Glucose induced MAPK signalling influences NeuroD1-mediated activation and nuclear localization

AbstractThe helix–loop–helix transcription factor NeuroD1 (also known as Beta2) is involved in β-cell survival during development and insulin gene transcription in adults. Here we show NeuroD1 is primarily cytoplasmic at non-stimulating glucose concentrations (i.e. 3 mM) in MIN6 β-cells and nuclear under stimulating conditions (i.e. 20 mM). Quantification revealed that NeuroD1 was in 40–45% of the nuclei at 3 mM and 80–90% at 20 mM. Treatment with the MEK inhibitor PD98059 or substitution of a serine for an alanine at a potential mitogen-activated protein kinase phosphorylation site (S274) in NeuroD1 significantly increased the cytoplasmic level at 20 mM glucose. The rise in NeuroD1-mediated transcription in response to glucose also correlated with the change in sub-cellular localization, a response attenuated by PD98059. The data strongly suggest that glucose-stimulation of the MEK–ERK signalling pathway influences NeuroD1 activity at least partially through effects on sub-cellular localization

Insulin gene regulation and islet development as studied in genetically modified tumors and transgenic laboratory animals

The pancreatic islet of Langerhans is composed of four highly distinct cell types specialized to mass produce a particular hormone. Insulin is thus the main product released from the islet B—cell in response to elevated glucose.The four cell types maturate during fetal development. Pluripotent rat islet tumors can to a certain degree undergo similar maturation processes when passaged in vivo. Such a model has been used to study the B—cell specific process of insulin gene activation. Transgenic mice have been instrumental in defining the functional regulatory elements involved in restricting the insulin gene activity to the pancreatic B-cell. The tissue-specific enhancer/promoter has thus been identified and used in combination with a series of other genes which in transgenic mice targets expression of the gene in question selectively to the B-cell. Important transacting factors have been identified and cloned which are in part responsible for mediating tissue specific insulin gene expression. One such factor when "knocked-out" results in a phenotype lacking the entire pancreas. Future developments in targeting "knockout" of genes to particular cell types will help dissecting out the multiple functions of such regulatory transacting factors

Species and abundance of ectoparasitic flies (Diptera) in pied flycatcher nests in Fennoscandia

Peer reviewe

Vesicular Stomatitis Virus Infection Promotes Immune Evasion by Preventing NKG2D-Ligand Surface Expression

Vesicular stomatitis virus (VSV) has recently gained attention for its oncolytic ability in cancer treatment. Initially, we hypothesized that VSV infection could increase immune recognition of cancer cells through induction of the immune stimulatory NKG2D-ligands. Here we show that VSV infection leads to a robust induction of MICA mRNA expression, however the subsequent surface expression is potently hindered. Thus, VSV lines up with human cytomegalovirus (HCMV) and adenovirus, which actively subvert the immune system by negatively affecting NKG2D-ligand surface expression. VSV infection caused an active suppression of NKG2D-ligand surface expression, affecting both endogenous and histone deacetylase (HDAC)-inhibitor induced MICA, MICB and ULBP-2 expression. The classical immune escape mechanism of VSV (i.e., the M protein blockade of nucleocytoplasmic mRNA transport) was not involved, as the VSV mutant strain, VSVΔM51, which possess a defective M protein, prevented MICA surface expression similarly to wild-type VSV. The VSV mediated down modulation of NKG2D-ligand expression did not involve apoptosis. Constitutive expression of MICA bypassed the escape mechanism, suggesting that VSV affect NKG2D-ligand expression at an early post-transcriptional level. Our results show that VSV possess an escape mechanism, which could affect the immune recognition of VSV infected cancer cells. This may also have implications for immune recognition of cancer cells after combined treatment with VSV and chemotherapeutic drugs

Barriers and facilitators for implementing a new screening tool in an emergency department: A qualitative study applying the Theoretical Domains Framework

Aim. The aim was to identify the factors that were perceived as most important as facilitators or barriers to the introduction and intended use of a new tool in the emergency department among nurses and a geriatric team. Background. A high incidence of functional decline after hospitalisation for acute medical illness has been shown in the oldest patients and those who are physically frail. In Denmark, more than 35% of older medical patients acutely admitted to the emergency department are readmitted within 90 days after discharge. A new screening tool for use in the emergency department aiming to identify patients at particularly high risk of functional decline and readmission was developed. Design. Qualitative study based on semistructured interviews with nurses and a geriatric team in the emergency department and semistructured single interviews with their managers. Methods. The Theoretical Domains Framework guided data collection and analysis. Content analysis was performed whereby new themes and themes already existing within each domain were described. Results. Six predominant domains were identified: (1) professional role and identity; (2) beliefs about consequences; (3) goals; (4) knowledge; (5) optimism and (6) environmental context and resources. The content analysis identified three themes, each containing two subthemes. The themes were professional role and identity, beliefs about consequences and preconditions for a successful implementation. Conclusions. Two different cultures were identified in the emergency department. These cultures applied to different professional roles and identity, different actions and sense making and identified how barriers and facilitators linked to the new screening tool were perceived.Funding Agencies|Capital Region</p