Continent‐scale global change attribution in European birds ‐ combining annual and decadal time scales

Species attributes are commonly used to infer impacts of environmental change on multiyear species trends, e.g. decadal changes in population size. However, by themselves attributes are of limited value in global change attribution since they do not measure the changing environment. A broader foundation for attributing species responses to global change may be achieved by complementing an attributes‐based approach by one estimating the relationship between repeated measures of organismal and environmental changes over short time scales. To assess the benefit of this multiscale perspective, we investigate the recent impact of multiple environmental changes on European farmland birds, here focusing on climate change and land use change. We analyze more than 800 time series from 18 countries spanning the past two decades. Analysis of long‐term population growth rates documents simultaneous responses that can be attributed to both climate change and land‐use change, including long‐term increases in populations of hot‐dwelling species and declines in long‐distance migrants and farmland specialists. In contrast, analysis of annual growth rates yield novel insights into the potential mechanisms driving long‐term climate induced change. In particular, we find that birds are affected by winter, spring, and summer conditions depending on the distinct breeding phenology that corresponds to their migratory strategy. Birds in general benefit from higher temperatures or higher primary productivity early on or in the peak of the breeding season with the largest effect sizes observed in cooler parts of species' climatic ranges. Our results document the potential of combining time scales and integrating both species attributes and environmental variables for global change attribution. We suggest such an approach will be of general use when high‐resolution time series are available in large‐scale biodiversity surveys.     

Presynaptic inhibition upon CB1 or mGlu2/3 receptor activation requires ERK/MAPK phosphorylation of Munc18‐1

Presynaptic cannabinoid (CB1R) and metabotropic glutamate receptors (mGluR2/3) regulate synaptic strength by inhibiting secretion. Here, we reveal a presynaptic inhibitory pathway activated by extracellular signal‐regulated kinase (ERK) that mediates CB1R‐ and mGluR2/3‐induced secretion inhibition. This pathway is triggered by a variety of events, from foot shock‐induced stress to intense neuronal activity, and induces phosphorylation of the presynaptic protein Munc18‐1. Mimicking constitutive phosphorylation of Munc18‐1 results in a drastic decrease in synaptic transmission. ERK‐mediated phosphorylation of Munc18‐1 ultimately leads to degradation by the ubiquitin–proteasome system. Conversely, preventing ERK‐dependent Munc18‐1 phosphorylation increases synaptic strength. CB1R‐ and mGluR2/3‐induced synaptic inhibition and depolarization‐induced suppression of excitation (DSE) are reduced upon ERK/MEK pathway inhibition and further reduced when ERK‐dependent Munc18‐1 phosphorylation is blocked. Thus, ERK‐dependent Munc18‐1 phosphorylation provides a major negative feedback loop to control synaptic strength upon activation of presynaptic receptors and during intense neuronal activity.     

Co‐expression of the protease furin in Nicotiana benthamiana leads to efficient processing of latent transforming growth factor‐β1 into a biologically active protein

Transforming growth factor beta (TGF‐β) is a signalling molecule that plays a key role in developmental and immunological processes in mammals. Three TGF‐β isoforms exist in humans, and each isoform has unique therapeutic potential. Plants offer a platform for the production of recombinant proteins, which is cheap and easy to scale up and has a low risk of contamination with human pathogens. TGF‐β3 has been produced in plants before using a chloroplast expression system. However, this strategy requires chemical refolding to obtain a biologically active protein. In this study, we investigated the possibility to transiently express active human TGF‐β1 in Nicotiana benthamiana plants. We successfully expressed mature TGF‐β1 in the absence of the latency‐associated peptide (LAP) using different strategies, but the obtained proteins were inactive. Upon expression of LAP‐TGF‐β1, we were able to show that processing of the latent complex by a furin‐like protease does not occur in planta. The use of a chitinase signal peptide enhanced the expression and secretion of LAP‐TGF‐β1, and co‐expression of human furin enabled the proteolytic processing of latent TGF‐β1. Engineering the plant post‐translational machinery by co‐expressing human furin also enhanced the accumulation of biologically active TGF‐β1. This engineering step is quite remarkable, as furin requires multiple processing steps and correct localization within the secretory pathway to become active. Our data demonstrate that plants can be a suitable platform for the production of complex proteins that rely on specific proteolytic processing.     

The Ethics of Deprescribing in Older Adults

Deprescribing is the term used to describe the process of withdrawal of an inappropriate medication supervised by a clinician. This article presents a discussion of how the Four Principles of biomedical ethics (beneficence, non-maleficence, autonomy, and justice) that may guide medical practitioners’ prescribing practices apply to deprescribing medications in older adults. The view of deprescribing as an act creates stronger moral duties than if viewed as an omission. This may explain the fear of negative outcomes which has been reported by prescribers as a barrier to deprescribing. Respecting the autonomy of older adults is complex as they may not wish to be active in the decision-making process; they may also have reduced cognitive function and family members may therefore have to step in as surrogate decision-makers. Informed consent is intended as a process of information giving and reflection, where consent can be withdrawn at any time. However, people are rarely updated on the altered risks and benefits of their long-term medications as they age. Cessation of inappropriate medication use has a large financial benefit to the individual and the community. However, the principle of justice also dictates equal rights to treatment regardless of age.     

Further evidence of the involvement of the Wnt signaling pathway in Dupuytren’s disease

Genetic background plays an important role in the development of Dupuytren’s disease. A genome-wide association study (GWAS) showed that nine loci are associated with the disease, six of which contain genes that are involved in Wnt signaling (WNT2, WNT4, WNT7B, RSPO2, SFRP4, SULF1). To obtain insight in the role of these genes, we performed expression studies on affected and unaffected patient’s tissues. Surgically obtained nodules and cords from eight Dupuytren’s patients were compared to patient-matched control tissue (unaffected transverse palmar fascia). The Wnt-related genes found in the GWAS, the classical Wnt-downstream protein β-catenin, as well as (myo)fibroblast markers were analyzed using real-time qPCR and immunohistochemical stainings for mRNA levels and protein levels, respectively. The collagen-coding genes COL1A1 and COL3A1 were highly upregulated on mRNA level, both in cords and nodules. Three Wnt-related genes were found to be differently regulated compared to control tissue: WNT2 was downregulated in nodules, WNT7B was upregulated in nodules, and SFRP4 was upregulated in nodules and cords. Immunohistochemistry revealed significantly less staining of Wnt2 in cords, but significantly more staining for Wnt7b in nodules. There was significantly more staining of α-SMA in nodules and cord and β-catenin in nodules than in control tissue. We found differences in expression, both at mRNA and protein level, in several Wnt-related genes found earlier to be associated with Dupuytren’s disease. Of these, Wnt7b was upregulated and found in close association with both α-SMA and β-catenin expressing cells, making it a candidate pro-fibrotic mediator in Dupuytren’s disease.     

The effect of bongkrekic acid on the Ca-stimulated oxidation in rat-liver mitochondria and its relation to the efflux of intramitochondrial adenine nucleotides

1. Bongkrekic acid inhibits the uncoupling of succinate oxidation induced by addition of Ca²⁺ and P_i.

2. It also inhibits the efflux of intramitochondrial adenine nucleotides induced by this treatment.

3. It is concluded that the inhibitory action of bongkrekic acid on the adenine nucleotide translocator is favoured by the presence of endogenous adenine nucleotides.     

Distinct effect of forskolin and interferon-gamma on cell proliferation and regulation of histocompatibility antigen expression in hematopoietic cells

The adenylate cyclase activator, forskolin, was found to induce expression of class I and class II major histocompatibility complex antigens in a B precursor cell line, Reh, as well as in a B lymphoid cell line, Raji. No such effect was, however, observed when the promyelocytic cells line HL-60 was treated with either forskolin or the cAMP analogue 8-bromoadenosine cyclic monophosphate. As expected, all three cell lines showed reduced proliferation upon forskolin treatment. Forskolin induced expression of class I and class II major histocompatibility complex antigens in cell lines not affected by interferon-gamma and vice versa, indicating that cAMP is not involved in the regulation of histocompatibility antigens by interferon-gamma. We also compared the effect of interferon-gamma and 12-O-tetradecanoylphorbol 13-acetate on major histocompatibility complex class I and class II expression, and despite differences in the response on the tested cell lines, we can not at this point exclude the possibility that protein kinase C is involved in the action of interferon-gamma.