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Application of the Key Characteristics of Carcinogens to Per and Polyfluoroalkyl Substances
No full textPer- and polyfluoroalkyl substances (PFAS) constitute a large class of environmentally persistent chemicals used in industrial and consumer products. Human exposure to PFAS is extensive, and PFAS contamination has been reported in drinking water and food supplies as well as in the serum of nearly all people. The most well-studied member of the PFAS class, perfluorooctanoic acid (PFOA), induces tumors in animal bioassays and has been associated with elevated risk of cancer in human populations. GenX, one of the PFOA replacement chemicals, induces tumors in animal bioassays as well. Using the Key Characteristics of Carcinogens framework for cancer hazard identification, we considered the existing epidemiological, toxicological and mechanistic data for 26 different PFAS. We found strong evidence that multiple PFAS induce oxidative stress, are immunosuppressive, and modulate receptor-mediated effects. We also found suggestive evidence indicating that some PFAS can induce epigenetic alterations and influence cell proliferation. Experimental data indicate that PFAS are not genotoxic and generally do not undergo metabolic activation. Data are currently insufficient to assess whether any PFAS promote chronic inflammation, cellular immortalization or alter DNA repair. While more research is needed to address data gaps, evidence exists that several PFAS exhibit one or more of the key characteristics of carcinogens
CpeF is the bilin lyase that ligates the doubly linked phycoerythrobilin on -phycoerythrin in the cyanobacterium Fremyella diplosiphon
No full textPhycoerythrin (PE) is a green light–absorbing protein present in the light-harvesting complex of cyanobacteria and red algae. The spectral characteristics of PE are due to its prosthetic groups, or phycoerythrobilins (PEBs), that are covalently attached to the protein chain by specific bilin lyases. Only two PE lyases have been identified and characterized so far, and the other bilin lyases are unknown. Here, using in silico analyses, markerless deletion, biochemical assays with purified and recombinant proteins, and site-directed mutagenesis, we examined the role of a putative lyase-encoding gene, cpeF, in the cyanobacterium Fremyella diplosiphon. Analyzing the phenotype of the cpeF deletion, we found that cpeF is required for proper PE biogenesis, specifically for ligation of the doubly linked PEB to Cys-48/Cys-59 residues of the CpeB subunit of PE. We also show that in a heterologous host, CpeF can attach PEB to Cys-48/Cys-59 of CpeB, but only in the presence of the chaperone-like protein CpeZ. Additionally, we report that CpeF likely ligates the A ring of PEB to Cys-48 prior to the attachment of the D ring to Cys-59. We conclude that CpeF is the bilin lyase responsible for attachment of the doubly ligated PEB to Cys-48/Cys-59 of CpeB and together with other specific bilin lyases contributes to the post-translational modification and assembly of PE into mature light-harvesting complexes
Lay evaluations of police and civilian use of force: Action severity scales
No full textIn modern societies, citizens cede the legitimate use of violence to law enforcement agents who act on their behalf. However, little is known about the extent to which lay evaluations of forceful actions align with or diverge from official use-of-force policies and heuristics that officers use to choose appropriate levels of responsive force. Moreover, it is impossible to accurately compare official policies and lay intuitions without first measuring the perceived severity of a set of representative actions. To map these psychometric scale values precisely, we presented participants (N = 411 Amazon Mechanical Turk workers, N = 395 undergraduates) with minimal vignettes describing officer and civilian actions that span the entire range of force options (from polite dialogue to lethal force), and asked them to rate physical magnitude and moral appropriateness. We used Bayesian methods to model the ratings as functions of simultaneously estimated scale values of the actions. Results indicated that the perceived severity of actions across all physical but nonlethal categories clustered tightly together, while actions at the extreme levels were relatively spread out. Moreover, less normative officer actions were perceived as especially morally severe. Broadly, our findings reveal divergence between lay perceptions of force severity and official law enforcement policies, and they imply that the groundwork for disagreement about the legitimacy of police and civilian actions may be partially rooted in the differential way that action severity is perceived by law enforcement relative to civilian observers. (PsycInfo Database Record (c) 2020 APA, all rights reserved
Neuregulin and ErbB expression is regulated by development and sensory experience in mouse visual cortex
No full textNeuregulins (NRGs) are protein ligands that impact neural development and circuit function. NRGs signal through the ErbB receptor tyrosine kinase family. NRG1/ErbB4 signaling in parvalbumin‐expressing (PV) inhibitory interneurons is critical for visual cortical plasticity. There are multiple types of NRGs and ErbBs that can potentially contribute to visual cortical plasticity at different developmental stages. Thus, it is important to understand the normal developmental expression profiles of NRGs and ErbBs in specific neuron types in the visual cortex, and to study whether and how their expression changes in PV inhibitory neurons and excitatory neurons track with sensory perturbation. Cell type‐specific translating ribosome affinity purification and qPCR was used to compare mRNA expression of nrg1,2,3,4 and erbB1,2,3,4 in PV and excitatory neurons in mouse visual cortex. We show that the expression of nrg1 and nrg3 decreases in PV neurons at the critical period peak, postnatal day 28 (P28) after monocular deprivation and dark rearing, and in the adult cortex (at P104) after 2‐week long dark exposure. In contrast, nrg1 expression by excitatory neurons is unchanged at P28 and P104 following sensory deprivation, whereas nrg3 expression by excitatory neurons shows changes depending on the age and the mode of sensory deprivation. ErbB4 expression in PV neurons remains consistently high and does not appear to change in response to sensory deprivation. These data provide new important details of cell type‐specific NRG/ErbB expression in the visual cortex and support that NRG1/ErbB4 signaling is implicated in both critical period and adult visual cortical plasticity
Gene-by-gene interactions associated with the risk of conotruncal heart defects
No full textBackground: The development of conotruncal heart defects (CTDs) involves a complex relationship among genetic variants and maternal lifestyle factors. In this article, we focused on the interactions between 13 candidate genes within folate, homocysteine, and transsulfuration pathways for potential association with CTD risk. Methods: Targeted sequencing was used for 328 case‐parental triads enrolled in the National Birth Defects Prevention Study (NBDPS). To evaluate the interaction of two genes, we applied a conditional logistic regression model for all possible SNP pairs within two respective genes by contrasting the affected infants with their pseudo‐controls. The findings were replicated in an independent sample of 86 NBDPS case‐parental triads genotyped by DNA microarrays. The results of two studies were further integrated by a fixed‐effect meta‐analysis. Results: One SNP pair (i.e., rs4764267 and rs6556883) located in gene MGST1 and GLRX, respectively, was found to be associated with CTD risk after multiple testing adjustment using simpleM, a modified Bonferroni correction approach (nominal p‐value of 4.62e‐06; adjusted p‐value of .04). Another SNP pair (i.e., rs11892646 and rs56219526) located in gene DNMT3A and MTRR, respectively, achieved marginal significance after multiple testing adjustment (adjusted p‐value of .06). Conclusion Further studies with larger sample sizes are needed to confirm and elucidate these potential interactions
Mitochondrial DNA alterations in aged macrophage migration inhibitory factor-knockout mice
No full textThe age-induced, exponential accumulation of mitochondrial DNA (mtDNA) deletion mutations contributes to muscle fiber loss. The causes of these mutations are not known. Systemic inflammation is associated with decreased muscle mass in older adults and is implicated in the formation of sporadic mtDNA deletions. Macrophage migration inhibitory factor knockout (MIF-KO) mice are long-lived with decreased inflammation. We hypothesized that aged MIF-KO mice would have lower mtDNA deletion frequencies and fewer electron transport chain (ETC) deficient fibers. We measured mtDNA copy number and mutation frequency as well as the number and length of ETC deficient fibers in 22-month old MIF-KO and F2 hybrid control mice. We also measured mtDNA copy number and deletion frequency in female UM-HET3 mice, a strain whose lifespan matches the MIF-KO mice. We did not observe a significant effect of MIF ablation on muscle mtDNA deletion frequency. There was a significantly lower mtDNA copy number in the MIF-KO mice and the lifespan-matched UM-HET3 mice compared to the F2 hybrids, suggesting the importance of genetic background in mtDNA copy number control. Our data do not support a definitive role for MIF in age-induced mtDNA deletions
Peri Theon: The Renaissance Confronts the Gods
No full textThis essay traces the legacy of the ancient Greek sophists in the European Renaissance with particular attention to the study of religion as a human institution. Vernacular writers such as Niccolò Machiavelli and Michel de Montaigne follow the lead of the sophists in their effort to bring religion into the field of social thought. Montaigne himself offers a particularly interesting variation on the sole remaining fragment of Protagoras of Abdera’s Peri theon. In this way, these thinkers inscribe themselves in a genealogy of sophistic that continues from Classical Greece to the Enlightenment
Understanding the Land Carbon Cycle with Space Data: Current Status and Prospects
No full textOur understanding of the terrestrial carbon cycle has been greatly enhanced since satellite observations of the land surface started. The advantage of remote sensing is that it provides wall-to-wall observations including in regions where in situ monitoring is challenging. This paper reviews how satellite observations of the biosphere have helped improve our understanding of the terrestrial carbon cycle. First, it details how remotely sensed information of the land surface has provided new means to monitor vegetation dynamics and estimate carbon fluxes and stocks. Second, we present examples of studies which have used satellite products to evaluate and improve simulations from global vegetation models. Third, we focus on model data integration approaches ranging from bottom-up extrapolation of single variables to carbon cycle data assimilation system able to ingest multiple types of observations. Finally, we present an overview of upcoming satellite missions which are likely to further improve our understanding of the terrestrial carbon cycle and its response to climate change and extremes
Noradrenergic depletion causes sex specific alterations in the endocannabinoid system in the Murine prefrontal cortex
No full textBrain endocannabinoids (eCB), acting primarily via the cannabinoid type 1 receptor (CB1r), are involved in the regulation of many physiological processes, including behavioral responses to stress. A significant neural target of eCB action is the stress-responsive norepinephrine (NE) system, whose dysregulation is implicated in myriad psychiatric and neurodegenerative disorders. Using Western blot analysis, the protein expression levels of a key enzyme in the biosynthesis of the eCB 2-arachidonoylglycerol (2-AG), diacylglycerol lipase-α (DGL-α), and two eCB degrading enzymes monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH) were examined in a mouse model that lacks the NE-synthesizing enzyme, dopamine β-hydroxylase (DβH-knockout, KO) and in rats treated with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4). In the prefrontal cortex (PFC), DGL-α protein expression was significantly increased in male and female DβH-KO mice (P < 0.05) compared to wild-type (WT) mice. DβH-KO male mice showed significant decreases in FAAH protein expression compared to WT male mice. Consistent with the DβH-KO results, DGL-α protein expression was significantly increased in male DSP-4-treated rats (P < 0.05) when compared to saline-treated controls. MGL and FAAH protein expression levels were significantly increased in male DSP-4 treated rats compared to male saline controls. Finally, we investigated the anatomical distribution of MGL and FAAH in the NE containing axon terminals of the PFC using immunoelectron microscopy. MGL was predominantly within presynaptic terminals while FAAH was localized to postsynaptic sites. These results suggest that the eCB system may be more responsive in males than females under conditions of NE perturbation, thus having potential implications for sex-specific treatment strategies of stress-related psychiatric disorders
Learning-accelerated discovery of immune-tumour interactions
No full textWe present an integrated framework for enabling dynamic exploration of design spaces for cancer immunotherapies with detailed dynamical simulation models on high-performance computing resources. Our framework combines PhysiCell, an open source agent-based simulation platform for cancer and other multicellular systems, and EMEWS, an open source platform for extreme-scale model exploration. We build an agent-based model of immunosurveillance against heterogeneous tumours, which includes spatial dynamics of stochastic tumour–immune contact interactions. We implement active learning and genetic algorithms using high-performance computing workflows to adaptively sample the model parameter space and iteratively discover optimal cancer regression regions within biological and clinical constraints