RCAN1 regulates vesicle recycling and quantal release kinetics via effects on calcineurin activity

Author version made available in accordance with the publisher's policy.We have previously shown that Regulator of Calcineurin 1 (RCAN1) regulates multiple stages of vesicle exocytosis. However, the mechanisms by which RCAN1 affects secretory vesicle exocytosis and quantal release kinetics remain unknown. Here we use carbon fiber amperometry to detect exocytosis from chromaffin cells and identify these underlying mechanisms. We observe reduced exocytosis with repeated stimulations in chromaffin cells overexpressing RCAN1 (RCAN1ox), but not in wild type (WT) cells, indicating a negative effect of RCAN1 on vesicle recycling and endocytosis. Acute exposure to calcineurin inhibitors, cyclosporine A and FK-506, replicates this effect in WT cells but has no additional effect in RCAN1ox cells. When we chronically expose WT cells to cyclosporine A and FK-506 we find that catecholamine release per vesicle and pre-spike foot (PSF) signal parameters are decreased, similar to that in RCAN1ox cells. Inhibiting calcineurin activity in RCAN1ox cells has no additional effect on the amount of catecholamine release per vesicle but further reduces PSF signal parameters. Electron microscopy studies indicate these changes are not due to altered vesicle number or distribution in RCAN1ox cells but reduced vesicle release may be cause by decreased vesicle and dense core size in RCAN1ox cells. Thus, our results indicate that RCAN1 may negatively affects vesicle recycling and quantal release kinetics via the inhibition of calcineurin activity

Adaptive immunity to rhinoviruses: sex and age matter

Background: Rhinoviruses (RV) are key triggers in acute asthma exacerbations. Previous studies suggest that men suffer from infectious diseases more frequently and with greater severity than women. Additionally, the immune response to most infections and vaccinations decreases with age. Most immune function studies do not account for such differences, therefore the aim of this study was to determine if the immune response to rhinovirus varies with sex or age

Predicting invasive species impacts: a community module functional response approach reveals context dependencies

1. Predatory functional responses play integral roles in predator–prey dynamics, and their assessment promises greater understanding and prediction of the predatory impacts of invasive species. . 2. Other interspecific interactions, however, such as parasitism and higher-order predation, have the potential to modify predator–prey interactions and thus the predictive capability of the comparative functional response approach. . 3. We used a four-species community module (higher-order predator; focal native or invasive predators; parasites of focal predators; native prey) to compare the predatory functional responses of native Gammarus duebeni celticus and invasive Gammarus pulex amphipods towards three invertebrate prey species (Asellus aquaticus, Simulium spp., Baetis rhodani), thus, quantifying the context dependencies of parasitism and a higher-order fish predator on these functional responses. . 4. Our functional response experiments demonstrated that the invasive amphipod had a higher predatory impact (lower handling time) on two of three prey species, which reflects patterns of impact observed in the field. The community module also revealed that parasitism had context-dependent influences, for one prey species, with the potential to further reduce the predatory impact of the invasive amphipod or increase the predatory impact of the native amphipod in the presence of a higher-order fish predator. . 5. Partial consumption of prey was similar for both predators and occurred increasingly in the order A. aquaticus, Simulium spp. and B. rhodani. This was associated with increasing prey densities, but showed no context dependencies with parasitism or higher-order fish predator. . 6. This study supports the applicability of comparative functional responses as a tool to predict and assess invasive species impacts incorporating multiple context dependencies.

Gastric Helicobacter infection induces iron deficiency in the INS-GAS mouse

There is increasing evidence from clinical and population studies for a role of H. pylori infection in the aetiology of iron deficiency. Rodent models of Helicobacter infection are helpful for investigating any causal links and mechanisms of iron deficiency in the host. The aim of this study was to investigate the effects of gastric Helicobacter infection on iron deficiency and host iron metabolism/transport gene expression in hypergastrinemic INS-GAS mice. INS-GAS mice were infected with Helicobacter felis for 3, 6 and 9 months. At post mortem, blood was taken for assessment of iron status and gastric mucosa for pathology, immunohistology and analysis of gene expression. Chronic Helicobacter infection of INS- GAS mice resulted in decreased serum iron, transferrin saturation and hypoferritinemia and increased Total iron binding capacity (TIBC). Decreased serum iron concentrations were associated with a concomitant reduction in the number of parietal cells, strengthening the association between hypochlorhydria and gastric Helicobacter-induced iron deficiency. Infection with H. felis for nine months was associated with decreased gastric expression of iron metabolism regulators hepcidin, Bmp4 and Bmp6 but increased expression of Ferroportin 1, the iron efflux protein, iron absorption genes such as Divalent metal transporter 1, Transferrin receptor 1 and also Lcn2 a siderophore-binding protein. The INS-GAS mouse is therefore a useful model for studying Helicobacter-induced iron deficiency. Furthermore, the marked changes in expression of gastric iron transporters following Helicobacter infection may be relevant to the more rapid development of carcinogenesis in the Helicobacter infected INS-GAS model

Tears of the fascia cruris demonstrate characteristic sonographic features: a case series analysis

BACKGROUND: fascia cruris (FC) tears have recently been recognised in the literature, although little is known about their characteristic ultrasound findings. The aim was to describe the echo-graphic features of FC tears in order to improve recognition and diagnosis. METHODS: the ultrasound reports and images of >600 patients attending a specialist musculoskeletal clinic for Achilles tendon ultrasound scans between October 2010–May 2014 were reviewed. Any patient diagnosed with a FC tear had a structured data set extracted. All ultrasound images were performed by one consultant radiologist. Bilateral Achilles images were available for analysis. RESULTS: sixteen patients from >600 subjects were diagnosed with a FC tear. Fourteen subjects were male and two female (mean age 37.8; range 23–61), with seven elite level sports men. Nine tears were right sided and seven left, with eight situated laterally and seven medially. Seven of the tears were situated in the musculotendinous junction. Symptomatic Achilles tendinopathy co-existed in ten of sixteen subjects (average transverse diameter of Achilles tendon = 7.1±2.0 mm). CONCLUSION: FC tears should be considered in the differential diagnoses for Achillodynia, diagnosed using their characteristic ultrasound findings, with a hypoechoic area at the medial or lateral attachment to the Achilles tendon in the transverse plane

Transcript Profiling of Elf5+/− Mammary Glands during Pregnancy Identifies Novel Targets of Elf5

Background: Elf5, an epithelial specific Ets transcription factor, plays a crucial role in the pregnancy-associated development of the mouse mammary gland. Elf5 2/2 embryos do not survive, however the Elf5 +/2 mammary gland displays a severe pregnancy-associated developmental defect. While it is known that Elf5 is crucial for correct mammary development and lactation, the molecular mechanisms employed by Elf5 to exert its effects on the mammary gland are largely unknown. Principal Findings: Transcript profiling was used to investigate the transcriptional changes that occur as a result of Elf5 haploinsufficiency in the Elf5 +/2 mouse model. We show that the development of the mouse Elf5 +/2 mammary gland is delayed at a transcriptional and morphological level, due to the delayed increase in Elf5 protein in these glands. We also identify a number of potential Elf5 target genes, including Mucin 4, whose expression, is directly regulated by the binding of Elf5 to an Ets binding site within its promoter. Conclusion: We identify novel transcriptional targets of Elf5 and show that Muc4 is a direct target of Elf5, further elucidatin

The impact of an intervention to increase uptake to structured self-management education for people with type 2 diabetes mellitus in primary care (the embedding package), compared to usual care, on glycaemic control: study protocol for a mixed methods study incorporating a wait-list cluster randomised controlled trial

Abstract: Background: Approximately 425 million people globally have diabetes, with ~ 90% of these having Type 2 Diabetes Mellitus (T2DM). This is a condition that leads to a poor quality of life and increased risk of serious health complications. Structured self-management education (SSME) has been shown to be effective in improving glycaemic control and patient related outcome measures and to be cost-effective. However, despite the demonstrated benefits, attendance at SSME remains low. An intervention has been developed to embed SSME called the ‘Embedding Package’. The intervention aims to address barriers and enhance enablers to uptake of SSME at patient, healthcare professional and organisational levels. It comprises a marketing strategy, user friendly and effective referral pathways, new roles to champion SSME and a toolkit of resources. Methods: A mixed methods study incorporating a wait-list cluster randomised trial and ethnographic study, including 66 UK general practices, will be conducted with two intervention start times (at 0 and 9 months), each followed by an active delivery phase. At 18 months, the intervention will cease to be actively delivered and a 12 month observational follow-up phase will begin. The intervention, the Embedding Package, aims to increase SSME uptake and subsequent improvements in health outcomes, through a clear marketing strategy, user friendly and effective referral pathways, a local clinical champion and an ‘Embedder’ and a toolkit of resources for patients, healthcare professionals and other key stakeholders. The primary aim is, through increasing uptake to and attendance at SSME, to reduce HbA1c in people with T2DM compared with usual care. Secondary objectives include: assessing whether there is an increase in referral to and uptake of SSME and improvements in biomedical and psychosocial outcomes; an assessment of the sustainability of the Embedding Package; contextualising the process of implementation, sustainability of change and the ‘fit’ of the Embedding Package; and an assessment of the cost-effectiveness of the Embedding Package. Discussion: This study will assess the effectiveness, cost-effectiveness and sustainability of the Embedding Package, an intervention which aims to improve biomedical and psychosocial outcomes of people with T2DM, through increased referral to and uptake of SSME. Trial registration: International Standard Randomised Controlled Trials Number ISRCTN23474120. Assigned 05/04/2018. The study was prospectively registered. On submission of this manuscript practice recruitment is complete, participant recruitment is ongoing and expected to be completed by the end of 2019

Multispecies Storytelling in Intermedial Practices

Multispecies Storytelling in Intermedial Practices is a speculative endeavor asking how we may represent, relay, and read worlds differently by seeing other species as protagonists in their own rights. What other stories are to be invented and told from within those many-tongued chatters of multispecies collectives? Could such stories teach us how to become human otherwise? Often, the human is defined as the sole creature who holds language, and consequently is capable of articulating, representing, and reflecting upon the world. And yet, the world is made and remade by ongoing and many-tongued conversations between various organisms reverberating with sound, movement, gestures, hormones, and electrical signals. Everywhere, life is making itself known, heard, and understood in a wide variety of media and modalities. Some of these registers are available to our human senses, while some are not. Facing a not-so-distant future catastrophe, which in many ways and for many of us is already here, it is becoming painstakingly clear that our imaginaries are in dire need of corrections and replacements. How do we cultivate and share other kinds of stories and visions of the world that may hold promises of modest, yet radical hope? If we keep reproducing the same kind of languages, the same kinds of scientific gatekeeping, the same kinds of stories about “our” place in nature, we remain numb in the face of collapse. Multispecies Storytelling in Intermedial Practices offers steps toward a (self)critical multispecies philosophy which interrogates and qualifies the broad and seemingly neutral concept of humanity utilized in and around conversations grounded within Western science and academia. Artists, activists, writers, and scientists give a myriad of different interpretations of how to tell our worlds using different media – and possibly gives hints as to how to change it, too

Do RCAN1 proteins link chronic stress with neurodegeneration?

It has long been suspected that chronic stress can exacerbate, or even cause, disease. We now propose that the RCAN1 gene, which can generate several RCAN1 protein isoforms, may be at least partially responsible for this phenomenon. We review data showing that RCAN1 proteins can be induced by multiple stresses, and present new data also implicating psychosocial/emotional stress in RCAN1 induction. We further show that transgenic mice overexpressing the RCAN1-1L protein exhibit accumulation of hyperphosphorylated tau protein (AT8 antibody), an early precursor to the formation of neurofibrillary tangles and neurodegeneration of the kind seen in Alzheimer disease. We propose that, although transient induction of the RCAN1 gene might protect cells against acute stress, persistent stress may cause chronic RCAN1 overexpression, resulting in serious side effects. Chronically elevated levels of RCAN1 proteins may promote or exacerbate various diseases, including tauopathies such as Alzheimer disease. We propose that the mechanism by which stress can lead to these diseases involves the inhibition of calcineurin and the induction of GSK-3 beta by RCAN1 proteins. Both inhibition of calcineurin and induction of GSK-3 beta contribute to accumulation of phosphorylated tau, formation of neurofibrillary tangles, and eventual neurodegeneration.-Ermak, G., Pritchard, M. A., Dronjak, S., Niu, B., Davies, K. J. A. Do RCAN1 proteins link chronic stress with neurodegeneration? FASEB J. 25, 3306-3311 (2011). www.fasebj.or