Tumor suppressor gene silencing through cytosine methylation contributes to cancer formation. Whether DNA demethylation enzymes counteract this oncogenic effect is unknown. Here, we show that TET1, a dioxygenase involved in cytosine demethylation, is downregulated in prostate and breast cancer tissues. TET1 depletion facilitates cell invasion, tumor growth, and cancer metastasis in prostate xenograft models and correlates with poor survival rates in breast cancer patients. Consistently, enforced expression of TET1 reduces cell invasion and breast xenograft tumor formation. Mechanistically, TET1 suppresses cell invasion through its dioxygenase and DNA binding activities. Furthermore, TET1 maintains the expression of tissue inhibitors of metalloproteinase (TIMP) family proteins 2 and 3 by inhibiting their DNA methylation. Concurrent low expression of TET1 and TIMP2 or TIMP3 correlates with advanced node status in clinical samples. Together, these results illustrate a mechanism by which TET1 suppresses tumor development and invasion partly through downregulation of critical gene methylation.

four-electron/four-proton transfer, which causes sluggish kinetics. Pt-based materials are the state-of-the-art electrocatalysts for ORR due to their outstanding catalytic activity, selectivity, and long-term stability under operating conditions. [1] However, their scarcity and, thus, high cost limit their applications.Accordingly, research on non-noble metal catalysts increased substantially over the past decades. The most promising material classes so far are transitionmetal-nitrogen-carbon complexes [2][3][4] with Fe or Co as the metal center, [5,6] metal-N 4 organometallic complexes [7] or metal-free catalysts such as nitrogen-doped carbon species utilizing carbon nanotubes or graphene. [8][9][10] These catalysts show promising activity; however, they still fall short in their overall performance compared to Pt. Hence, new materials capable of replacing Pt-based catalysts for ORR are yet to be found.One approach in exploring novel materials is to increase their chemical complexity. Multinary metal alloys require a more challenging synthesis pathway, but enable a virtually unlimited amount of different compositions. For instance, over 2 × 10 6 combinations for quinary alloys selected from a list of 50 elements are possible, each with a different composition. Therefore, selection of candidate materials to be tested is necessary, e.g., based on abundance and toxicity of elements. Some of these largely unexplored multinary compositions might show unique physical and chemical properties. For many alloys, comprising typically five principal elements or more, an unexpected stability as a single solid solution phase was observed in spite of their chemical complexity. This stability is usually explained by the so-called high-entropy effect. [11][12][13] The proposed underlying rational include i) stabilization of the multinary single phase due to increasing entropy with an increasing number of constituents, ii) a lattice distortion effect, and iii) sluggish diffusion. [14] This special state of a complex solid solution may result in unusual properties which are not observed for heterogeneous multiphase alloys comprising intermetallic phases. Their advantages in mechanical, physical, and chemical properties such as structural stability [15] as well as corrosion [16] and oxidation resistance have been evaluated over the past years. [17] Potential applications in (electro)catalysis have only been reported for

Therapeutic options for the highly pathogenic human coronavirus (HCoV) infections are urgently needed. Anticoronavirus therapy is however challenging, as coronaviruses are biologically diverse and rapidly mutating. In this work, the antiviral activity of seven different carbon quantum dots (CQDs) for the treatment of human coronavirus HCoV-229E infections was investigated. The first generation of antiviral CQDs was derived from hydrothermal carbonization of ethylenediamine/citric acid as carbon precursors and postmodified with boronic acid ligands. These nanostructures showed a concentration-dependent virus inactivation with an estimated EC 50 of 52 ± 8 μg mL −1 . CQDs derived from 4-aminophenylboronic acid without any further modification resulted in the second-generation of anti-HCoV nanomaterials with an EC 50 lowered to 5.2 ± 0.7 μg mL −1 . The underlying mechanism of action of these CQDs was revealed to be inhibition of HCoV-229E entry that could be due to interaction of the functional groups of the CQDs with HCoV-229E entry receptors; surprisingly, an equally large inhibition activity was observed at the viral replication step.

The retinoblastoma binding protein RBP2 (KDM5A) is a histone demethylase that promotes gastric cancer cell growth and is enriched in drug-resistant lung cancer cells. In tumor-prone mice lacking the tumor suppressor gene RB or MEN1, genetic ablation of RBP2 can suppress tumor initiation, but the pathogenic breadth and mechanistic aspects of this effect relative to human tumors have not been defined. Here, we approached this question in the context of lung cancer. RBP2 was overexpressed in human lung cancer tissues where its depletion impaired cell proliferation, motility, migration, invasion, and metastasis. RBP2 oncogenicity relied on its demethylase and DNA-binding activities. RBP2 upregulated expression of cyclins D1 and E1 while suppressing the expression of cyclin-dependent kinase inhibitor p27 (CDKN1B), each contributing to RBP2-mediated cell proliferation. Expression microarray analyses revealed that RBP2 promoted expression of integrin-b1 (ITGB1), which is implicated in lung cancer metastasis. Mechanistic investigations established that RBP2 bound directly to the p27, cyclin D1, and ITGB1 promoters and that exogenous expression of cyclin D1, cyclin E1, or ITGB1 was sufficient to rescue proliferation or migration/invasion, respectively. Taken together, our results establish an oncogenic role for RBP2 in lung tumorigenesis and progression and uncover novel RBP2 targets mediating this role. Cancer Res; 73(15); 4711-21. Ó2013 AACR.

Cortical and subcortical plastic reorganization occurs in the course of motor recovery after stroke. It is largely accepted that plasticity of ipsilesional motor cortex primarily contributes to recovery of motor function, while the contributions of contralesional motor cortex are not completely understood. As a result of damages to motor cortex and its descending pathways and subsequent unmasking of inhibition, there is evidence of upregulation of reticulospinal tract (RST) excitability in the contralesional side. Both animal studies and human studies with stroke survivors suggest and support the role of RST hyperexcitability in post-stroke spasticity. Findings from animal studies demonstrate the compensatory role of RST hyperexcitability in recovery of motor function. In contrast, RST hyperexcitability appears to be related more to abnormal motor synergy and disordered motor control in stroke survivors. It does not contribute to recovery of normal motor function. Recent animal studies highlight laterality dominance of corticoreticular projections. In particular, there exists upregulation of ipsilateral corticoreticular projections from contralesional premotor cortex (PM) and supplementary motor area (SMA) to medial reticular nuclei. We revisit and revise the previous theoretical framework and propose a unifying account. This account highlights the importance of ipsilateral PM/SMA-cortico-reticulospinal tract hyperexcitability from the contralesional motor cortex as a result of disinhibition after stroke. This account provides a pathophysiological basis for post-stroke spasticity and related movement impairments, such as abnormal motor synergy and disordered motor control. However, further research is needed to examine this pathway in stroke survivors to better understand its potential roles, especially in muscle strength and motor recovery. This account could provide a pathophysiological target for developing neuromodulatory interventions to manage spasticity and thus possibly to facilitate motor recovery.

Purpose:To evaluate diffusion-weighted imaging (DWI) for detection of pelvic lymph node metastasis in patients with cervical and uterine cancers. Materials and Methods:Fifty patients scheduled for pelvic lymph node dissection were enrolled for 3T magnetic resonance imaging (MRI) using a single-shot echo-planar DWI technique, body-phased array coil, b ϭ 0, 1000 s/mm 2 . We measured short/long-axis diameters, mean apparent diffusion coefficient (ADC) values of all identifiable nodes, relative ADC values between tumors and nodes, and utilized their cutoff values to validate the diagnostic accuracy internally. Histopathologic results served as the reference standard. Results:The relative ADC values between tumor and nodes were significantly lower in metastatic than in benign nodes (0.06 vs. 0.21 ϫ 10 Ϫ3 mm 2 /s, P Ͻ 0.001; cutoff value 0.10 ϫ 10 Ϫ3 mm 2 /s). Compared to conventional MRI, the method combining size and relative ADC values resulted in better sensitivity (25% vs. 83%) and similar specificity (98% vs. 99%). The smallest metastatic lymph node detected by this method measured 5 mm on its short axis. Conclusion:The combination of size and relative ADC values was useful in detecting pelvic lymph node metastasis in patients with cervical and uterine cancers.

Breakthroughs toward effective water‐splitting electrocatalysts for mass hydrogen production will necessitate material design strategies based on unexplored material chemistries. Herein, Ni‐metalloid (B, Si, P, As, Te) alloys are reported as an emergent class of highly promising electrocatalysts for the oxygen evolution reaction (OER) and insight is offered into the origin of activity enhancement on the premise of the surface electronic structure, the OER activation energy, influence of the guest metalloid elements on the lattice structure of the host metal (Ni), and surface‐oxidized metalloid oxoanions. The metalloids modify the lattice structure of Ni, causing changes in the nearest Ni–Ni interatomic distance (dNi–Ni). The activation energy Ea scales with dNi–Ni indicating an apparent dependence of the OER activity on lattice properties. During the OER, surface Ni atoms are oxidized to nickel oxyhydroxide, which is the active state of the catalyst, meanwhile, the surface metalloids are oxidized to the corresponding oxoanions that affect the interfacial electrode/electrolyte properties and hence the adsorption/desorption interaction energies of the reacting species.

Abstract2D layered materials, including metal‐di‐chalcogenides and transition metal layered double hydroxides, among others, are intensively studied because of new properties that emerge from their 2D confinement, which are attractive for advanced applications. Herein, 2D cobalt ion (Co2+) and benzimidazole (bIm) based zeolite‐imidazole framework nanosheets, ZIF‐9(III), are reported as exceptionally efficient electrocatalysts for the oxygen evolution reaction (OER). Specifically, liquid‐phase ultrasonication is applied to exfoliate a [Co4(bIm)16] zeolite‐imidazole framework (ZIF), named as ZIF‐9(III) phase, into nanoscale sheets. ZIF‐9(III) is selectively prepared through simple mechanical grinding of cobalt nitrate and benzimidazole in the presence of a small amount of ethanol. The resultant exfoliated nanosheets exhibit significantly higher OER activity in alkaline conditions than the corresponding bulk phases ZIF‐9 and ZIF‐9(III). The electrochemical and physicochemical characterization data support the assignment of the OER activity of the exfoliated nanosheet derived material to nitrogen coordinated cobalt oxyhydroxide N4CoOOH sites, following a mechanism known for Co‐porphyrin and related systems. Thus, exfoliated 2D nanosheets hold promise as potential alternatives to commercial noble metal electrocatalysts for the OER.