Heterochromatin loosening by the Oct4 linker region facilitates Klf4 binding and iPSC reprogramming.

The success of Yamanaka factor reprogramming of somatic cells into induced pluripotent stem cells suggests that some factor(s) must remodel the nuclei from a condensed state to a relaxed state. How factor-dependent chromatin opening occurs remains unclear. Using FRAP and ATAC-seq, we found that Oct4 acts as a pioneer factor that loosens heterochromatin and facilitates the binding of Klf4 and the expression of epithelial genes in early reprogramming, leading to enhanced mesenchymal-to-epithelial transition. A mutation in the Oct4 linker, L80A, which shows impaired interaction with the BAF complex component Brg1, is inactive in heterochromatin loosening. Oct4-L80A also blocks the binding of Klf4 and retards MET. Finally, vitamin C or Gadd45a could rescue the reprogramming deficiency of Oct4-L80A by enhancing chromatin opening and Klf4 binding. These studies reveal a cooperation between Oct4 and Klf4 at the chromatin level that facilitates MET at the cellular level and shed light into the research of multiple factors in cell fate determination.

miR-203, fine-tunning neuroinflammation by juggling different components of NF-κB signaling.

BACKGROUND: miR-203 was first indicated in maintaining skin homeostasis and innate immunity. Aberrant expression of miR-203 was found associated with pathological progressions of immune disorders, cancers, as well as neurodegenerations. Recently, increasing data on miR-203 in regulating neuroinflammation and neuronal apoptosis has raised extensive concern about the biological function of this microRNA. METHODS: Mouse model with ectopic miR-203 expression in the hippocampus was constructed by stereotactic injection of lentiviral expression vector of pre-miR-203. Association of miR-203 and mRNA of Akirin2, as well as the competition for miR-203 targeting between Akirin2 3'UTR and another recently characterized miR-203 target, 14-3-3θ, was verified using Dual-Luciferase Reporter Gene Assay and western blot. Microglia activation and pro-inflammatory cytokines expression in the hippocampus of mice overexpressing miR-203 was evaluated using immunohistochemistry analysis and western blot. Neuronal cell death was monitored using anti-caspase 8 in immunohistochemistry as well as TUNEL assay. Cognition of mice was assessed with a behavior test battery consisting of nesting behavior test, Barnes maze and fear conditioning test. RESULTS: Akirin2, an activator of NF-κB signaling, was identified as a direct target of miR-203. By also targeting 14-3-3θ, a negative regulator of NF-κB signaling, miR-203 displayed an overall pro-inflammatory role both in vitro and in vivo. Promoted nuclear translocation of NF-κB and increased expression of proinflammatory cytokines were observed in cultured BV2 cells transfected with miR-203 mimics. Microglia activation and upregulation of NF-κB, IL-1ß and IL-6 were observed in mouse hippocampus with overexpression of miR-203. In addition, promoted neuronal cell death in the hippocampus and impaired neuronal activities resulted in cognitive dysfunction of mice with ectopic miR-203 expression in the hippocampus. CONCLUSION: A pro-inflammatory and neurodisruptive role of miR-203 was addressed based on our data in this study. Given the identification of Akirin2 as a direct target of miR-203 and the competition with 14-3-3θ for miR-203 targeting, together with the findings of other signaling molecules in NF-κB pathway as targets of miR-203, we proposed that miR-203 was a master modulator, fine-tunning neuroinflammation by juggling different components of NF-κB signaling.

Surgical Ligation for the Treatment of an Unusual Presentation of Type II Abernethy Malformation.

Abernethy malformation is a very rare congenital vascular malformation consisting of diversion of portal blood away from liver, and it is commonly associated with multiple congenital anomalies. Here, we present a case of a male from China with nonspecific abdominal pain associated with an unusual pattern of type II Abernethy malformation, whose was diagnosed with a portosystemic shunt via a giant portal-inferior vena cava fistula (17.22 mm in diameter). The patient underwent a surgical ligation of the portocaval shunt and recovered well. We believe that this is the first case of a type II Abernethy malformation presenting as a portosystemic shunt via the giant portal-inferior vena cava fistula.

Plumbagin inhibits the proliferation of nasopharyngeal carcinoma 6-10B cells by upregulation of reactive oxygen species.

Plumbagin (PLB) is the primary component of the traditional Chinese medicine Baihua Dan, and possesses anti-infection and anticancer effects, with the ability to enhance the sensitivity of tumor cells to radiation therapy. However, the anticancer effect of PLB on nasopharyngeal carcinoma and the underlying mechanisms remain unclear. In this study, we investigated the anticancer effects of PLB on nasopharyngeal carcinoma 6-10B cells and clarified its molecular mechanisms in vitro. The results showed that PLB was effective against 6-10B cells proliferation in a dose-dependent manner by inducing G2/M phase cell cycle arrest. Furthermore, our data showed that PLB induced reactive oxygen species accumulation, which inhibited the GSK3ß/STAT3 pathway and arrested the G2/M phase. Therefore, our results provided new insight into the mechanism of the antitumor effects of PLB, supporting PLB as a prospective therapeutic drug in nasopharyngeal carcinoma by modulating intracellular redox balance.

Srebp-1 Interacts with c-Myc to Enhance Somatic Cell Reprogramming.

Somatic cell reprogramming is accompanied by changes in lipid metabolism. While attempting to dissect the molecular mechanisms of the lipid metabolic switch during reprogramming, we found that overexpression of sterol regulatory element binding protein-1 (Srebp-1), a transcriptional factor required for lipid homeostasis, enhances reprogramming efficiency, while knockdown or pharmaceutical inhibition of Srebp-1 is inhibitory. Srebp-1 overexpression blocks the formation of partially reprogrammed cells, and functions in the early phase of reprogramming. Furthermore, Srebp-1 functions in nucleus and depends on its transcriptional activity but not its ability to bind the E-box motif and regulation of canonical targets. Mechanistically, Srebp-1 interacts with c-Myc, facilitates its binding to downstream pluripotent targets, strengthens the function of c-Myc in enhancing other Yamanaka factors' binding, and thereby promotes the expression of pluripotent genes. These results elucidate a novel role for Srebp-1 in somatic cell reprogramming and provide insights into understanding the metabolic switch during reprogramming.

Air-Working Electrochromic Artificial Muscles.

Artificial muscles are indispensable components for next-generation robotics to mimic the sophisticated movements of living systems and provide higher output energies when compared with real muscles. However, artificial muscles actuated by electrochemical ion injection have problems with single actuation properties and difficulties in stable operation in air. Here, air-working electrochromic artificial muscles (EAMs) with both color-changing and actuation functions are reported, which are constructed based on vanadium pentoxide nanowires and carbon tube yarn. Each EAM can generate a contractile stroke of ≈12% during stable operation in the air with multiple color changes (yellow-green-gray) under ±4 V actuation voltages. The reflectance contrast is as high as 51%, demonstrating the excellent versatility of the EAMs. In addition, a torroidal EAM arrangement with fast response and high resilience is constructed. The EAM's contractile stroke can be displayed through visual color changes, which provides new ideas for future artificial muscle applications in soft robots and artificial limbs.

Cellular and Molecular Insights into the Divergence of Neural Stem Cells on Matrigel and Poly-l-lysine Interfaces.

Poly-l-lysine (PLL) and Matrigel, both classical coating materials for culture substrates in neural stem cell (NSC) research, present distinct interfaces whose effect on NSC behavior at cellular and molecular levels remains ambiguous. Our investigation reveals intriguing disparities: although both PLL and Matrigel interfaces are hydrophilic and feature amine functional groups, Matrigel stands out with lower stiffness and higher roughness. Based on this diversity, Matrigel surpasses PLL, driving NSC adhesion, migration, and proliferation. Intriguingly, PLL promotes NSC differentiation into astrocytes, whereas Matrigel favors neural differentiation and the physiological maturation of neurons. At the molecular level, Matrigel showcases a wider upregulation of genes linked to NSC behavior. Specifically, it enhances ECM-receptor interaction, activates the YAP transcription factor, and heightens glycerophospholipid metabolism, steering NSC proliferation and neural differentiation. Conversely, PLL upregulates genes associated with glial cell differentiation and amino acid metabolism and elevates various amino acid levels, potentially linked to its support for astrocyte differentiation. These distinct transcriptional and metabolic activities jointly shape the divergent NSC behavior on these substrates. This study significantly advances our understanding of substrate regulation on NSC behavior, offering novel insights into optimizing and targeting the application of these surface coating materials in NSC research.

Toward nanotechnology-enabled application of bilirubin in the treatment and diagnosis of various civilization diseases.

Bilirubin, an open chain tetrapyrrole, has powerful antioxidant, anti-inflammatory, immuno-suppressive, metabolic-modulating and anti-proliferative activities. Bilirubin is a natural molecule that is produced and metabolized within the human body, making it highly biocompatible and well suited for clinical use. However, the use of bilirubin has been hampered by its poor water solubility and instability. With advanced construction strategies, bilirubin-derived nanoparticles (BRNPs) have not only overcome the disadvantages of bilirubin but also enhanced its therapeutic effects by targeting damaged tissues, passing through physiological barriers, and ensuring controlled sustained release. We review the mechanisms underlying the biological activities of bilirubin, BRNP preparation strategies and BRNP applications in various disease models. Based on their superior performance, BRNPs require further exploration of their efficacy, biodistribution and long-term biosafety in nonhuman primate models that recapitulate human disease to promote their clinical translation.

Surface Functional Modification by Ti3 C2 Tx MXene on PLLA Nanofibers for Optimizing Neural Stem Cell Engineering.

Optimizing cell substrates by surface modification of neural stem cells (NSCs), for efficient and oriented neurogenesis, represents a promising strategy for treating neurological diseases. However, developing substrates with the advanced surface functionality, conductivity, and biocompatibility required for practical application is still challenging. Here, Ti3 C2 Tx MXene is introduced as a coating nanomaterial for aligned poly(l-lactide) (PLLA) nanofibers (M-ANF) to enhance NSC neurogenesis and simultaneously tailor the cell growth direction. Ti3 C2 Tx MXene treatment provides a superior conductivity substrate with a surface rich in functional groups, hydrophilicity, and roughness, which can provide biochemical and physical cues to support NSC adhesion and proliferation. Moreover, Ti3 C2 Tx MXene coating significantly promotes NSC differentiation into both neurons and astrocytes. Interestingly, Ti3 C2 Tx MXene acts synergistically with the alignment of nanofibers to promote the growth of neurites, indicating enhanced maturation of these neurons. RNA sequencing analysis further reveals the molecular mechanism by which Ti3 C2 Tx MXene modulates the fate of NSCs. Notably, surface modification by Ti3 C2 Tx MXene mitigates the in vivo foreign body response to implanted PLLA nanofibers. This study confirms that Ti3 C2 Tx MXene provides multiple advantages for decorating the aligned PLLA nanofibers to cooperatively improve neural regeneration.

Epigenome-Metabolome-Epigenome signaling cascade in cell biological processes.

Cell fate determination as a fundamental question in cell biology has been extensively studied at different regulatory levels for many years. However, the mechanisms of multilevel regulation of cell fate determination remain unclear. Recently, we have proposed an Epigenome-Metabolome-Epigenome (E-M-E) signaling cascade model to describe the cross-over cooperation during mouse somatic cell reprogramming. In this review, we summarize the broad roles of E-M-E signaling cascade in different cell biological processes, including cell differentiation and dedifferentiation, cell specialization, cell proliferation, and cell pathologic processes. Precise E-M-E signaling cascades are critical in these cell biological processes, and it is of worth to explore each step of E-M-E signaling cascade. E-M-E signaling cascade model sheds light on and may open a window to explore the mechanisms of multilevel regulation of cell biological processes.

Interfacing Perforated Eardrums with Graphene-Based Membranes for Broadband Hearing Recovery.

Eardrum perforation and associated hearing loss is a global health problem. Grafting perforated eardrum with autologous tissues in clinic can restore low-frequency hearing but often leaves poor recovery of high-frequency hearing. In this study, the potential of incorporating a thin multilayered graphene membrane (MGM) into the eardrum for broadband hearing recovery in rats is examined. The MGM shows good biocompatibility and biostability to promote the growth of eardrum cells in a regulated manner with little sign of tissue rejection and inflammatory response. After three weeks of implantation, the MGM is found to be encapsulated by a thin layer of newly grown tissue on both sides without a significant folded overgrowth that is often seen in natural healing. The perforation is well sealed, and broadband hearing recovery (1-32 kHz) is enabled and maintained for at least 2 months. Mechanical simulations show that the high elastic modulus of MGM and thin thickness of the reconstructed eardrum play a critical role in the recovery of high-frequency hearing. This work demonstrates the promise of the use of MGM as a functional graft for perforated eardrum to recover hearing in the broadband frequency region and suggests a new acoustics-related medical application for graphene-related 2D materials.

Plin2-mediated lipid droplet mobilization accelerates exit from pluripotency by lipidomic remodeling and histone acetylation.

Metabolic switch is critical for cell fate determination through metabolic functions, epigenetic modifications, and gene expression. However, the mechanisms underlying these alterations and their functional roles remain unclear. Here, we show that Plin2-mediated moderate lipid hydrolysis is critical for pluripotency of embryonic stem cells (ESCs). Upon exit from pluripotency, lipid droplet (LD)-associated protein Plin2 is recognized by Hsc70 and degraded via chaperone-mediated autophagy to facilitate LD mobilization. Enhancing lipid hydrolysis by Plin2 knockout promotes pluripotency exit, which is recovered by ATGL inhibition. Mechanistically, excessive lipid hydrolysis induces a dramatic lipidomic remodeling characterized by decreased cardiolipin and phosphatidylethanolamine, which triggers defects in mitochondrial cristae and fatty acid oxidation, resulting in reduced acetyl-CoA and histone acetylation. Our results reveal how LD mobilization is regulated and its critical role in ESC pluripotency, and indicate the mechanism linking LD homeostasis to mitochondrial remodeling and epigenetic regulation, which might shed light on development and diseases.

MAP2K6 remodels chromatin and facilitates reprogramming by activating Gatad2b-phosphorylation dependent heterochromatin loosening.

Somatic cell reprogramming is an ideal model for studying epigenetic regulation as it undergoes dramatic chromatin remodeling. However, a role for phosphorylation signaling in chromatin protein modifications for reprogramming remains unclear. Here, we identified mitogen-activated protein kinase kinase 6 (Mkk6) as a chromatin relaxer and found that it could significantly enhance reprogramming. The function of Mkk6 in heterochromatin loosening and reprogramming requires its kinase activity but does not depend on its best-known target, P38. We identified Gatad2b as a novel target of Mkk6 phosphorylation that acts downstream to elevate histone acetylation levels and loosen heterochromatin. As a result, Mkk6 over-expression facilitates binding of Sox2 and Klf4 to their targets and promotes pluripotency gene expression during reprogramming. Our studies not only reveal an Mkk phosphorylation mediated modulation of chromatin status in reprogramming, but also provide new rationales to further investigate and improve the cell fate determination processes.

Nuclear localization of mitochondrial TCA cycle enzymes modulates pluripotency via histone acetylation.

Pluripotent stem cells hold great promise in regenerative medicine and developmental biology studies. Mitochondrial metabolites, including tricarboxylic acid (TCA) cycle intermediates, have been reported to play critical roles in pluripotency. Here we show that TCA cycle enzymes including Pdha1, Pcb, Aco2, Cs, Idh3a, Ogdh, Sdha and Mdh2 are translocated to the nucleus during somatic cell reprogramming, primed-to-naive transition and totipotency acquisition. The nuclear-localized TCA cycle enzymes Pdha1, Pcb, Aco2, Cs, Idh3a promote somatic cell reprogramming and primed-to-naive transition. In addition, nuclear-localized TCA cycle enzymes, particularly nuclear-targeted Pdha1, facilitate the 2-cell program in pluripotent stem cells. Mechanistically, nuclear Pdha1 increases the acetyl-CoA and metabolite pool in the nucleus, leading to chromatin remodeling at pluripotency genes by enhancing histone H3 acetylation. Our results reveal an important role of mitochondrial TCA cycle enzymes in the epigenetic regulation of pluripotency that constitutes a mitochondria-to-nucleus retrograde signaling mode in different states of pluripotent acquisition.

Identification of the transcription factor, AFF4, as a new target of miR-203 in CNS.

MiR-203 was identified as a hub of a potential regulatory miRNA network in central nervous system. Overexpressing of miR-203 in the frontal cortex of C57BL/6J wild type mouse induced neurodegeneration by increasing the apoptotic pathway and neuron death. AFF4, a transcription factor, was identified as a new bona fida protein target of miR-203 in CNS. The miRNA:mRNA interaction of miR-203 and AFF4 was verified using Dural-luciferase assay. Down-regulated expression of AFF4 was induced by overexpressing miR-203 both in vitro and in vivo. Open field test, Y maze and Morris water maze test were conducted for the behavioral assessment of the mice with stereotactic injection of lentiviral vector overexpressing miR-203 in the hippocampus. No anxiety-like behavior or impaired cognition was noticed in these mice. Consistent with the results of the behavioral assessment, the electron micrograph and Nissl staining revealed no significant change in the synaptic density and no neuron injuries in the hippocampus of mice overexpressing miR-203, respectively. Our results indicated that instead of promoting neurodegenerative phenotype, a more profound function should be ascribed to miR-203 in regulating neuron behavioral activities and cognition. Neuron-type specific functions of miR-203 are likely to be executed via its various downstream protein interactors.

Scalable fluid-spinning nanowire-based inorganic semiconductor yarns for electrochromic actuators.

Semiconductor yarns with unique functional characteristics have great potential applications in next-generation electronic devices. However, scalable inorganic semiconductor yarns with excellent mechanical and electrical properties, and environmental stability have not been discovered. In this study, we explored a unique fluid-spinning strategy to obtain a series of scalable inorganic semiconductor yarns including neat and hybrid semiconductor yarns. Different from the conventional yarn spinning strategy through a mechanical motor, we utilized the fluid force from the triple-phase interface to assemble and twist inorganic nanofiber building blocks simultaneously, and eventually obtained highly oriented inorganic nanowire-based semiconductor yarns. The obtained semiconductor yarns showed an excellent flexibility (curvature exceeding 2 cm-1) and mechanical strength (tensile strength of 443 MPa) because of their highly oriented hierarchical nanostructures, which make them coiling able with highly twisted insertion. Additionally, coiled yarns were obtained by combining the host core material and functional guest sheath in a fluid-spinning process, which are flexible in deep cryogenic temperature owing to the pure inorganic building blocks (26.28% tensile strain in liquid nitrogen). In particular, inorganic yarn-based electrochromic actuators can obtain as high as 15.3% tensile stroke and 0.82 J g-1 work capacity by electrochemical charge injection-associated multicolor switching.

Continuous preparation of dual-responsive sensing fibers for smart textiles.

Continuous preparation of sensing fibers that respond to multiple stimuli is of great significance to the development of smart textile and clothing. However, in most cases, the production of sensing fibers is restricted to laboratory scale by factors of equipment and technology, thus it is still challenging to achieve industrial-scale fibers. In this study, continuous preparation of dual-responsive sensing fibers (DRSF) by a set of process designs with custom-built equipment, which consists of core fibers, functional layers, parallel electrodes and protective layers are reported. Combining vanadium pentoxide (V2O5) nanobelts with a unique device design, DRSFs exhibited a significant electrical output when stimulated by heat or blue light (460 nm), where the factors of the aspect ratio of one-dimensional nanostructures have also been explored. Furthermore, proof-of-concept electronic textiles with DRSFs woven into fabric were demonstrated.

Mechanical design of brush coating technology for the alignment of one-dimension nanomaterials.

Widespread approaches to fabricate surfaces with aligned nanostructured topographies have been stimulated by opportunities to enhance interface performance by combing physical and chemical effects, in which brush-coating technology (BCT) is a cost-effective and feasible method for aligned film and large-scale production. Here, we reported a BCT process to realize the alignment of various 1D nanostructures through mechanical design that provides a more precise and higher shear force. By regulating the viscosity of dispersion, shear force is proved to be 24 and 20.3 times larger (when the volume ratio of water and glycerol is 1:3) according to the theoretical calculation and ANSYS simulating calculation results respectively, which plays a vital role in brush coating process. The universality was demonstrated by the alignment of one-dimension nanomaterials with different diameters, including silver nanowires (~80 nm), molybdenum trioxide nanobelts (~150 nm), vanadium pentoxide nanobelts (~150 nm) and bismuth sulfide nanobelts (~200 nm), et al., which in consequence have different alignment ratios. Meanwhile, anisotropic and flexible electrical conductors (the resistance anisotropic ratio was 2) and thermoelectric films (Seebeck coefficient was calculated to be 56.7 µV/K) were demonstrated.

Correction: Dishevelled1-3 contribute to multidrug resistance in colorectal cancer via activating Wnt/ß-catenin signaling.

[This corrects the article DOI: 10.18632/oncotarget.23253.].

Topology-dependent, bifurcated mitochondrial quality control under starvation.

Selective elimination of mitochondria by autophagy is a critical strategy for a variety of physiological processes, including development, cell-fate determination and stress response. Although several mechanisms have been identified as responsible for selective degradation of mitochondria, such as the PINK1-PRKN/PARKIN- and receptor-dependent pathways, aspects of the mechanisms and particularly the principles underlying the selection process of mitochondria remain obscure. Here, we addressed a new selection strategy in which the selective elimination of mitochondria is dependent on organellar topology. We found that populations of mitochondria undergo different topological transformations under serum starvation, either swelling or forming donut shapes. Swollen mitochondria are associated with mitochondrial membrane potential dissipation and PRKN recruitment, which promote their selective elimination, while the donut topology maintains mitochondrial membrane potential and helps mitochondria resist autophagy. Mechanistic studies show that donuts resist autophagy even after depolarization through preventing recruitment of autophagosome receptors CALCOCO2/NDP52 and OPTN even after PRKN recruitment. Our results demonstrate topology-dependent, bifurcated mitochondrial recycling under starvation, that is swollen mitochondria undergo removal by autophagy, while donut mitochondria undergo fission and fusion cycles for reintegration. This study reveals a novel morphological selection for control of mitochondrial quality and quantity under starvation.