Of the 149 miners with ≥2 radiographs available, 48 (32%) showed progression after exercising part 90 and had more severe disease prior to exercising, compared with miners who did not progress (severity score of 2.8 vs 1.7, p=0.0002). CONCLUSION The part 90 job transfer option programme is not routinely used as intended to prevent progression of pneumoconiosis among US coal miners. The one-third of miners who participated in part 90 and continued to progress, exercised their part 90 option at a later stage of disease compared with non-progressors. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.To determine whether Cav1.2 voltage-gated Ca++ channels contribute to astrocyte activation, we generated an inducible conditional knockout mouse in which the Cav1.2 alpha subunit was deleted in GFAP positive astrocytes. This astrocytic Cav1.2 knockout mouse was tested in the cuprizone model of myelin injury and repair which causes astrocyte and microglia activation in the absence of a lymphocytic response. Deletion of Cav1.2 channels in GFAP positive astrocytes during cuprizone-induced demyelination leads to a significant reduction in the degree of astrocyte and microglia activation and proliferation in mice of either sex. Concomitantly, the production of pro-inflammatory factors such as TNFα, IL1β and TGFβ1 was significantly decreased in the corpus callosum and cortex of Cav1.2 knockout mice through demyelination. Furthermore, this mild inflammatory environment promotes oligodendrocyte progenitor cells maturation and myelin regeneration across the remyelination phase of the cuprizone model. Similar results were found in animals treated with nimodipine, a Cav1.2 Ca++ channel inhibitor with high affinity to the CNS. Mice of either sex injected with nimodipine during the demyelination stage of the CPZ treatment displayed a reduced number of reactive astrocytes and showed a faster and more efficient brain remyelination. Together, these results indicate that Cav1.2 Ca++ channels play a crucial role in the induction and proliferation of reactive astrocytes during demyelination; and attenuation of astrocytic voltage-gated Ca++ influx may be an effective therapy to reduce brain inflammation and promote myelin recovery in demyelinating diseases.SIGNIFICANCE STATEMENT Reducing voltage-gated Ca++ influx in astrocytes during brain demyelination significantly attenuates brain inflammation and astrocyte reactivity. Furthermore, these changes promote myelin restoration and oligodendrocyte maturation throughout remyelination. Copyright © 2020 Zamora et al.Nitric oxide (NO) is an important signaling molecule that fulfills diverse functional roles as a neurotransmitter or diffusible second messenger in the developing and adult CNS. Although the impact of NO on different behaviours such as movement, sleep, learning, and memory has been well documented, the identity of its molecular and cellular targets is still an area of ongoing investigation. Here, we identify a novel role for NO in strengthening inhibitory GABAA receptor-mediated transmission in molecular layer interneurons (MLIs) of the mouse cerebellum. NO levels are elevated by the activity of neuronal nitric oxide synthase (nNOS) following Ca2+ entry through extrasynaptic NMDA-type ionotropic glutamate receptors (NMDARs). NO activates protein kinase G (PKG) with the subsequent production of cyclic GMP (cGMP) which prompts the stimulation of NADPH oxidase and protein kinase C (PKC). The activation of PKC promotes the selective strengthening of α3-containing GABAA receptor synapses through a γ-aminobutyric ahe widespread expression of NMDARs and nNOS in the mammalian brain, we speculate that NO control of GABAergic synapse efficacy may be more widespread than has been appreciated. Copyright © 2020 Larson et al.The aerial epidermis of plants plays a major role in environmental interactions, and the development of the cellular components of the aerial epidermis – trichomes, stomata and pavement cells – is still not fully understood. We have performed a detailed screen of the leaf epidermis of two generations of the well-established Solanum lycopersicum cv. M82 x Solanum pennellii ac. LA716 introgression line (IL) population using a combination of scanning electron microscopy techniques. Quantification of the trichome and stomatal densities in the ILs revealed 4 genomic regions with a consistently low trichome density. We also found ILs with abnormal proportions of different trichome types and aberrant trichome morphologies. This work has led to the identification of new, unexplored genomic regions with roles in trichome formation in tomato. We have investigated one interval in IL2-6 and identified a new function for SlMixta-like in determining trichome patterning in leaves. This illustrates how the SEM images, publicly available to the research community, provide an important dataset for further studies on epidermal development in tomato and other species of the family, Solanaceae. © 2020 American Society of Plant Biologists. All rights reserved.Protein folding is a complex cellular process often assisted by chaperones, but it can also be facilitated by interactions with lipids. Disulfide bond formation is a common mechanism to stabilize a protein. This can help maintain functionality amidst changes in the biochemical milieu, including those relating to energy-transducing membranes. Plastidic Type I Signal Peptidase 1 (Plsp1) is an integral thylakoid membrane signal peptidase which requires an intramolecular disulfide bond for in vitro activity. We have investigated the interplay between disulfide bond formation, lipids, and pH in the folding and activity of Plsp1. By combining biochemical approaches with a genetic complementation assay, we provide evidence that interactions with lipids in the thylakoid membrane have reconstitutive chaperoning activity towards Plsp1. Further, the disulfide bridge appears to prevent an inhibitory conformational change resulting from proton motive force-mimicking pH conditions. Broader implications related to the folding of proteins in energy-transducing membranes are discussed. © 2020 American Society of Plant Biologists. All rights reserved.In plants, changes in cell size and shape during development fundamentally depend upon the ability to synthesize and modify cell wall polysaccharides. The main classes of cell wall polysaccharides of terrestrial plants are cellulose, hemicelluloses, and pectins. Members of the Cellulose synthases (CESA) and Cellulose Synthase-Like (CSL) families encode glycosyltransferases that synthesize the β-1,4-linked glycan backbones of cellulose and most hemicellulosic polysaccharides that comprise plant cell walls. Cellulose microfibrils are the major load bearing components in plant cell walls, and are assembled from individual β-1,4-glucan polymers synthesized by cellulose synthase CESA proteins that are organized into multimeric complexes, called cellulose synthase complexes (CSCs) in the plant plasma membrane. During distinct modes of polarized cell wall deposition, such as in tip-growth that occurs during the formation of root hairs and pollen tubes, or de novo formation of cell plates during plant cytokinesis, newly synthesized cell wall polysaccharides are deposited in a restricted region of the cell. These processes requires the activity of members of the cellulose synthase-like D subfamily. However, while these CSLD polysaccharide synthases are essential, the nature of the polysaccharides they synthesize has remained elusive. Here, we use a combination of genetic rescue experiments with CSLD-CESA chimeric proteins, in vitro biochemical reconstitution, and supporting computational modeling and simulation, to demonstrate that CSLD3 is a UDP-glucose dependent β-1,4-glucan synthases that forms protein complexes displaying similar ultrastructural features to those formed by the cellulose synthase, CESA6. © 2020 American Society of Plant Biologists. All rights reserved.Nitrogen (N) is an essential macronutrient for plants, and a major limiting factor for plant growth and crop production. Nitrate is the main source of N available for plants in agricultural soils and in many natural environments. Sustaining agricultural productivity is of paramount importance in the current scenario of increasing world population, diversification of crop uses, and climate change. Plant productivity for major crops around the world is still supported by excess application of N-based fertilizers with detrimental economic and environmental impacts. Thus, understanding how plants regulate nitrate uptake and metabolism is key for developing new crops with enhanced N use efficiency (NUE) and to cope with future world food demands. The study of plant responses to nitrate has gained considerable interest over the last thirty years. This review provides an overview of key findings in nitrate research, spanning biochemistry, molecular genetics, genomics and systems biology. We discuss how we reached our current understanding of nitrate transport, local and systemic nitrate sensing/signaling, and the regulatory networks underlying nitrate-controlled outputs in plants. We hope this summary serves not only as a time-line and information repository, but also as a base to outline important open questions for future research. © 2020 American Society of Plant Biologists. All rights reserved.AIM The inverse care law suggests that those with the greatest need for services are least likely to receive them. Our aim of this study was to test the inverse care law in relation to the use of health services by children aged 4-5 years in Australia who were developmentally vulnerable and socioeconomically disadvantaged. METHOD Cross-sectional data were collected from the Longitudinal Study of Australian Children birth cohort when the children were aged 4-5 years. Children were grouped according to the combination of developmental vulnerability (yes, no) and socioeconomic disadvantage (lower, higher), resulting in four groups (reference group developmentally vulnerable and disadvantaged). Multivariate regression was used to examine the impact of the combination of developmental vulnerability and disadvantage on health service use, adjusting for other sociodemographic characteristics. RESULTS 3967 (90%) of children had data on developmental vulnerability at 4-5 years. A third of children (32.6%) were classified as developmentally vulnerable, and 10%-25% of these children had used health services. Non-disadvantaged children who were developmentally vulnerable (middle need) had 1.4-2.0 times greater odds of using primary healthcare, specialist and hospital services; and non-disadvantaged children who were not developmentally vulnerable (lowest need) had 1.6-1.8 times greater odds of using primary healthcare services, compared with children who were developmentally vulnerable and disadvantaged (highest need). CONCLUSION We found some evidence of the inverse care law. Equity in service delivery remains a challenge that is critically important to tackle in ensuring a healthy start for children. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.