Inflammation is essential for host defense but can cause tissue damage and organ failure if unchecked. How the inflammation is resolved remains elusive. Here we report that the transcription factor Miz1 was required for terminating lipopolysaccharide (LPS)-induced inflammation. Genetic disruption of the Miz1 POZ domain, which is essential for its transactivation or repression activity, resulted in hyper-inflammation, lung injury and increased mortality in LPS-treated mice while reduced bacterial load and mortality in mice with Pseudomonas aeruginosa pneumonia. Loss of the Miz1 POZ domain prolonged pro-inflammatory cytokine expression. Upon stimulation, Miz1 was phosphorylated at Ser178, which is required for recruiting histone deacetylase 1 to repress transcription of C/EBP-δ, an amplifier of inflammation. Our data provide a long-sought mechanism underlying resolution of LPS-induced inflammation.
Non-targeted nanoparticles are capable of entering cells, passing through different subcellular compartments and accumulating on their surface a protein corona that changes over time. In this study, we used metal oxide nanoparticles with iron-oxide core covered with titanium dioxide shell (Fe3O4@TiO2), with a single layer of covalently bound dopamine covering the nanoparticle surface. Mixing nanoparticles with cellular protein isolates showed that these nanoparticles can form complexes with numerous cellular proteins. The addition of non-toxic quantities of nano-particles to HeLa cell culture resulted in their non-specific uptake and accumulation of protein corona on nanoparticle surface. TfRC, Hsp90 and PARP were followed as representative protein components of nanoparticle corona; each protein bound to nanoparticles with different affinity. The presence of nanoparticles in cells also mildly modulated gene expression on the level of mRNA. In conclusion, cells exposed to non-targeted nanoparticles show subtle but numerous changes that are consistent from one experiment to another.
Studies of ionizing radiation effects through the archiving of data began with standardizing medical treatments in the early 1900s shortly after the discovery of X-rays. Once the breadth of the delayed effects of ionizing radiation was recognized, the need for long-term follow up became apparent. There are now many human archives of data from nuclear disasters and accidents, occupational exposures, and medical procedures. Planned animal irradiation experiments began around the time of the Cold War and included a variety of doses, fractions, dose rates, and types of ionizing radiation. The goal of most of these studies was to supplement information coming from human data through carefully planned experimental conditions and immediate and uninterrupted data collection. This review aims to highlight major archives and databases that have shaped the field of radiation biology and provide a broad range of the types of datasets currently available. By preserving all of these data and tissue sets, radiation biologists can combine databases and conduct large-scale analyses of detailed existing data and perform new assays with cutting edge scientific approaches.
Human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) is biologically distinct from HPV-negative HNSCC. Outside of HPV-status, few tumor-intrinsic variables have been identified that correlate to improved survival. As part of exploratory analysis into the trace elemental composition of oropharyngeal squamous cell carcinoma (OPSCC), we performed elemental quanitification by X-ray fluorescence microscopy (XFM) on a small cohort (n = 32) of patients with HPV-positive and -negative OPSCC and identified in HPV-positive cases increased zinc (Zn) concentrations in tumor tissue relative to normal tissue. Subsequent immunohistochemistry of six Zn-binding proteins—zinc-α2-glycoprotein (AZGP1), Lipocalin-1, Albumin, S100A7, S100A8 and S100A9—revealed that only AZGP1 expression significantly correlated to HPV-status (p < 0.001) and was also increased in tumor relative to normal tissue from HPV-positive OPSCC tumor samples. AZGP1 protein expression in our cohort significantly correlated to a prolonged recurrence-free survival (p = 0.029), similar to HNSCC cases from the TCGA (n = 499), where highest AZGP1 mRNA levels correlated to improved overall survival (p = 0.023). By showing for the first time that HPV-positive OPSCC patients have increased intratumoral Zn levels and AZGP1 expression, we identify possible positive prognostic biomarkers in HNSCC as well as possible mechanisms of increased sensitivity to chemoradiation in HPV-positive OPSCC.
With increasing medical radiation exposures, it is important to understand how different modes of delivery of ionizing radiation as well as total doses of exposure impact health outcomes. Our lab studied the risks associated with ionizing radiation by analyzing the Northwestern University Radiation Archive for animals (NURA). NURA contains detailed data from a series of 10 individual neutron and gamma irradiation experiments conducted on over 50,000 mice. Rigorous statistical testing on control mice from all Janus experiments enabled us to select studies that could be compared to one another and uncover unexpected differences among the controls as well as experimental animals. For controls, mice sham irradiated with 300 fractions died significantly earlier than those with fewer sham fractions and were excluded from the pooled dataset. Using the integrated dataset of gamma irradiated and control mice, we found that fractionation significantly decreased the death hazard for animals dying of lymphomas, tumors, non-tumors, and unknown causes. Gender differences in frequencies of causes of death were identified irrespective of irradiation and dose fractionation, with female mice being at a greater risk for all causes of death, except for lung tumors. Irradiated and control male mice were at a significantly greater risk for lung tumors, the opposite from observations noted in humans. Additionally, we discovered that lymphoma deaths can occur quickly after exposures to high doses of gamma rays. This study systematically cross-compared outcomes of different modes of fractionation evaluated across different Janus experiments and across a wide span of total doses. It demonstrates that protraction modulated survival and disease status differently based on the total dose, cause of death, and sex of an animal. This novel method for analyzing the Janus datasets will lead to insightful new mechanistic hypotheses and research in the fields of radiation biology and protection.
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