Role of condensates in modulating DNA repair pathways and its implication for chemoresistance

For cells, it is important to repair DNA damage, such as double-strand and single-strand DNA breaks, because unrepaired DNA can compromise genetic integrity, potentially leading to cell death or cancer. Cells have multiple DNA damage repair pathways that have been the subject of detailed genetic, biochemical, and structural studies. Recently, the scientific community has started to gain evidence that the repair of DNA double-strand breaks may occur within biomolecular condensates and that condensates may also contribute to DNA damage through concentrating genotoxic agents used to treat various cancers. Here, we summarize key features of biomolecular condensates and note where they have been implicated in the repair of DNA double-strand breaks. We also describe evidence suggesting that condensates may be involved in the repair of other types of DNA damage, including single-strand DNA breaks, nucleotide modifications (e.g., mismatch and oxidized bases), and bulky lesions, among others. Finally, we discuss old and new mysteries that could now be addressed considering the properties of condensates, including chemoresistance mechanisms

Chlorosome‐Like Molecular Aggregation of Chlorophyll Derivative on Ti₃C₂Tₓ MXene Nanosheets for Efficient Noble Metal‐Free Photocatalytic Hydrogen Evolution

Efficient photocatalytic hydrogen evolution reaction (HER) in the visible‐to‐near infrared region at a low cost remains a challenging issue. This work demonstrates the fabrication of organic‐inorganic composites by deposition of supramolecular aggregates of a chlorophyll derivative, namely, zinc methyl 3‐devinyl‐3‐hydroxymethyl‐pyropheophorbide a (Chl) on the surface of Ti3C2Tx MXene with 2D accordion‐like morphology. This composite material is employed as noble metal‐free catalyst in photocatalytic HER under the white light illumination, where Chl serves as a small molecule organic semiconductor component instead of ordinary inorganic and polymer organic semiconductors such as TiO2 and g‐C3N4, and Ti3C2Tx serves as a co‐catalyst. Different composition ratios of Chl/Ti3C2Tx are compared for their light‐harvesting ability, morphology, charge transfer efficiency, and photocatalytic performance. The best HER performance is found to be as high as 52 ± 5 µmol h−1 gcat−1 after optimization. Such a large HER activity is attributed to the efficient light harvesting followed by exciton transfer in Chl aggregates and the resultant charge separation at the interface of Chl/Ti3C2Tx

Performance improvement of MXene-based perovskite solar cells upon property transition from metallic to semiconductive by oxidation of Ti₃C₂Tₓ in air

The unique properties of MXenes that arise from terminating functional groups and oxidation of MXenes make them attractive for application in photovoltaic devices like perovskite solar cells (PSCs). Here, oxidation of Ti3C2Tx hydrocolloid was carried out to tune its properties desirable for an electron transport layer (ETL) in low-temperature processed PSCs. The calculations of the energy levels were carried out using the Vienna ab initio simulation package (VASP) code based on density functional theory (DFT). Oxidation of Ti_{3}C_{2}T_{x} can generate Ti–O bonds and effectively reduce the macroscopic defects of the film fabricated by spin-coating, while a transition from metallic material to semiconductor occurred after heavy oxidation. A better matching of energy levels between perovskite and ETL layer in the case of a hybrid of oxidized and pristine Ti_{3}C_{2}T_{x} renders a champion power conversion efficiency (PCE) of 18.29%. The improvement in PCE can be attributed to the increased electron mobility in the ETL, which promotes electron transport and reduces the electron–hole recombination. Hence, by presenting a simple method for high performance in PSCs by MXene-derived materials, this work demonstrates the great potential of these materials for applications in low-temperature processed PSCs and other photovoltaic technologies

Seedling production Cattleya eldorado in substrates with nutritive solution under shading screens.

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Screen-printable microscale hybrid device based on MXene and layered double hydroxide electrodes for powering force sensors

Coplanar energy storage devices with interdigitated electrodes have attracted a significant amount of attention as micropower units for portable and flexible electronics, and self-powered systems. Herein, we propose a simple, cost-effective, and scalable two-step screen-printing process to fabricate flexible coplanar asymmetric microscale hybrid device (MHD) with a higher energy density compared to carbon-based microsupercapacitors. 2D titanium carbide MXene (Ti 3 C 2 T x ) with a large inlayer spacing is selected as negative electrode, and Co-Al layered double hydroxide (LDH) nanosheets are selected as positive electrode. The assembled coplanar, all-solid-state, asymmetric MHD possesses a higher energy density (8.84 μWh cm −2 ) compared to the MXene-based, coplanar, symmetric microsupercapacitors (3.38 μWh cm −2 ), and exhibit excellent flexibility and reliability, as well as cycling stability (92% retention of the initial capacitance after 10,000 cycles). Moreover, we integrate the coplanar asymmetric MHDs with the force sensing resistors as portable power source units to fabricate lightweight and inexpensive integrated force sensors, which can be used to detect applied pressure variation. The two-step screen-printing method can also be extended to other MXenes and various positive electrode materials for fabrication of coplanar asymmetric MHDs on flexible substrates. Therefore, we believe that the two-step screen-printing method opens up new avenues toward developing flexible coplanar asymmetric MHDs, thus promoting the application of MHDs based on MXenes for flexible integrated electronic devices

The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance

Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We report here that IR is incorporated into dynamic clusters at the plasma membrane, in the cytoplasm and in the nucleus of human hepatocytes and adipocytes. Insulin stimulation promotes further incorporation of IR into these dynamic clusters in insulin-sensitive cells but not in insulin-resistant cells, where both IR accumulation and dynamic behavior are reduced. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue IR accumulation and the dynamic behavior of these clusters. This rescue is associated with metformin’s role in reducing reactive oxygen species that interfere with normal dynamics. These results indicate that changes in the physico-mechanical features of IR clusters contribute to insulin resistance and have implications for improved therapeutic approaches

g-C3N4/Ti3C2Tx (MXenes) composite with oxidized surface groups for efficient photocatalytic hydrogen evolution

Ti3C2Tx is a 2-dimensional titanium carbide material featuring outstanding electrochemical properties. In spite of this, application of Ti3C2Tx as co-catalyst in photo-catalysis is rarely explored, probably because of its metallic nature and hydrophilic surface. Given that Ti3C2Tx with different surface terminations exhibits large differences in catalytic, electrochemical and chemical properties, we demonstrate an improvement of the photocatalytic activity of Ti3C2Tx as a co-catalyst by annealing a composite of carbon nitride and Ti3C2Tx. Ti3C2Tx with an oxygen terminated surface improved the separation of electron-hole pairs and resulted in a 105% enhancement in the production ratio of hydrogen evolution compared to control samples. The best hydrogen production performance reached as high as 88 μmol h-1 gcat-1. The apparent quantum yield (AQY) reached as high as 1.27%. The DFT calculations also demonstrate a better hydrogen evolution on Ti3C2 with oxygen surface termination

Pharmacological inhibition of EZH2 as a promising differentiation therapy in embryonal RMS

Background: Embryonal Rhabdomyosarcoma (RMS) is a pediatric soft-tissue sarcoma derived from myogenic precursors that is characterized by a good prognosis in patients with localized disease. Conversely, metastatic tumors often relapse, leading to a dismal outcome. The histone methyltransferase EZH2 epigenetically suppresses skeletal muscle differentiation by repressing the transcription of myogenic genes. Moreover, de-regulated EZH2 expression has been extensively implied in human cancers. We have previously shown that EZH2 is aberrantly over-expressed in RMS primary tumors and cell lines. Moreover, it has been recently reported that EZH2 silencing in RD cells, a recurrence-derived embryonal RMS cell line, favors myofiber-like structures formation in a pro-differentiation context. Here we evaluate whether similar effects can be obtained also in the presence of growth factor-supplemented medium (GM), that mimics a pro-proliferative microenvironment, and by pharmacological targeting of EZH2 in RD cells and in RD tumor xenografts.Methods: Embryonal RMS RD cells were cultured in GM and silenced for EZH2 or treated with either the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) that induces EZH2 degradation, or with a new class of catalytic EZH2 inhibitors, MC1948 and MC1945, which block the catalytic activity of EZH2. RD cell proliferation and myogenic differentiation were evaluated both in vitro and in vivo.Results: Here we show that EZH2 protein was abnormally expressed in 19 out of 19 (100%) embryonal RMS primary tumors and cell lines compared to their normal counterparts. Genetic down-regulation of EZH2 by silencing in GM condition reduced RD cell proliferation up-regulating p21Cip1. It also resulted in myogenic-like differentiation testified by the up-regulation of myogenic markers Myogenin, MCK and MHC. These effects were reverted by enforced over-expression of a murine Ezh2, highlighting an EZH2-specific effect. Pharmacological inhibition of EZH2 using either DZNep or MC inhibitors phenocopied the genetic knockdown of EZH2 preventing cell proliferation and restoring myogenic differentiation both in vitro and in vivo.Conclusions: These results provide evidence that EZH2 function can be counteracted by pharmacological inhibition in embryonal RMS blocking proliferation even in a pro-proliferative context. They also suggest that this approach could be exploited as a differentiation therapy in adjuvant therapeutic intervention for embryonal RMS. © 2014 Ciarapica et al.; licensee BioMed Central Ltd

The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)

The Polycomb group (PcG) proteins regulate stem cell differentiation via the repression of gene transcription, and their deregulation has been widely implicated in cancer development. The PcG protein Enhancer of Zeste Homolog 2 (EZH2) works as a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) by methylating lysine 27 on histone H3 (H3K27me3), a hallmark of PRC2-mediated gene repression. In skeletal muscle progenitors, EZH2 prevents an unscheduled differentiation by repressing muscle-specific gene expression and is downregulated during the course of differentiation. In rhabdomyosarcoma (RMS), a pediatric soft-tissue sarcoma thought to arise from myogenic precursors, EZH2 is abnormally expressed and its downregulation in vitro leads to muscle-like differentiation of RMS cells of the embryonal variant. However, the role of EZH2 in the clinically aggressive subgroup of alveolar RMS, characterized by the expression of PAX3-FOXO1 oncoprotein, remains unknown. We show here that EZH2 depletion in these cells leads to programmed cell death. Transcriptional derepression of F-box protein 32 (FBXO32) (Atrogin1/MAFbx), a gene associated with muscle homeostasis, was evidenced in PAX3-FOXO1 RMS cells silenced for EZH2. This phenomenon was associated with reduced EZH2 occupancy and H3K27me3 levels at the FBXO32 promoter. Simultaneous knockdown of FBXO32 and EZH2 in PAX3-FOXO1 RMS cells impaired the pro-apoptotic response, whereas the overexpression of FBXO32 facilitated programmed cell death in EZH2-depleted cells. Pharmacological inhibition of EZH2 by either 3-Deazaneplanocin A or a catalytic EZH2 inhibitor mirrored the phenotypic and molecular effects of EZH2 knockdown in vitro and prevented tumor growth in vivo. Collectively, these results indicate that EZH2 is a key factor in the proliferation and survival of PAX3-FOXO1 alveolar RMS cells working, at least in part, by repressing FBXO32. They also suggest that the reducing activity of EZH2 could represent a novel adjuvant strategy to eradicate high-risk PAX3-FOXO1 alveolar RMS. © 2014 Macmillan Publishers Limited

Eosin Y-sensitized partially oxidized Ti₃C₂, MXene for photocatalytic hydrogen evolution

Ti₃C₂, though one of the most extensively studied 2D MXenes, is rarely reported in dye-sensitized photocatalysis. Platinum is commonly used as a co-catalyst in photocatalytic hydrogen evolution but it increases the cost and hence restricts the commercialization of this technology. Eosin Y (EY) is widely studied in dye-sensitized systems as it is not only low-cost and easily commercially available, but also exhibits excellent visible light absorption ability. Herein, we oxidized Ti₃C₂ MXene in water at 60 °C for different times, to form TiO₂/Ti₃C₂ on amorphous carbon (AC) composites. The oxidized MXene was used as a photocatalyst in a dye-sensitized system for hydrogen evolution to replace noble metal co-catalysts such as Pt. The highest hydrogen production rate of 33.4 μmol h⁻¹ g⁻¹ was achieved by the TiO₂/Ti₃C₂ @AC-48h composite with the sensitization of 1 mM EY, which was 110 times higher than that of oxidized Ti₃C₂ without EY. This work shows the potential of 2D MXenes used in dye-sensitized photocatalysis for hydrogen evolution