AR-12 Has a Bactericidal Activity and a Synergistic Effect with Gentamicin against Group A Streptococcus

Streptococcus pyogenes (group A Streptococcus (GAS) is an important human pathogen that can cause severe invasive infection, such as necrotizing fasciitis and streptococcal toxic shock syndrome. The mortality rate of streptococcal toxic shock syndrome ranges from 20% to 50% in spite of antibiotics administration. AR-12, a pyrazole derivative, has been reported to inhibit the infection of viruses, intracellular bacteria, and fungi. In this report, we evaluated the bactericidal activities and mechanisms of AR-12 on GAS infection. Our in vitro results showed that AR-12 dose-dependently reduced the GAS growth, and 2.5 μg/mL of AR-12 significantly killed GAS within 2 h. AR-12 caused a remarkable reduction in nucleic acid and protein content of GAS. The expression of heat shock protein DnaK and streptococcal exotoxins was also inhibited by AR-12. Surveys of the GAS architecture by scanning electron microscopy revealed that AR-12-treated GAS displayed incomplete septa and micro-spherical structures protruding out of cell walls. Moreover, the combination of AR-12 and gentamicin had a synergistic antibacterial activity against GAS replication for both in vitro and in vivo infection. Taken together, these novel findings obtained in this study may provide a new therapeutic strategy for invasive GAS infection.     

Novel Aurora A Kinase Inhibitor Fangchinoline Enhances Cisplatin–DNA Adducts and Cisplatin Therapeutic Efficacy in OVCAR-3 Ovarian Cancer Cells-Derived Xenograft Model

Aurora A kinase (Aurora A) is a serine/threonine kinase regulating control of multiple events during cell-cycle progression. Playing roles in promoting proliferation and inhibiting cell death in cancer cells leads Aurora A to become a target for cancer therapy. It is overexpressed and associated with a poor prognosis in ovarian cancer. Improving cisplatin therapy outcomes remains an important issue for advanced-stage ovarian cancer treatment, and Aurora A inhibitors may improve it. In the present study, we identified natural compounds with higher docking scores than the known Aurora A ligand through structure-based virtual screening, including the natural compound fangchinoline, which has been associated with anticancer activities but not yet investigated in ovarian cancer. The binding and inhibition of Aurora A by fangchinoline were verified using cellular thermal shift and enzyme activity assays. Fangchinoline reduced viability and proliferation in ovarian cancer cell lines. Combination fangchinoline and cisplatin treatment enhanced cisplatin–DNA adduct levels, and the combination index revealed synergistic effects on cell viability. An in vivo study showed that fangchinoline significantly enhanced cisplatin therapeutic effects in OVCAR-3 ovarian cancer-bearing mice. Fangchinoline may inhibit tumor growth and enhance cisplatin therapy in ovarian cancer. This study reveals a novel Aurora A inhibitor, fangchinoline, as a potentially viable adjuvant for ovarian cancer therapy.     

Preparation of a DNA aptamer-Pt complex and its use in the colorimetric sensing of thrombin and anti-thrombin antibodies

DNA aptamers carrying Pt nanoparticles were prepared by the reaction of DNA aptamers (without functionalization with biotin, thiol, or other reactive groups) with K 2[PtCl 4] in solution at 60-90 degrees C. The DNA-Pt complexes possessed peroxidase enzymatic activity while retaining the specific binding ability of the aptamers. The enzymatic reaction of these complexes obeyed Michaelis-Menten kinetics. K M for the DNA-Pt complex was found to be on the same order as K M for hemin and hemin-DNA complex but 1 or 2 orders of magnitude higher than that of horseradish peroxidase. The rate of the reaction catalyzed by the DNA-Pt complex, k cat, was found to be on the same order as that of hemin and hemin-DNA complex but 2 or 3 orders of magnitude lower than that of horseradish peroxidase. Two types of DNAzyme-linked aptamer assays (DLAAs) were developed using these complexes, which successfully detected target proteins, with the sandwich type of DLAA targeting thrombin and the competitive type of DLAA targeting anti-thrombin IgA/G/M in serum. The DNA-Pt complexes retained their peroxidase enzymatic activity even after heat treatment. DLAAs having high thermal stability were developed using these complexes, which were free of animal and plant matter because neither antibodies nor horseradish peroxidase were used in their synthesis.     

Growth and characterization of n-type InP/InGaAs quantum well infrared photodetectors for response at 8.93 µm

We present experimental results on the growth and characterization of n-type InGaAs/InP quantum-well intersubband photodetectors for use at 8.93 μm. High-quality InGaAs/InP multiple quantum wells were grown by gas source molecular beam expitaxy, and then characterized by double-crystal x-ray diffraction and cross-sectional transmission electron microscopy. Based upon the structural parameters determined by these methods, the photocurrent response spectra were simulated using a six-band effective bond-orbital model. The theoretical results are in excellent agreement with experimental data. Additional important device characteristics such as dark current, spectral response, and absolute responsivity are also presented.     

Exploration of Diazaspiro Cores as Piperazine Bioisosteres in the Development of σ2 Receptor Ligands

A series of σ2R compounds containing benzimidazolone and diazacycloalkane cores was synthesized and evaluated in radioligand binding assays. Replacing the piperazine moiety in a lead compound with diazaspiroalkanes and the fused octahydropyrrolo[3,4-b] pyrrole ring system resulted in a loss in affinity for the σ2R. On the other hand, the bridged 2,5-diazabicyclo[2.2.1]heptane, 1,4-diazepine, and a 3-aminoazetidine analog possessed nanomolar affinities for the σ2R. Computational chemistry studies were also conducted with the recently published crystal structure of the σ2R/TMEM97 and revealed that hydrogen bond interactions with ASP29 and π-stacking interactions with TYR150 were largely responsible for the high binding affinity of small molecules to this protein.     

T Cells in Multisystem Inflammatory Syndrome in Children (MIS-C) Have a Predominant CD4+ T Helper Response to SARS-CoV-2 Peptides and Numerous Virus-Specific CD4− CD8− Double-Negative T Cells

We studied SARS-CoV-2-specific T cell responses in 22 subacute MIS-C children enrolled in 2021 and 2022 using peptide pools derived from SARS-CoV-2 spike or nonspike proteins. CD4+ and CD8+ SARS-CoV-2-specific T cells were detected in 5 subjects, CD4+ T helper (Th) responses alone were detected in 12 subjects, and CD8+ cytotoxic T cell (CTL) responses alone were documented in 1 subject. Notably, a sizeable subpopulation of CD4− CD8− double-negative (DN) T cells out of total CD3+ T cells was observed in MIS-C (median: 14.5%; IQR 8.65–25.3) and recognized SARS-CoV-2 peptides. T cells bearing the Vβ21.3 T cell receptor (TcRs), previously reported as pathogenic in the context of MIS-C, were detected in high frequencies, namely, in 2.8% and 3.9% of the CD4+ and CD8+ T cells, respectively. However, Vβ21.3 CD8+ T cells that responded to SARS-CoV-2 peptides were detected in only a single subject, suggesting recognition of nonviral antigens in the majority of subjects. Subjects studied 6–14 months after MIS-C showed T cell epitope spreading, meaning the activation of T cells that recognize more SARS-CoV-2 peptides following the initial expansion of T cells that see immunodominant epitopes. For example, subjects that did not recognize nonspike proteins in the subacute phase of MIS-C showed good Th response to nonspike peptides, and/or CD8+ T cell responses not appreciable before arose over time and could be detected in the 6–14 months’ follow-up. The magnitude of the Th and CTL responses also increased over time. In summary, patients with MIS-C associated with acute lymphopenia, a classical feature of MIS-C, showed a physiological response to the virus with a prominent role for virus-specific DN T cells.     

Quantitative Comparison of Color Performances Between IPS and MVA LCDs

Color gamut and color shifts of the film-compensated multi-domain in-plane-switching (IPS) and multi-domain vertical alignment (MVA) liquid crystal displays (LCDs) are calculated quantitatively using light-emitting diodes (LEDs) and cold-cathode fluorescent lamp (CCFL) backlight. Simulation results indicate that the LED backlight exhibits better angular color uniformity and smaller color shifts than CCFL. In addition, the color gamut can be further widened and the color shift reduced when using color-sequential RGB-LED backlight without color filters. In general, both IPS and MVA LCDs show relatively small color shift under different backlights, but MVA has a lower color shift using the optimized uniaxial compensation films     

Enhanced/suppressed interdiffusion of InGaAs-GaAs-AlGaAs strained layers by controlling impurities and gallium vacancies

The interdiffusion of In and Ga at an InGaAs-GaAs interface subjected to different annealing temperatures, times, and environments is demonstrated. The interdiffusion coefficients and activation energies are determined by correlating the shift in the photoluminescence peaks with the calculated quantum well transition energies based on an error function composition profile. The results indicate that a higher In composition In_xGa_1-xGaAs single quantum well (SQW) leads to a higher interdiffusion coefficient of In and Ga in an As overpressure annealing condition. Also, As overpressure increases the interdiffusion, whereas Ga overpressure reduces the interdiffusion. The thermal activation energies for different In composition InGaAs-GaAs SQW’s (x = 0.057, 0.10, 0.15) range from 3.3 to 2.6 eV for an As overpressure environment and from 3 to 2.23 eV for the Ga overpressure situation. With respect to impurity induced disordering by Zn using a Ga or As overpressure significantly effects the depth of the Zn diffusion front but significant mixing does occur in either case when the impurity front reaches the quantum well.     

Antitumor agents. 178. Synthesis and biological evaluation of substituted 2-aryl-1,8-naphthyridin-4(1H)-ones as antitumor agents that inhibit tubulin polymerization

As part of our continuing search for potential anticancer drug candidates in the 2-aryl-1,8-naphthyridin-4(1H)-one series, we have synthesized two series of 3'-substituted 2-phenyl-1,8-naphthyridin-4(1H)-ones and 2-naphthyl-1,8-naphthyridin-4(1H)-ones. All compounds showed significant cytotoxic effects (log GI50 < -4.0; log molar drug concentration required to cause 50% growth inhibition) against a variety of human tumor cell lines of the National Cancer Institute's in vitro screen, including cells derived from solid tumors such as non-small cell lung, colon, central nervous system, melanoma, ovarian, prostate, and breast cancers. All 3'-substituted compounds demonstrated strong cytotoxic effects in almost all tumor cell lines. Introduction of an aromatic ring at the 2'- and 3'-positions also generated compounds with potent antitumor activity. Incorporation of an aromatic ring at the 3'- and 4'-positions produced compounds with reduced activity. Interestingly, introduction of a halogen at the 3'-position yielded compounds with different selectivity for the tumor cell lines tested. All 3'-halogenated compounds (29-36) and compounds 38 and 42-44 were potent inhibitors of tubulin polymerization with activities nearly comparable to those of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4. Active agents also inhibited the binding of [3H]colchicine to tubulin.