While transfusion of donor blood is a reasonably safe and well-established procedure, artificial oxygen carriers offer several advantages over blood transfusions. These benefits include compatibility with all blood types, thus avoiding the need for cross matching, availability, lack of infection, and long-term storage. Hemoglobin (Hb)-based oxygen carriers (HBOCs) are being explored as an "oxygen bridge" to replace or complement standard blood transfusions in extreme, life-threatening situations such as trauma in remote locations or austere battlefield or when blood is not an option due to compatibility issues or patient refusal due to religious objections. Herein, a novel HBOC was prepared using the layer-by-layer technique. A poly(lactide-co-glycolide) core was fabricated and subsequently decorated with Hb and nanozymes. The Hb was coated with poly(dopamine), and preservation of the protein structure and functionality was demonstrated. Next, cerium oxide nanoparticles were incorporated as nanozymes, and their ability to deplete reactive oxygen species (ROS) was shown. Finally, decorating the nanocarrier surface with poly(ethylene glycol) decreased protein adsorption and cell association/uptake. The as-prepared Hb-based oxygen nanocarriers were shown to be hemo- and bio-compatible. Their catalytic potential was furthermore demonstrated in terms of superoxide radical- and peroxide-scavenging abilities, which were retained over multiple cycles. Overall, these results demonstrate that the reported nanocarriers show potential as novel oxygen delivery systems with prolonged catalytic activity against ROS.Mechanisms underlying adverse birth and later in life health effects from exposure to air pollution during the prenatal period have not been not fully elucidated, especially in the context of mixtures. We assessed the effects of prenatal exposure to mixtures of air pollutants of particulate matter (PM), PM2.5, PM10, nitrogen oxides, NO2, NO x , ultrafine particles (UFP), and oxidative potential (OP) of PM2.5 on infant birthweight in four European birth cohorts and the mechanistic underpinnings through cross-omics of metabolites and inflammatory proteins. The association between mixtures of air pollutants and birthweight z-scores (standardized for gestational age) was assessed for three different mixture models, using Bayesian machine kernel regression (BKMR). We determined the direct effect for PM2.5, PM10, NO2, and mediation by cross-omic signatures (identified using sparse partial least-squares regression) using causal mediation BKMR models. There was a negative association with birthweight z-scores and exposure to mixtures of air pollutants, where up to -0.21 or approximately a 96 g decrease in birthweight, comparing the 75th percentile to the median level of exposure to the air pollutant mixture could occur. Shifts in birthweight z-scores from prenatal exposure to PM2.5, PM10, and NO2 were mediated by molecular mechanisms, represented by cross-omics scores. Interleukin-17 and epidermal growth factor were identified as important inflammatory responses underlyingair pollution-associated shifts in birthweight. Our results signify that by identifying mechanisms through which mixtures of air pollutants operate, the causality of air pollution-associated shifts in birthweight is better supported, substantiating the need for reducing exposure in vulnerable populations.Fine control of the expression levels of proteins constitutes a major challenge in synthetic biology and metabolic engineering. However, the dependence of translation initiation on the downstream coding sequence (CDS) obscures accurate prediction of the protein expression levels from mRNA sequences. Here, we present a tunable gene-expression system comprising 24 expression cassettes that produce predefined relative expression levels of proteins ranging from 0.001 to 1 without being influenced by the downstream CDS. To validate the practical utility of the tunable expression system, it was applied to a synthetic circuit displaying three states of fluorescence depending on the difference in protein expression levels. To demonstrate the suitability of application to metabolic engineering, this system was used to diversify the levels of key metabolic enzymes. As a result, expression-optimized strains were capable of producing 2.25 g/L of cadaverine, 2.59 g/L of L-proline, and 95.7 mg/L of 1-propanol. Collectively, the tunable expression system could be utilized to optimize genetic circuits for desired operation and to optimize metabolic fluxes through biosynthetic pathways for enhancing production yields of bioproducts. This tunable system will be useful for studying basic and applied biological sciences in addition to applications in synthetic biology and metabolic engineering.Cancer immunotherapy has been a favorable strategy for facilitating antitumor immunity. However, immune tolerance and an ultimate immunosuppressive tumor microenvironment (ITM) are primary obstacles. To achieve the goals of remodeling the ITM and promoting cancer immunotherapy, a versatile nanoparticle codelivering shikonin (SK) and PD-L1 knockdown siRNA (SK/siR-NPs) was reported. SK/siR-NPs are demonstrated to tellingly induce the immunogenic cell death (ICD) of tumor cells, leading to increased dendritic cell maturation. Moreover, SK/siR-NPs can cause an efficacious inhibition of PD-L1, leading to enhanced cytotoxic T lymphocyte response to tumor cells. Most importantly, SK/siR-NPs can restrain lactate production via the downregulation of pyruvate kinase-M2 (PKM2) and eventually repolarize tumor associated macrophages (TAMs) from the M2-subtype to M1-subtype states. Meanwhile, SK/siR-NPs suppress regulatory T lymphocytes to fight with the ITM. Overall, the developed co-delivery system presents a significant potential for cancer immunotherapy through simultaneously inducing ICD, repolarizing M2-TAMs, and relieving PD-L1 pathway-regulated immune tolerance.Synthetic analogues of the marine natural product sintokamides have been prepared in order to investigate the structure-activity relationships for the androgen receptor N-terminal domain (AR NTD) antagonist activity of the sintokamide scaffold. An in vitro LNCaP cell-based transcriptional activity assay with an androgen-driven luciferase (Luc) reporter was used to monitor the potency of analogues. The data have shown that the chlorine atoms on the leucine side chains are essential for potent activity. Analogues missing the nonchlorinated methyl groups of the leucine side chains (C-1 and C-17) are just as active and in some cases more active than the natural products. Analogues with the natural R configuration at C-10 and the unnatural R configuration at C-4 are most potent. Replacing the natural propionamide N-terminus cap with the more sterically hindered pivaloylamide N-terminus cap leads to enhanced potency. selleck kinase inhibitor The tetramic acid fragment and the methyl ether on the tetramic acid fragment are essential for activity.