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Ubiquinol-10, the reduced form of coenzyme Q10, has higher bioavailability but lower stability than ubiquinone-10, the oxidized form of coenzyme Q10. During the development of ubiquinol-fortified foods, ensuring a long shelf life of the ubiquinol content without sacrificing the flavor of the food is crucial. In this study, we determined the stability of ubiquinol-10 in natural miso, a fermented food made from soybean, salt, and koji, matured at 20–25 °C and stored in a refrigerator for up to three months. Three types of natural miso were developed, differing in their composition and the duration of maturation, using three different forms of ubiquinol-10: raw powder, stabilized powder, and stabilized granules. The ratio of ubiquinol-10 to total coenzyme Q10 was more than 90% during the maturation and storage of natural miso under standard conditions, regardless of the ubiquinol form and type of natural miso. Contrary to expectations, the ubiquinol-10 ratio in a more pigmented natural miso seemed to increase during the maturation period, one month after preparation, when an unstabilized bulk ubiquinol powder was used. These results suggest that naturally occurring antioxidants, which are constituents of miso ingredients and are produced during the maturation process of natural miso, could maintain the reduced state of ubiquinol-10, without the addition of artificial antioxidants or the preservation of anaerobic conditions.

DNA enzymes (DNAzymes), which cleave target RNA with high specificity, have been widely investigated as potential oligonucleotide-based therapeutics. Recently, xeno-nucleic acid (XNA)-modified DNAzymes (XNAzymes), exhibiting cleavage activity in cultured cells, have been developed. However, a versatile approach to modify XNAzymes that function in cells has not yet been established. Here, we report an X-ray crystal structure-based approach to modify 8–17 DNAzymes; this approach enables us to effectively locate suitable XNAs to modify. Our approach, combined with a modification strategy used in designing antisense oligonucleotides (ASOs), rationally modified 8–17 DNAzyme (X8–17) that achieved high potency in terms of RNA cleavage and biostability against nucleases. In cells, X8–17, modified with 2′-OMe RNA, locked nucleic acid, and phosphorothioate, successfully induced endogenous MALAT-1and SRB1 RNA knockdown. This approach may help in developing XNAzyme-based novel therapeutic agents.

Chemical modifications have been extensively used for therapeutic oligonucleotides because they strongly enhance the stability against nucleases, binding affinity to the targets, and efficacy. We previously reported that oligonucleotides modified with an N-methylguanidine-bridged nucleic acid (GuNA[Me]) bearing the thymine (T) nucleobase show excellent biophysical properties for applications in antisense technology. In this paper, we describe the synthesis of GuNA[Me] phosphoramidites bearing other typical nucleobases including adenine (A), guanine (G), and 5-methylcytosine (mC). The phosphoramidites were successfully incorporated into oligonucleotides following the method previously developed for the GuNA[Me]-T-modified oligonucleotides. The binding affinity of the oligonucleotides modified with GuNA[Me]-A, -G, or -mC toward the complementary single-stranded DNAs or RNAs was systematically evaluated. All of the GuNA[Me]-modified oligonucleotides were found to have a strong affinity for RNAs. These data indicate that GuNA[Me] could be a useful modification for therapeutic antisense oligonucleotides.

Target identification (target-ID) is an important step in elucidating the mechanisms of action of bioactive small molecules. In the past few decades, a number of target-ID methods have been developed. Among these, affinity labeling has been reliably used for specific modifications, as well as for the identification of weakly interacting protein targets, membrane-associated protein targets, and target-interacting proteins under native cellular conditions, which are generally difficult to achieve by conventional pull-down methods. In general, affinity labeling utilizes chemical probes composed of a bioactive small molecule, a reactive group, and a detection unit. However, the design and synthesis of highly functionalized chemical probes is often time-consuming. To address this issue, we have recently developed some simple affinity labeling methods using small fluorogenic tags, such as 4-alkoxy-7-nitro-2,1,3-benzoxadiazole (O-NBD), 2,3-dichloromaleimide (diCMI), and 4-azidophthalimide (AzPI), and successfully achieved the specific fluorescent labeling of target proteins, even in living cells. These methods should be useful for target-ID in phenotypic drug discovery.

In the present paper, we define a notion of good coverings of Alexandrov spaces with curvature bounded below, and prove that every Alexandrov space admits such a good covering and that it has the same homotopy type as the nerve of the good covering. We also prove the stability of the isomorphism classes of the nerves of good coverings in the non-collapsing case. In the proof, we need a version of Perelman's fibration theorem, which is also proved in this paper., Minor change basically on the proof of Theorem 1.2 in Section 5

Previous reports have shown that azithromycin (AZM), a macrolide antibiotic, affects collagen synthesis and cytokine production in human gingival fibroblasts (hGFs). However, there are few reports on the effect of AZM on human periodontal ligament fibroblasts (hPLFs). In the present study, we comparatively examined the effects of AZM on hGFs and hPLFs. We monitored the reaction of AZM under lipopolysaccharide (LPS) stimulation or no stimulation in hGFs and hPLFs. Gene expression analyses of interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-2 (MMP-2), and Type 1 collagen were performed using reverse transcription-polymerase chain reaction (RT-PCR). Subsequently, we performed Western blotting for the analysis of the intracellular signal transduction pathway. In response to LPS stimulation, the gene expression levels of IL-6 and IL-8 in hGFs increased due to AZM in a concentration-dependent manner, and phosphorylation of nuclear factor kappa B (NF-&kappa, B) was also promoted. Additionally, AZM caused an increase in MMP-1 expression in hGFs, whereas it did not affect the expression of any of the analyzed genes in hPLFs. Our findings indicate that AZM does not affect hPLFs and acts specifically on hGFs. Thus, AZM may increase the expression of IL-6 and IL-8 under LPS stimulation to modify the inflammatory response and increase the expression of MMP-1 to promote connective tissue remodeling.

To enable positron emission tomography (PET) imaging of the in vivo kinetics of ubiquinone and ubiquinol, which is referred to as coenzyme Q10 , their 11 C-radiolabeled counterparts were synthesized herein. 11 C-Labeled ubiquinone [11 C]-1 was realized by Pd-mediated rapid C-[11 C]methylation of [11 C]CH3 I with 39-demethyl-39-(pinacolboryl)ubiquinone, prepared by Ru-catalyzed olefin metathesis of unradiolabeled ubiquinone with 2-(pinacolboryl)propene. Subsequent reduction of [11 C]-1 using Na2 S2 O4 yielded 11 C-labeled ubiquinol [11 C]-2. The synthesis time and [11 C]CH3 I-based radiochemical yield of [11 C]-1 were within 36 minutes and up to 53%, while those of [11 C]-2 were within 38 minutes and up to 39%, respectively. After radiopharmaceutical formulation, the qualities of [11 C]-1 and [11 C]-2 were confirmed to be applicable for animal PET studies. The analytical values of [11 C]-1 and [11 C]-2 are as follows: radioactivity of up to 3.5 and 1.4 GBq, molar activity of 21 to 78 and 48 to 76 GBq/μmol, radiochemical purity of greater than 99% and greater than 95%, and chemical purity of greater than 99% and 77%, respectively. The concept behind this radiolabeling procedure is that unradiolabeled natural ubiquinone can be converted to 11 C-radiolabeled ubiquinone and ubiquinol via a pinacolborane-substituted ubiquinone derivative. Each PET probe was used for molecular imaging using rats to investigate the in vivo kinetics and biodistribution of the coenzyme Q10 .

Ethynylphosphonate (EP)-linked thymidine dimers were synthesized via a palladium-catalyzed cross-coupling reaction and successfully incorporated into oligonucleotides. The oligonucleotides containing EP linkages appropriately formed a duplex with their complementary single-stranded RNA (ssRNA) and single-stranded DNA. The oligonucleotides containing both the EP linkages and 2'

We introduce a new geometric invariant called the obtuse constant of spaces with curvature bounded below. We first find relations between this invariant and the normalized volume. We also discuss the case of maximal obtuse constant equal to $\pi/2$, where we prove some rigidity for spaces. Although we consider Alexandrov spaces with curvature bounded below, the results are new even in the Riemannian case., Comment: We have changed the definition of obtuse constants in the first vertion "Comaparison angles and volume" because of an error in the first verson

A structure-activity relationship (SAR) for the oxadiazole class of antibacterials was evaluated by syntheses of 72 analogs and determination of the minimal-inhibitory concentrations (MICs) against the ESKAPE panel of bacteria. Selected compounds were further evaluated for in vitro toxicity, plasma protein binding, pharmacokinetics (PK), and a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) infection. Oxadiazole 72c shows potent in vitro antibacterial activity, exhibits low clearance, a high volume of distribution, and 41% oral bioavailability, and shows efficacy in mouse models of MRSA infection. Fil: Boudreau, Marc A.. University of Notre Dame; Estados Unidos Fil: Ding, Derong. University of Notre Dame; Estados Unidos Fil: Meisel, Jayda E.. University of Notre Dame; Estados Unidos Fil: Janardhanan, Jeshina. University of Notre Dame; Estados Unidos Fil: Spink, Edward. University of Notre Dame; Estados Unidos Fil: Peng, Zhihong. University of Notre Dame; Estados Unidos Fil: Qian, Yuanyuan. University of Notre Dame; Estados Unidos Fil: Yamaguchi, Takao. University of Notre Dame; Estados Unidos Fil: Testero, Sebastian Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. University of Notre Dame; Estados Unidos Fil: O'Daniel, Peter I.. University of Notre Dame; Estados Unidos Fil: Leemans, Erika. University of Notre Dame; Estados Unidos Fil: Lastochkin, Elena. University of Notre Dame; Estados Unidos Fil: Song, Wei. University of Notre Dame; Estados Unidos Fil: Schroeder, Valerie A.. University of Notre Dame; Estados Unidos Fil: Wolter, William R.. University of Notre Dame; Estados Unidos Fil: Suckow, Mark A.. University of Notre Dame; Estados Unidos Fil: Mobashery, Shahriar. University of Notre Dame; Estados Unidos Fil: Chang, Mayland. University of Notre Dame; Estados Unidos

We previously reported the synthesis and evaluation of 2′-O,4′-C-spirocyclopropylene-bridged nucleic acid (scpBNA) bearing a thymine (T) nucleobase. Oligonucleotides (ONs) modified with scpBNA-T exhibited strong binding affinity to complementary single-stranded RNA (ssRNA) and high enzymatic stability. These biophysical properties suggest that scpBNAs are well suited for use in antisense strategies. Herein, we describe the synthesis of scpBNA monomers bearing 5-methylcytosine (mC), adenine (A), and guanine (G) nucleobases for use in a variety of sequences. The prepared scpBNA monomers were incorporated into ONs at various positions. The scpBNA-modified ONs exhibited excellent duplex-forming ability with the complementary ssRNA comparable to ONs modified with 2′-O,4′-C-methylene-bridged nucleic acid (2′,4′-BNA/LNA). Moreover, ON modified with scpBNA-mC, -A, and -G showed higher enzymatic stability than the corresponding 2′,4′-BNA/LNA-modified ON. These results demonstrated a promising role for the incorpor...

Oligonucleotides modified with 2′-O,4′-C-spirocyclopropylene-bridged nucleic acid (scpBNA) exhibit excellent duplex-forming ability with their complementary single-stranded RNA (ssRNA). Here, we demonstrate that scpBNA bearing a 2-thiothymine (scpBNA-S2T) or 2-selenothymine (scpBNA-Se2T) nucleobase provides robust mismatch discrimination capabilities to oligonucleotides without compromising their high binding affinities toward the full complementary ssRNA. X-ray crystallographic analysis of a self-assembling oligonucleotide featuring 2′,4′-BNA/LNA-2-thiothymine (2′,4′-BNA/LNA-S2T, where 2′,4′-BNA and LNA stand for “2′-O,4′-C-methylene-bridged nucleic acid” and “locked nucleic acid”, respectively), a prototype of scpBNA-S2T, revealed that the 2-thiocarbonyl moiety plays a crucial role in the destabilization of thymine–guanine mismatched wobble base pairs.

In this paper, we study collapsed manifolds with boundary, where we assume a lower sectional curvature bound, two sides bounds on the second fundamental forms of boundaries and upper diameter bound. Our main concern is the case when inradii of manifolds converge to zero. This is a typical case of collapsing manifolds with boundary. We determine the limit spaces of inradius collapsed manifolds as Alexandrov spaces with curvature uniformly bounded below. When the limit space has co-dimension one, we completely determined the topology of inradius collapsed manifold in terms of singular $I$-bundles. Genral inradius collapse to almost regular spaces are also characterized. In the general case of unbounded diameters, we prove that the number of boundary components of inradius collapsed manifolds is at most two, where the disconnected boundary happens if and only if the manifold has a topological product structure., Comment: 57 pages, mainly Sections 4,6 and 7 revised

To enable positron emission tomography (PET) imaging of the in vivo kinetics of ubiquinone and ubiquinol, which is referred to as coenzyme Q10, their 11C‐radiolabeled counterparts were synthesized herein. 11C‐Labeled ubiquinone [11C]‐1 was realized by Pd‐mediated rapid C‐[11C]methylation of [11C]CH3I with 39‐demethyl‐39‐(pinacolboryl)ubiquinone, prepared by Ru‐catalyzed olefin metathesis of unradiolabeled ubiquinone with 2‐(pinacolboryl)propene. Subsequent reduction of [11C]‐1 using Na2S2O4 yielded 11C‐labeled ubiquinol [11C]‐2. The synthesis time and [11C]CH3I‐based radiochemical yield of [11C]‐1 were within 36 minutes and up to 53%, while those of [11C]‐2 were within 38 minutes and up to 39%, respectively. After radiopharmaceutical formulation, the qualities of [11C]‐1 and [11C]‐2 were confirmed to be applicable for animal PET studies. The analytical values of [11C]‐1 and [11C]‐2 are as follows: radioactivity of up to 3.5 and 1.4 GBq, molar activity of 21 to 78 and 48 to 76 GBq/μmol, radiochemical purity of greater than 99% and greater than 95%, and chemical purity of greater than 99% and 77%, respectively. The concept behind this radiolabeling procedure is that unradiolabeled natural ubiquinone can be converted to 11C‐radiolabeled ubiquinone and ubiquinol via a pinacolborane‐substituted ubiquinone derivative. Each PET probe was used for molecular imaging using rats to investigate the in vivo kinetics and biodistribution of the coenzyme Q10.

An N-methylguanidine-bridged nucleic acid (GuNA[NMe]), a guanidine-bridged nucleic acid (GuNA) bearing a methyl substituent at the bridge, was successfully synthesised and incorporated into oligonucleotides. By employing an acetyl protecting group, GuNA[NMe]-modified oligonucleotides bearing acid-sensitive purine nucleobases were successfully prepared. The obtained GuNA[NMe]-modified oligonucleotides exhibit excellent binding affinity towards the complementary single-stranded RNA and DNA. Furthermore, even a single GuNA[NMe] modification provides robust enzymatic stability, similar to that achieved by the well-established phosphorothioate backbone modification. These data indicate that such a GuNA[NMe] represents a valuable modification for the development of therapeutic oligonucleotides.

Chemical probes comprising a ligand moiety, a reactive group (e.g. epoxide, haloacetyl or photoreactive group) and a tag unit (e.g. fluorophore or radioisotope) are widely used in affinity labeling to identify the target proteins of bioactive molecules. However, design and synthesis of highly functionalized chemical probes are often time-consuming. In this paper, we propose a simple design strategy for chemical probes bearing a small 2,3-dichloromaleimide (diCMI) unit, which serves as a combined reactive group and tag unit by reacting with a nucleophilic lysine residue near the ligand-binding site of the target protein to generate the 2-amino-3-chloromaleimide fluorophore. Model ligand-protein experiments confirmed that the diCMI unit has suitable reactivity and fluorogenic capability for efficient affinity labeling.

Bromodomains are epigenetic 'readers' of histone acetylation. The first potent bromodomain and extra-terminal domain (BET) inhibitors, (+)-JQ1 and I-BET762 (also known as GSK525762), were reported in 2010. Some BET inhibitors are already under clinical trial for the treatment of cancers, but so far, only a few chemical scaffolds are available. We have reported potent N(6)-benzoyladenine-based inhibitors of BRD4, a BET family member that serves as a key mediator of transcriptional elongation. Here we present an analysis of the structure-activity relationships of these inhibitors. Among the compounds examined, 20, 28 and 29 enhanced all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation and inhibited tumor necrosis factor (TNF)-α production by THP-1 cells.

We recently developed 4-azidophthalimide (AzPI) as a compact fluorogenic photoreactive tag that can be attached to ligands to achieve selective fluorescence labeling of target proteins even in the presence of a large excess of non-target proteins. To further establish the utility of the AzPI tag, we focused here on streptavidin labeling with biotin-AzPI conjugates, and evaluated the relation between the amount of covalently labeled streptavidin (labeling rate) and fluorescence intensity. The labeling rate was proportional to the fluorescence intensity under standardized photo-irradiation conditions. Prolongation of the photo-irradiation time led to a marked increase in the labeling rate, but this was accompanied by a gradual decrease in the fluorescence intensity, which appeared to be due at least in part to photo-induced degradation of the target streptavidin. These findings should be helpful for achieving sensitive fluorescence detection of target proteins by using the AzPI tag.

In this paper, we introduce the notion of asymptotic self-similar sets on general doubling metric spaces by extending the notion of self-similar sets, and determine their Hausdorff dimensions, which gives an extension of Balogh and Rohner 's result. This is carried out by introducing the notions of almost similarity maps and asymptotic similarity systems. These notions have an advantage of making geometric constructions possible. Actually, as an application, we determined the Hausdorff dimension of general Sierpinski gaskets on complete surfaces constructed by a geometric way in a natural manner., to appear in Journal of Fractal Geometry

In the present paper, we determine the topologies of three-dimensional closed Alexandrov spaces which converge to lower dimensional spaces in the Gromov-Hausdorff topology.

Software for correcting the dynamic error of the force sensor in the impact force measurement, which uses an output signal of the sensor itself, has been improved. The software corrects the output waveform of the sensor by using the output waveform itself and estimates its uncertainty. In the experiment, the dynamic error of the sensor is evaluated using the Levitation Mass Method (LMM). In the LMM, the impact force applied to the sensor is accurately determined as an inertial force of the moving part of the aerostatic linear bearing. The parameter for correcting the dynamic error is determined from the results of one set of impact measurements of the sensor. Then the validity of the parameter is evaluated by using the results of measurements of the sensor. The uncertainty of the un-corrected force and that of the corrected force are also estimated. In the previous version of the software, the user input “input text-file” which contains force that is calculated based on the static calibration results. On the other hand, the output signal from the sensor is not force. This time, the software has been modified to load input text-file which contains the output signal from the sensor.

A method for evaluating the dynamic characteristics of force transducers against small and short-duration impact forces is developed. In this method, a small mass collides with a force transducer and the impact force is measured with high accuracy as the inertial force of the mass. A pneumatic linear bearing is used to achieve linear motion with sufficiently small friction acting on the mass, which is the moving part of the bearing. Small and short-duration impact forces with a maximum impact force of approximately 5 N and minimum half-value width of approximately 1 ms are applied to a force transducer and the impulse responses are evaluated.

Recently, we proved that every finite dimensional Alexandrov space is strongly locally Lipschitz contractible. In the present paper, we consider the set $$\mathcal M$$ of all isometry classes of Alexandrov spaces of curvature $$\ge -1$$ and of fixed dimension having upper diameter bound and lower volume bound, and prove that there exists a constant $$N$$ depending on the parameters determining $$\mathcal M$$ such that every space in $$\mathcal M$$ can be covered by at most $$N$$ strongly Lipschitz contractible balls. Also, we prove that there exists a constant $$N^\prime $$ depending on $$\mathcal M$$ such that every space in $$\mathcal M$$ can be covered by at most $$N^\prime $$ strongly Lipschitz contractible and convex regions.

Infections caused by hard-to-treat methicillin-resistant Staphylococcus aureus (MRSA) are a serious global public-health concern, as MRSA has become broadly resistant to many classes of antibiotics. We disclose herein the discovery of a new class of non-β-lactam antibiotics, the oxadiazoles, which inhibit penicillin-binding protein 2a (PBP2a) of MRSA. The oxadiazoles show bactericidal activity against vancomycin- and linezolid-resistant MRSA and other Gram-positive bacterial strains, in vivo efficacy in a mouse model of infection, and have 100% oral bioavailability.

Loudspeakers are designed for reproducing the original sound field as faithfully as possible. In order to faithfully reproduce sound, it is important to understand the relationships among the physical characteristics of the loudspeaker. This paper focuses on the cone, the edge, and the behavior of air around the voice coil, which are important elements in the design of cone loudspeakers and evaluates their effects on the acoustic characteristics of the loudspeaker.

We previously reported the synthesis and evaluation of 2'-O,4'-C-spirocyclopropylene-bridged nucleic acid (scpBNA) bearing a thymine (T) nucleobase. Oligonucleotides (ONs) modified with scpBNA-T exhibited strong binding affinity to complementary single-stranded RNA (ssRNA) and high enzymatic stability. These biophysical properties suggest that scpBNAs are well suited for use in antisense strategies. Herein, we describe the synthesis of scpBNA monomers bearing 5-methylcytosine (

This study optimized the design parameters of a cone loudspeaker as an example of high flexibility of the product design. We developed an acoustic analysis software program that considers the impact of damping caused by air viscosity. In sound reproduction, it is difficult to optimize each parameter of the loudspeaker design. To overcome the limitation of the design problem in practice, this study presents an acoustic analysis algorithm to optimize the design parameters of the loudspeaker. The material character of cone paper and the loudspeaker edge were the design parameters, and the vibration displacement of the cone paper was the objective function. The results of the analysis showed that the design had high accuracy as compared to the predicted value. These results suggested that although the parameter design is difficult, with experience and intuition, the design can be performed easily using the optimized design found with the acoustic analysis software., {"references":["W. N. Brown Jr, \"Theory of conical sound radiators,\" J. Acoust. Soc. Am., Vol. 13, no. 1, pp. 20–22, 1941.7.","P. G. Bordoni, \"The conical sound source,\" J. Acoust. Soc. Am., vol. 28, no. 2, pp. 123–126, 1945.","T. Nimura, E. Matsui, K. Shibayama, K. Kido, \"Study on the cone type dynamic loudspeakers,\" J. Acoust. Soc. Jpn., vol. 7, no. 2, pp. 16–28, 1952.","F. J. Frankfort, \"Vibration and sound radiation of loudspeaker cones,\" Thesis, Delft(1975); also Philips Res. Rep. Suppl., no. 2, 1975","T. Ueno, K. Takahashi, K. Ichida, S. Ishii, \"The vibration analysis of a cone loudspeaker by the finite element method,\" J. Acoust. Soc. Jpn., vol. 34, no. 8, pp. 470–477, 1978.","I. Suzuki, K.Nomoto, \"Computerized analysis and observation of the vibration modes of a loudspeaker cone,\" Journal audio Eng. Soc., no.1280, pp.1-9, 1982.","N. Kyouno,T. Usagawa, T. Yamabuchi, Y. Kagawa, \"Acoustic response analysis of a cone-type loudspeaker by the finite element method,\" J. Acoust. Soc. Jpn., vol. 61, no. 6, pp. 312–319, 2005.","Y. Nomura, K. Nagasawa, \"Design of the phase inverter loudspeaker system by nonlinear optimization method,\" J. Acoust. Soc. Jpn., vol. 34, no. 8, pp. 462–469, 1978.","F. Kusudo, \"Design of loudspeaker by optimization method,\" Reports of the spring meeting the Acoustical Society of Japan, pp. 263–264, 1979\n[10]\tM. Sasajimai T. Yamaguchi, M. Watanabe, Y. Koike, \"FEM analysis of a narrow acoustic sound pathway with rectangular cross section,\" Society of Damping Technology, vol. 12, 2014.\n[11]\tX. Zhao, \"Some new problems and measure with structural optimization software development,\" Proceedings of the Conference on Computational Engineering and Science, vol. 12, no. 1, 129–132, 2007\n[12]\tX. Zhao, Y. Hu, I. Hagiwara, \"Optimal design for crash characteristics of cylindrical thin-walled structure using origami engineering,\" The Japan Society of Mechanical Engineers, vol. 76, no. 761, 2010"]}

Bromodomains are epigenetic 'readers' of histone acetylation. The first potent bromodomain and extra-terminal domain (BET) inhibitors, (+)-JQ1 and I-BET762 (also known as GSK525762), were reported in 2010. Some BET inhibitors are already under clinical trial for the treatment of cancers, but so far, only a few chemical scaffolds are available. We have reported potent N(6)-benzoyladenine-based inhibitors of BRD4, a BET family member that serves as a key mediator of transcriptional elongation. Here we present an analysis of the structure-activity relationships of these inhibitors. Among the compounds examined, 20, 28 and 29 enhanced all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation and inhibited tumor necrosis factor (TNF)-α production by THP-1 cells.

Gram-negative bacteria have evolved an elaborate process for the recycling of their cell wall, which is initiated in the periplasmic space by the action of lytic transglycosylases. The product of this reaction, β-d-N-acetylglucosamine-(1→4)-1,6-anhydro-β-d-N-acetylmuramyl-l-Ala-γ-d-Glu-meso-DAP-d-Ala-d-Ala (compound 1), is internalized to begin the recycling events within the cytoplasm. The first step in the cytoplasmic recycling is catalyzed by the NagZ glycosylase, which cleaves in a hydrolytic reaction the N-acetylglucosamine glycosidic bond of metabolite 1. The reactions catalyzed by both the lytic glycosylases and NagZ are believed to involve oxocarbenium transition species. We describe herein the synthesis and evaluation of four iminosaccharides as possible mimetics of the oxocarbenium species, and we disclose one as a potent (compound 3, Ki = 300 ± 15 nM) competitive inhibitor of NagZ.

This paper describes vibration analysis using finite element method for box structures consisting of elastic flat plates and damping layers on their bottom plates. The box structures are supported by nonlinear concentrated springs on the bottom plate. The restoring force of the springs have cubic nonlinearity and linear hysteresis damping. Finite element for the nonlinear springs are expressed and are connected to the elastic plates modeled by linear solid finite elements in consideration of complex modulus of elasticity. Further, the discretized equations in physical coordinate are transformed into the nonlinear ordinary coupled equations using normal coordinate corresponding to linear natural modes. Using material damping and shares of strain energy for the parts (i.e. the plates, the damping layer and the springs), we evaluate damping couplings among the parts. Further, we clarify influences of the damping couplings on nonlinear impact responses.