Looking at Alzheimer’s disease pathogenesis from the nuclear side

Alzheimer’s disease (AD) is a neurodegenerative disorder representing the most common form of dementia. It is biologically characterized by the deposition of extracellular amyloid‐β (Aβ) senile plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated tau protein. The key protein in AD pathogenesis is the amyloid precursor protein (APP), which is cleaved by secretases to produce several metabolites, including Aβ and APP intracellular domain (AICD). The greatest genetic risk factor associated with AD is represented by the Apolipoprotein E ε4 (APOE ε4) allele. Importantly, all of the above‐mentioned molecules that are strictly related to AD pathogenesis have also been described as playing roles in the cell nucleus. Accordingly, evidence suggests that nuclear functions are compromised in AD. Furthermore, modulation of transcription maintains cellular homeostasis, and alterations in transcriptomic profiles have been found in neurodegenerative diseases. This report reviews recent advancements in the AD players‐mediated gene expression. Aβ, tau, AICD, and APOE ε4 localize in the nucleus and regulate the transcription of several genes, part of which is involved in AD pathogenesis, thus suggesting that targeting nuclear functions might provide new therapeutic tools for the disease

Voorziening voor verzoeken tot snelle verwijdering van onrechtmatige online content

The report provides insight into the legal and practical feasibility of a new procedure for the removal of unlawful online content that affects people personally. Unlawful content online is information, posted by people on the internet, that is unlawful because of its harmful effects and/or because it seriously affects the interests of others. One can think of examples such as online threats, privacy infringements or revenge pornography. The aim of the research is to investigate whether there could be a suitable procedure in the Netherlands that enables people to remove this unlawful online content as quickly as possible. The research focuses on unlawful online content that falls within the scope of the right to private life under Article 8 of the European Convention on Human Rights (“ECHR”).Dit onderzoek is uitgegeven als onderdeel van het speerpunt van de Minister voor Rechtsbescherming om de positie van slachtoffers van onrechtmatige uitingen op het internet te verbeteren. Aanleiding is dat het voor mensen als te moeilijk ervaren wordt om onrechtmatige online content snel verwijderd te krijgen. Dit rapport biedt inzicht in de juridische en praktische haalbaarheid van een voorziening voor de verwijdering van onrechtmatige online content die mensen persoonlijk raakt. Onrechtmatige content is informatie, door mensen op het internet geplaatst, die in strijd is met het recht, vanwege de schadelijke gevolgen ervan en/of omdat de belangen van anderen daardoor op ernstige wijze worden aangetast. Hierbij moet, bijvoorbeeld, gedacht worden aan bedreigingen, privacy-inbreuken of wraakporno. Het doel van de onderzochte voorziening is om mensen in staat te stellen deze onrechtmatige online content zo snel mogelijk te verwijderen. Het onderzoek focust op onrechtmatige online content die mensen in hun persoon raakt en daarmee onder het recht op privéleven uit artikel 8 Europees Verdrag voor de Rechten van de Mens (“EVRM”) valt. INHOUD: 1. Introductie 2. De problematiek van onrechtmatige online content 3. Grondrechtelijk kader en internationale context 4. Bestaande juridisch kader voor verwijdering en knelpunten 5. Knelpuntenanalyse en oplossingsrichting 6. Conclusi

Dendritic Spines in Alzheimer’s Disease: How the Actin Cytoskeleton Contributes to Synaptic Failure

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by Aβ-driven synaptic dysfunction in the early phases of pathogenesis. In the synaptic context, the actin cytoskeleton is a crucial element to maintain the dendritic spine architecture and to orchestrate the spine’s morphology remodeling driven by synaptic activity. Indeed, spine shape and synaptic strength are strictly correlated and precisely governed during plasticity phenomena in order to convert short-term alterations of synaptic strength into long-lasting changes that are embedded in stable structural modification. These functional and structural modifications are considered the biological basis of learning and memory processes. In this review we discussed the existing evidence regarding the role of the spine actin cytoskeleton in AD synaptic failure. We revised the physiological function of the actin cytoskeleton in the spine shaping and the contribution of actin dynamics in the endocytosis mechanism. The internalization process is implicated in different aspects of AD since it controls both glutamate receptor membrane levels and amyloid generation. The detailed understanding of the mechanisms controlling the actin cytoskeleton in a unique biological context as the dendritic spine could pave the way to the development of innovative synapse-tailored therapeutic interventions and to the identification of novel biomarkers to monitor synaptic loss in AD

Long-term interferon-alpha treatment of childrenwith chronic hepatitis delta: a multicentre study.

We assessed the efficacy of prolonged interferon-alpha (IFN) therapy in children with chronic hepatitis caused by hepatitis delta virus (HDV) by treating 26 paediatric cases with IFN-alpha 2b (5 MU m-2, then 3 MU m-2 three times weekly for 12 (medium-term group MTG) or 24 months (long-term group, LTG). Compliance and tolerability were acceptable. At the end of therapy a complete biochemical response [normalization of alanine aminotransferase (ALT)] occurred in 12 children (5/13 in MTG and 7/13 in LTG). A relapse occurred after stopping IFN in 10 cases (five in MTG and five in LTG). Two patients from the LTG had normal liver function tests during 12 months of follow-up. Six of the eight hepatitis B e antigen (HBeAg) positive children lost HBeAg, while all six hepatitis B virus (HBV) DNA positive patients lost HBV DNA during treatment. HBeAg reappeared later in two children. HDV RNA, present in 10/10 cases of MTG before treatment, persisted after 12 months IFN therapy in 3/10. One year after stopping therapy, 8/10 patients were again HDV RNA positive. Two children cleared hepatitis delta antigen (HDVAg) from the liver. No significant improvements in liver histology were seen in both groups. Our experience suggests that IFN-alpha treatment in children with chronic type D hepatitis has a transient effect, and long-term treatment does not appear to induce a greater therapeutic benefit in terms of biochemical and virological respons

Voorziening voor verzoeken tot snelle verwijdering van onrechtmatige online content

The report provides insight into the legal and practical feasibility of a new procedure for the removal of unlawful online content that affects people personally. Unlawful content online is information, posted by people on the internet, that is unlawful because of its harmful effects and/or because it seriously affects the interests of others. One can think of examples such as online threats, privacy infringements or revenge pornography. The aim of the research is to investigate whether there could be a suitable procedure in the Netherlands that enables people to remove this unlawful online content as quickly as possible. The research focuses on unlawful online content that falls within the scope of the right to private life under Article 8 of the European Convention on Human Rights (“ECHR”)