Impaired β-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations.

Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic GRN mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in GRN mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with GRN mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with GRN mutations (FTD-GRN) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid-metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-GRN patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only β-glucocerebrosidase exhibited impairment in FTD-GRN patients. Brains from FTD-GRN patients had lower activity than controls, which was associated with lower levels of mature β-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated β-glucocerebrosidase. Immunostaining revealed loss of neuronal β-glucocerebrosidase in FTD-GRN patients. To investigate the effects of progranulin insufficiency on β-glucocerebrosidase outside of the context of neurodegeneration, we investigated β-glucocerebrosidase activity in progranulin-insufficient mice. Brains from Grn-/- mice had lower β-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs β-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired β-glucocerebrosidase processing

Supervision and Scholarly Writing: Writing to Learn - Learning to Write

This paper describes an action research project on postgraduate students’ scholarly writing in which I employed reflective approaches to examine and enhance my postgraduate supervisory practice. My reflections on three distinct cycles of supervision illustrate a shift in thinking about scholarly writing and an evolving understanding of how to support postgraduate students’ writing. These understandings provide the foundation for a future-oriented fourth cycle of supervisory practice, which is characterised by three principles, namely the empowerment of students as writers, the technological context of contemporary writing, and ethical issues in writing

Key ethical challenges in the European Medical Information Framework

The European Medical Information Framework (EMIF) project, funded through the IMI programme (Innovative Medicines Initiative Joint Undertaking under Grant Agreement No. 115372), has designed and implemented a federated platform to connect health data from a variety of sources across Europe, to facilitate large scale clinical and life sciences research. It enables approved users to analyse securely multiple, diverse, data via a single portal, thereby mediating research opportunities across a large quantity of research data. EMIF developed a code of practice (ECoP) to ensure the privacy protection of data subjects, protect the interests of data sharing parties, comply with legislation and various organisational policies on data protection, uphold best practices in the protection of personal privacy and information governance, and eventually promote these best practices more widely. EMIF convened an Ethics Advisory Board (EAB), to provide feedback on its approach, platform, and the EcoP. The most important challenges the ECoP team faced were: how to define, control and monitor the purposes (kinds of research) for which federated health data are used; the kinds of organisation that should be permitted to conduct permitted research; and how to monitor this. This manuscript explores those issues, offering the combined insights of the EAB and EMIF core ECoP team. For some issues, a consensus on how to approach them is proposed. For other issues, a singular approach may be premature but the challenges are summarised to help the community to debate the topic further. Arguably, the issues and their analyses have application beyond EMIF, to many research infrastructures connected to health data sources

Enhancing Quality in Psychiatry with Psychiatrists (EQUIPP)—Results from a Pilot Study

To pilot a pharmacist-led, patient centered medication management program

Dispersal ability, trophic position and body size mediate species turnover processes: Insights from a multi‐taxa and multi‐scale approach

Aim: Despite increasing interest in β-diversity, that is the spatial and temporal turno-ver of species, the mechanisms underlying species turnover at different spatial scales are not fully understood, although they likely differ among different functional groups. We investigated the relative importance of dispersal limitations and the en-vironmental filtering caused by vegetation for local, multi-taxa forest communities differing in their dispersal ability, trophic position and body size.Location: Temperate forests in five regions across Germany.Methods: In the inter-region analysis, the independent and shared effects of the re-gional spatial structure (regional species pool), landscape spatial structure (dispersal limitation) and environmental factors on species turnover were quantified with a 1-ha grain across 11 functional groups in up to 495 plots by variation partitioning. In the intra-region analysis, the relative importance of three environmental factors related to vegetation (herb and tree layer composition and forest physiognomy) and spatial structure for species turnover was determined.Results: In the inter-region analysis, over half of the explained variation in community composition (23% of the total explained 35%) was explained by the shared effects of several factors, indicative of spatially structured environmental filtering. Among the independent effects, environmental factors were the strongest on average over 11 groups, but the importance of landscape spatial structure increased for less disper-sive functional groups. In the intra-region analysis, the independent effect of plant species composition had a stronger influence on species turnover than forest physi-ognomy, but the relative importance of the latter increased with increasing trophic position and body size.Main conclusions: Our study revealed that the mechanisms structuring assemblage composition are associated with the traits of functional groups. Hence, conserva-tion frameworks targeting biodiversity of multiple groups should cover both envi-ronmental and biogeographical gradients. Within regions, forest management can enhance β-diversity particularly by diversifying tree species composition and forest physiognomy

Reflectivity of Venus’s Dayside Disk During the 2020 Observation Campaign: Outcomes and Future Perspectives

We performed a unique Venus observation campaign to measure the disk brightness of Venus over a broad range of wavelengths in 2020 August and September. The primary goal of the campaign was to investigate the absorption properties of the unknown absorber in the clouds. The secondary goal was to extract a disk mean SO2 gas abundance, whose absorption spectral feature is entangled with that of the unknown absorber at ultraviolet wavelengths. A total of three spacecraft and six ground-based telescopes participated in this campaign, covering the 52–1700 nm wavelength range. After careful evaluation of the observational data, we focused on the data sets acquired by four facilities. We accomplished our primary goal by analyzing the reflectivity spectrum of the Venus disk over the 283–800 nm wavelengths. Considerable absorption is present in the 350–450 nm range, for which we retrieved the corresponding optical depth of the unknown absorber. The result shows the consistent wavelength dependence of the relative optical depth with that at low latitudes, during the Venus flyby by MESSENGER in 2007, which was expected because the overall disk reflectivity is dominated by low latitudes. Last, we summarize the experience that we obtained during this first campaign, which should enable us to accomplish our second goal in future campaigns

Global solar wind variations over the last four centuries

The most recent “grand minimum” of solar activity, the Maunder minimum (MM, 1650–1710), is of great interest both for understanding the solar dynamo and providing insight into possible future heliospheric conditions. Here, we use nearly 30 years of output from a data-constrained magnetohydrodynamic model of the solar corona to calibrate heliospheric reconstructions based solely on sunspot observations. Using these empirical relations, we produce the first quantitative estimate of global solar wind variations over the last 400 years. Relative to the modern era, the MM shows a factor 2 reduction in near-Earth heliospheric magnetic field strength and solar wind speed, and up to a factor 4 increase in solar wind Mach number. Thus solar wind energy input into the Earth’s magnetosphere was reduced, resulting in a more Jupiter-like system, in agreement with the dearth of auroral reports from the time. The global heliosphere was both smaller and more symmetric under MM conditions, which has implications for the interpretation of cosmogenic radionuclide data and resulting total solar irradiance estimates during grand minima

The σE stress response is required for stress-induced mutation and amplification in Escherichia coli

Pathways of mutagenesis are induced in microbes under adverse conditions controlled by stress responses. Control of mutagenesis by stress responses may accelerate evolution specifically when cells are maladapted to their environments, i.e. are stressed. Stress-induced mutagenesis in the Escherichia coli Lac assay occurs either by ‘point’ mutation or gene amplification. Point mutagenesis is associated with DNA double-strand-break (DSB) repair and requires DinB error-prone DNA polymerase and the SOS DNA-damage- and RpoS general-stress responses. We report that the RpoE envelope-protein-stress response is also required. In a screen for mutagenesis-defective mutants, we isolated a transposon insertion in the rpoE P2 promoter. The insertion prevents rpoE induction during stress, but leaves constitutive expression intact, and allows cell viability. rpoE insertion and suppressed null mutants display reduced point mutagenesis and maintenance of amplified DNA. Furthermore, σE acts independently of stress responses previously implicated: SOS/DinB and RpoS, and of σ32, which was postulated to affect mutagenesis. I-SceI-induced DSBs alleviated much of the rpoE phenotype, implying that σE promoted DSB formation. Thus, a third stress response and stress input regulate DSB-repair-associated stress-induced mutagenesis. This provides the first report of mutagenesis promoted by σE, and implies that extracytoplasmic stressors may affect genome integrity and, potentially, the ability to evolve