A quasi-one-dimensional model for ion-aerosol interactions and aerosol charge state downwind of corona-producing alternating current (AC) HVPL under stable atmospheric conditions.

Corona ions produced by high voltage power lines (HVPL) can alter the local atmospheric electrical environment downwind, potentially increasing electrostatic charge on airborne particulates via ion-aerosol attachment. However, previous epidemiological assessments attempting to assess this 'corona ion hypothesis' have used proxies e.g. ion concentration or distance from HVPL, rather than aerosol charge state directly, due to difficulties in modeling this quantity. We present a quasi-1D model incorporating both Gaussian plume dynamics and ion-aerosol and ion-ion interaction microphysics which could be applied to future studies of charged aerosol near HVPL. The response of the model to changes in a range of input parameters is characterized, and validation is attempted by means of comparison with previous work where ion- and aerosol concentrations and properties (including electrical mobility and electric charge states) upwind and downwind of HVPL are measured.

Overhead AC powerlines and rain can alter the electric charge distribution on airborne particles - Implications for aerosol dispersion and lung deposition.

Corona ions from high voltage power lines (HVPL) can increase electrostatic charge on airborne pollutant particulates, possibly increasing received dose upon inhalation. To investigate the potential increased risk of childhood leukemia associated with residence near alternating current (AC) HVPL, we measured the particle charge state and atmospheric electricity parameters upwind, downwind and away from HVPL. Although we observed noticeable charge state alteration from background levels, most HVPL do not significantly increase charge magnitude. Particular HVPL types are shown to have most effect, increasing net charge to 15 times that at background. However, the magnitude of charge alteration during rainfall is comparable with the most extreme HVPL measurement. On current evidence, based on the current adult lung model, we suggest that although charge is sometimes enhanced to levels which may alter atmospheric particle dynamics, increased lung deposition is unlikely.

Genomic and Targeted Approaches Unveil the Cell Membrane as a Major Target of the Antifungal Cytotoxin Amantelide A.

Amantelide A, a polyhydroxylated macrolide isolated from a marine cyanobacterium, displays broad-spectrum activity against mammalian cells, bacterial pathogens, and marine fungi. We conducted comprehensive mechanistic studies to identify the molecular targets and pathways affected by amantelide A. Our investigations relied on chemical structure similarities with compounds of known mechanisms, yeast knockout mutants, yeast chemogenomic profiling, and direct biochemical and biophysical methods. We established that amantelide A exerts its antifungal action by binding to ergosterol-containing membranes followed by pore formation and cell death, a mechanism partially shared with polyene antifungals. Binding assays demonstrated that amantelide A also binds to membranes containing epicholesterol or mammalian cholesterol, thus suggesting that the cytotoxicity to mammalian cells might be due to its affinity to cholesterol-containing membranes. However, membrane interactions were not completely dependent on sterols. Yeast chemogenomic profiling suggested additional direct or indirect effects on actin. Accordingly, we performed actin polymerization assays, which suggested that amantelide A also promotes actin polymerization in cell-free systems. However, the C-33 acetoxy derivative amantelide B showed a similar effect on actin dynamics in vitro but no significant activity against yeast. Overall, these studies suggest that the membrane effects are the most functionally relevant for amantelide A mechanism of action.

Investigating the background and local contribution of the oxidants in London and Bangkok.

The contribution of NOx emissions and background O3 to the sources and partitioning of the oxidants [OX (= O3 + NO2)] at the Marylebone Road site in London during the 2000s and 2010s has been investigated to see the impact of the control measures or technology changes inline with the London Mayor's Air Quality Strategy. The abatement of the pollution emissions has an impact on the trends of local and background oxidants, [OX]L and [OX]B, decreasing by 1.4% per year and 0.4% per year, respectively from 2000 to 2019. We also extend our study to three roadside sites (Din Daeng, Thonburi and Chokchai) in another megacity, Bangkok, to compare [OX]L and [OX]B and their behavioural changes with respect to the Marylebone Road site. [OX]L and [OX]B at the Marylebone Road site (0.21[NOx] and 32 ppbv) are comparable with the roadside sites of Thailand (0.12[NOx] to 0.26[NOx] and 29 to 32 ppbv). The seasonal variation of [OX]B levels displays a spring maximum for London, which is due to the higher northern hemispheric ozone baseline, but a maximum during the dry season is found for Bangkok which is likely due to regional-scale long-range transport from the Asian continent. The diurnal variations of [OX]L for both London and Bangkok roadside sites confirm the dominance of the oxidants from road transport emissions, which are found to be higher throughout the daytime. WRF-Chem-CRI model simulations of the distribution of [OX] showed that the model performed well for London background sites when predicting [OX] levels compared with the measured [OX] levels suggesting that the model is treating the chemistry of the oxidants correctly. However, there are large discrepancies for the model-measurement [OX] levels at the traffic site because of the difficulties in the modelling of [OX] at large road networks in megacities for the complex sub grid-scale dynamics that are taking place, both in terms of atmospheric processes and time-varying sources, such as traffic volumes. For roadside sites in Bangkok, the trend in changes of [OX] is predicted by the model correctly but overestimated in absolute magnitude. We suggest that this large deviation is likely to be due to discrepancies in the EDGAR emission inventory (emission overestimates) beyond the resolution of the model.

A systematic review of the intervention characteristics, and behavior change theory and techniques used in mother-daughter interventions targeting physical activity.

Growing gender disparities in levels of physical inactivity put women and female youths at a greater risk of associated health problems. Mother-daughter interventions have been proposed as means to promote physical activity in this at-risk cohort. However, there is a lack of clarity as to if and why these types of interventions might be effective. This systematic review examined the intervention characteristics, and behavior change theory and techniques used in these interventions to promote physical activity for mothers and daughters. PubMed, EMBASE, PsycINfO, CINAHL and Cochrane Library (Wiley) databases were searched for English language studies from inception to 13th May 2020. Interventions of any design that targeted daughters and mothers' physical activity were included. Data was extracted using the Template for Intervention Description and Replication (TIDieR) checklist, and the Behavior Change Technique (BCT) Taxonomy v1. 4962 articles were screened and 11 unique studies met the inclusion criteria. The risk of bias in studies was generally high. Narrative summary highlighted that many studies used social cognitive theory as a theoretical foundation, were based in the community and less than three months in duration with multiple sessions per week. Thirty-seven behavior change techniques were identified across studies. Some techniques were deemed potentially effective including credible source, information on the health consequences of the behavior and the self-regulatory techniques of goal-setting, self-monitoring and problem-solving. Future research should consider the use of the TIDieR guidelines and BCT Taxonomy v1 to improve the quality of information for intervention development, implementation, and reporting phases.

Challenges in coupling atmospheric electricity with biological systems.

The atmosphere is host to a complex electric environment, ranging from a global electric circuit generating fluctuating atmospheric electric fields to local lightning strikes and ions. While research on interactions of organisms with their electrical environment is deeply rooted in the aquatic environment, it has hitherto been confined to interactions with local electrical phenomena and organismal perception of electric fields. However, there is emerging evidence of coupling between large- and small-scale atmospheric electrical phenomena and various biological processes in terrestrial environments that even appear to be tied to continental waters. Here, we synthesize our current understanding of this connectivity, discussing how atmospheric electricity can affect various levels of biological organization across multiple ecosystems. We identify opportunities for research, highlighting its complexity and interdisciplinary nature and draw attention to both conceptual and technical challenges lying ahead of our future understanding of the relationship between atmospheric electricity and the organization and functioning of biological systems.

Glossary on atmospheric electricity and its effects on biology.

There is an increasing interest to study the interactions between atmospheric electrical parameters and living organisms at multiple scales. So far, relatively few studies have been published that focus on possible biological effects of atmospheric electric and magnetic fields. To foster future work in this area of multidisciplinary research, here we present a glossary of relevant terms. Its main purpose is to facilitate the process of learning and communication among the different scientific disciplines working on this topic. While some definitions come from existing sources, other concepts have been re-defined to better reflect the existing and emerging scientific needs of this multidisciplinary and transdisciplinary area of research.

E-cadherin can limit the transforming properties of activating ß-catenin mutations.

Wnt pathway deregulation is a common characteristic of many cancers. Only colorectal cancer predominantly harbours mutations in APC, whereas other cancer types (hepatocellular carcinoma, solid pseudopapillary tumours of the pancreas) have activating mutations in ß-catenin (CTNNB1). We have compared the dynamics and the potency of ß-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of ß-catenin took much longer to achieve Wnt deregulation and acquire a crypt-progenitor cell (CPC) phenotype than Apc or Gsk3 loss. Within the colon, a single activating mutation of ß-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of ß-catenin mutation to differentially transform the SI versus the colon correlated with higher expression of E-cadherin and a higher number of E-cadherin:ß-catenin complexes at the membrane. Reduction in E-cadherin synergised with an activating mutation of ß-catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of ß-catenin that is required to drive transformation, and E-cadherin can act as a buffer to sequester mutated ß-catenin.

Evaluation of an E-Learning Training Program to Support Implementation of a Group-Based, Theory-Driven, Self-Management Intervention For Osteoarthritis and Low-Back Pain: Pre-Post Study.

BACKGROUND: By adaptation of the face-to-face physiotherapist-training program previously used in the Self-management of Osteoarthritis and Low back pain through Activity and Skills (SOLAS) feasibility trial, an asynchronous, interactive, Web-based, e-learning training program (E-SOLAS) underpinned by behavior and learning theories was developed. OBJECTIVE: This study investigated the effect of the E-SOLAS training program on relevant outcomes of effective training and implementation. METHODS: Thirteen physiotherapists from across Ireland were trained via E-SOLAS by using mixed methods, and seven physiotherapists progressed to implementation of the 6-week group-based SOLAS intervention. The effectiveness of E-SOLAS was evaluated using the Kirkpatrick model at the levels of reaction (physiotherapist engagement and satisfaction with E-SOLAS training methods and content), learning (pre- to posttraining changes in physiotherapists' confidence and knowledge in delivering SOLAS content and self-determination theory-based communication strategies, administered via a SurveyMonkey questionnaire), and behavior (fidelity to delivery of SOLAS content using physiotherapist-completed weekly checklists). During implementation, five physiotherapists audio recorded delivery of one class, and the communication between physiotherapists and clients was assessed using the Health Care Climate Questionnaire (HCCQ), the Controlling Coach Behaviour Scale (CCBS), and an intervention-specific measure (ISM; 7-point Likert scale). A range of implementation outcomes were evaluated during training and delivery (ie, acceptability, appropriateness, feasibility, fidelity, and sustainability of E-SOLAS) using a posttraining feedback questionnaire and individual semistructured telephone interviews. RESULTS: With regard to their reaction, physiotherapists (n=13) were very satisfied with E-SOLAS posttraining (median 5.0; interquartile range 1.0; min-max 4.0-5.0) and completed training within 3-4 weeks. With regard to learning, there were significant increases in physiotherapists' confidence and knowledge in delivery of all SOLAS intervention components (P<.05). Physiotherapists' confidence in 7 of 10 self-determination theory-based communication strategies increased (P<.05), whereas physiotherapists' knowledge of self-determination theory-based strategies remained high posttraining (P>.05). In terms of behavior, physiotherapists delivered SOLAS in a needs supportive manner (HCCQ: median 5.2, interquartile range 1.3, min-max 3.7-5.8; CCBS: median 6.6, interquartile range 1.0, min-max 5.6-7.0; ISM: median 4.5, interquartile range 1.2, min-max 2.8-4.8). Fidelity scores were high for SOLAS content delivery (total %mean fidelity score 93.5%; SD 4.9%). The posttraining questionnaire and postdelivery qualitative interviews showed that physiotherapists found E-SOLAS acceptable, appropriate, feasible, and sustainable within primary care services to support the implementation of the SOLAS intervention. CONCLUSIONS: This study provides preliminary evidence of the effectiveness, acceptability, and feasibility of an e-learning program to train physiotherapists to deliver a group-based self-management complex intervention in primary care settings, which is equivalent to face-to-face training outcomes and would support inclusion of physiotherapists in a definitive trial of SOLAS.

The nucleus is irreversibly shaped by motion of cell boundaries in cancer and non-cancer cells.

Actomyosin stress fibers impinge on the nucleus and can exert compressive forces on it. These compressive forces have been proposed to elongate nuclei in fibroblasts, and lead to abnormally shaped nuclei in cancer cells. In these models, the elongated or flattened nuclear shape is proposed to store elastic energy. However, we found that deformed shapes of nuclei are unchanged even after removal of the cell with micro-dissection, both for smooth, elongated nuclei in fibroblasts and abnormally shaped nuclei in breast cancer cells. The lack of shape relaxation implies that the nuclear shape in spread cells does not store any elastic energy, and the cellular stresses that deform the nucleus are dissipative, not static. During cell spreading, the deviation of the nucleus from a convex shape increased in MDA-MB-231 cancer cells, but decreased in MCF-10A cells. Tracking changes of nuclear and cellular shape on micropatterned substrata revealed that fibroblast nuclei deform only during deformations in cell shape and only in the direction of nearby moving cell boundaries. We propose that motion of cell boundaries exert a stress on the nucleus, which allows the nucleus to mimic cell shape. The lack of elastic energy in the nuclear shape suggests that nuclear shape changes in cells occur at constant surface area and volume.

Effect of lipopolysaccharide on the expression of inflammatory mRNAs and microRNAs in the mouse oviduct.

Infection with Gram-negative bacteria is a major cause of aberrant inflammation in the oviduct; consequences can include tubal-based infertility and/or ectopic pregnancy. Understanding the inflammatory response is necessary for the development of novel treatment options that counter inflammation-induced infertility. The aim of the present study was to determine the effect of intraperitoneal (i.p.) administration of Escherichia coli-derived lipopolysaccharide (LPS) on the acute expression of inflammatory mRNAs and microRNAs (miRNAs) in the oviduct. On the day of oestrus, 6- to 8-week-old CD1 mice were injected i.p. with 0, 2 or 10µg LPS in 100µL phosphate-buffered saline. Mice were killed 24h later and the oviducts collected for gene expression analyses. The effect of treatment on the expression of mRNAs and miRNAs was evaluated by one-way analysis of variance (ANOVA), with treatment means of differentially expressed (P<0.05) transcripts separated using Scheffé's test. LPS treatment affected 49 of 179 targeted inflammatory mRNAs and 51 of 578 miRNAs (P<0.05). The identity of differentially expressed miRNAs predicted as regulators of chemokine and interleukin ligand mRNAs was then extracted using the microRNA.org database. The results of the present study indicate that systemic treatment with LPS induces a robust inflammatory response in the oviducts of mice, and identify key mRNAs and putative miRNAs modulating this effect.

Structural Analysis by Enhanced Raman Scattering.

Gold nanostructures focus light to a molecular length scale at their surface, creating the possibility to visualize molecular structure. The high optical intensity leads to surface enhanced Raman scattering (SERS) from nearby molecules. SERS spectra contain information on molecular position and orientation relative to the surface but are difficult to interpret quantitatively. Here we describe a ratiometric analysis method that combines SERS and unenhanced Raman spectra with theoretical calculations of the optical field and molecular polarizability. When applied to the surfactant layer on gold nanorods, the alkane chain is found to be tilted 25° to the surface normal, which matches previous reports of the layer thickness. The analysis was also applied to fluid phase phospholipid bilayers that contain tryptophan on the surface of gold nanorods. The lipid double bond was found to be oriented normal to the bilayer and 13 Å from the nitrogen atom. Tryptophan was found to sit near the glycerol headgroup region with its indole ring 43° from the bilayer normal. This new method can determine specific interfacial structure under ambient conditions, with microscopic quantities of material, and without molecular labels.

A Tryptoline Ring-Distortion Strategy Leads to Complex and Diverse Biologically Active Molecules from the Indole Alkaloid Yohimbine.

High-throughput screening (HTS) is the primary driver to current drug-discovery efforts. New therapeutic agents that enter the market are a direct reflection of the structurally simple compounds that make up screening libraries. Unlike medically relevant natural products (e.g., morphine), small molecules currently being screened have a low fraction of sp3 character and few, if any, stereogenic centers. Although simple compounds have been useful in drugging certain biological targets (e.g., protein kinases), more sophisticated targets (e.g., transcription factors) have largely evaded the discovery of new clinical agents from screening collections. Herein, a tryptoline ring-distortion strategy is described that enables the rapid synthesis of 70 complex and diverse compounds from yohimbine (1); an indole alkaloid. The compounds that were synthesized had architecturally complex and unique scaffolds, unlike 1 and other scaffolds. These compounds were subjected to phenotypic screens and reporter gene assays, leading to the identification of new compounds that possessed various biological activities, including antiproliferative activities against cancer cells with functional hypoxia-inducible factors, nitric oxide inhibition, and inhibition and activation of the antioxidant response element. This tryptoline ring-distortion strategy can begin to address diversity problems in screening libraries, while occupying biologically relevant chemical space in areas critical to human health.

SHP-1: the next checkpoint target for cancer immunotherapy?

The immense power of the immune system is harnessed in healthy individuals by a range of negative regulatory signals and checkpoints. Manipulating these checkpoints through inhibition has resulted in striking immune-mediated clearance of otherwise untreatable tumours and metastases; unfortunately, not all patients respond to treatment with the currently available inhibitors of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Combinatorial studies using both anti-CTLA-4 and anti-PD-1 demonstrate synergistic effects of targeting multiple checkpoints, paving the way for other immune checkpoints to be targeted. Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) is a widely expressed inhibitory protein tyrosine phosphatase (PTP). In T-cells, it is a negative regulator of antigen-dependent activation and proliferation. It is a cytosolic protein, and therefore not amenable to antibody-mediated therapies, but its role in activation and proliferation makes it an attractive target for genetic manipulation in adoptive transfer strategies, such as chimeric antigen receptor (CAR) T-cells. This review will discuss the potential value of SHP-1 inhibition in future tumour immunotherapy.

Pitiamides A and B, Multifunctional Fatty Acid Amides from Marine Cyanobacteria.

Two geometric isomers related to pitiamide A, termed 1E-pitiamide B (1) and 1Z-pitiamide B (2), were isolated from a marine cyanobacterium collected from the shallow reef flat at Piti Bomb Holes, Guam, Mariana Islands. The structures of these analogues were elucidated using 1D and 2D NMR analysis. Pitiamide A, which has been previously described, but has not been investigated in bioassays, was co-isolated. Pitiamides A and B were subjected to a biological evaluation and they both showed antiproliferative effects on HCT116 cells with IC50 values of 1-5 µM. Pitiamide A was investigated individually and caused plasma membrane hyperpolarization and an increase of intracellular calcium in HCT116 cells.

Analysis of Phospholipid Bilayers on Gold Nanorods by Plasmon Resonance Sensing and Surface-Enhanced Raman Scattering.

Surface-enhanced Raman scattering (SERS) and localized surface plasmon resonance sensing (LSPR) have been applied for a detailed analysis of lipid bilayers at the surface of gold nanorods. The spatial dependence of surface enhancement and the optical effects of the lipid phase transition confirm the presence of a bilayer membrane structure. Deuterated lipids exchanged rapidly between the nanorod surface and lipid vesicles in solution, suggesting a loosely bound, natural membrane structure. However, at a low solution concentration of lipid vesicles, the lipids on the gold nanorod surface convert to a nonbilayer structure, which could impact biological applications of these nanomaterials.

Effect of a self-determination theory-based communication skills training program on physiotherapists' psychological support for their patients with chronic low back pain: a randomized controlled trial.

OBJECTIVE: To examine the effects of communication skills training on physiotherapists' supportive behavior during clinical practice. DESIGN: Randomized trial. SETTING: Hospital outpatient physiotherapy clinics. PARTICIPANTS: Physiotherapists (N=24) and patients (N=24) with chronic low back pain. INTERVENTIONS: Two hospital clinics were randomly assigned to the intervention arm. Physiotherapists (n=12) received 8 hours of communication skills training focused on supporting patients' psychological needs. Physiotherapists (n=12) from 2 other hospital clinics formed a waitlist control arm. MAIN OUTCOME MEASURES: Verbal communication between each physiotherapist and a patient was recorded on an audiotape, and independent, blinded raters used the Health Care Climate Questionnaire to assess physiotherapists' needs-supportive behavior (primary outcome). RESULTS: Independent raters' Health Care Climate Questionnaire scores favored the intervention arm (Cohen's d=2.27; P<.01). CONCLUSIONS: Compared with controls, independent ratings demonstrated that physiotherapists who completed the Communication style and exercise compliance in physiotherapy training were found to provide greater support for patients' needs in a single assessed session. Long-term maintenance of this needs-supportive behavior should be examined.