A non-BRICHOS surfactant protein c mutation disrupts epithelial cell function and intercellular signaling

We show that I73T mutation leads to impaired processing of proSP-C in alveolar type II cells, alters their stress tolerance and surfactant lipid composition, and activates cells of the immune system. In addition, we show that some of the mentioned cellular aspects behind the disease can be modulated by application of pharmaceutical drugs commonly applied in the ILD therapy

The decarbonisation of Europe powered by lifestyle changes

Decision makers increasingly recognise the importance of lifestyle changes in reaching low emission targets. How the mitigation potential of changes in mobility, dietary, housing or consumption behaviour compare to those of ambitious technological changes in terms of decarbonisation remains a key question. To evaluate the interplay of behaviour and technological changes, we make use of the European Calculator model and show that changes in behaviour may contribute more than 20% of the overall greenhouse gas (GHG) emission reductions required for net-zero by 2050. Behaviour and technology-oriented scenarios are tested individually and in combination for the EU plus the UK and Switzerland. The impacts of behavioural change vary across sectors, with significant GHG emission reduction potential and broader benefits. Changes in travel behaviour limit the rising demand for electricity, natural resources and infrastructure costs from the electrification of passenger transport. Adopting a healthy diet reduces emissions substantially compared to intensifying agricultural practices, while at the same time making cropland available for conservation or bioenergy crops. The trade-offs between energy and food may be substantially alleviated when deploying technological and behavioural changes simultaneously. The results suggest that without behavioural change, the dependency of Europe on carbon removal technologies for its net-zero ambitions increases. Structural changes will be necessary to achieve full decarbonisation by 2050, yet changes in lifestyles are crucial, contributing to achieving climate targets sooner

Quantitative Characterization of the Filiform Mechanosensory Hair Array on the Cricket Cercus

Crickets and other orthopteran insects sense air currents with a pair of abdominal appendages resembling antennae, called cerci. Each cercus in the common house cricket Acheta domesticus is approximately 1 cm long, and is covered with 500 to 750 filiform mechanosensory hairs. The distribution of the hairs on the cerci, as well as the global patterns of their movement vectors, have been characterized semi-quantitatively in studies over the last 40 years, and have been shown to be very stereotypical across different animals in this species. Although the cercal sensory system has been the focus of many studies in the areas of neuroethology, development, biomechanics, sensory function and neural coding, there has not yet been a quantitative study of the functional morphology of the receptor array of this important model system.We present a quantitative characterization of the structural characteristics and functional morphology of the cercal filiform hair array. We demonstrate that the excitatory direction along each hair's movement plane can be identified by features of its socket that are visible at the light-microscopic level, and that the length of the hair associated with each socket can also be estimated accurately from a structural parameter of the socket. We characterize the length and directionality of all hairs on the basal half of a sample of three cerci, and present statistical analyses of the distributions.The inter-animal variation of several global organizational features is low, consistent with constraints imposed by functional effectiveness and/or developmental processes. Contrary to previous reports, however, we show that the filiform hairs are not re-identifiable in the strict sense

The surfactant protein C mutation A116D alters cellular processing, stress tolerance, surfactant lipid composition, and immune cell activation

<p>Abstract</p> <p>Background</p> <p>Surfactant protein C (SP-C) is important for the function of pulmonary surfactant. Heterozygous mutations in <it>SFTPC</it>, the gene encoding SP-C, cause sporadic and familial interstitial lung disease (ILD) in children and adults. Mutations mapping to the BRICHOS domain located within the SP-C proprotein result in perinuclear aggregation of the proprotein. In this study, we investigated the effects of the mutation A116D in the BRICHOS domain of SP-C on cellular homeostasis. We also evaluated the ability of drugs currently used in ILD therapy to counteract these effects.</p> <p>Methods</p> <p>SP-C^A116Dwas expressed in MLE-12 alveolar epithelial cells. We assessed in vitro the consequences for cellular homeostasis, immune response and effects of azathioprine, hydroxychloroquine, methylprednisolone and cyclophosphamide.</p> <p>Results</p> <p>Stable expression of SP-C^A116Din MLE-12 alveolar epithelial cells resulted in increased intracellular accumulation of proSP-C processing intermediates. SP-C^A116Dexpression further led to reduced cell viability and increased levels of the chaperones Hsp90, Hsp70, calreticulin and calnexin. Lipid analysis revealed decreased intracellular levels of phosphatidylcholine (PC) and increased lyso-PC levels. Treatment with methylprednisolone or hydroxychloroquine partially restored these lipid alterations. Furthermore, SP-C^A116Dcells secreted soluble factors into the medium that modulated surface expression of CCR2 or CXCR1 receptors on CD4⁺lymphocytes and neutrophils, suggesting a direct paracrine effect of SP-C^A116Don neighboring cells in the alveolar space.</p> <p>Conclusions</p> <p>We show that the A116D mutation leads to impaired processing of proSP-C in alveolar epithelial cells, alters cell viability and lipid composition, and also activates cells of the immune system. In addition, we show that some of the effects of the mutation on cellular homeostasis can be antagonized by application of pharmaceuticals commonly applied in ILD therapy. Our findings shed new light on the pathomechanisms underlying SP-C deficiency associated ILD and provide insight into the mechanisms by which drugs currently used in ILD therapy act.</p

The decarbonisation of Europe powered by lifestyle changes

Decision makers increasingly recognise the importance of lifestyle changes in reaching low emission targets. How the mitigation potential of changes in mobility, dietary, housing or consumption behaviour compare to those of ambitious technological changes in terms of decarbonisation remains a key question. To evaluate the interplay of behaviour and technological changes, we make use of the European Calculator model and show that changes in behaviour may contribute more than 20% of the overall greenhouse gas (GHG) emission reductions required for net-zero by 2050. Behaviour and technology-oriented scenarios are tested individually and in combination for the EU plus the UK and Switzerland. The impacts of behavioural change vary across sectors, with significant GHG emission reduction potential and broader benefits. Changes in travel behaviour limit the rising demand for electricity, natural resources and infrastructure costs from the electrification of passenger transport. Adopting a healthy diet reduces emissions substantially compared to intensifying agricultural practices, while at the same time making cropland available for conservation or bioenergy crops. The trade-offs between energy and food may be substantially alleviated when deploying technological and behavioural changes simultaneously. The results suggest that without behavioural change, the dependency of Europe on carbon removal technologies for its net-zero ambitions increases. Structural changes will be necessary to achieve full decarbonisation by 2050, yet changes in lifestyles are crucial, contributing to achieving climate targets sooner

Phelan-McDermid syndrome: a classification system after 30 years of experience

Phelan-McDermid syndrome (PMS) was initially called the 22q13 deletion syndrome based on its etiology as a deletion of the distal long arm of chromosome 22. These included terminal and interstitial deletions, as well as other structural rearrangements. Later, pathogenetic variants and deletions of the SHANK3 gene were found to result in a phenotype consistent with PMS. The association between SHANK3 and PMS led investigators to consider disruption/deletion of SHANK3 to be a prerequisite for diagnosing PMS. This narrow definition of PMS based on the involvement of SHANK3 has the adverse effect of causing patients with interstitial deletions of chromosome 22 to "lose" their diagnosis. It also results in underreporting of individuals with interstitial deletions of 22q13 that preserve SHANK3. To reduce the confusion for families, clinicians, researchers, and pharma, a simple classification for PMS has been devised. PMS and will be further classified as PMS-SHANK3 related or PMS-SHANK3 unrelated. PMS can still be used as a general term, but this classification system is inclusive. It allows researchers, regulatory agencies, and other stakeholders to define SHANK3 alterations or interstitial deletions not affecting the SHANK3 coding region