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Carbamazepine (CBZ, an antiepileptic) is metabolized by multiple CYP enzymes to its epoxide and hydroxides; however, whether it is genotoxic remains unclear. In this study, molecular docking (CBZ to CYPs) and cytogenotoxic toxicity assays were employed to investigate the activation of CBZ for mutagenic effects, in various mammalian cell models. Docking results indicated that CBZ was valid as a substrate of human CYP2B6 and 2E1, while not for CYP1A1, 1A2, 1B1 or 3A4. In the Chinese hamster (V79) cell line and its derivatives genetically engineered for the expression of human CYP1A1, 1A2, 1B1, 2E1 or 3A4 CBZ (2.5 ~ 40 μM) did not induce micronucleus, while in human CYP2B6-expressing cells CBZ significantly induced micronucleus formation. In a human hepatoma C3A cell line, which endogenously expressed CYP2B6 twofold higher than in HepG2 cells, CBZ induced micronucleus potently, which was blocked by 1-aminobenzotriazole (inhibitor of CYPs) and ticlopidine (specific CYP2B6 inhibitor). In HepG2 cells CBZ did not induce micronucleus; however, pretreatment of the cells with CICTO (CYP2B6 inducer) led to micronucleus formation by CBZ, while rifampicin (CYP3A4 inducer) or PCB126 (CYP1A inducer) did not change the negative results. Immunofluorescent assay showed that CBZ selectively induced centromere-free micronucleus. Moreover, CBZ induced double-strand DNA breaks (γ-H2AX elevation, by Western blot) and PIG-A gene mutations (by flowcytometry) in C3A (threshold being 5 μM, lower than its therapeutic serum concentrations, 17 ~ 51 μM), with no effects in HepG2 cells. Clearly, CBZ may induce clastogenesis and gene mutations at its therapeutic concentrations, human CYP2B6 being a major activating enzyme. [ABSTRACT FROM AUTHOR]

This work describes two new colorimetric methods for smartphone-based point-of-care nanosensing of toxic Ag+ ions. They were based on the analyte-triggered in situ "off–on" of Tyndall effect (TE) of non-plasmonic colloid or plasmonic metal nanoprobes. The first TE-inspired assay (TEA) focused on the initial analytical application of precipitation reactions where a non-plasmonic AgCl colloid could be formed once mixing the analyte with a NaCl solution. Such AgCl colloid displayed strong visual TE signals after their irradiation by a laser pointer pen, which unexpectedly achieved a detection limit of ~ 400 nM. The second TEA was further designed to reduce the limit down to ~ 78 nM using the analyte's oxidizability towards 3,3′,5,5′-tetramethylbenzidine molecules. The redox reaction could create positively charged products that could make negatively charged plasmonic gold nanoparticles aggregate through electrostatic interactions to remarkably amplify their TE responses. Both limits were lower than the minimum allowable Ag+ level (~ 460 nM) in drinking water issued by the World Health Organization. The satisfactory recovery results for detecting Ag+ ions in river, pond, tap, and drinking water additionally demonstrated good selectivity, accuracy and practicality of the proposed methods for potential point-of-need uses in environmental analysis, public health, water safety, etc. [ABSTRACT FROM AUTHOR]

The ability to generate mutations is a prerequisite to functional genetic analysis. Despite a long history of using mice as a model system for genetic analysis, the scientific community has not generated a comprehensive collection of multiple alleles for most mouse genes. The chemical mutagen of choice for mouse has been N-ethyl-N-nitrosourea (ENU), an alkylating agent that mainly causes base substitutions in DNA, and therefore allows for recovery of complete and partial loss-, as well as gain-, of-function alleles. Specific locus tests designed to detect recessive mutations showed that ENU is the most efficient mutagen in mouse with an approximate mutation rate of 1 in 1,000 gametes,. In fact, several genome-wide and region-specific screens based on phenotypes have been carried out. The anticipation of the completion of the human and mouse genome projects, however, now emphasizes genotype-driven genetics-from sequence to mutants. To take advantage of the mutagenicity of ENU and its ability to create allelic series of mutations, we have developed a complementary approach to generating mutations using mouse embryonic stem (ES) cells. We show that a high mutation frequency can be achieved and that modulating DNA-repair activities can enhance this frequency. The treated cells retain germline competency, thereby rendering this approach applicable for efficient generation of an allelic series of mutations pivotal to a fine-tuned dissection of biological pathways. [ABSTRACT FROM AUTHOR]

Particulate matter (PM) induces and enhances oxidative stress and inflammation, leading to a variety of respiratory diseases, including acute lung injury. Exploring new treatments for PM-induced lung injury has long been of interest to researchers. Palmatine (PAL) is a natural extract derived from plants that has been reported in many studies to alleviate inflammatory diseases. Our study was designed to explore whether PAL can alleviate acute lung injury caused by PM. The acute lung injury model was established by instilling PM (4 mg/kg) into the airway of mice, and PAL (50 mg/kg and 100 m/kg) was administrated orally as the treatment groups. The effect and mechanism of PAL treatment were examined by immunofluorescence, immunohistochemistry, Western Blotting, ELISA, and other experiments. The results showed that oral administration of PAL (50 mg/kg and 100 m/kg) could significantly alleviate lung inflammation and acute lung injury caused by PM. In terms of mechanism, we found that PAL (50 mg/kg) exerts anti-inflammatory and anti-damage effects mainly by enhancing the activation of the Nrf2-related antioxidant pathway and inhibiting the activation of the NLRP3-related pyroptosis pathway in mice. These mechanisms have also been verified in our cell experiments. Further cell experiments showed that PAL may reduce intracellular reactive oxygen species (ROS) by activating Nrf2-related pathways, thereby inhibiting the activation of NLRP3-related pyroptosis pathway induced by PM in Beas-2B cell. Our study suggests that PAL can be a new option for PM-induced acute lung injury. [ABSTRACT FROM AUTHOR]

Exhausted CD8+ T lymphocytes and tumor-associated macrophages play critical roles in determining cancer prognosis and the efficacy of immunotherapy. Our study revealed a negative correlation between exhausted CD8+ T lymphocytes and prognosis in thyroid carcinoma (THCA). Consensus clustering divided patients into two subgroups of exhaustion with different prognoses, as defined by marker genes of exhausted CD8+ T cells. Subsequently, we constructed an eight-gene prognostic signature, and developed a risk score named the exhaustion-related gene score (ERGS) to forecast both prognosis and immunotherapy response in THCA. Bulk RNA sequencing analysis revealed a higher prevalence of M2 macrophages, indicative of an immunosuppressive tumor microenvironment (TME), in the high-ERGS group. Single-cell RNA sequencing showed that SPP1+ macrophages and CD14+ monocytes infiltrations were positively associated with higher ERGS. Functionally, it was determined that SPP1+ macrophages exert an immunosuppressive role, while CD14+ monocytes were implicated in promoting tumor progression and angiogenesis. Analysis of cell–cell interactions between SPP1+ macrophages and T cells highlighted the activation of the SPP1-CD44 and MIF-CD74 axes, both of which could foster an immunosuppressive TME. Therapeutic strategies that target SPP1+ macrophages, CD14+ monocytes, and the SPP1-CD44 and MIF-CD74 axes may potentially improve the prognosis and amplify the immunotherapy response in THCA patients. [ABSTRACT FROM AUTHOR]

We introduce a construct called "humanness sensitivity," which we define as the ability to recognize uniquely human characteristics. To evaluate the construct, we used a "concurrent study design" to conduct an internet-based study with a convenience sample of 42,063 people from 88 countries (52.4% from the U.S. and Canada).We sought to determine to what extent people could identify subtle characteristics of human behavior, thinking, emotions, and social relationships which currently distinguish humans from non-human entities such as bots. Many people were surprisingly poor at this task, even when asked simple questions about human relationships or anatomy. Participants were best at identifying subtle aspects of human cognition and worst at identifying subtle aspects of human communication. Test scores were good predictors of whether someone was employed and modest predictors of other self-reported criterion measures. We also found that people identifying themselves in marginal societal categories (e.g., in the "other" category for gender or sexual orientation) identified themselves as less human and also scored lower on our test. As computers continue to become more human-like, our study suggests that the vast majority of humankind will likely have great difficulty distinguishing them from people. Can methods be devised for improving this ability? Might humanness sensitivity help people to make such distinctions? Will people who excel at differentiating humans and non-human entities—like the "blade runners" in the 1982 and 2017 feature films—someday hold a special place in society? [ABSTRACT FROM AUTHOR]

This study aimed to investigate the risk factors for bloodstream infection (BSI) caused by extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli (E. coli) and related mortality. The clinical data of 388 patients with E. coli BSI were analyzed. Blood cultures were performed and the antimicrobial susceptibility profiles of the resulting isolates were determined. Four single-nucleotide polymorphisms (rs231775, rs12343816, rs16944, and rs2233406) were genotyped using real-time PCR. ESBL were detected by disk diffusion confirmatory testing. Univariate and multivariate regression analyses were applied to identify the risk factors for ESBL-producing isolates and the BSI-induced mortality. The prevalence of ESBL-producing E. coli in BSI patients was 40.98%. E. coli isolates were commonly susceptible to carbapenem and β-lactam/β-lactamase inhibitor combinations. The major ESBL genes were CTX-M-14, CTX-M-55, CTX-M-15, and CTX-M-27. The proportion of CTX-M-15 was significantly higher in patients over 70 years and those receiving stomach tube catheterization. Nosocomial infection, biliary tract infection, stomach tube catheterization, and previous cephalosporin administration were independent risk factors for ESBL-producing isolates. ESBL positivity, nosocomial infection, and cancer were independent risk factors of mortality. Two genetic polymorphisms associated with inflammation activation, rs231775 A allele and rs2233406 T allele, significantly increased the mortality risk of E. coli BSI with a risk ratio (95% CI) of 1.93 (1.05–3.55) and 4.38 (2.07–9.29), respectively. For patients with nosocomial infection, biliary tract infection, and cancer, the monitor of BSI and antibiotic susceptibility should be enhanced. The invasive procedures should be minimized. rs231775 and rs2233406 are promising prognostic markers for E. coli BSI patients. [ABSTRACT FROM AUTHOR]

In mammals, dosage compensation of X-linked genes is achieved by the transcriptional silencing of one X chromosome in the female (reviewed in ref. 1). This process, called X inactivation, is usually random in the embryo proper. In marsupials and the extra-embryonic region of the mouse, however, X inactivation is imprinted: the paternal X chromosome is preferentially inactivated whereas the maternal X is always active. Having more than one active X chromosome is deleterious to extra-embryonic development in the mouse. Here we show that the gene eed (embryonic ectoderm development), a member of the mouse Polycomb group (Pc-G) of genes, is required for primary and secondary trophoblast giant cell development in female embryos. Results from mice carrying a paternally inherited X-linked green fluorescent protein (GFP) transgene implicate eed in the stable maintenance of imprinted X inactivation in extra-embryonic tissues. Based on the recent finding that the Eed protein interacts with histone deacetylases, we suggest that this maintenance activity involves hypoacetylation of the inactivated paternal X chromosome in the extra-embryonic tissues. [ABSTRACT FROM AUTHOR]