Pathologically Activated Neuroprotection via Uncompetitive Blockade of \u3cem\u3eN\u3c/em\u3e-Methyl-d-aspartate Receptors with Fast Off-rate by Novel Multifunctional Dimer Bis(propyl)-cognitin

Uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists with fast off-rate (UFO) may represent promising drug candidates for various neurodegenerative disorders. In this study, we report that bis(propyl)-cognitin, a novel dimeric acetylcholinesterase inhibitor and γ-aminobutyric acid subtype A receptor antagonist, is such an antagonist of NMDA receptors. In cultured rat hippocampal neurons, we demonstrated that bis(propyl)-cognitin voltage-dependently, selectively, and moderately inhibited NMDA-activated currents. The inhibitory effects of bis(propyl)-cognitin increased with the rise in NMDA and glycine concentrations. Kinetics analysis showed that the inhibition was of fast onset and offset with an off-rate time constant of 1.9 s. Molecular docking simulations showed moderate hydrophobic interaction between bis(propyl)-cognitin and the MK-801 binding region in the ion channel pore of the NMDA receptor. Bis(propyl)-cognitin was further found to compete with [3H]MK-801 with a Ki value of 0.27 μm, and the mutation of NR1(N616R) significantly reduced its inhibitory potency. Under glutamate-mediated pathological conditions, bis(propyl)-cognitin, in contrast to bis(heptyl)-cognitin, prevented excitotoxicity with increasing effectiveness against escalating levels of glutamate and much more effectively protected against middle cerebral artery occlusion-induced brain damage than did memantine. More interestingly, under NMDA receptor-mediated physiological conditions, bis(propyl)-cognitin enhanced long-term potentiation in hippocampal slices, whereas MK-801 reduced and memantine did not alter this process. These results suggest that bis(propyl)-cognitin is a UFO antagonist of NMDA receptors with moderate affinity, which may provide a pathologically activated therapy for various neurodegenerative disorders associated with NMDA receptor dysregulation

Bmi1 Is a Key Epigenetic Barrier to Direct Cardiac Reprogramming

Direct reprogramming of induced cardiomyocytes (iCMs) suffers from low efficiency and requires extensive epigenetic repatterning, although the underlying mechanisms are largely unknown. To address these issues, we screened for epigenetic regulators of iCM reprogramming and found that reducing levels of the polycomb complex gene Bmi1 significantly enhanced induction of beating iCMs from neonatal and adult mouse fibroblasts. The inhibitory role of Bmi1 in iCM reprogramming is mediated through direct interactions with regulatory regions of cardiogenic genes, rather than regulation of cell proliferation. Reduced Bmi1 expression corresponded with increased levels of the active histone mark H3K4me3 and reduced levels of repressive H2AK119ub at cardiogenic loci, and de-repression of cardiogenic gene expression during iCM conversion. Furthermore, Bmi1 deletion could substitute for Gata4 during iCM reprogramming. Thus, Bmi1 acts as a critical epigenetic barrier to iCM production. Bypassing this barrier simplifies iCM generation and increases yield, potentially streamlining iCM production for therapeutic purposes

Characterization of Adenocarcinoma\u27s Autofluorescence Properties Using Multiexcitation Analysis Method

General purpose of this research is to get an early cancer detection method based on the properties of optical analysis between normal and adenocarsinoma tissue using the multiexcitation autofluorescence method. Observation of autofluorescence properties was done on the biopsy sample of adenocarcinoma tissues, GR mice transplanted by adenocarsinoma, and cell culture SM 1. Excitation on tissue was done by using  the lamp Light Emitting Diode (LED) at some visible light wavelength range. This research obtained that the value of Intensity Auto fluorescence (IAF) at range red wavelength of cells and adenocarsinoma tissues tend to lower compared to the cells normal tissues if its were excited by blue LED. On the contrary, the value of IAF at infra red wavelength from cells and carcinoma tissues tend to higher compared to the cells and normal tissues if its were excited by red LED

Vitamin B1 Helps to Limit Mycobacterium tuberculosis Growth via Regulating Innate Immunity in a Peroxisome Proliferator-Activated Receptor-γ-Dependent Manner

It is known that vitamin B1 (VB1) has a protective effect against oxidative retinal damage induced by anti-tuberculosis drugs. However, it remains unclear whether VB1 regulates immune responses during Mycobacterium tuberculosis (MTB) infection. We report here that VB1 promotes the protective immune response to limit the survival of MTB within macrophages and in vivo through regulation of peroxisome proliferator-activated receptor γ (PPAR-γ). VB1 promotes macrophage polarization into classically activated phenotypes with strong microbicidal activity and enhanced tumor necrosis factor-α and interleukin-6 expression at least in part by promoting nuclear factor-κB signaling. In addition, VB1 increases mitochondrial respiration and lipid metabolism and PPAR-γ integrates the metabolic and inflammatory signals regulated by VB1. Using both PPAR-γ agonists and deficient mice, we demonstrate that VB1 enhances anti-MTB activities in macrophages and in vivo by down-regulating PPAR-γ activity. Our data demonstrate important functions of VB1 in regulating innate immune responses against MTB and reveal novel mechanisms by which VB1 exerts its function in macrophages

Purification and Characterization of White Laccase from the White-rot Fungus Panus conchatus

Laccase is a kind of polyphenol oxidase having potential in applications for pulp bleaching, waste water treatment in mills, and removal of phenols in the food industry. The normal laccase from fungus or bacterial contains four copper atoms per protein molecular, imparting a blue color. Here it is reported that a white laccase is produced by a white rot fungus Panus conchatus from its solid-state fermentation. The activity center of this laccase is Cu2FeZn, which lacks the typical type-1 blue copper color. The polyacrylamide gel electrophoresis of purified laccase showed a main polypeptide with a molecular weight of about 60 kDa. Laccase substrate 2,6-dimethoxylphenol and others, such as syringaldazine, o-tolidine, and ABTS, were readily oxidized, among which the Km for syringaldazine was the highest. The isoelectric point of this enzyme was 3.6 and it was stable at temperatures below 45 °C over a wide range of pH (4-12)

Inducing nonlocal reactions with a local probe

The scanning tunneling microscope (STM) has evolved continually since its invention, as scientists have expanded its use to encompass atomic-scale manipulation, momentum-resolved electronic characterization, localized chemical reactions (bond breaking and bond making) in adsorbed molecules, and even chain reactions at surfaces. This burgeoning field has recently expanded to include the use of the STM to inject hot electrons into substrate surface states; the injected electrons can travel laterally and induce changes in chemical structure in molecules located up to 100 nm from the STM tip. We describe several key demonstrations of this phenomenon, including one appearing in this issue of ACS Nano by Chen et al. Possible applications for this technique are also discussed, including characterizing the dispersion of molecule−substrate interface states and the controlled patterning of molecular overlayers

H-Bonding Control of Supramolecular Ordering of Diketopyrrolopyrroles

Diketopyrrolopyrrole (DPP) is a widely used building block for high-mobility ambipolar semiconductors. Hydrogen bonding of N-unsubstituted DPPs has recently been identified as a tool for controlling their solid state structure and properties of semiconducting films, yet little is known about supramolecular packing of H-bonded DPP derivatives. Here we report a comparative study of three archetypical DPP derivatives, difurylDPP (DFDPP), diphenylDPP (DPDPP), and dithienylDPP (DTDPP), at the interface and in bulk crystals. Using scanning tunneling microscopy (STM) combined with X-ray crystallographic analysis, we demonstrate how the interactions of the (hetero)­aromatic substituents interplay with H-bonding, causing dramatic differences in the supramolecular ordering of these structurally similar building blocks. Under all explored conditions, DPDPP exclusively forms H-bonded homoassemblies; DFDPP strongly prefers to co-assemble with alkanoic acids, through a rare lactam···carboxylic acid H-bonded complex, and DTDPP, depending on conditions, either co-assembles with alkanoic acids or self-assembles in one of two H-bonded polymorphs. One of these polymorphs suggests an out-of-plane twist of thiophene rings that form π-stacks running along the surface plane; this is unexpected considering the large energetic penalty of DTDPP deplanarization. The results are explained in terms of inter- versus intramolecular interactions, which are quantified with density functional theory calculations. This work shows that aryl substituents can strongly influence H-bonding assembly of DPP derivatives that is likely to affect their charge-transport properties

2D Self-Assembly of Fused Oligothiophenes: Molecular Control of Morphology

We report the synthesis and properties of two π-functional heteroaromatic tetracarboxylic acids (isomeric tetrathienoanthracene derivatives 2-TTATA and 3-TTATA) and their self-assembly on highly oriented pyrolytic graphite. Using scanning tunneling microscopy at the liquid–solid interface we show how slight geometric differences between the two isomers (position of sulfur in the molecule) lead to dramatic changes in monolayer structure. While 3-TTATA self-assembles exclusively in a highly ordered porous network <i>via</i> dimeric R²₂(8) hydrogen-bonding connection (synthon), 2-TTATA is polymorphic, forming a less ordered porous network <i>via</i> R²₂(8) synthons as well as a close-packed network <i>via</i> rare tetrameric R⁴₄(16) synthons. Density functional theory calculations show that the self-assembly direction is governed by the angle between the carboxylic groups and secondary interactions with sulfur atoms

Supramolecular ordering in oligothiophene−fullerene monolayers

Scanning tunneling microscopy (STM) of monolayers comprising oligothiophene and fullerene molecular semiconductors reveals details of their molecular-scale phase separation and ordering with potential implications for the design of organic electronic devices, in particular future bulk heterojunction solar cells. Prochiral terthienobenzenetricarboxylic acid (TTBTA) self-assembles at the solution/graphite interface into either a porous chicken wire network linked by dimeric hydrogen bonding associations of COOH groups (R22(8)) or a close-packed network linked in a novel hexameric hydrogen bonding motif (R66(24)). Analysis of high-resolution STM images shows that the chicken wire phase is racemically mixed, whereas the close-packed phase is enantiomerically pure. The cavities of the chicken wire structure can efficiently host C60 molecules, which form ordered domains with either one, two, or three fullerenes per cavity. The observed monodisperse filling and long-range co-alignment of fullerenes is described in terms of a combination of an electrostatic effect and the commensurability between the graphite and molecular network, which leads to differentiation of otherwise identical adsorption sites in the pores