BACKGROUND: Perfluorooctanoic acid (PFOA) is a poly-and perfluoroalkyl substance (PFAS) associated with adverse pregnancy outcomes in mice and humans, but little is known regarding one of its replacements, hexafluoropropylene oxide dimer acid (HFPO-DA, referred to here as GenX), both of which have been reported as contaminants in drinking water. OBJECTIVES: We compared the toxicity of PFOA and GenX in pregnant mice and their developing embryo-placenta units, with a specific focus on the placenta as a hypothesized target. METHODS: Pregnant CD-1 mice were exposed daily to PFOA (0, 1, or 5 mg=kg) or GenX (0, 2, or 10 mg=kg) via oral gavage from embryonic day (E) 1.5 to 11.5 or 17.5 to evaluate exposure effects on the dam and embryo-placenta unit. Gestational weight gain (GWG), maternal clinical chemistry, maternal liver histopathology, placental histopathology, embryo weight, placental weight, internal chemical dosimetry, and placental thyroid hormone levels were determined. RESULTS: Exposure to GenX or PFOA resulted in increased GWG, with increase in weight most prominent and of shortest latency with 10 mg=kg=d GenX exposure. Embryo weight was significantly lower after exposure to 5 mg=kg=d PFOA (9.4% decrease relative to controls). Effect sizes were similar for higher doses (5 mg=kg=d PFOA and 10 mg=kg=d GenX) and lower doses (1 mg=kg=d PFOA and 2 mg=kg=d GenX), including higher maternal liver weights, changes in liver histopathology, higher placental weights and embryo-placenta weight ratios, and greater incidence of placental abnormalities relative to controls. Histopathological features in placentas suggested that PFOA and GenX may exhibit divergent mechanisms of toxicity in the embryo-placenta unit, whereas PFOA-and GenX-exposed livers shared a similar constellation of adverse pathological features. CONCLUSIONS: Gestational exposure to GenX recapitulated many documented effects of PFOA in CD-1 mice, regardless of its much shorter reported half-life; however, adverse effects toward the placenta appear to have compound-specific signatures.
Resistance to the intestinal parasitic helminth Trichuris muris requires T-helper 2 (TH2) cellular and associated IgG1 responses, with expulsion typically taking up to 4 weeks in mice. Here, we show that the time-of-day of the initial infection affects efficiency of worm expulsion, with strong TH2 bias and early expulsion in morning-infected mice. Conversely, mice infected at the start of the night show delayed resistance to infection, and this is associated with feeding-driven metabolic cues, such that feeding restriction to the day-time in normally nocturnal-feeding mice disrupts parasitic expulsion kinetics. We deleted the circadian regulator BMAL1 in antigen-presenting dendritic cells (DCs) in vivo and found a loss of time-of-day dependency of helminth expulsion. RNAseq analyses revealed that IL-12 responses to worm antigen by circadian-synchronised DCs were dependent on BMAL1. Therefore, we find that circadian machinery in DCs contributes to the TH1/TH2 balance, and that environmental, or genetic perturbation of the DC clock results in altered parasite expulsion kinetics.
ObjectivesTo explore how formative OSCEs influence student performance and perception when undertaking summative OSCEs.MethodsWe introduced formative OSCEs for second-year medical students at a large London medical school. Examination data from both formative and subsequent summative OSCEs were analysed to determine the effect on summative OSCE performance. We gathered student perceptions using an anonymous online survey tool. The data was investigated using a standard scale of 1 to 5 and qualitative analysis of free text.ResultsOverall, 46.6% and 85.0% of students passed the formative and summative OSCEs respectively. Formative OSCEs did not improve overall pass rates in summative OSCEs. Inclusion of an individual formative station was associated with improved performance in that station in summative OSCEs, with one exception. Formative OSCEs had a positive predictive value of 92.5% for passing the summative OSCE but limited negative predictive value. Students who passed fewer than two out of three formative OSCE stations were significantly more likely to fail the summative OSCE (78.2% vs 89.7%, p <0.001). Students felt formative OSCEs were good exam preparation and suggested logistical changes.Conclusion Formative OSCEs were associated with improved performance in subsequent summative OSCEs only for identical stations. They did not improve overall pass rates in summative OSCEs, and did not predict performance well. Students viewed the formative OSCE as a positive and useful activity. However, to maximise its benefit as a tool for learning, students need better communication about the role and purpose of formative OSCEs.
This study demonstrates the impact of visual cues in eliciting sensations of itch and provoking a scratch response, and may provide behavioural evidence linking contagious itch to the mirror neuron system.
SUMMARY1. Cultured chick heart cells challenged by hyposmotic stress underwent regulatory volume decrease (RVD) that was attenuated by prior depletion of intracellular chloride.2. During hyposmotic swelling, cell aggregates experienced an initial increase in spontaneous contractile activity followed by eventual quiescence. Conventional microelectrode studies revealed an underlying increase in spontaneous electrical activity, followed by a sustained depolarization beyond threshold.3. Whole-cell patch clamp studies, with K+ currents blocked, indicated that exposure of cells to hyposmotic solution (NaCl reduction) resulted in a rapid osmotic swelling followed by a substantial increase in whole-cell conductance which persisted for the duration of hyposmotic exposure and was almost completely reversed on return to isosmotic bath solution.4. For a variety of Cl-concentrations, the reversal potentials (Erev) of the measured swelling-activated current closely followed the calculated Cl-equilibrium potential (Ecl) with a linear regression slope of
Over the past few years, human exposure to per- and polyfluoroalkyl substances (PFAS) has garnered increased attention. Research has focused on PFAS exposure via drinking water and diet, and fewer studies have focused on exposure in the indoor environment. To support more research on the latter exposure pathway, we conducted a study to evaluate PFAS in indoor dust. Dust samples from 184 homes in North Carolina and 49 fire stations across the United States and Canada were collected and analyzed for a suite of PFAS using liquid and gas chromatography–mass spectrometry. Fluorotelomer alcohols (FTOHs) and di-polyfluoroalkyl phosphoric acid esters (diPAPs) were the most prevalent PFAS in both fire station and house dust samples, with medians of approximately 100 ng/g dust or greater. Notably, perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonate, perfluorononanoic acid, and 6:2 diPAP were significantly higher in dust from fire stations than from homes, and 8:2 FTOH was significantly higher in homes than in fire stations. Additionally, when comparing our results to earlier published values, we see that perfluoroalkyl acid levels in residential dust appear to decrease over time, particularly for PFOA and PFOS. These results highlight a need to better understand what factors contribute to PFAS levels in dust and to understand how much dust contributes to overall human PFAS exposure.
1. Changes in myocardial cell volume and whole‐cell currents were measured simultaneously during hyposmotically induced cell swelling. In the conventional patch clamp configuration, hyposmotic challenge caused myocytes to swell continuously and was associated with the development of a sustained, swelling‐induced chloride conductance (ICl). In contrast, perforated patch‐clamped myocytes demonstrated regulatory volume decreases (RVD) during hyposmotic challenge, and ICl was not generated. 2. The swelling‐induced ICl in conventionally patch‐clamped myocytes was inhibited by application of forskolin (15 microM) and was prevented when the pipette filling solution contained cAMP (10 microM) and isobutylmethylxanthine (IBMX, 1 mM). ICl could also be prevented by inhibition of protein phosphatase activity, using okadaic acid (100 nM). Conversely, a swelling‐induced current could be generated in myocytes under perforated patch clamp by inhibition of protein kinase A, using the antagonist Rp‐cAMPS (10 microM). These data demonstrate that cAMP‐dependent protein phosphorylation is both necessary and sufficient to prevent development of ICl during cell swelling. 3. Unlike other chloride currents described previously in heart muscle, generation of the novel swelling‐induced ICl requires dephosphorylation of a cAMP‐dependent protein phosphorylation site; hence it can be prevented by stimulation of cAMP‐dependent protein phosphorylation or by inhibition of protein phosphatase activity.
Large conductance, calcium-activated potassium channels (BK Ca or maxi-K) are important determinants of membrane excitability in many cell types. We used patch clamp techniques to study the biochemical regulation of native BK Ca channel proteins by endogenous Ser/Thr-directed protein kinases and phosphatases in cell-free membrane patches from rat pituitary tumor cells (GH 4 C 1 ). When protein kinase activity was blocked by removing ATP, endogenous protein phosphatases slowly increased BK Ca channel activity approximately 3-fold. Dephosphorylated channels could be activated fully by physiological increases in cytoplasmic calcium or membrane depolarization. In contrast, endogenous protein kinases inhibited BK Ca channel activity at two functionally distinct sites. A closely associated, cAMPdependent protein kinase rapidly reduced channel activity in a conditional manner that could be overcome completely by increasing cytoplasmic free calcium 3-fold or 20 mV further depolarization. Phosphorylation at a pharmacologically distinct site inhibited channel activity unconditionally by reducing availability to approximately half that of maximum at all physiological calcium and voltages. Conditional versus unconditional inhibition of BK Ca channel activity through different protein kinases provides cells with a powerful computational mechanism for regulating membrane excitability.Large conductance, calcium-activated potassium channels (BK Ca or maxi-K channels) are uniquely powerful determinants of electrical activity in the nervous, endocrine, and vascular systems, since they respond directly to both membrane depolarization and calcium accumulation (1). The sensitivity of BK Ca channels to such physiological stimuli can be modified by enzyme pathways mediating reversible phosphorylation of the ion channel proteins or other closely associated regulatory proteins (2). Such reversible protein phosphorylation is the primary mechanism for regulating ion channel activity on the physiological time scale of seconds and minutes (2-4). Modification of the behavior of BK Ca channels has profound effects on the frequency and duration of action potentials in excitable cells, thereby controlling the physiological function of these cells.Electrophysiological measurements indicate that the activity of BK Ca channels in native cells may be up-or down-regulated by reversible protein phosphorylation. For example, protein kinase-induced phosphorylation enhances calcium-activated potassium currents in smooth muscle (5, 6), whereas in photoreceptors (7), hippocampal neurones (8 -11), and neurendocrine cells (12), the currents are inhibited by kinase activity. BK Ca channels exist as multimeric protein complexes composed of two integral membrane subunits, the pore-forming ␣ subunit and the regulatory  subunit (1). All ␣ subunits are apparently coded by the same gene, the slo gene, but alternative RNA splicing during development produces functionally distinct channel proteins in different cell types (13-15). Hence, opposite modulatory effects ...
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