Small variations in nanoparticle structure dictate differential cellular stress responses and mode of cell death

For optimal exploitation of nanoparticles (NPs) in biomedicine, and to predict nanotoxicity, detailed knowledge of the cellular responses to cell-bound or internalized NPs is imperative. The final outcome of NP-cell interaction is dictated by the type and magnitude of the NP insult and the cellular response. Here, this has been systematically studied by using poly(alkylcyanoacrylate) (PACA) particles differing only in their alkyl side chains; butyl (PBCA), ethylbutyl (PEBCA), or octyl (POCA), respectively. Surprisingly, these highly similar NPs induced different stress responses and modes of cell death in human cell lines. The POCA particles generally induced endoplasmic reticulum stress and apoptosis. In contrast, PBCA and PEBCA particles induced oxidative stress and lipid peroxidation depending on the level of the glutathione precursor cystine and transcription of the cystine transporter SLC7A11. The latter was induced as a protective response by the transcription factors ATF4 and Nrf2. PBCA particles strongly activated ATF4 downstream of the eIF2α kinase HRI, whereas PEBCA particles more potently induced Nrf2 antioxidant responses. Intriguingly, PBCA particles activated the cell death mechanism ferroptosis; a promising option for targeting multidrug-resistant cancers. Our findings highlight that even minor differences in NP composition can severely impact the cellular response to NPs. This may have important implications in therapeutic settings.acceptedVersionThis is an Accepted Manuscript of an article published by Taylor & Francis, available at https://doi.org/10.1080/17435390.2019.157623

A novel community driven software for functional enrichment analysis of extracellular vesicles data.

Bioinformatics tools are imperative for the in depth analysis of heterogeneous high-throughput data. Most of the software tools are developed by specific laboratories or groups or companies wherein they are designed to perform the required analysis for the group. However, such software tools may fail to capture "what the community needs in a tool". Here, we describe a novel community-driven approach to build a comprehensive functional enrichment analysis tool. Using the existing FunRich tool as a template, we invited researchers to request additional features and/or changes. Remarkably, with the enthusiastic participation of the community, we were able to implement 90% of the requested features. FunRich enables plugin for extracellular vesicles wherein users can download and analyse data from Vesiclepedia database. By involving researchers early through community needs software development, we believe that comprehensive analysis tools can be developed in various scientific disciplines

Proteomic studies of hepatocytic autophagosomes

Doktorand Anders Øverbye har jobbet ved Institutt for kreftforskning ved Radiumhospitalet med sin avhandling innenfor de raskt voksende fagfeltene proteomikk og autofagi. Proteomikk innebærer utforskning av komplekse proteinsammensetninger slik som fullstendige proteinpopulasjoner i en organisme, et vev eller en celletype i engitt situasjon; dette betegnes som et proteom. Proteomiske metoder inkluderer vidstrakt bruk av massespektrometri og andre proteinkarakteriserende virkemidler, samt separasjonsmetoder forproteiner. Autofagi er en cellebiologisk prosess som foretar en kontinuerlig utskifting av en celles innhold, inkludert nedbryting av overflødige, skadete eller forandrete proteiner, organeller og andre makromolekyler. Det er en lysosomal nedbrytingsprosess som iverksettes av diverse, strengt regulerte stimuli og kjennetegnes av definerte steg. En del av cytoplasma omsluttes av en membrancisterne kjent som en fagofor som danner en autofag vakuole med doble membraner, autofagosomet. Denne organellen kan enten direkte smelte sammen med lysosomet, eller slutte seg til endocytiske organeller. Ved fusjonering med lysosomet, vil innholdet i autofagosomet brytes ned av hydrolaser og andre enzymer tilstede i lysosomet. Lite vites om detaljer for dannelse av autofagosomer fra fagoforer. Utsiden av autofagosomet har vist seg å være særs proteinfattig. En kartlegging av eventuelle proteiner assosierte med disse organellenes membraner vil gi innsikt i mekanismer knyttet til denne essensielle prosessen, som i senere tid har fått økt interesse, særlig grunnet autofagiens rolle i flere utbredte sykdommer som Huntingtons, Alzheimers, Parkinsons sykdom og ikke minst kreft. Doktoranden har oppdaget og karakterisert proteiner assosiert med autofagosomale membraner. Dette har vært mulig ved benyttelse av en metode for rensing av autofagosomer utarbeidet i vårt laboratorium. Undersøkelsene ble utført ved flerdimensjonal fraksjonering av cellekomponenter og påfølgende proteinseparasjon. Sammenlikning med proteinpopulasjoner for andre organeller i cellens cytoplasma avdekket rundt 50 proteiner som var sterkt anriket i autofagosom-membranene. Videre undersøkelse av to metyltransferaser og to dehydrogenaser har gitt ny kunnskap om disse proteinene og innsikt i prosesser for degradering av materiale gjennom autofagi. Et av disse enzymene, betain:homocystein metyltransferase, regulerer mengden av den skadelige aminosyren homocystein, som kan forårsake hjerte- og karsykdommer og ryggmargsbrokk. Et annet enzym, katekol metyltransferase, er ansvarlig for omdannelsen av dopamin, epinefrin, som spiller en viktig rolle i nevrodegenerative sykdommer, bl.a. Parkinsons sykdom

Differential longitudinal changes in cortical thickness, surface area and volume across the adult lifespan: Regions of accelerating and decelerating change

Human cortical thickness and surface area are genetically independent, emerge through different neurobiological events during development, and are sensitive to different clinical conditions. However, the relationship between changes in the two over time is unknown. Additionally, longitudinal studies have almost invariably been restricted to older adults, precluding the delineation of adult life span trajectories of change in cortical structure. In this longitudinal study, we investigated changes in cortical thickness, surface area, and volume after an average interval of 3.6 years in 207 well screened healthy adults aged 23–87 years. We hypothesized that the relationships among metrics are dynamic across the life span, that the primary contributor to cortical volume reductions in aging is cortical thinning, and that magnitude of change varies with age and region. Changes over time were seen in cortical area (mean annual percentage change [APC], −0.19), thickness (APC, −0.35), and volume (APC, −0.51) in most regions. Volume changes were primarily explained by changes in thickness rather than area. A negative relationship between change in thickness and surface area was found across several regions, where more thinning was associated with less decrease in area, and vice versa. Accelerating changes with increasing age was seen in temporal and occipital cortices. In contrast, decelerating changes were seen in prefrontal and anterior cingulate cortices. In conclusion, a dynamic relationship between cortical thickness and surface area changes exists throughout the adult life span. The mixture of accelerating and decelerating changes further demonstrates the importance of studying these metrics across the entire adult life span

Electrophysiological and behavioral indices of cognitive conflict processing across adolescence

Cognitive control enables goal-oriented adaptation to a fast-changing environment and has a protracted development spanning into young adulthood. The neurocognitive processes underlying this development are poorly understood. In a cross-sectional sample of participants 8–19 years old (n = 108), we used blind source separation of EEG data recorded in a Flanker task to derive electrophysiological measures of attention and conflict processing, including a N2-like frontal negative component and a P3-like parietal positive component. Outside the recording session, we examined multiple behavioral measures of interference control derived from the Flanker, Stroop, and Anti-saccade tasks. We found a positive association between age and P3 amplitude, but no relationship between age and N2 amplitude. A stronger N2 was age-independently related to better performance on Stroop and Anti-saccade measures of interference control. A Gratton effect was found on the Flanker task, with slower reaction times on current congruent and better accuracy on current incongruent trials when preceded by incongruent as opposed to congruent trials. The Gratton effect on accuracy was positively associated with age. Together, the findings suggest a multifaceted developmental pattern of the neurocognitive processes involved in conflict processing across adolescence, with a more protracted development of the P3 compared to the N2

Error processing in the adolescent brain: Age-related differences in electrophysiology, behavioral adaptation, and brain morphology

Detecting errors and adjusting behaviour appropriately are fundamental cognitive abilities that are known to improve through adolescence. The cognitive and neural processes underlying this development, however, are still poorly understood. To address this knowledge gap, we performed a thorough investigation of error processing in a Flanker task in a cross-sectional sample of participants 8 to 19 years of age (n = 98). We examined age-related differences in event-related potentials known to be associated with error processing, namely the error-related negativity (ERN) and the error positivity (Pe), as well as their relationships with task performance, post-error adjustments and regional cingulate cortex thickness and surface area. We found that ERN amplitude increased with age, while Pe amplitude remained constant. A more negative ERN was associated with higher task accuracy and faster reaction times, while a more positive Pe was associated with higher accuracy, independently of age. When estimating post-error adjustments from trials following both incongruent and congruent trials, post-error slowing and post-error improvement in accuracy both increased with age, but this was only found for post-error slowing when analysing trials following incongruent trials. There were no age-independent associations between either ERN or Pe amplitude and cingulate cortex thickness or area measures