Circadian Clock Gene Expression and Drug/Toxicant Interactions as Novel Targets of Chronopharmacology and Chronotoxicology

Circadian rhythms are driven and maintained by circadian clock gene networks in both brain and peripheral organs. In the liver, circadian rhythms produce oscillation in drug Phase-I, Phase-II, and Phase-III (transporters) metabolism genes, which in turn would affect drug disposition and detoxication, resulting in diurnal variations of efficacy and toxicity when drugs are given at different times of the day. On the other hand, drugs and toxicants could affect circadian clock gene expression to produce biological effects leading to therapeutic or toxic outcomes. This chapter reviewed the relevant literature and a dozen of publications from our work, discussed the interactions of circadian clock genes with drugs and/or toxicants to better understand the importance of circadian clock gene expression as novel targets in Pharmacology and Toxicology

Dirac-Surface-State Modulated Spin Dynamics in a Ferrimagnetic Insulator at Room Temperature

This work demonstrates dramatically modified spin dynamics of magnetic insulator (MI) by the spin-momentum locked Dirac surface states of the adjacent topological insulator (TI) which can be harnessed for spintronic applications. As the Bi-concentration x is systematically tuned in 5 nm thick (BixSb1-x)2Te3 TI film, the weight of the surface relative to bulk states peaks at x = 0.32 when the chemical potential approaches the Dirac point. At this concentration, the Gilbert damping constant of the precessing magnetization in 10 nm thick Y3Fe5O12 MI film in the MI/TI heterostructures is enhanced by an order of magnitude, the largest among all concentrations. In addition, the MI acquires additional strong magnetic anisotropy that favors the in-plane orientation with similar Bi-concentration dependence. These extraordinary effects of the Dirac surface states distinguish TI from other materials such as heavy metals in modulating spin dynamics of the neighboring magnetic layer

INSTITUTIONAL ENVIRONMENT AND INSTITUTIONAL LOGICS IN CONSTRUCTION SAFETY MANAGEMENT: THE CASE OF CLIMATIC HEAT STRESS ON SITE

Although climatic heat stress can be fully brought under control and prevented from causing short-term or long-term damage to the human body in laboratory experiments, the expected effect of interventions are however often lost in the practice on construction site as frontline personnel are driven by conflicting institutional logics in their specific institutional environment. The paper presents a comparative study between Hong Kong and Mainland China in the case of climatic heat stress management on construction sites. Specifically, we look into how societal culture as institutional logics leads workers and managers to their pragmatic or normative behaviours that deviate from the expected outcome of safety management. Two competing institutional logics in construction safety management are identified and discussed, i.e., production logic and prevention logic. Comparative analysis of the Chinese samples under two different institutional environments identifies two distinct society-level cultural logics that shape personal strategies of reconciling safety and production goals, i.e., Confucianism logic and Chinese pragmatism logic. Their implications on construction safety management are further discussed

Investigation of lattice capacity effect on Cu²+-doped SnO₂ solid solution catalysts to promote reaction performance toward NOx-SCR with NH₃

To understand the effect of the doping amount of Cu²+ on the structure and reactivity of SnO₂ in NOx-SCR with NH3, a series of Sn-Cu-O binary oxide catalysts with different Sn/Cu ratios have been prepared and thoroughly characterized. Using the XRD extrapolation method, the SnO2 lattice capacity for Cu²+ cations is determined at 0.10 g CuO per g of SnO2, equaling a Sn/Cu molar ratio of 84/1

Effectiveness of adjuvant chemotherapy for elderly patients with triple-negative breast cancer

There is little evidence determining whether elderly patients (from 70 to 90 years old) with triple-negative breast cancer could benefit from adjuvant chemotherapy (AC).  This study explores the effect of AC in these population following surgery. A total of 4610 patients were identified in the Surveillance, Epidemiology, and End Results database (2010-2018). Multiple imputation by chained equations was performed to impute missing data. Inverse probability of treatment weighting (IPTW) was applied to reduce the selection bias. IPTW-adjusted Kaplan-Meiers survival analysis and Cox proportional hazards models were performed to compare breast cancer specific survival (BCSS) and overall survival (OS) in the two treatment groups. The patients were classified into the chemotherapy (n=1989) and the observation (n=2621) groups. The percentage of patients receiving AC versus observation increased significantly from 2010 to 2018 (estimated annual percentage change, 1.49%; 95%CI, 0.75-2.16%, p=0.002). The 5-year IPTW-adjusted rates of BCSS and OS in AC group were better than that in observation group (BCSS: 82.32% vs. 78.42%, p=0.010; OS: 75.54% vs. 64.65%, p0.050). In conclusion, we presented a BCSS and OS benefit from AC in elderly patients with triple-negative breast cancer (TNBC). AC remained a reasonable treatment approach in these specific patients. For the patients with T1ab, de-escalated treatment would be administrated with caution

Light-responsive nanogated ensemble based on polymer grafted mesoporous silica hybrid nanoparticles

Mesoporous silica nanoparticles grafted with light-responsive polymer on the outer surface were developed as novel nanogated ensembles, which allow encapsulation and release of drug and biological molecules under light irradiation.National Natural Science Foundation of China [20875079, 20835005]; Planned Science and Technology Project of Xiamen, China [3502z20080011]; Specialized Research Fund for the Doctoral Program of Higher Education of China [200803840007

Light-triggered covalent assembly of gold nanoparticles in aqueous solution

UV light irradiation triggers Au NPs that are respectively functionalized on the surface by o-nitrobenzyl alcohol and benzylamine to proceed with a covalent ligation reaction, which leads to assembling of Au NPs into anisotropic one-dimensional (1D) arrays in aqueous solution via indazolone linkages.National Natural Science Foundation of China[20875079, 20835005]; The Planned Science and Technology Project of Xiamen, China[3502z20080011]; Specialized Research Fund for Doctoral Program of Higher Education of China[200803840007

Observation of many-body Fock space dynamics in two dimensions

Quantum many-body simulation provides a straightforward way to understand fundamental physics and connect with quantum information applications. However, suffering from exponentially growing Hilbert space size, characterization in terms of few-body probes in real space is often insufficient to tackle challenging problems such as quantum critical behavior and many-body localization (MBL) in higher dimensions. Here, we experimentally employ a new paradigm on a superconducting quantum processor, exploring such elusive questions from a Fock space view: mapping the many-body system onto an unconventional Anderson model on a complex Fock space network of many-body states. By observing the wave packet propagating in Fock space and the emergence of a statistical ergodic ensemble, we reveal a fresh picture for characterizing representative many-body dynamics: thermalization, localization, and scarring. In addition, we observe a quantum critical regime of anomalously enhanced wave packet width and deduce a critical point from the maximum wave packet fluctuations, which lend support for the two-dimensional MBL transition in finite-sized systems. Our work unveils a new perspective of exploring many-body physics in Fock space, demonstrating its practical applications on contentious MBL aspects such as criticality and dimensionality. Moreover, the entire protocol is universal and scalable, paving the way to finally solve a broader range of controversial many-body problems on future larger quantum devices.Comment: 8 pages, 4 figures + supplementary informatio

Screening and characterization of the scFv for chimeric antigen receptor T cells targeting CEA-positive carcinoma

IntroductionChimeric antigen receptor T (CAR-T) cell therapy presents a promising treatment option for various cancers, including solid tumors. Carcinoembryonic antigen (CEA) is an attractive target due to its high expression in many tumors, particularly gastrointestinal cancers, while limited expression in normal adult tissues. In our previous clinical study, we reported a 70% disease control rate with no severe side effects using a humanized CEA-targeting CAR-T cell. However, the selection of the appropriate single-chain variable fragment (scFv) significantly affects the therapeutic efficacy of CAR-T cells by defining their specific behavior towards the target antigen. Therefore, this study aimed to identify the optimal scFv and investigate its biological functions to further optimize the therapeutic potential of CAR-T cells targeting CEA-positive carcinoma.MethodsWe screened four reported humanized or fully human anti-CEA antibodies (M5A, hMN-14, BW431/26, and C2-45), and inserted them into a 3rd-generation CAR structure. We purified the scFvs and measured the affinity. We monitored CAR-T cell phenotype and scFv binding stability to CEA antigen through flow cytometry. We performed repeated CEA antigen stimulation assays to compare the proliferation potential and response of the four CAR-T cells, then further evaluated the anti-tumor efficacy of CAR-T cells ex vivo and in vivo.ResultsM5A and hMN-14 CARs displayed higher affinity and more stable CEA binding ability than BW431/26 and C2-45 CARs. During CAR-T cell production culture, hMN-14 CAR-T cells exhibit a larger proportion of memory-like T cells, while M5A CAR-T cells showed a more differentiated phenotype, suggesting a greater tonic signal of M5A scFv. M5A, hMN-14, and BW431/26 CAR-T cells exhibited effective tumor cell lysis and IFN-γ release when cocultured with CEA-positive tumor cells in vitro, correlating with the abundance of CEA expression in target cells. While C2-45 resulted in almost no tumor lysis or IFN-γ release. In a repeat CEA antigen stimulation assay, M5A showed the best cell proliferation and cytokine secretion levels. In a mouse xenograft model, M5A CAR-T cells displayed better antitumor efficacy without preconditioning.DiscussionOur findings suggest that scFvs derived from different antibodies have distinctive characteristics, and stable expression and appropriate affinity are critical for robust antitumor efficacy. This study highlights the importance of selecting an optimal scFv in CAR-T cell design for effective CEA-targeted therapy. The identified optimal scFv, M5A, could be potentially applied in future clinical trials of CAR-T cell therapy targeting CEA-positive carcinoma