Biochem Soc Trans

Abnormal protein aggregation and intracellular or extracellular accumulation of misfolded and aggregated proteins are key events in the pathogenesis of different neurodegenerative diseases. Furthermore, endoplasmic reticulum stress and impairment of the ubiquitin-proteasome system probably contribute to neurodegeneration in these diseases. A characteristic feature of AD (Alzheimer's disease) is the abnormal accumulation of Abeta (amyloid beta-peptide) in the brain. Evidence shows that the AD-associated PS (presenilin) also forms aggregates under certain conditions and that another AD-associated protein, ubiquilin-1, controls protein aggregation and deposition of aggregated proteins. Here, we review the current knowledge of ubiquilin-1 and PS in protein aggregation and related events that potentially influence neurodegeneration

Luokanopettajien näkemyksiä yhteisopettajuudesta

Tiivistelmä. Tässä pro gradu -tutkielmassa tarkastelemme yhteisopettajuutta, sen etuja ja haasteita sekä ammatillista kasvua. Yhteisopettajuus on keino toteuttaa opetusta sekä oppilaita että opettajia hyödyttävällä tavalla. Opetusmuotona yhteisopettajuutta ei vielä tunneta kovinkaan yleisesti ja tutkimusta siitä ei Suomessa ole juuri tehty. Aiemmissa tutkimuksissa yhteisopettajuudessa toinen opettaja on erityisopettaja. Tämän vuoksi perehdyimme yhteisopettajuuteen kahden luokanopettajan välillä. Tutkielmamme tutkimuskysymyksillä pyrimme perehtymään opettajien näkemyksiin siitä, mitä yhteisopettajuus on, millaisia etuja ja haasteita siinä ilmenee sekä miten yhteisopettajuus vaikuttaa opettajien ammatilliseen kasvuun. Tutkielmamme taustalla oleva teoria määrittää yhteisopettajuuden kahden opettajan väliseksi yhteistoiminnaksi heterogeenisessä ryhmässä. Yhteisopettajuudella on monia toimintamalleja sekä erilaisia etuja ja haasteita. Yhteisopettajuus on nähty yhtenä ammatillisen kasvun keinona. Ammatillinen kasvu koostuu opettajien ammatillisesta oppimisesta ja kehityksestä. Tutkielmamme on laadullinen tutkimus, joka toteutettiin fenomenografisella tutkimusotteella teemahaastattelun avulla. Haastateltavina oli neljä yhteisopettajuutta toteuttavaa opettajaa. Haastatteluissa oli tarkoitus saada opettajien näkemyksiä yhteisopettajuuteen. Tutkimustulokset muotoutuivat aineistolähtöisen sisällönanalyysin avulla. Tutkielmassamme saimme selville opettajien näkemyksiä yhteisopettajuudesta. Opettajat määrittivät yhteisopettajuuden tärkeimmäksi olemukseksi työn jakamisen. Yhteisopettajuuden etuina nähtiin kollegiaalinen yhteistyö sekä oppilaiden saama hyöty useamman aikuisen läsnäolosta. Haasteena pidettiin suuria oppilasmääriä, jotka saattavat hankaloittaa opetusta. Yhteisopettajuudessa ammatillista kasvua nähtiin tapahtuvan toista opettajaa seuraamalla sekä opettajuudesta keskustelemalla. Tutkimustuloksistamme voidaan päätellä yhteisopettajuuden olevan laajempaa yhteistyötä, kuin miten aiempi tutkimus on sen määritellyt. Yhteisopettajuuden ei välttämättä tarvitse tapahtua samassa luokkatilassa jatkuvasti. Haastateltavamme toteuttivat yhteisopettajuutta eri tavoilla. Osa opettajista toteutti yhteisopettajuutta kokonaisvaltaisesti yhdessä ja osalla toiminta oli keskittynyt tiettyihin oppiaineisiin. Yhteisopettajuus nähtiin helpottavan opettajan työtä laajasti, koska työtä voitiin jakaa ja asioista keskustella. Mielestämme yhteisopettajuutta voidaan hyödyntää keinona vastaamaan jatkuvasti muuttuvaan koulumaailmaan

Svalbard reindeer winter diets: Long-term dietary shifts to graminoids in response to a changing climate

Arctic ecosystems are changing dramatically with warmer and wetter conditions resulting in complex interactions between herbivores and their forage. We investigated how Svalbard reindeer (Rangifer tarandus platyrhynchus) modify their late winter diets in response to long-term trends and interannual variation in forage availability and accessibility. By reconstructing their diets and foraging niches over a 17-year period (1995–2012) using serum δ13C and δ15N values, we found strong support for a temporal increase in the proportions of graminoids in the diets with a concurrent decline in the contributions of mosses. This dietary shift corresponds with graminoid abundance increases in the region and was associated with increases in population density, warmer summer temperatures and more frequent rain-on-snow (ROS) in winter. In addition, the variance in isotopic niche positions, breadths, and overlaps also supported a temporal shift in the foraging niche and a dietary response to extreme ROS events. Our long-term study highlights the mechanisms by which winter and summer climate changes cascade through vegetation shifts and herbivore population dynamics to alter the foraging niche of Svalbard reindeer. Although it has been anticipated that climate changes in the Svalbard region of the Arctic would be detrimental to this unique ungulate, our study suggests that environmental change is in a phase where conditions are improving for this subspecies at the northernmost edge of the Rangifer distribution

Protein kinase C-activating isophthalate derivatives mitigate Alzheimer's disease-related cellular alterations

Abnormal protein kinase C (PKC) function contributes to many pathophysiological processes relevant for Alzheimer's disease (AD), such as amyloid precursor protein (APP) processing. Phorbol esters and other PKC activators have been demonstrated to enhance the secretion of soluble APP alpha (sAPP alpha), reduce the levels of beta-amyloid (A beta), induce synaptogenesis, and promote neuroprotection. We have previously described isophthalate derivatives as a structurally simple family of PKC activators. Here, we characterised the effects of isophthalate derivatives HMI-1a3 and HMI-1b11 on neuronal viability, neuroinflammatory response, processing of APP and dendritic spine density and morphology in in vitro. HMI-1a3 increased the viability of embryonic primary cortical neurons and decreased the production of the pro-inflammatory mediator TNF alpha, but not that of nitric oxide, in mouse neuron-BV2 microglia co-cultures upon LPS- and IFN-gamma-induced neuroinflammation. Furthermore, both HMI-1a3 and HMI-1b11 increased the levels of sAPPa relative to total sAPP and the ratio of A beta 42/A beta 40 in human SH-Sv5v neuroblastoma cells. Finally, bryostatin-1, but not HMI-1a3, increased the number of mushroom spines in proportion to total spine density in mature mouse hippocampal neuron cultures. These results suggest that the PKC activator HMI-1a3 exerts neuroprotective functions in the in vitro models relevant for AD by reducing the production of TNF alpha and increasing the secretion of neuroprotective sAPPa.Peer reviewe

PTCHD1 Binds Cholesterol but Not Sonic Hedgehog, Suggesting a Distinct Cellular Function

Deleterious mutations in the X-linked Patched domain-containing 1 (PTCHD1) gene may account for up to 1% of autism cases. Despite this, the PTCHD1 protein remains poorly understood. Structural similarities to Patched family proteins point to a role in sterol transport, but this hypothesis has not been verified experimentally. Additionally, PTCHD1 has been suggested to be involved in Hedgehog signalling, but thus far, the experimental results have been conflicting. To enable a variety of biochemical and structural experiments, we developed a method for expressing PTCHD1 in Spodoptera frugiperda cells, solubilising it in glycol-diosgenin, and purifying it to homogeneity. In vitro and in silico experiments show that PTCHD1 function is not interchangeable with Patched 1 (PTCH1) in canonical Hedgehog signalling, since it does not repress Smoothened in Ptch1−/− mouse embryonic fibroblasts and does not bind Sonic Hedgehog. However, we found that PTCHD1 binds cholesterol similarly to PTCH1. Furthermore, we identified 13 PTCHD1-specific protein interactors through co-immunoprecipitation and demonstrated a link to cell stress responses and RNA stress granule formation. Thus, our results support the notion that despite structural similarities to other Patched family proteins, PTCHD1 may have a distinct cellular function

Neurosci Lett

Recently, the P86L alteration in CALHM1 (calcium homeostasis modulator-1) was reported to be associated with Alzheimer's disease (AD). Moreover, the risk allele increased amyloid-beta (A beta) levels in conditioned media from cultured cells. Therefore, we hypothesized that CALHM1 P86L may modulate A beta or tau levels in cerebrospinal fluid (CSF). Nearly 200 individuals with AD or other cognitive disorders were included for CSF analysis and CALHM1 genotyping. No significant differences in CSF levels of A beta 42, tau or phospho-tau were found across the various CALHM1 genotypes. In conclusion, we found no evidence that CALHM1 P86L is associated with altered CSF levels of the investigated AD biomarkers

Preverbs: an introduction

The notion ‘preverb’ is a traditional descriptive notion in Indo-European linguistics. It refers to morphemes that appear in front of a verb, and which form a close semantic unit with that verb. In many cases, the morpheme that functions as a preverb can also function without a preverbal context, often as an adverb or an adposition. Most linguists use the notion ‘preverb’ as a cover term for preverbal words and preverbal prefixes. The preverb may be separated from the verb whilst retaining its close cohesion with the verb, which is called ‘tmesis’. It may also develop into a bound morpheme, that is, a prefix inseparable from the verb, with concomitant reduction of phonological form in some cases. If the preverb has become a real prefix, we may use the more specific notion of ‘complex verb’, whereas we take the notion ‘complex predicate’ to refer generally to multi-morphemic expressions with verbal valency. That is, we make a terminological distinction between complex predicates and complex verbs. The latter are multi-morphemic, but behave as single grammatical words

Presynaptic vesicle protein SEPTIN5 regulates the degradation of APP C-Terminal fragments and the levels of Aβ

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Alzheimer's disease (AD) is a neurodegenerative disease characterized by aberrant amyloid-β (Aβ) and hyperphosphorylated tau aggregation. We have previously investigated the involvement of SEPTIN family members in AD-related cellular processes and discovered a role for SEPTIN8 in the sorting and accumulation of β-secretase. Here, we elucidated the potential role of SEPTIN5, an interaction partner of SEPTIN8, in the cellular processes relevant for AD, including amyloid precursor protein (APP) processing and the generation of Aβ. The in vitro and in vivo studies both revealed that the downregulation of SEPTIN5 reduced the levels of APP C-terminal fragments (APP CTFs) and Aβ in neuronal cells and in the cortex of Septin5 knockout mice. Mechanistic elucidation revealed that the downregulation of SEPTIN5 increased the degradation of APP CTFs, without affecting the secretory pathway-related trafficking or the endocytosis of APP. Furthermore, we found that the APP CTFs were degraded, to a large extent, via the autophagosomal pathway and that the downregulation of SEPTIN5 enhanced autophagosomal activity in neuronal cells as indicated by altered levels of key autophagosomal markers. Collectively, our data suggest that the downregulation of SEPTIN5 increases the autophagy-mediated degradation of APP CTFs, leading to reduced levels of Aβ in neuronal cells.This research was supported by the Academy of Finland (grant numbers 307866 and 315459), the Sigrid Jusélius Foundation, the Strategic Neuroscience Funding of the University of Eastern Finland, and the National Institute of Mental Health of the National Institutes of Health (grant numbers R01MH099660, R01DC015776, R21HD053114, and U54HD090260). Catarina B. Ferreira is a PhD Fellow (NeurULisboa - Integrated Neurosciences PhD program, supported by an individual grant from Fundação para a Ciência e Tecnologia (FCT), (PD/BD/128390/2017, SFRH/PD/BD/114441/2016, PD/BD/128091/2016). Work was also supported by Santa Casa da Misericórdia de Lisboa (MB37-2017) and SynaNet (LISBOA-01-0145-FEDER-0073919), under the grant agreement no. 692340, and the project was co-financed by FEDER, POR Lisboa 2020, Programa Operacional Regional de Lisboa, from PORTUGAL 2020 and by Fundação para a Ciência e a Tecnologia.info:eu-repo/semantics/publishedVersio

Post-SARS-CoV-2-vaccination cerebral venous sinus thrombosis : an analysis of cases notified to the European Medicines Agency

Background and purpose Cerebral venous sinus thrombosis (CVST) has been described after vaccination against SARS-CoV-2. The clinical characteristics of 213 post-vaccination CVST cases notified to the European Medicines Agency are reported. Methods Data on adverse drug reactions after SARS-CoV-2 vaccination notified until 8 April 2021 under the Medical Dictionary for Regulatory Activities Term 'Central nervous system vascular disorders' were obtained from the EudraVigilance database. Post-vaccination CVST was compared with 100 European patients with CVST from before the COVID-19 pandemic derived from the International CVST Consortium. Results In all, 213 CVST cases were identified: 187 after AstraZeneca/Oxford (ChAdOx1 nCov-19) vaccination and 26 after a messenger RNA (mRNA) vaccination (25 with Pfizer/BioNTech, BNT162b2, and one with Moderna, mRNA-1273). Thrombocytopenia was reported in 107/187 CVST cases (57%, 95% confidence interval [CI] 50%-64%) in the ChAdOx1 nCov-19 group, in none in the mRNA vaccine group (0%, 95% CI 0%-13%) and in 7/100 (7%, 95% CI 3%-14%) in the pre-COVID-19 group. In the ChAdOx1 nCov-19 group, 39 (21%) reported COVID-19 polymerase chain reaction tests were performed within 30 days of CVST symptom onset, and all were negative. Of the 117 patients with a reported outcome in the ChAdOx1 nCov-19 group, 44 (38%, 95% CI 29%-47%) had died, compared to 2/10 (20%, 95% CI 6%-51%) in the mRNA vaccine group and 3/100 (3%, 95% CI 1%-8%) in the pre-COVID-19 group. Mortality amongst patients with thrombocytopenia in the ChAdOx1 nCov-19 group was 49% (95% CI 39%-60%). Conclusions Cerebral venous sinus thrombosis occurring after ChAdOx1 nCov-19 vaccination has a clinical profile distinct from CVST unrelated to vaccination. Only CVST after ChAdOx1 nCov-19 vaccination was associated with thrombocytopenia.Peer reviewe