Discovery of a Novel Scaffold as an Indoleamine 2,3‐Dioxygenase 1 (IDO1) Inhibitor Based on the Pyrrolopiperazinone Alkaloid,Longamide B

Indoleamine 2,3‐dioxygenase 1 (IDO1) has emerged as a key target for cancer therapy, as IDO1 plays a critical role in the capacity of tumor cells to evade the immune system. The pyrrolopiperazinone alkaloid longamide B and its derivatives were identified as novel IDO1 inhibitors based on docking studies and small library synthesis. The thioamide derivative showed higher IDO1 inhibitory activity than longamide B, and displayed an activity similar to that of a representative IDO1 inhibitor, 1‐methyl‐tryptophan. These results suggest that the pyrrolopiperazinone scaffold of longamide B could be used in the development of IDO1 inhibitors.     

The Role of a Nonribosomal Peptide Synthetase in l‐Lysine Lactamization During Capuramycin Biosynthesis

Capuramycins are one of several known classes of natural products that contain an l ‐Lys‐derived l ‐α‐amino‐?‐caprolactam (l ‐ACL) unit. The α‐amino group of l ‐ACL in a capuramycin is linked to an unsaturated hexuronic acid component through an amide bond that was previously shown to originate by an ATP‐independent enzymatic route. With the aid of a combined in vivo and in vitro approach, a predicted tridomain nonribosomal peptide synthetase CapU is functionally characterized here as the ATP‐dependent amide‐bond‐forming catalyst responsible for the biosynthesis of the remaining amide bond present in l ‐ACL. The results are consistent with the adenylation domain of CapU as the essential catalytic component for l ‐Lys activation and thioesterification of the adjacent thiolation domain. However, in contrast to expectations, lactamization does not require any additional domains or proteins and is likely a nonenzymatic event. The results set the stage for examining whether a similar NRPS‐mediated mechanism is employed in the biosynthesis of other l ‐ACL‐containing natural products and, just as intriguingly, how spontaneous lactamization is avoided in the numerous NRPS‐derived peptides that contain an unmodified l ‐Lys residue.     

Fracture behaviour and numerical study of resistance spot welded joints in high-strength steel sheet

Cross tension tests of resistance spot welded joints with varying nugget diameter were carried out using 980 MPa high strength steel sheet of 1.6 mm thickness. In proportion, as nugget diameter increased from 3√t to 5√t (where t is thickness), cross tension strength (CTS) increased while fracture morphology simultaneously transferred from interface fracture to full plug fracture. In cases of interface fracture, circumferential crack initiation due to separation of the corona bond arose at an early stage of loading. The crack opening process without propagation was recognized until just before fracture and then the crack propagated to the nugget immediately in a brittle manner around CTS. In full plug fracture, main ductile crack initiation from the notch-like part at the end of sheet separation occurred with the sub-crack initiated at an early stage. The ductile crack propagated toward the HAZ and base material to form full plug fracture. The mode I stress intensity factor was considered as a suitable fracture parameter because the circumferential crack behaved pre-crack for brittle fracture in the nugget region at the final stage. Based on the FE analysis, the mode I stress intensity factor was calculated as 116 MPa √m at CTS as fracture toughness for the nugget. With respect to full plug fracture, ductile crack initiation behaviour from the notch-like part was expressed by concentration of equivalent plastic strain. On the assumption that the ductile crack arose in critical value of equivalent plastic strain, the value was calculated as 0.34 by FE analysis. Reasonable interpretation for interface fracture and full plug fracture in the resistance spot welded joint was proposed due to first crack initiation by stress concentration, brittle fracture by using mode I stress intensity factor, and ductile crack initiation by using equivalent plastic strain.     

MicroRNA-331-3p Suppresses Cervical Cancer Cell Proliferation and E6/E7 Expression by Targeting NRP2

Aberrant expression of microRNAs (miRNAs) is involved in the development and progression of various types of cancers. In this study, we investigated the role of miR-331-3p in cell proliferation and the expression of keratinocyte differentiation markers of uterine cervical cancer cells. Moreover, we evaluated whether neuropilin 2 (NRP2) are putative target molecules that regulate the human papillomavirus (HPV) related oncoproteins E6 and E7. Cell proliferation in the human cervical cancer cell lines SKG-II, HCS-2, and HeLa was assessed using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. Cellular apoptosis was measured using the TdT-mediated dUTP nick end labeling (TUNEL) and Annexin V assays. Quantitative RT-PCR was used to measure the messenger RNA (mRNA) expression of the NRP2, E6, E7, p63, and involucrin (IVL) genes. A functional assay for cell growth was performed using cell cycle analyses. Overexpression of miR-331-3p inhibited cell proliferation, and induced G2/M phase arrest and apoptosis in SKG-II, HCS-2 and HeLa cells. The luciferase reporter assay of the NRP2 3′-untranslated region revealed the direct regulation of NRP2 by miR-331-3p. Gene expression analyses using quantitative RT-PCR in SKG-II, HCS-2, and HeLa cells overexpressing miR-331-3p or suppressing NRP2 revealed down-regulation of E6, E7, and p63 mRNA and up-regulation of IVL mRNA. Moreover, miR-331-3p overexpression was suppressed NRP2 expression in protein level. We showed that miR-331-3p and NRP2 were key effectors of cell proliferation by regulating the cell cycle, apoptosis. NRP-2 also regulates the expression of E6/E7 and keratinocyte differentiation markers. Our findings suggest that miR-331-3p has an important role in regulating cervical cancer cell proliferation, and that miR-331-3p may contribute to keratinocyte differentiation through NRP2 suppression. miR-331-3p and NRP2 may contribute to anti-cancer effects.     

Nanostructured poly(3-hexylthiophene-2,5-diyl) films with tunable dimensions through self-assembly with polystyrene

Poly(3-hexylthiophene-2,5-diyl) is among the most widely used conjugated polymers for opto-electronic applications. To enhance its properties, researchers have attempted to nanostructure this polymer using various processes including breath figure arrays, nanolithography and elaborated organic synthesis. We here demonstrate a simple process to nanostructure the conjugated polymer using self-assembly with polystyrene and selective removal of one of the phases. The influence of the molecular weight of each polymer on the thin film morphology was systematically studied by atomic force microscopy. Using this approach, we observe two types of nanostructure, namely, nanoporous and nanoisland structures, of which the dimensions can be tuned by modifying the molecular weight of each polymer in the blend. This simple process introduces a cost-effective alternative to produce thin films of conjugated polymer with average nano-features from 100 nm up to 500 nm which could be used in a wide range of applications.     

Effects of various ester groups in γ-radiation degradation of syndiotactic poly(methacrylate)s

The γ irradiation of poly(methacrylate)s with various ester groups at room temperature was investigated by gel permeation chromatography and NMR techniques. The G values for scission and crosslinking for each of the polymers were estimated from the changes in the molecular weights and molecular weight distributions. The new structures formed during γ irradiation were examined by ¹H-NMR spectroscopy. All of the investigated poly(alkanemethacrylate)s were found to produce the alkane formates during γ irradiation, and for poly(2-methyl heptyl methacrylate) G(S) was less than 4G(X), indicating gel formation in this polymer. In the investigation of poly(benzyl methacrylate), no formate ester was found, but some small molecule compounds formed from the benzyl radical were detected. The benzyl group was also found to stabilize the polymer against radiation damage. © 1996 John Wiley & Sons, Inc.     

Multilayered reasoning by means of conceptual fuzzy sets

The real world consists of instances of events and continuous numeric values, while people represent and process their knowledge in terms of symbols. Fuzzy sets provide a strong notation connecting the symbolic representation to the real world. In previously proposed Conceptual Fuzzy Sets (CFS), the meaning of a concept is represented by the distribution of activations of labels in a bidirectional associative memory. In particular, a multilayered structured CFS represents the meaning of the same concept as it is used in various expressions in each layer. The propagation of activations corresponds to reasoning. Therefore, we propose a multilayered reasoning method associated to a multilayered structured CFS, which has the following features: (1) capable of simultaneous symbolic and quantitative processing, (2) capable of simultaneous top-down and bottom-up processing. The effectiveness of the proposed method is illustrated by practical examples of decision regarding the amount of steering in the task of parking a car, and recognition of facial expressions for an image understanding system. © 1996 John Wiley & Sons, Inc.     

Synthesis and chemical properties of polyethyleneimines crosslinked by penta-2,4-dienylideneammonium unit

The reaction of N-(2,4-dinitrophenyl)pyridinium anion ( salt(A) ; A = Cl⁻, FeCl₄⁻, and (CN)₂N⁻) with linear polyethyleneimine (LPEI; M_n = 20 380) and branched polyethyleneimines (BPEI1; M_n = 600, BPEI2; M_n = 10 000) at various molar feed ratios without using a catalyst resulted in pyridinium ring opening to yield ionic LPEI and BPEIs that were crosslinked by conjugated penta-2,4-dienylideneammonium (PDA) units, LPEI-PDA , BPEI1-PDA , and BPEI2-PDA , respectively. A model compound was synthesized by the reaction of salt(Cl) with diethylamine. The solubilities of BPEI1-PDA and BPEI2-PDA depended on the feed ratios between salt(Cl) and BPEI1 or BPEI2. Dipping LPEI-PDA into water and methanol yielded hydro- and organogels, respectively. UV–vis and reflection measurements revealed an expanded π-conjugation length between the polymer chains due to the through-space orbital interaction of the electrons on the two nitrogen atoms at the crosslinked positions in LPEI-PDA , BPEI1-PDA , and BPEI2-PDA . Cyclic voltammetry analysis suggested that the polymers underwent electrochemical oxidation. Measurement using a superconducting quantum interference device (SQUID) indicated that LPEI-PDA having FeCl₄⁻ anions was paramagnetic. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48712.     

Size-dependent separation of graphene oxide by deformation of packed-gel in a chromatographic column

ABSTRACT

A deformable gel-packed chromatographic column was used to separate as-synthesized graphite oxide with different sizes. The synthesized gel (56 µm) was deformed by pressure of the fluid flow and the gaps in the gels showed a range of sizes. A suspension of graphene oxide (0.1 g/L, 10 mL) was injected, and graphene oxide in the elution had a size at 0.56 μm and 0.14 μm, whereas in half upper and bottom domain of the gel layer graphene oxide had a size at 33 µm and 2.9 µm, respectively, demonstrating that graphene oxide suspension was separated by size through gel layer.     

Effect of morphology on shear viscosity for binary blends of polycarbonate and polystyrene

The structure and rheological properties of binary blends of polycarbonate (PC) and polystyrene (PS) were investigated using various PS samples with different molecular weights, namely PS1k (M_w = 1,000), PS53k (M_w = 53,000), and PS240k (M_w = 240,000). The blends with PS53k and PS240k show phase-separated structures, whereas the blend with PS1k is miscible. The shear viscosity decreases greatly on addition of PS53k and PS240k, especially at high shear rates, which would be a great advantage at processing operations. Because the nonlinear response occurs in the small strain region for multilayered films of PC and PS240k, the origin of the significant viscosity drop for the phase-separated system is interfacial slippage at the phase boundary.