The alpha 7 nicotinic receptor agonist PHA-543613 hydrochloride inhibits <i>Porphyromonas gingivalis</i>-induced expression of interleukin-8 by oral keratinocytes

Objective: The alpha 7 nicotinic receptor (α7nAChR) is expressed by oral keratinocytes. α7nAChR activation mediates anti-inflammatory responses. The objective of this study was to determine if α7nAChR activation inhibited pathogen-induced interleukin-8 (IL-8) expression by oral keratinocytes.&lt;p&gt;&lt;/p&gt; Materials and methods: Periodontal tissue expression of α7nAChR was determined by real-time PCR. OKF6/TERT-2 oral keratinocytes were exposed to &lt;i&gt;Porphyromonas gingivalis&lt;/i&gt; in the presence and absence of a α7nAChR agonist (PHA-543613 hydrochloride) alone or after pre-exposure to a specific α7nAChR antagonist (α-bungarotoxin). Interleukin-8 (IL-8) expression was measured by ELISA and real-time PCR. Phosphorylation of the NF-κB p65 subunit was determined using an NF-κB p65 profiler assay and STAT-3 activation by STAT-3 in-cell ELISA. The release of ACh from oral keratinocytes in response to &lt;i&gt;P. gingivalis&lt;/i&gt; lipopolysaccharide was determined using a GeneBLAzer M3 CHO-K1-blacell reporter assay.&lt;p&gt;&lt;/p&gt; Results: Expression of α7nAChR mRNA was elevated in diseased periodontal tissue. PHA-543613 hydrochloride inhibited &lt;i&gt;P. Gingivalis&lt;/i&gt;-induced expression of IL-8 at the transcriptional level. This effect was abolished when cells were pre-exposed to a specific α7nAChR antagonist, α-bungarotoxin. PHA-543613 hydrochloride downregulated NF-κB signalling through reduced phosphorylation of the NF-κB p65-subunit. In addition, PHA-543613 hydrochloride promoted STAT-3 signalling by maintenance of phosphorylation. Furthermore, oral keratinocytes upregulated ACh release in response to &lt;i&gt;P. Gingivalis&lt;/i&gt; lipopolysaccharide.&lt;p&gt;&lt;/p&gt; Conclusion: These data suggest that α7nAChR plays a role in regulating the innate immune responses of oral keratinocytes.&lt;p&gt;&lt;/p&gt

Giant lobelias exemplify convergent evolution

Giant lobeliads on tropical mountains in East Africa and Hawaii have highly unusual, giant-rosette growth forms that appear to be convergent on each other and on those of several independently evolved groups of Asteraceae and other families. A recent phylogenetic analysis by Antonelli, based on sequencing the widest selection of lobeliads to date, raises doubts about this paradigmatic example of convergent evolution. Here I address the kinds of evidence needed to test for convergent evolution and argue that the analysis by Antonelli fails on four points. Antonelli's analysis makes several important contributions to our understanding of lobeliad evolution and geographic spread, but his claim regarding convergence appears to be invalid. Giant lobeliads in Hawaii and Africa represent paradigmatic examples of convergent evolution

Childhood Brain Tumours: Associations With Parental Occupational Exposure to Solvents

Background: Parental occupational exposures have been associated with childhood brain tumours (CBT), but results are inconsistent. Few studies have studied CBT risk and parental solvent exposure, suggesting a possible association. We examined the association between CBT and parental occupational exposure to solvents in a case–control study.Methods: Parents of 306 cases and 950 controls completed detailed occupational histories. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for both maternal and paternal exposure to benzene, other aromatics, aliphatics and chlorinated solvents in key time periods relative to the birth of their child. Adjustments were made for matching variables (child’s age, sex and state of residence), best parental education and occupational exposure to diesel exhaust.Results: An increased risk of CBT was observed with maternal occupational exposures to chlorinated solvents (OR=8.59, 95% CI 0.94–78.9) any time before birth. Paternal exposure to solvents in the year before conception was associated with an increased CBT risk: OR=1.55 (95% CI 0.99–2.43). This increased risk appeared to be mainly attributable to exposure to aromatic solvents: OR=2.72 (95% CI 0.94–7.86) for benzene and OR=1.76 (95% CI 1.10–2.82) for other aromatics.Conclusions: Our results indicate that parental occupational exposures to solvents may be related to an increased risk of CBT

Academic Performance and Behavioral Patterns

Identifying the factors that influence academic performance is an essential part of educational research. Previous studies have documented the importance of personality traits, class attendance, and social network structure. Because most of these analyses were based on a single behavioral aspect and/or small sample sizes, there is currently no quantification of the interplay of these factors. Here, we study the academic performance among a cohort of 538 undergraduate students forming a single, densely connected social network. Our work is based on data collected using smartphones, which the students used as their primary phones for two years. The availability of multi-channel data from a single population allows us to directly compare the explanatory power of individual and social characteristics. We find that the most informative indicators of performance are based on social ties and that network indicators result in better model performance than individual characteristics (including both personality and class attendance). We confirm earlier findings that class attendance is the most important predictor among individual characteristics. Finally, our results suggest the presence of strong homophily and/or peer effects among university students

Zircon ages in granulite facies rocks: decoupling from geochemistry above 850 °C?

Granulite facies rocks frequently show a large spread in their zircon ages, the interpretation of which raises questions: Has the isotopic system been disturbed? By what process(es) and conditions did the alteration occur? Can the dates be regarded as real ages, reflecting several growth episodes? Furthermore, under some circumstances of (ultra-)high-temperature metamorphism, decoupling of zircon U–Pb dates from their trace element geochemistry has been reported. Understanding these processes is crucial to help interpret such dates in the context of the P–T history. Our study presents evidence for decoupling in zircon from the highest grade metapelites (> 850 °C) taken along a continuous high-temperature metamorphic field gradient in the Ivrea Zone (NW Italy). These rocks represent a well-characterised segment of Permian lower continental crust with a protracted high-temperature history. Cathodoluminescence images reveal that zircons in the mid-amphibolite facies preserve mainly detrital cores with narrow overgrowths. In the upper amphibolite and granulite facies, preserved detrital cores decrease and metamorphic zircon increases in quantity. Across all samples we document a sequence of four rim generations based on textures. U–Pb dates, Th/U ratios and Ti-in-zircon concentrations show an essentially continuous evolution with increasing metamorphic grade, except in the samples from the granulite facies, which display significant scatter in age and chemistry. We associate the observed decoupling of zircon systematics in high-grade non-metamict zircon with disturbance processes related to differences in behaviour of non-formula elements (i.e. Pb, Th, U, Ti) at high-temperature conditions, notably differences in compatibility within the crystal structure

Reverse Genetics in Ecological Research

By precisely manipulating the expression of individual genetic elements thought to be important for ecological performance, reverse genetics has the potential to revolutionize plant ecology. However, untested concerns about possible side-effects of the transformation technique, caused by Agrobacterium infection and tissue culture, on plant performance have stymied research by requiring onerous sample sizes. We compare 5 independently transformed Nicotiana attenuata lines harboring empty vector control (EVC) T-DNA lacking silencing information with isogenic wild types (WT), and measured a battery of ecologically relevant traits, known to be important in plant-herbivore interactions: phytohormones, secondary metabolites, growth and fitness parameters under stringent competitive conditions, and transcriptional regulation with microarrays. As a positive control, we included a line silenced in trypsin proteinase inhibitor gene (TPI) expression, a potent anti-herbivore defense known to exact fitness costs in its expression, in the analysis. The experiment was conducted twice, with 10 and 20 biological replicates per genotype. For all parameters, we detected no difference between any EVC and WT lines, but could readily detect a fitness benefit of silencing TPI production. A statistical power analyses revealed that the minimum sample sizes required for detecting significant fitness differences between EVC and WT was 2–3 orders of magnitude larger than the 10 replicates required to detect a fitness effect of TPI silencing. We conclude that possible side-effects of transformation are far too low to obfuscate the study of ecologically relevant phenotypes

Ras-association domain family 1C protein promotes breast cancer cell migration and attenuates apoptosis

<p>Abstract</p> <p>Background</p> <p>The Ras association domain family 1 (RASSF1) gene is a Ras effector encoding two major mRNA forms, RASSF1A and RASSF1C, derived by alternative promoter selection and alternative mRNA splicing. RASSF1A is a tumor suppressor gene. However, very little is known about the function of RASSF1C both in normal and transformed cells.</p> <p>Methods</p> <p>Gene silencing and over-expression techniques were used to modulate RASSF1C expression in human breast cancer cells. Affymetrix-microarray analysis was performed using T47D cells over-expressing RASSF1C to identify RASSF1C target genes. RT-PCR and western blot techniques were used to validate target gene expression. Cell invasion and apoptosis assays were also performed.</p> <p>Results</p> <p>In this article, we report the effects of altering RASSF1C expression in human breast cancer cells. We found that silencing RASSF1C mRNA in breast cancer cell lines (MDA-MB231 and T47D) caused a small but significant decrease in cell proliferation. Conversely, inducible over-expression of RASSF1C in breast cancer cells (MDA-MB231 and T47D) resulted in a small increase in cell proliferation. We also report on the identification of novel RASSF1C target genes. RASSF1C down-regulates several pro-apoptotic and tumor suppressor genes and up-regulates several growth promoting genes in breast cancer cells. We further show that down-regulation of caspase 3 via overexpression of RASSF1C reduces breast cancer cells' sensitivity to the apoptosis inducing agent, etoposide. Furthermore, we found that RASSF1C over-expression enhances T47D cell invasion/migration <it>in vitro</it>.</p> <p>Conclusion</p> <p>Together, our findings suggest that RASSF1C, unlike RASSF1A, is not a tumor suppressor, but instead may play a role in stimulating metastasis and survival in breast cancer cells.</p

Comprehensive geriatric assessment for people with both COPD and frailty starting pulmonary rehabilitation: a mixed-methods feasibility trial

Data availablility: All data requests should be submitted to M. Maddocks ([email protected]) for consideration. Access to anonymised data might be granted following investigator review.Supplementary material is available online at: https://publications.ersnet.org/content/erjor/10/4/00774-2023/DC1/embed/inline-supplementary-material-1.pdf . Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.Introduction: Many people with COPD experience frailty. Frailty increases risk of poor health outcomes, including non-completion of pulmonary rehabilitation. Integrated approaches to support people with COPD and frailty throughout and following rehabilitation are indicated. The aim of the present study was to determine the feasibility of conducting a randomised controlled trial of integrating comprehensive geriatric assessment (CGA) for people with COPD and frailty starting pulmonary rehabilitation. Methods; A multicentre mixed-methods randomised controlled feasibility trial (“Breathe Plus”; ISRCTN13051922) was carried out. People with COPD, aged ≥50 years, Clinical Frailty Scale ≥5 and referred for pulmonary rehabilitation were randomised 1:1 to usual pulmonary rehabilitation, or pulmonary rehabilitation plus CGA. Remote intervention delivery was used during COVID-19 restrictions. Outcomes (physical, psychosocial, service use) were measured at baseline, 90 and 180 days, alongside process data and qualitative interviews. Results: Recruitment stopped at 31 participants (mean±sd age 72.4±10.1 years, 68% Medical Research Council Dyspnoea Scale 4–5), due to COVID-19-related disruptions. Recruitment (46% eligible recruited) and retention (87% at 90- and 180-day follow-up) were acceptable. CGAs occurred on average 60.5 days post-randomisation (range 8–129) and prompted 46 individual care recommendations (median 3 per participant, range 0–12), 65% of which were implemented during follow-up. The most common domains addressed during CGA were nutrition and cardiovascular health. Participants valued the holistic approach of CGA but questioned the optimal time to introduce it. Conclusion: Integrating CGA alongside pulmonary rehabilitation is feasible and identifies unmet multidimensional need in people with COPD and frailty. Given challenges around timing and inclusivity, the integration of geriatric and respiratory care should not be limited to rehabilitation services.This project was funded by a National Institute for Health and Care Research (NIHR) Career Development Fellowship (CDF-2017-10-009) held by M. Maddocks. L.J. Brighton was funded by an ESRC Post-Doctoral Fellowship (ES/X005259/1). C.J. Evans was supported by a Health Education England/NIHR Senior Clinical Lectureship (ICA-SCL-2015-01-001). This research was supported by the NIHR Collaboration for Leadership in Applied Health Research and Care South London, now recommissioned as NIHR Applied Research Collaboration South London

Regression of Moral Reasoning during Medical Education: Combined Design Study to Evaluate the Effect of Clinical Study Years

BACKGROUND: Moral reasoning is important for developing medical professionalism but current evidence for the relationship between education and moral reasoning does not clearly apply to medical students. We used a combined study design to test the effect of clinical teaching on moral reasoning. METHODS: We used the Defining Issues Test-2 as a measure of moral judgment, with 3 general moral schemas: Personal Interest, Maintaining Norms, and Postconventional Schema. The test was applied to 3 consecutive cohorts of second year students in 2002 (n = 207), 2003 (n = 192), and 2004 (n = 139), and to 707 students of all 6 study years in 2004 cross-sectional study. We also tested 298 age-matched controls without university education. RESULTS: In the cross-sectional study, there was significant main effect of the study year for Postconventional (F(5,679) = 3.67, P = 0.003) and Personal Interest scores (F(5,679) = 3.38, P = 0.005). There was no effect of the study year for Maintaining Norms scores. 3(rd) year medical students scored higher on Postconventional schema score than all other study years (p<0.001). There were no statistically significant differences among 3 cohorts of 2(nd) year medical students, demonstrating the absence of cohort or point-of-measurement effects. Longitudinal study of 3 cohorts demonstrated that students regressed from Postconventional to Maintaining Norms schema-based reasoning after entering the clinical part of the curriculum. INTERPRETATION: Our study demonstrated direct causative relationship between the regression in moral reasoning development and clinical teaching during medical curriculum. The reasons may include hierarchical organization of clinical practice, specific nature of moral dilemmas faced by medical students, and hidden medical curriculum