Molecular misreading: The occurrence of frameshift proteins in different diseases

Neuronal homoeostasis requires a constant balance between biosynthetic and catabolic processes. Eukaryotic cells primarily use two distinct mechanisms for degradation: the proteasome and autophagy of aggregates by the lysosomes. We focused on the UPS (ubiquitin-proteasome system). As a result of molecular misreading, misframed UBB (ubiquitin B) (UBB+1) is generated. UBB+1 accumulates in the neuritic plaques and neurofibrillary tangles in all patients with AD (Alzheimer's disease) and in the neuronal and glial hallmarks of other tauopathies and in polyglutamine diseases such as Huntington's disease. UBB+1 is not present in synucleinopathies such as Parkinson's disease. We showed that UBB+1 causes UPS dysfunction, aggregation and apoptotic cell death. UBB+1 is also present in non-neurological cells, hepatocytes of the diseased liver and in muscles during inclusion body myositis. Other frequently occurring (age-related) diseases such as Type 2 (non-insulin-dependent) diabetes mellitus are currently under investigation. These findings point to the importance of the UPS in diseases and open new avenues for target identification of the main players of the UPS. Treatment of these diseases with tools (e.g. viral RNA interference constructs) to intervene with specific targets is the next step

Effecten van sociale afstand op zelfstandig wonende kwetsbare ouderen

Global Challenges (FSW

Hospital and community pharmacists' perceptions of which competences are important for their practice

The objective of the PHAR-QA (Quality assurance in European pharmacy education and training) project was to investigate how competence-based learning could be applied to a healthcare, sectoral profession such as pharmacy. This is the first study on evaluation of competences from the pharmacists’ perspective using an improved Delphi method with a large number of respondents from all over Europe. This paper looks at the way in which hospital pharmacists rank the fundamental competences for pharmacy practice. European hospital pharmacists (n = 152) ranked 68 competences for pharmacy practice of two types (personal and patient care), arranged into 13 clusters. Results were compared to those obtained from community pharmacists (n = 258). Generally, hospital and community pharmacists rank competences in a similar way. Nevertheless, differences can be detected. The higher focus of hospital pharmacists on knowledge of the different areas of science as well as on laboratory tests reflects the idea of a hospital pharmacy specialisation. The difference is also visible in the field of drug production. This is a necessary competence in hospitals with requests for drugs for rare diseases, as well as paediatric and oncologic drugs. Hospital pharmacists give entrepreneurship a lower score, but cost-effectiveness a higher one than community pharmacists. This reflects the reality of pharmacy practice where community pharmacists have to act as entrepreneurs, and hospital pharmacists are managers staying within drug budgets. The results are discussed in the light of a “hospital pharmacy” specialisation

Investigation of tutin, a naturally-occurring plant toxin, as a novel, culturally-acceptable rodenticide in New Zealand

He nui nga mātauranga a te Māori (Ngai Tūhoe) e pā ana ki nga momo hua tāokeoke (Toxins) etaea ana te whakarite hei rauemi tāwai i ngā riha kīrearea, pērā anō ki nga whiu takarangi o te tāoke 1080. I whakamātauhia e matou i nga ira tāoke o roto o te hua Tutu, ki rō taiwhanga pūtaiao. Mā te wero atu ki tētahi kiore (Norway Rat) i hua mai ngā mohiotanga o te nui me te momo o ngā tāokeoke kei roto i tēnei miro Māori, me te āhua o tēnei tāoke kia mau-rohā tonu tōna tuku whakahemo (Humaneness). Kei tua o te 55 mg kg⁻¹neke atu, te ine i tūtuki pai ai nga tāhawahawatanga o te miro Tutu, ā, e mau-roha tonu ana te kōhurutanga o te r iha. Ko te whakatau kia kawea atu tēnei kaupapa ki nga ahurewa rangahau e taea ai te waihanga i tētahi mōunu tāokeoke, kia whakamātauria ki rō ngāhere. Hei tāpiritanga ki tēnei, he roa rawa te wā e pakari ai te whanaketanga mai o tētahi tākoe e rerekē ana ki te 1080, anō nei, mā ngā kawenga o te mātauranga Māori ki tēnei take e whanake tika ai te kaupapa nei. New Zealand has many introduced mammalian species that are managed as pests of conservation and/or economic importance, including four rodent species. Vertebrate pesticides are the most important rodent management tool, largely dominated by anticoagulants such as brodifacoum, and by the metabolic disruptor, Compound 1080. There has been considerable opposition to these pesticides, primarily based on concerns about environmental persistence and non-target effects; Maori have been particularly vocal in opposition. Maori have place-based knowledge about naturally-occurring plant toxins that could be used as culturally-acceptable alternatives to existing rodenticides. In the context of the research presented here, the term ‘culturally-acceptable’ refers to new pest control options that have been co-designed with Matauranga Maori experts that inherently include Maori ways of thinking, being, and acting. Tuhoe researchers in our study wanted to pursue the most promising natural toxic compound found in native plants as a suitable alternative to current vertebrate pesticides. Therefore, we undertook an oral gavage trial to assess the toxicity of tutin, the toxin active in tutu (Coriaria arborea), to the Norway rat, (Rattus norvegicus). Tutin was toxic to this species at a dose of 55 mg kg⁻¹, with a quick, humane death compared to other existing rodenticides. At a dose rate of 55 mg kg⁻¹, all animals of both sexes died within an hour, and once neurological poisoning symptoms commenced these animals were unconscious within 5-10 minutes. We conclude it is warranted to take the next logical research step, which is to prove whether this dose rate would be technically attainable in the field. Although for now New Zealand remains reliant on 1080 and anti-coagulants for mammalian pest control, efforts should continue to develop more targeted toxins and delivery systems. We recommend incorporating Matauranga Maori to identify alternative control tools that could lead to more culturally acceptable pest control

Placental lactogens induce serotonin biosynthesis in a subset of mouse beta cells during pregnancy

AIMS/HYPOTHESIS: Upregulation of the functional beta cell mass is required to match the physiological demands of mother and fetus during pregnancy. This increase is dependent on placental lactogens (PLs) and prolactin receptors, but the mechanisms underlying these events are only partially understood. We studied the mRNA expression profile of mouse islets during pregnancy to gain a better insight into these changes. METHODS: RNA expression was measured ex vivo via microarrays and quantitative RT-PCR. In vivo observations were extended by in vitro models in which ovine PL was added to cultured mouse islets and MIN6 cells. RESULTS: mRNA encoding both isoforms of the rate-limiting enzyme of serotonin biosynthesis, tryptophan hydroxylase (TPH), i.e. Tph1 and Tph2, were strongly induced (fold change 25- to 200-fold) during pregnancy. This induction was mimicked by exposing islets or MIN6 cells to ovine PLs for 24 h and was dependent on janus kinase 2 and signal transducer and activator of transcription 5. Parallel to Tph1 mRNA and protein induction, islet serotonin content increased to a peak level that was 200-fold higher than basal. Interestingly, only a subpopulation of the beta cells was serotonin-positive in vitro and in vivo. The stored serotonin pool in pregnant islets and PL-treated MIN6 cells was rapidly released (turnover once every 2 h). CONCLUSIONS/INTERPRETATION: A very strong lactogen-dependent upregulation of serotonin biosynthesis occurs in a subpopulation of mouse islet beta cells during pregnancy. Since the newly formed serotonin is rapidly released, this lactogen-induced beta cell function may serve local or endocrine tasks, the nature of which remains to be identified

Exploring Functional β-Cell Heterogeneity In Vivo Using PSA-NCAM as a Specific Marker

BACKGROUND:The mass of pancreatic beta-cells varies according to increases in insulin demand. It is hypothesized that functionally heterogeneous beta-cell subpopulations take part in this process. Here we characterized two functionally distinct groups of beta-cells and investigated their physiological relevance in increased insulin demand conditions in rats. METHODS:Two rat beta-cell populations were sorted by FACS according to their PSA-NCAM surface expression, i.e. beta(high) and beta(low)-cells. Insulin release, Ca(2+) movements, ATP and cAMP contents in response to various secretagogues were analyzed. Gene expression profiles and exocytosis machinery were also investigated. In a second part, beta(high) and beta(low)-cell distribution and functionality were investigated in animal models with decreased or increased beta-cell function: the Zucker Diabetic Fatty rat and the 48 h glucose-infused rat. RESULTS:We show that beta-cells are heterogeneous for PSA-NCAM in rat pancreas. Unlike beta(low)-cells, beta(high)-cells express functional beta-cell markers and are highly responsive to various insulin secretagogues. Whereas beta(low)-cells represent the main population in diabetic pancreas, an increase in beta(high)-cells is associated with gain of function that follows sustained glucose overload. CONCLUSION:Our data show that a functional heterogeneity of beta-cells, assessed by PSA-NCAM surface expression, exists in vivo. These findings pinpoint new target populations involved in endocrine pancreas plasticity and in beta-cell defects in type 2 diabetes

Research on new toxins: striving for improvements in animal pest control

Introduced animal pests are destroying New Zealand’s biodiversity.This presentation outlines current solutions, then looks at new toxins and delivery systems