A critical review of the application of polymer of low concern and regulatory criteria to fluoropolymers.

Per- and polyfluoroalkyl substances (PFAS) are a group of fluorinated substances that are in the focus of researchers and regulators due to widespread presence in the environment and biota, including humans, of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). Fluoropolymers, high molecular weight polymers, have unique properties that constitute a distinct class within the PFAS group. Fluoropolymers have thermal, chemical, photochemical, hydrolytic, oxidative, and biological stability. They have negligible residual monomer and oligomer content and low to no leachables. Fluoropolymers are practically insoluble in water and not subject to long-range transport. With a molecular weight well over 100 000 Da, fluoropolymers cannot cross the cell membrane. Fluoropolymers are not bioavailable or bioaccumulative, as evidenced by toxicology studies on polytetrafluoroethylene (PTFE): acute and subchronic systemic toxicity, irritation, sensitization, local toxicity on implantation, cytotoxicity, in vitro and in vivo genotoxicity, hemolysis, complement activation, and thrombogenicity. Clinical studies of patients receiving permanently implanted PTFE cardiovascular medical devices demonstrate no chronic toxicity or carcinogenicity and no reproductive, developmental, or endocrine toxicity. This paper brings together fluoropolymer toxicity data, human clinical data, and physical, chemical, thermal, and biological data for review and assessment to show that fluoropolymers satisfy widely accepted assessment criteria to be considered as "polymers of low concern" (PLC). This review concludes that fluoropolymers are distinctly different from other polymeric and nonpolymeric PFAS and should be separated from them for hazard assessment or regulatory purposes. Grouping fluoropolymers with all classes of PFAS for "read across" or structure-activity relationship assessment is not scientifically appropriate. Integr Environ Assess Manag 2018;14:316-334. © 2018 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Evidence for coseismic subsidence events in a southern California coastal saltmarsh.

Paleoenvironmental records from a southern California coastal saltmarsh reveal evidence for repeated late Holocene coseismic subsidence events. Field analysis of sediment gouge cores established discrete lithostratigraphic units extend across the wetland. Detailed sediment analyses reveal abrupt changes in lithology, percent total organic matter, grain size, and magnetic susceptibility. Microfossil analyses indicate that predominantly freshwater deposits bury relic intertidal deposits at three distinct depths. Radiocarbon dating indicates that the three burial events occurred in the last 2000 calendar years. Two of the three events are contemporaneous with large-magnitude paleoearthquakes along the Newport-Inglewood/Rose Canyon fault system. From these data, we infer that during large magnitude earthquakes a step-over along the fault zone results in the vertical displacement of an approximately 5-km2 area that is consistent with the footprint of an estuary identified in pre-development maps. These findings provide insight on the evolution of the saltmarsh, coseismic deformation and earthquake recurrence in a wide area of southern California, and sensitive habitat already threatened by eustatic sea level rise.

A general approach to fabricate free-standing metal sulfide@carbon nanofiber networks as lithium ion battery anodes.

A general approach for fabricating free-standing metal sulfide and carbon nanofiber mats is developed via electrospinning, starting with cheap and abundant raw materials. The prepared free-standing samples have metal sulfide nanoparticles dispersed throughout the interconnected carbon fibers. When applied to LIB, the composites demonstrate excellent cyclability and rate capability.

Case report: an electrocardiogram of spontaneous pneumothorax mimicking arm lead reversal.

BACKGROUND: There are several previously documented findings for electrocardiograms (ECGs) of spontaneous pneumothorax. These findings include axis deviation, T-wave inversion, and right bundle branch block. When an ECG has the arm leads incorrectly placed, the ECG will display right axis deviation and inversion of the P waves in lead I. There have been no previously published ECGs of spontaneous pneumothorax that have shown the same findings as reversal of the limb leads of an ECG. OBJECTIVES: A possible finding of spontaneous pneumothorax is an identical finding to that of an ECG that has been flagged for limb lead reversal. CASE REPORT: A patient presented in the emergency setting with acute chest pain and shortness of breath caused by a tension pneumothorax. An ECG was administered; findings indicated reversal of the arm leads (right axis deviation and inverted P waves in lead I), but there was no actual limb lead reversal present. ECG findings resolved upon resolution of the pneumothorax. CONCLUSIONS: If a patient presents with chest pain and shortness of breath, and the patient's ECG is flagged for limb lead reversal despite being set up correctly, the physician should raise clinical suspicion for a possible spontaneous pneumothorax.

Up-regulation of gamma interferon receptor expression due to Chlamydia-toll-like receptor interaction does not enhance signal transducer and activator of transcription 1 signaling.

Gamma interferon (IFN-gamma)-induced indoleamine dioxygenase (IDO), which inhibits chlamydial replication by reducing the availability of tryptophan, is up-regulated by interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha). The mechanisms by which this occurs include an increase in the synthesis of interferon regulatory factor-1 as well as a nuclear factor-kappaB (NF-kappaB)-dependent increase in the expression of IFN-gamma receptors (IFN-gammaR). Although Chlamydia is susceptible to IDO, it up-regulates IFN-gammaR expression to a greater degree than either IL-1beta or TNF-alpha, perhaps through interaction with Toll-like receptors (TLR). The purpose of this study was to determine the mechanism by which Chlamydia psittaci up-regulates IFN-gammaR expression and evaluate this effect on IDO induction. Infection of HEK 293 cells with C. psittaci increased IFN-gammaR expression only in cells expressing either TLR2 or TLR4 and the adaptor protein MD-2. In addition, up-regulation of IFN-gammaR expression in Chlamydia-infected HeLa cells could be blocked either by neutralizing TLRs with anti-TLR2 and/or anti-TLR4 or by inhibiting NF-kappaB transactivation with a proteasome inhibitor. Although the newly expressed IFN-gammaR in Chlamydia-infected cells were capable of binding IFN-gamma, they did not enhance IFN-gamma-induced IDO activity in a manner similar to those observed for IL-1beta and TNF-alpha. Instead, IDO activation in Chlamydia-infected cells was no different than that induced in uninfected cells, despite the increase in IFN-gammaR expression. Furthermore, the amount of IFN-gamma-induced signal transducer and activator of transcription 1 (STAT-1) activation in infected cells paralleled that observed in uninfected cells, suggesting that STAT-1 activation by these newly expressed receptors was impaired.

NF-kappa B activation contributes to indoleamine dioxygenase transcriptional synergy induced by IFN-gamma and tumor necrosis factor-alpha.

Interferon (IFN)-gamma-induced expression of indoleamine 2,3-dioxygenase (IDO), an enzyme that inhibits some pathogens by limiting tryptophan availability, is transcriptionally enhanced by tumor necrosis factor (TNF)-alpha. The expression of interferon responsive factor (IRF)-1, an IFN-gamma-induced transcriptional activator critical to IDO regulation, is also enhanced synergistically in response to IFN-gamma and TNF-alpha. The IRF-1 regulatory region contains an IFN-gamma-activated sequence (GAS) and a kappaB site, which bind STAT-1 and NF-kappaB, respectively. The TNF-alpha-mediated increase in STAT-1 activation in IFN-gamma-treated cells enhances IRF-1 transcription; however, the contribution of TNF-alpha-mediated increases in nuclear NF-kappaB is uncertain. To identify whether binding of NF-kappaB upstream of the IRF-1 gene is rate-limiting in IRF-1 expression in response to IFN-gamma and TNF-alpha, a proteasome inhibitor was utilized to maintain nuclear translocation of NF-kappaB at constitutive levels; its effect on IRF-1 expression and IDO-specific transcription was evaluated. By limiting NF-kappaB nuclear translocation, IRF-1 expression in IFN-gamma and TNF-alpha treated cells was maintained at a level comparable to that achieved in response to IFN-gamma alone, and the synergistic increase IDO transcription was blocked, suggesting that increases in NF-kappaB translocation are required for synergistic IDO expression in response to IFN-gamma and TNF-alpha.

Chlamydiae modulate gamma interferon, interleukin-1 beta, and tumor necrosis factor alpha receptor expression in HeLa cells.

Chlamydia psittaci was found to modulate receptor expression for the cytokine receptors that are involved in the synergistic induction of indoleamine dioxygenase in epithelial cells. Increases in receptor expression were seen even with inactivated Chlamydia, suggesting that chlamydial antigens and not products of infection are important for up-regulating cytokine receptor expression.

Upregulation of IFN-gamma receptor expression by proinflammatory cytokines influences IDO activation in epithelial cells.

Interferon-gamma (IFN-gamma) induces the enzyme indoleamine dioxygenase (IDO) in a variety of human cell types. Furthermore, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) synergistically increase IFN-induced IDO activity. Inasmuch as cytokines can upregulate cytokine receptor expression, one mechanism of cytokine synergy may be at the level of receptor expression. To test the hypothesis that this mechanism of IDO regulation is active in epithelial cells, HeLa cells were treated with IFN-gamma, TNF-alpha, or IL-1beta to determine optimal cytokine concentrations and time for maximal cytokine receptor expression. Flow cytometric analysis with antibodies to receptors for IFN-gamma, TNF-alpha, or IL-1beta indicated that each cytokine upregulated expression of the other cytokine receptors by 4 h, with maximal expression observed between 16 and 20 h after cytokine treatment. Furthermore, increases in IFN-gamma receptors (IFNGR) induced by IL-1beta were found to be dependent on NF-kappaB transactivation. To determine if increases in IFNGR expression alone contributes to synergistic IDO induction, cells were stimulated with IL-1beta to upregulate receptor expression, and the NF-kappaB concentration was allowed to return to basal levels. When treated with IFN-gamma, enhanced Stat1 signaling and IDO induction were still observed, indicating that increased cytokine receptor expression contributes to synergistic increases in IDO activity.

The role of IFN-gamma and TNF-alpha-responsive regulatory elements in the synergistic induction of indoleamine dioxygenase.

Indoleamine 2,3-dioxygenase (IDO), which enzymatically depletes tryptophan, is an important antimicrobial defense mechanism against susceptible pathogens. In human epithelial cells, interferon-gamma (IFN-gamma)-induced IDO expression is transcriptionally enhanced by tumor necrosis factor-alpha(TNF-alpha). The purpose of this study was to identify those regulatory mechanisms responsible for this synergistic transcriptional activation of IDO. Nuclear concentrations of signal transducer and activator of transcription-1 (Stat1) and IFN regulatory factor-1 (IRF-1), transcription factors that bind gamma-activated sequences (GAS) and IFN-stimulated response elements (ISRE), respectively, were found to increase after stimulation with IFN-gamma and TNF-alpha relative to stimulation with individual cytokines. Additionally, CCAAT enhancer binding protein-beta (C/EBP-beta) bound to one of three consensus C/EBP-beta sites in the IDO regulatory region in response to TNF-alpha alone or combined with IFN-gamma. A transcriptional reporter containing green fluorescent protein (GFP) under the control of the IDO regulatory region was used to analyze the contribution of these enhancer elements to synergistic IDO gene expression in response to IFN-gamma and TNF-alpha. Transcriptional activity following mutation of individual enhancers or large deletions within the regulatory region indicates that increased binding of IFN-gamma-transactivated factors to GAS and ISRE sites alone is responsible for synergistic transcriptional activation of the IDO gene.

Synergistic transcriptional activation of indoleamine dioxygenase by IFN-gamma and tumor necrosis factor-alpha.

Interferon-gamma (IFN-gamma)-induced indoleamine 2,3-dioxygenase (IDO) activity inhibits the growth of susceptible intracellular pathogens by catalyzing the oxidative cleavage of the indole ring of L-tryptophan and depleting pools of the essential amino acid. Tumor necrosis factor-alpha (TNF-alpha) synergistically enhances the IDO activity induced by IFN-gamma at the level of transcription in human epithelial cells. The purpose of this study was to characterize the molecular mechanisms responsible for synergistic gene expression in response to IFN-gamma and TNF-alpha. It was found that IFN-gamma-induced mechanisms, such as the binding of Stat1 to gamma activation sequences (GAS) and IFN regulatory factor-1 (IRF-1) to IFN-stimulated response elements (ISREs), are more highly activated following treatment with IFN and TNF-alpha. This enhanced signal transduction may be due to the increase in IFN-gamma receptor (IFNGR) expression following combined cytokine stimulation and is a likely contributor to the synergy. Additionally, the contribution of a third previously uncharacterized GAS element that forms a complex with Stat1 was investigated using a plasmid reporter system that controls for copy number. When the GAS-3 sequence was included in the regulatory region, gene expression was significantly increased relative to a region containing the mutated GAS-3. This suggests that GAS-3 is transcriptionally active and contributes to IFN-gamma-induced regulation of the IDO gene.