, an MTC component, to facilitate methylation of promoter-associated RNAs. RBM15 also physically interacts with YTHDC1 and recruits polycomb repressive complex 2 (PRC2) to the RBFOX2-bound loci for chromatin silencing and transcription suppression. Furthermore, we found that this RBFOX2/m⁶A/RBM15/YTHDC1/PRC2 axis plays a critical role in myeloid leukaemia. Downregulation of RBFOX2 notably inhibits survival/proliferation of acute myeloid leukaemia cells and promotes their myeloid differentiation. RBFOX2 is also required for self-renewal of leukaemia stem/initiation cells and acute myeloid leukaemia maintenance. Our study presents a pathway of m⁶A MTC recruitment and m⁶A deposition on caRNAs, resulting in locus-selective chromatin regulation, which has potential therapeutic implications in leukaemia.

Abstract Noise or fluctuations play an important role in the modeling and understanding of the behavior of various complex systems in nature. Fokker–Planck equations are powerful mathematical tools to study behavior of such systems subjected to fluctuations. In this paper we establish local well-posedness result of a new nonlinear Fokker–Planck equation. Such equations appear in the modeling of the grain boundary dynamics during microstructure evolution in the polycrystalline materials and obey special energy laws.

The choroid plexus (ChP) is a complex structure in the human brain that is responsible for the secretion of cerebrospinal fluid (CSF) and forming the blood–CSF barrier (B-CSF-B). Human-induced pluripotent stem cells (hiPSCs) have shown promising results in the formation of brain organoids in vitro; however, very few studies to date have generated ChP organoids. In particular, no study has assessed the inflammatory response and the extracellular vesicle (EV) biogenesis of hiPSC-derived ChP organoids. In this study, the impacts of Wnt signaling on the inflammatory response and EV biogenesis of ChP organoids derived from hiPSCs was investigated. During days 10–15, bone morphogenetic protein 4 was added along with (+/−) CHIR99021 (CHIR, a small molecule GSK-3β inhibitor that acts as a Wnt agonist). At day 30, the ChP organoids were characterized by immunocytochemistry and flow cytometry for TTR (~72%) and CLIC6 (~20%) expression. Compared to the −CHIR group, the +CHIR group showed an upregulation of 6 out of 10 tested ChP genes, including CLIC6 (2-fold), PLEC (4-fold), PLTP (2–4-fold), DCN (~7-fold), DLK1 (2–4-fold), and AQP1 (1.4-fold), and a downregulation of TTR (0.1-fold), IGFBP7 (0.8-fold), MSX1 (0.4-fold), and LUM (0.2–0.4-fold). When exposed to amyloid beta 42 oligomers, the +CHIR group had amore »more sensitive response as evidenced by the upregulation of inflammation-related genes such as TNFα, IL-6, and MMP2/9 when compared to the −CHIR group. Developmentally, the EV biogenesis markers of ChP organoids showed an increase over time from day 19 to day 38. This study is significant in that it provides a model of the human B-CSF-B and ChP tissue for the purpose of drug screening and designing drug delivery systems to treat neurological disorders such as Alzheimer’s disease and ischemic stroke.« less

This work employs single-mode equations to study convection and double-diffusive convection in a porous medium where the Darcy law provides large-scale damping. We first consider thermal convection with salinity as a passive scalar. The single-mode solutions resembling steady convection rolls reproduce the qualitative behavior of root-mean-square and mean temperature profiles of time-dependent states at high Rayleigh numbers from direct numerical simulations (DNS). We also show that the single-mode solutions are consistent with the heat-exchanger model that describes well the mean temperature gradient in the interior. The Nusselt number predicted from the single-mode solutions exhibits a scaling law with Rayleigh number close to that followed by exact 2D steady convection rolls, although large aspect ratio DNS results indicate a faster increase. However, the single-mode solutions at a high wavenumber predict Nusselt numbers close to the DNS results in narrow domains. We also employ the single-mode equations to analyze the influence of active salinity, introducing a salinity contribution to the buoyancy, but with a smaller diffusivity than the temperature. The single-mode solutions are able to capture the stabilizing effect of an imposed salinity gradient and describe the standing and traveling wave behaviors observed in DNS. The Sherwood numbers obtained from single-mode solutionsmore »show a scaling law with the Lewis number that is close to the DNS computations with passive or active salinity. This work demonstrates that single-mode solutions can be successfully applied to this system whenever periodic or no-flux boundary conditions apply in the horizontal.« less

Bifurcation analysis of confined salt-finger convection using single-mode equations obtained from a severely truncated Fourier expansion in the horizontal is performed. Strongly nonlinear staircase-like solutions having, respectively, one (S1), two (S2) and three (S3) regions of mixed salinity in the vertical direction are computed using numerical continuation, and their stability properties are determined. Near onset, the one-layer S1 solution is stable and corresponds to maximum salinity transport among the three solutions. The S2 and S3 solutions are unstable but exert an influence on the statistics observed in direct numerical simulations (DNS) in larger two-dimensional (2-D) domains. Secondary bifurcations of S1 lead either to tilted-finger (TF1) or to travelling wave (TW1) solutions, both accompanied by the spontaneous generation of large-scale shear, a process favoured for lower density ratios and Prandtl numbers ( $Pr$ ). These states at low $Pr$ are associated, respectively, with two-layer and three-layer staircase-like salinity profiles in the mean. States breaking reflection symmetry in the midplane are also computed. In two dimensions and for low $Pr$ , the DNS results favour direction-reversing tilted fingers resembling the pulsating wave state observed in other systems. Two-layer and three-layer mean salinity profiles corresponding to reversing tilted fingers and TW1 are observedmore »in 2-D DNS averaged over time. The single-mode solutions close to the high wavenumber onset are in an excellent agreement with 2-D DNS in small horizontal domains and compare well with 3-D DNS.« less

Abstract Stars grazing supermassive black holes (SMBHs) on bound orbits may survive tidal disruption, causing periodic flares. Inspired by the recent discovery of the periodic nuclear transient ASASSN-14ko, a promising candidate for a repeating tidal disruption event (TDE), we study the tidal deformation of stars approaching SMBHs on eccentric orbits. With both analytical and hydrodynamic methods, we show the overall tidal deformation of a star is similar to that in a parabolic orbit provided that the eccentricity is above a critical value. This allows one to make use of existing simulation libraries from parabolic encounters to calculate the mass fallback rate in eccentric TDEs. We find the flare structures of eccentric TDEs show a complicated dependence on both the SMBH mass and the orbital period. For stars orbiting SMBHs with relatively short periods, we predict significantly shorter-lived duration flares than those in parabolic TDEs, which can be used to predict repeating events if the mass of the SMBH can be independently measured. Using an adiabatic mass-loss model, we study the flare evolution over multiple passages, and show the evolved stars can survive many more passages than main-sequence stars. We apply this theoretical framework to the repeating TDE candidate ASASSN-14ko andmore »suggest that its recurrent flares originate from a moderately massive ( M ≳ 1 M ⊙ ), extended (likely ≈10 R ⊙ ), evolved star on a grazing, bound orbit around the SMBH. Future hydrodynamic simulations of multiple tidal interactions will enable realistic models on the individual flare structure and the evolution over multiple flares.« less