Tauopathy-Associated Tau Fragment Ending at Amino Acid 224 Is Generated by Calpain-2 Cleavage

BACKGROUND: Tau aggregation in neurons and glial cells characterizes tauopathies as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Tau proteolysis has been proposed as a trigger for tau aggregation and tau fragments have been observed in brain and cerebrospinal fluid (CSF). Our group identified a major tau cleavage at amino acid (aa) 224 in CSF; N-terminal tau fragments ending at aa 224 (N-224) were significantly increased in AD and lacked correlation to total tau (t-tau) and phosphorylated tau (p-tau) in PSP and CBD. OBJECTIVE: Previous studies have shown cleavage from calpain proteases at sites adjacent to aa 224. Our aim was to investigate if calpain-1 or -2 could be responsible for cleavage at aa 224. METHODS: Proteolytic activity of calpain-1, calpain-2, and brain protein extract was assessed on a custom tau peptide (aa 220-228), engineered with fluorescence resonance energy transfer (FRET) technology. Findings were confirmed with in-gel trypsination and mass spectrometry (MS) analysis of brain-derived bands with proteolytic activity on the FRET substrate. Finally, knock-down of the calpain-2 catalytic subunit gene (CAPN2) was performed in a neuroblastoma cell line (SH-SY5Y). RESULTS: Calpain-2 and brain protein extract, but not calpain-1, showed proteolytic activity on the FRET substrate. MS analysis of active gel bands revealed presence of calpain-2 subunits, but not calpain-1. Calpain-2 depletion and chemical inhibition suppressed proteolysis of the FRET substrate. CAPN2 knock-down caused a 76.4% reduction of N-224 tau in the cell-conditioned media. CONCLUSIONS: Further investigation of the calpain-2 pathway in the pathogenesis of tauopathies is encouraged

Increasing awareness and reputation of MERCK S.A. Portugal through employee advocacy

Merck KGaA is a global Science and Technology company, focusing on the Healthcare Industry, Life Science and Performance Materials. Merck in Portugal is a relatively small subsidiary with a midsized office employing approximately 114 employees. Merck S.A. Portugal focuses mainly on the Healthcare Market. As the company went through a major transformation in 2016, it created a need to communicate on a low cost basis and in an efficient way, using digital as its main channel. The current paper shows the implementation of an employee advocacy strategic plan as a solution to digital communication. Employee Advocacy is a new communications concept derived from employee social media usage and employee word of mouth. It has been noted that employee networks are wider than company’s own and employee word of mouth is more trustworthy. Before the tool could be implemented a research on what motivates employees to commit to Brand Citizenship Behavior was performed. Findings revealed that in the case of Merck S.A. Portugal employees individual internal drive and brand knowledge are factors affecting willingness to share on social media. Based on the results a series of internal strategies were applied on- and offline.info:eu-repo/semantics/acceptedVersio

Outer membrane protein folding from an energy landscape perspective

The cell envelope is essential for the survival of Gram-negative bacteria. This specialised membrane is densely packed with outer membrane proteins (OMPs), which perform a variety of functions. How OMPs fold into this crowded environment remains an open question. Here, we review current knowledge about OFMP folding mechanisms in vitro and discuss how the need to fold to a stable native state has shaped their folding energy landscapes. We also highlight the role of chaperones and the β-barrel assembly machinery (BAM) in assisting OMP folding in vivo and discuss proposed mechanisms by which this fascinating machinery may catalyse OMP folding

Strategisches Handeln von Startups im Kontext der Mediatisierung

Junge Gründer und Start-ups müssen sich in einer schnell wandelnden und mediatisierten Wettbewerbsumwelt behaupten. Ihr Handeln wird geprägt von sozialen Netzwerkmedien wie Facebook, LinkedIn oder Instagram. Um auf diesen Medien-plattformen erfolgreich zu sein, müssen Markenführung und Markenkommunikation strategisch verankert sein. Der Aufsatz präsentiert daher eine qualitative Analyse empirischer Daten aus dem Kontext des Start-up-Incubator neudeli der Bauhaus-Universität Weimar und verdeutlicht, dass die Mediatisierung grundlegend in die strategische Entwicklung der Marke von jungen Gründern und Start-ups eingreift. Die Studie verdeutlicht das Verständnis strategischer Markenführung in mediatisierten Kontexten und zeigt, dass drei idealtypische Praktiken zur Markenführung und strategischen Entwicklung beitragen: 1) Bürokratische Medienarbeit, 2) Mediale Kreativarbeit, 3) Netzwerkarbeit durch Medien

The Heidelberg Milestones Communication Approach (MCA) for patients with prognosis <12 months: protocol for a mixed-methods study including a randomized controlled trial

Background: The care needs of patients with a limited prognosis (<12 months median) are complex and dynamic. Patients and caregivers must cope with many challenges, including physical symptoms and disabilities, uncertainty. and compromised self-efficacy. Healthcare is often characterized by disruptions in the transition between healthcare providers. The Milestones Communication Approach (MCA) is a structured, proactive, interprofessional concept that involves physicians and nurses and is aimed at providing coherent care across the disease trajectory. This study aims to evaluate these aspects of MCA: (1) the training of healthcare professionals, (2) implementation context and outcomes, (3) patient outcomes, and (4) effects on interprofessional collaboration. Methods/design: A multiphase mixed-methods design will be used for the study. A total of 100 patients and 120 healthcare professionals in a specialized oncology hospital will be involved. The training outcomes will be documented using a questionnaire. Implementation context and outcomes will be explored through semi-structured interviews and written questionnaires with healthcare professionals and with the training participants and through a content analysis of patient files. Patient outcomes will be assessed in a pragmatic non-blinded randomized controlled trial and in qualitative interviews with patients and caregivers. Trial outcomes are supportive care needs (SCNS-SF34-G), quality of life (SeiQol and Fact-L), depression and anxiety symptoms (PHQ-4), and distress (Distress Thermometer). Qualitative semi-structured interviews on patients’ views will focus on shared decision-making, communication needs, feeling empathy, and further utilization of healthcare services. Interprofessional collaboration will be explored using the UWE-IP-D before the implementation of MCA (t0) and after 3 (t1), 9 (t2), and 12 (t3) months. Discussion: Using guideline-concordant early palliative care, MCA aims to foster patient-centered communication with shared decision-making and facilitation of advance care planning including end-of-life decisions, thus increasing patient quality of life and decreasing aggressive medical care at the end of life. It is assumed that the communication skills training and interprofessional coaching will improve the communication behavior of healthcare providers and influence team communications and team processes. Trial registration German Clinical Trials Register, DRKS00013649 and DRKS00013469. Registered on 22 December 2017

De archeologische begeleiding van het leggen van kabels en leidingen rond de locatie van het Groninger Forum in het centrum van de stad Groningen (Gr): ARC-Rapporten 2010-243

In opdracht van de Dienst RO/EZ van de gemeente Groningen heeft Archaeological Research & Consultancy (ARC bv) tussen 7 september 2009 en 13 november 2009 het leggen van kabels en leidingen rondom de geplande locatie van de nieuwbouw van het Groninger Forum in het centrum van Groningen archeologisch begeleid. Aan de Grote Markt-oostzijde en in de kop van de Oosterstraat en de Poelestraat zijn fundamenten aangetroffen van in oorsprong middeleeuwse huizen. Aan de Grote Markt-oostzijde is bovendien een deel van het souterrain van het Scholtenhuis waargenomen en een plavuisvloer van een ouder pand, het Alberdahuis. In de Oosterstraat en onder de huidige rijbaan aan de Grote Markt-oostzijde lagen resten van een keienplaveisel uit de Middeleeuwen. Aan de Grote Markt-zuidzijde was alleen sprake van ophogingslagen. In de noordoostelijke hoek van het middenplein van de markt zijn geen sporen van vroegmiddeleeuwse graven aangetroffen. Enkele langwerpige kuilen in de uitmonding van het Martinikerkhof op de markt zouden grafkuilen kunnen zijn, al liggen ze buiten de bekende begrenzing van het kerkhof en werden er geen botmateriaal en/of kisten waargenomen. In de Schoolstraat was sprake van het restant van een middeleeuws wal-lichaam en van fundamenten van huizen die hier na de slechting van de wal gebouwd werden. Een enkel bouwdeel heeft mogelijk deel uitgemaakt van een aanbouw aan de binnenzijde van de stadsmuur

Eine programmtechnische Realisierung von Matrizenalgorithmen der Methode der Finiten Elemente für Aufgaben der Festkörpermechanik

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