Chiral conglomerate phases possessing a saddle‐splay curvature have attracted much attention from researchers. A rigid bent shape is recognized to be necessary for their formations, as the tilted ...orientation of the bent‐core molecules in the layers drives the layers to twist, producing the saddle‐splay curvature. We prepared an achiral liquid crystal trimer, 2‐{4‐9‐(4‐(4‐octyloxyazobenzene‐4’‐yloxy)nonyloxy)phenyl‐5‐{9‐4‐(5‐octyloxypyrimidin‐2‐yl)phenyloxynonyloxy}pyrimidine, and investigated the thermal transitions and the photo‐induced isothermal transitions. The trimer exhibited nematic and dark chiral conglomerate (DC) phases. When the trimer was exposed to UV light with wavelength 365 nm in the soft crystalline DC phase, it changed to an achiral liquid crystalline phase consisting of short correlation length layer structures. The photo‐induced phase did not appear in the thermal phase sequence. In light of this, we discuss how this photo‐driven on/off switching of the chirality occurs. Furthermore, we show that it can be applied to control the nanostructure of the DC phase.
The photo‐driven reversible chirality switching transforms the sponge structure in the dark conglomerate phase to a more ordered porous structure via a novel achiral liquid crystalline phase consisting of short correlation length layer structures.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Interleukin (IL)-12 and IL-23 share a common subunit (p40) and function in T-helper (Th) 1 and Th17 immunity, respectively. Anti-IL-12/23p40 and specific anti-IL-23 antibodies are currently in ...clinical use for psoriasis and undergoing trials for autoimmune diseases. Since expression levels of the IL-23 receptor are likely to be much lower than those of IL-23, an anti-IL-23 receptor antibody might offer greater promise in inhibiting the IL-23-IL-17 pathways involved in inflammatory disorders. To our knowledge, no anti-IL-23 receptor antibody has been trialed in clinical studies to date. This study describes the generation and characterization of AS2762900-00, a fully human monoclonal antibody against the IL-23 receptor. AS2762900-00 bound both human and cynomolgus monkey IL-23 receptors. AS2762900-00 showed potent inhibitory effects on IL-23-induced Kit-225 cell proliferation compared to the existing anti-IL-12/23p40 antibody, ustekinumab. In a single dose administration pharmacodynamics study in cynomolgus monkeys, 1 mg/kg of AS2762900-00 significantly inhibited (> 85%) IL-23-induced STAT3 phosphorylation in blood for up to 84 days. Therefore, AS2762900-00 represents a potent novel IL-23-IL-17 pathway inhibitor with the potential to be developed into a new therapy for the treatment of autoimmune diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The phosphorylation of the human estrogen receptor (ER) serine residue at position 118 is required for full activity of the ER activation function 1 (AF-1). This Ser$^{118}$ is phosphorylated by ...mitogen-activated protein kinase (MAPK) in vitro and in cells treated with epidermal growth factor (EGF) and insulin-like growth factor (IGF) in vivo. Overexpression of MAPK kinase (MAPKK) or of the guanine nucleotide binding protein Ras, both of which activate MAPK, enhanced estrogen-induced and antiestrogen (tamoxifen)-induced transcriptional activity of wild-type ER, but not that of a mutant ER with an alanine in place of Ser$^{118}$. Thus, the activity of the amino-terminal AF-1 of the ER is modulated by the phosphorylation of Ser$^{118}$ through the Ras-MAPK cascade of the growth factor signaling pathways.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Induced pluripotent stem cells (iPSCs) are attractive for use in early drug discovery because they can differentiate into any cell type. Maintenance cultures and differentiation processes for iPSCs, ...however, require a high level of technical expertise. To overcome this problem, technological developments such as enhanced automation are necessary to replace manual operation. In addition, a robot system with the flexibility and expandability to carry out maintenance culture and each of the required differentiation processes would also be important. In this study, we established a platform to enable the multiple processes required for iPSC experiments using the Maholo LabDroid, which is a humanoid robotic system with excellent reproducibility and flexibility. The accuracy and robustness of Maholo LabDroid enabled us to cultivate undifferentiated iPSCs for 63 days while maintaining their ability to differentiate into the three embryonic germ layers. Maholo LabDroid maintained and harvested iPSCs in six-well plates, then seeded them into 96-well plates, induced differentiation, and implemented immunocytochemistry. As a result, Maholo LabDroid was confirmed to be able to perform the processes required for myogenic differentiation of iPSCs isolated from a patient with muscular disease and achieved a high differentiation rate with a coefficient of variation (CV) <10% in the first trial. Furthermore, the expandability and flexibility of Maholo LabDroid allowed us to experiment with multiple cell lines simultaneously.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Due to their physiological relevance, cell-based assays using human-induced pluripotent stem cell (iPSC)-derived cells are a promising in vitro pharmacological evaluation system for drug candidates. ...However, cell-based assays involve complex processes such as long-term culture, real-time and continuous observation of living cells, and detection of many cellular events. Automating multi-sample processing through these assays will enhance reproducibility by limiting human error and reduce researchers’ valuable time spent conducting these experiments. Furthermore, this integration enables continuous tracking of morphological changes, which is not possible with the use of stand-alone devices.
This report describes a new laboratory automation system called the Screening Station, which uses novel automation control and scheduling software called Green Button Go to integrate various devices. To integrate the above-mentioned processes, we established three workflows in Green Button Go: 1) For long-term cell culture, culture plates and medium containers are transported from the automatic CO2 incubator and cool incubator, respectively, and the cell culture medium in the microplates is exchanged daily using the Biomek i7 workstation; 2) For time-lapse live-cell imaging, culture plates are automatically transferred between the CQ1 confocal quantitative image cytometer and the SCALE48W automatic CO2 incubator; 3) For immunofluorescence imaging assays, in addition to the above-mentioned devices, the 405LS microplate washer allows for formalin-fixation and immunostaining of cells. By scheduling various combinations of the three workflows, we successfully automated the culture and medium exchange processes for iPSCs derived from patients with facioscapulohumeral muscular dystrophy, confirmation of their differentiation status by live-cell imaging, and confirmation of the presence of differentiation markers by immunostaining. In addition, deep learning analysis enabled us to quantify the degree of iPSC differentiation from live-cell imaging data. Further, the results of the fully automated experiments could be accessed via the intranet, enabling experiments and analysis to be conducted remotely once the necessary reagents and labware were prepared. We expect that the ability to perform clinically and physiologically relevant cell-based assays from remote locations using the Screening Station will facilitate global research collaboration and accelerate the discovery of new drug candidates.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In this study, we investigated CIS reaction (clamping-mediated incorporation of single-stranded DNA with concomitant DNA syntheses) of Moloney murine leukaemia virus reverse transcriptase (MMLV-RT), ...and established a set of conditions with which single-stranded DNA is ligated to a G-tailed model substrate DNA at efficiencies close to 100%. Prior to the CIS reaction, a target blunt-end DNA was 3' G-tailed by MMLV-RT in the presence of a tailing enhancer, deoxycytidine. In the CIS reaction, the G-tail reacted with a single-stranded DNA carrying a stretch of Cs on its 3' end (termed as GAO for guide adaptor oligonucleotide), and MMLV-RT performed DNA polymerization, starting from the 3' overhang, using the GAO as a template. We could append a given nucleotide sequence of as long as 72 nucleotides, which would be sufficient for various NGS-sequencing platforms. The high efficiency and the unique features of this MMLV-RT activity that enables the labelling of each DNA molecule with a unique degenerate sequence as a molecular identifier has many potential uses in biotechnology.
Chirality’s effects on physical properties of materials and how chirality arises have persisted as attractive issues in chemistry. We prepared a homologous series of achiral liquid crystal trimers in ...which three phenylpyrimidine units are connected via flexible heptamethylene spacers. An equimolecular mixture of a trimer with a nematic (N) phase and that with smectic A (SmA), smectic C (SmC), and smectic B phases was found to exhibit an N phase, a SmC phase, and a B4 phase composed of chiral domains with opposite handedness. The chiral characteristics of the B4 phase were confirmed by uncrossing the polarizers in opposite directions. XRD measurements reveal that both SmC and B4 phases have an interdigitated layer structure. That molecular interdigitation might form a supermolecular bent configuration that can produce saddle splay curvature to drive the B4 phase.
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IJS, KILJ, NUK, PNG, UL, UM
Chiral conglomerate phases have attracted much attention not only for the spontaneous mirror symmetry breaking but also for their nanostructures. We investigated both surface and bulk structures of a ...homologues series of an achiral liquid crystal trimer
I-(n,m)
exhibiting soft crystalline chiral conglomerate phases by atomic force microscopy (AFM) and scanning electron microscopy (SEM). The trimers were found to form bicontinuous networks. In particular, trimer
I-(9,9)
exhibited a single gyroid-like surface accompanying periodic distribution of dimples with a size of about 100 nm. It showed a sponge-like structure in the bulk of the material. The twist conformation of the flexible trimer
I-(n,m)
can cause layer deformation, which produces bicontinuous networks exhibiting optical activity.
An achiral flexible trimer exhibits a gyroid-like surface and a sponge-like structure in the bulk of the material.
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