Cancer-associated fibroblasts (CAFs) provide critical metabolites for tumor growth and undergo metabolic reprogramming to support glycolysis. However, the molecular mechanisms responsible for this change remain unclear. Here, we report that TGF-β1- or PDGF-induced CAFs switch from oxidative phosphorylation to aerobic glycolysis. We identify downregulation of isocitrate dehydrogenase 3α (IDH3α) as a marker for this switch. Furthermore, miR-424 downregulates IDH3α during CAF formation. Downregulation of IDH3α decreases the effective level of α-ketoglutarate (α-KG) by reducing the ratio of α-KG to fumarate and succinate, resulting in PHD2 inhibition and HIF-1α protein stabilization. The accumulation of HIF-1α, in turn, promotes glycolysis by increasing the uptake of glucose, upregulating expression of glycolytic enzymes under normoxic conditions, and inhibiting oxidative phosphorylation by upregulating NDUFA4L2. CAFs from tumor samples exhibit low levels of IDH3α, and overexpression of IDH3α prevents transformation of fibroblasts into CAFs. Our studies reveal IDH3α to be a critical metabolic switch in CAFs.

The separation properties of polyamide reverse osmosis and nanofiltration membranes, widely applied for desalination and water reuse, are constrained by the permeability-selectivity upper bound. Although thin-film nanocomposite (TFN) membranes incorporating nanomaterials exhibit enhanced water permeance, their rejection is only moderately improved or even impaired due to agglomeration of nanomaterials and formation of defects. A novel type of TFN membranes featuring an interlayer of nanomaterials (TFNi) has emerged in recent years. These novel TFNi membranes show extraordinary improvement in water flux (e.g., up to an order of magnitude enhancement) along with better selectivity. Such enhancements can be achieved by a wide selection of nanomaterials, ranging from nanoparticles, one-/two-dimensional materials, to interfacial coatings. The use of nanostructured interlayers not only improves the formation of polyamide rejection layers but also provides an optimized water transport path, which enables TFNi membranes to potentially overcome the longstanding trade-off between membrane permeability and selectivity. Furthermore, TFNi membranes can potentially enhance the removal of heavy metals and micropollutants, which is critical for many environmental applications. This review critically examines the recent developments of TFNi membranes and discusses the underlying mechanisms and design criteria. Their potential environmental applications are also highlighted.

How TGF-β1-mediated signaling pathways are finely tuned to orchestrate the generation of carcinoma-associated fibroblasts (CAFs) is poorly understood. Here, we demonstrate that miR-21 and the signaling of its target Smad 7 determine TGF-β1-induced CAF formation. In primary cultured fibroblasts, mature miR-21 increases after TGF-β1 treatment, whereas the Smad 7 protein level decreases. MiR-21 binds to the 3′ UTR of Smad7 mRNA and inhibits its translation, rather than causing its degradation. Most importantly, Smad 7 is bound to Smad 2 and 3, which are thought to competitively bind to TGFBR1, and prevents their activation upon TGF-β1 stimulation. The depletion of miR-21 or the overexpression of Smad 7 blocks TGF-β1-induced CAF formation, whereas the overexpression of miR-21 or the depletion of Smad 7 promotes CAF formation, even without TGF-β1 stimulation. Collectively, these findings clearly demonstrate that miR-21 and Smad7 are critical regulators of TGF-β1 signaling during the induction of CAF formation.

No abstract

DNA-dependent protein kinase (DNA-PK) has an important role in the repair of DNA damage and regulates the radiation sensitivity of glioblastoma cells. The VCP (valosine-containing protein), a chaperone protein that regulates ubiquitin-dependent protein degradation, is phosphorylated by DNA-PK and recruited to DNA double-strand break sites to regulate DNA damage repair. However, it is not clear whether VCP is involved in DNA-PKcs (DNA-PK catalytic subunit) degradation or whether it regulates the radiosensitivity of glioblastoma. Our data demonstrated that DNA-PKcs was ubiquitinated and bound to VCP. VCP knockdown resulted in the accumulation of the DNA-PKcs protein in glioblastoma cells, and the proteasome inhibitor MG132 synergised this increase. As expected, this increase promoted the efficiency of DNA repair in several glioblastoma cell lines; in turn, this enhanced activity decreased the radiation sensitivity and prolonged the survival fraction of glioblastoma cells in vitro. Moreover, the VCP knockdown in glioblastoma cells reduced the survival time of the xenografted mice with radiation treatment relative to the control xenografted glioblastoma mice. In addition, the VCP protein was also downregulated in ∼25% of GBM tissues from patients (WHO, grade IV astrocytoma), and the VCP protein level was correlated with patient survival (R2=0.5222, P<0.05). These findings demonstrated that VCP regulates DNA-PKcs degradation and increases the sensitivity of GBM cells to radiation.

Nanofiltration (NF) with high water flux and precise separation performance with high Li + /Mg 2+ selectivity is ideal for lithium brine recovery. However, conventional polyamidebased commercial NF membranes are ineffective in lithium recovery processes due to their undesired Li + /Mg 2+ selectivity. In addition, they are constrained by the water permeance selectivity trade-off, which means that a highly permeable membrane often has lower selectivity. In this study, we developed a novel nonpolyamide NF membrane based on metal-coordinated structure, which exhibits simultaneously improved water permeance and Li + /Mg 2+ selectivity. Specifically, the optimized Cu−mphenylenediamine (MPD) membrane demonstrated a high water permeance of 16.2 ± 2.7 LMH/bar and a high Li + /Mg 2+ selectivity of 8.0 ± 1.0, which surpassed the trade-off of permeance selectivity. Meanwhile, the existence of copper in the Cu−MPD membrane further enhanced anti-biofouling property and the metalcoordinated nanofiltration membrane possesses a pH-responsive property. Finally, a transport model based on the Nernst−Planck equations has been developed to fit the water flux and rejection of uncharged solutes to the experiments conducted. The model had a deviation below 2% for all experiments performed and suggested an average pore radius of 1.25 nm with a porosity of 21% for the Cu−MPD membrane. Overall, our study provides an exciting approach for fabricating a nonpolyamide high-performance nanofiltration membrane in the context of lithium recovery.

Privacy and security are the most important issues to the popularity of cloud computing service. In recent years, there are many research schemes of cloud computing privacy protection based on access control, attribute-based encryption (ABE), trust and reputation, but they are scattered and lack unified logic. In this paper, we systematically review and analyze relevant research achievements. First, we discuss the architecture, concepts and several shortcomings of cloud computing, and propose a framework of privacy protection; second, we discuss and analyze basic ABE, KP-ABE (key policy attribute-based encryption), CP-ABE (ciphertext policy attribute-based encryption), access structure, revocation mechanism, multiauthority, fine-grained, trace mechanism, proxy re-encryption(PRE), hierarchical encryption, searchable encryption(SE), trust, reputation, extension of tradition access control and hierarchical key; third, we propose the research challenge and future direction of the privacy protection in the cloud computing; finally, we point out corresponding privacy protection laws to make up for the technical deficiencies. INDEX TERMS Cloud computing, privacy, access control, attribute-based encryption, trust.

Polyamide surface morphology and its underneath nanosized voids have crucial influence on the separation performance of thin film composite (TFC) polyamide reverse osmosis membranes. Although there have been numerous studies reporting the impact of amine monomer concentration on polyamide formation and membrane performance, the observations and interpretations in the existing literature remain controversial. In this study, we performed interfacial polymerization (IP) of polyamide films over a wide range of m-phenylenediamine (MPD) concentration (0.05−8.0 w/w %). For the first time, we demonstrate that the water permeance of the resultant TFC membranes is governed by the competing effects of (1) promoted polyamide film growth for forming thicker polyamide films and (2) improved nanofoaming effect that results in more extensive nanovoids at higher MPD concentrations. To dissect these competing mechanisms, we further adopted a free-interface IP strategy to suppress the nanofoaming effect. The corresponding polyamide nanofilms had negligible nanovoids and monotonously increased film thickness, leading to decreased water permeance at high MPD concentrations. In contrast, the conventional TFC membranes exhibited optimal water permeance at the intermediate MPD concentration of 2.0 w/w %, which results from the trade-off between improved nanovoid formation (which promotes higher permeance) and increased film growth (which limits permeance). On the other hand, the better film growth at greater MPD concentration was generally beneficial for achieving better membrane rejection. The current study unveils the fundamental chemistry−morphology−performance relationship of TFC polyamide membranes and provides important implications on their synthesis and environmental applications.