Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder without effective neuroprotective therapy. Known genetic variants impair pathways, including RNA processing, axonal transport, and protein homeostasis. We report ALS-causing mutations within the gene encoding the glycosyltransferase GLT8D1. Exome sequencing in an autosomal-dominant ALS pedigree identified p.R92C mutations in GLT8D1, which co-segregate with disease. Sequencing of local and international cohorts demonstrated significant ALS association in the same exon, including additional rare deleterious mutations in conserved amino acids. Mutations are associated with the substrate binding site, and both R92C and G78W changes impair GLT8D1 enzyme activity. Mutated GLT8D1 exhibits in vitro cytotoxicity and induces motor deficits in zebrafish consistent with ALS. Relative toxicity of mutations in model systems mirrors clinical severity. In conclusion, we have linked ALS pathophysiology to inherited mutations that diminish the activity of a glycosyltransferase enzyme

TDP43 proteinopathy is associated with aberrant DNA methylation in human amyotrophic lateral sclerosis

Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neurone (MN) degeneration and death. ALS can be sporadic (sALS) or familial, with a number of associated gene mutations, including C9orf72 (C9ALS). DNA methylation is an epigenetic mechanism whereby a methyl group is attached to a cytosine (5mC), resulting in gene expression repression. 5mC can be further oxidized to 5‐hydroxymethylcytosine (5hmC). DNA methylation has been studied in other neurodegenerative diseases, but little work has been conducted in ALS. Aims To assess differences in DNA methylation in individuals with ALS and the relationship between DNA methylation and TDP43 pathology. Methods Post mortem tissue from controls, sALS cases and C9ALS cases were assessed by immunohistochemistry for 5mC and 5hmC in spinal cord, motor cortex and prefrontal cortex. LMNs were extracted from a subset of cases using laser capture microdissection. DNA from these underwent analysis using the MethylationEPIC array to determine which molecular processes were most affected. Results There were higher levels of 5mC and 5hmC in sALS and C9ALS in the residual lower motor neurones (LMNs) of the spinal cord. Importantly, in LMNs with TDP43 pathology there was less nuclear 5mC and 5hmC compared to the majority of residual LMNs that lacked TDP43 pathology. Enrichment analysis of the array data suggested RNA metabolism was particularly affected. Conclusions DNA methylation is a contributory factor in ALS LMN pathology. This is not so for glia or neocortical neurones

Quantifying epidemiological drivers of gambiense human African Trypanosomiasis across the Democratic Republic of Congo

Gambiense human African trypanosomiasis (gHAT) is a virulent disease declining in burden but still endemic in West and Central Africa. Although it is targeted for elimination of transmission by 2030, there remain numerous questions about the drivers of infection and how these vary geographically. In this study we focus on the Democratic Republic of Congo (DRC), which accounted for 84% of the global case burden in 2016, to explore changes in transmission across the country and elucidate factors which may have contributed to the persistence of disease or success of interventions in different regions. We present a Bayesian fitting methodology, applied to 168 endemic health zones ( 100,000 population size), which allows for calibration of a mechanistic gHAT model to case data (from the World Health Organization HAT Atlas) in an adaptive and automated framework. It was found that the model needed to capture improvements in passive detection to match observed trends in the data within former Bandundu and Bas Congo provinces indicating these regions have substantially reduced time to detection. Health zones in these provinces generally had longer burn-in periods during fitting due to additional model parameters. Posterior probability distributions were found for a range of fitted parameters in each health zone; these included the basic reproduction number estimates for pre-1998 (R0) which was inferred to be between 1 and 1.14, in line with previous gHAT estimates, with higher median values typically in health zones with more case reporting in the 2000s. Previously, it was not clear whether a fall in active case finding in the period contributed to the declining case numbers. The modelling here accounts for variable screening and suggests that underlying transmission has also reduced greatly { on average 96% in former Equateur, 93% in former Bas Congo and 89% in former Bandundu { Equateur and Bandundu having had the highest case burdens in 2000. This analysis also sets out a framework to enable future predictions for the country

Simulations of Electron Acceleration at Collisionless Shocks: The Effects of Surface Fluctuations

Energetic electrons are a common feature of interplanetary shocks and planetary bow shocks, and they are invoked as a key component of models of nonthermal radio emission, such as solar radio bursts. A simulation study is carried out of electron acceleration for high Mach number, quasi-perpendicular shocks, typical of the shocks in the solar wind. Two dimensional self-consistent hybrid shock simulations provide the electric and magnetic fields in which test particle electrons are followed. A range of different shock types, shock normal angles, and injection energies are studied. When the Mach number is low, or the simulation configuration suppresses fluctuations along the magnetic field direction, the results agree with theory assuming magnetic moment conserving reflection (or Fast Fermi acceleration), with electron energy gains of a factor only 2 - 3. For high Mach number, with a realistic simulation configuration, the shock front has a dynamic rippled character. The corresponding electron energization is radically different: Energy spectra display: (1) considerably higher maximum energies than Fast Fermi acceleration; (2) a plateau, or shallow sloped region, at intermediate energies 2 - 5 times the injection energy; (3) power law fall off with increasing energy, for both upstream and downstream particles, with a slope decreasing as the shock normal angle approaches perpendicular; (4) sustained flux levels over a broader region of shock normal angle than for adiabatic reflection. All these features are in good qualitative agreement with observations, and show that dynamic structure in the shock surface at ion scales produces effective scattering and can be responsible for making high Mach number shocks effective sites for electron acceleration.Comment: 26 pages, 12 figure

C9ORF72 hexanucleotide repeat exerts toxicity in a stable, inducible motor neuronal cell model, which is rescued by partial depletion of Pten.

Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease, characterised by progressive failure of the neuromuscular system. A (G4C2)n repeat expansion in C9ORF72 is the most common genetic cause of ALS and frontotemporal dementia (FTD). To date, the balance of evidence indicates that the (G4C2)n repeat causes toxicity and neurodegeneration via a gain-of-toxic function mechanism; either through direct RNA toxicity or through the production of toxic aggregating dipeptide repeat proteins. Here, we have generated a stable and isogenic motor neuronal NSC34 cell model with inducible expression of a (G4C2)102 repeat, to investigate the gain-of-toxic function mechanisms. The expression of the (G4C2)102 repeat produces RNA foci and also undergoes RAN translation. In addition, the expression of the (G4C2)102 repeat shows cellular toxicity. Through comparison of transcriptomic data from the cellular model with laser-captured spinal motor neurons from C9ORF72-ALS cases, we also demonstrate that the PI3K/Akt cell survival signalling pathway is dysregulated in both systems. Furthermore, partial knockdown of Pten rescues the toxicity observed in the NSC34 (G4C2)102 cellular gain-of-toxic function model of C9ORF72-ALS. Our data indicate that PTEN may provide a potential therapeutic target to ameliorate toxic effects of the (G4C2)n repeat

Faculty experiences and motivations in design thinking teaching and learning

Introduction: Design thinking (DT) is a creative, iterative approach to generating solutions that are desirable, feasible, and viable. Given its role in fostering creativity and innovation, a growing number of higher education instructors are teaching DT. Exploring how and what instructors know about DT and why they might teach it could provide critical insight into the ways in which DT is operationalized in higher education teaching and learning. Materials and methods: A convergent parallel mixed methods design was used for data collected from online surveys administered to faculty teaching DT. The survey included items about DT practices, outcomes from DT, demographic characteristics, and course characteristics. Five open-text survey items queried participants about their definition of DT, why they teach DT, and what additional outcomes they observed. Descriptive statistics were used to analyze quantitative items and thematic analysis was used to analyze qualitative items. Results: Participants (n = 49) represented various academic ranks, disciplines, types of institutions, and geographic locations. Analyses indicated clear congruence between quantitative and qualitative data. Definitions of DT aligned with well-known models of DT. Motivations for teaching DT included the promotion of personal development, DT proficiency, impact, and interpersonal skill development. Other positive student outcomes observed included increases in enthusiasm, self-awareness, empowerment, optimism, and a sense of belonging. Negative student outcomes included time constraints, teamwork conflicts, and student frustration. Conclusion: Faculty believe that DT leads to highly valuable social innovation skill sets for students. This cross-institutional, multi-disciplinary study provides critical insight into faculty experiences and motivations for teaching DT, offering various strategies for instructors and institutions interested in fostering the uptake of DT within higher education

Faculty experiences and motivations in design thinking teaching and learning

IntroductionDesign thinking (DT) is a creative, iterative approach to generating solutions that are desirable, feasible, and viable. Given its role in fostering creativity and innovation, a growing number of higher education instructors are teaching DT. Exploring how and what instructors know about DT and why they might teach it could provide critical insight into the ways in which DT is operationalized in higher education teaching and learning.Materials and methodsA convergent parallel mixed methods design was used for data collected from online surveys administered to faculty teaching DT. The survey included items about DT practices, outcomes from DT, demographic characteristics, and course characteristics. Five open-text survey items queried participants about their definition of DT, why they teach DT, and what additional outcomes they observed. Descriptive statistics were used to analyze quantitative items and thematic analysis was used to analyze qualitative items.ResultsParticipants (n = 49) represented various academic ranks, disciplines, types of institutions, and geographic locations. Analyses indicated clear congruence between quantitative and qualitative data. Definitions of DT aligned with well-known models of DT. Motivations for teaching DT included the promotion of personal development, DT proficiency, impact, and interpersonal skill development. Other positive student outcomes observed included increases in enthusiasm, self-awareness, empowerment, optimism, and a sense of belonging. Negative student outcomes included time constraints, teamwork conflicts, and student frustration.ConclusionFaculty believe that DT leads to highly valuable social innovation skill sets for students. This cross-institutional, multi-disciplinary study provides critical insight into faculty experiences and motivations for teaching DT, offering various strategies for instructors and institutions interested in fostering the uptake of DT within higher education

Temperature and territoriality in the Duke of Burgundy butterfly, Hamearis lucina

Abstract: The Duke of Burgundy butterfly (Hamearis lucina) has undergone severe declines over the last four decades. However, in recent years the UK population appears to have begun expanding again. This is likely to be due to beneficial management, although a warming regional climate may also have contributed to the resurgence of this spring-flying species. In this study, we investigated the effect of air temperature on the flight behaviour of adult male Duke of Burgundy butterflies. We also looked at the ability of adult males to behaviourally thermoregulate their body temperature and assessed their tendency to remain within small established territories. Increasing air temperature lead to a marked increase in the number and duration of flights associated with territorial behaviour but had no significant effect on other flights. This suggests that high temperatures are particularly important for sustaining energetically-demanding flights involved in territory defence and mate interception, which could impact the reproductive potential of Duke of Burgundy populations. We also found that butterflies had only a limited ability to regulate their body temperature behaviourally and may, therefore, be especially dependent on suitable environmental conditions to maintain the right temperatures for these flights. During observations, most males also remained confined to a few square meters within their territories, which could further restrict butterfly ability to thermoregulate by limiting relocation to other habitat types. However, we did find more males to leave the confines of their territories than expected from reports in previous studies. Our findings highlight the key role that warm, sheltered locations on reserves have in supporting the Duke of Burgundy. If this traditionally poor disperser is to take advantage of a warmer climate and extend its range North, a close network of such areas, appropriately managed, may be critical

Transcriptomic Analysis of Age-Associated Periventricular Lesions Reveals Dysregulation of the Immune Response.

White matter lesions (WML) are a common feature of the ageing brain associated with cognitive impairment. The gene expression profiles of periventricular lesions (PVL, n = 7) and radiologically-normal-appearing (control) periventricular white matter cases (n = 11) obtained from the Cognitive Function and Ageing Study (CFAS) neuropathology cohort were interrogated using microarray analysis and NanoString to identify novel mechanisms potentially underlying their formation. Histological characterisation of control white matter cases identified a subgroup (n = 4) which contained high levels of MHC-II immunoreactive microglia, and were classified as "pre-lesional." Microarray analysis identified 2256 significantly differentially-expressed genes (p ≤ 0.05, FC ≥ 1.2) in PVL compared to non-lesional control white matter (1378 upregulated and 878 downregulated); 2649 significantly differentially-expressed genes in "pre-lesional" cases compared to PVL (1390 upregulated and 1259 downregulated); and 2398 significantly differentially-expressed genes in "pre-lesional" versus non-lesional control cases (1527 upregulated and 871 downregulated). Whilst histological evaluation of a single marker (MHC-II) implicates immune-activated microglia in lesion pathology, transcriptomic analysis indicates significant downregulation of a number of activated microglial markers and suggests established PVL are part of a continuous spectrum of white matter injury. The gene expression profile of "pre-lesional" periventricular white matter suggests upregulation of several signalling pathways may be a neuroprotective response to prevent the pathogenesis of PVL

Consistent oviposition preferences of the Duke of Burgundy butterfly over 14 years on a chalk grassland reserve in Bedfordshire, UK

Funder: Christ's College, University of Cambridge (GB)Funder: Isaac Newton Trust; doi: http://dx.doi.org/10.13039/501100004815Funder: Museums Association and Esmée Fairbairn Collections Fund (GB)Abstract: The Duke of Burgundy butterfly (Hamearis lucina) is known to have specific habitat requirements for its larval foodplants. However, no studies have yet investigated whether these preferences vary over time or in relation to climate, and there is a paucity of data on whether management on reserves can replicate preferred conditions. Here, we build upon existing research to confirm which characteristics Duke of Burgundy prefer for their larval foodplants, whether preferences remain consistent across years, and whether conservation management on reserves can replicate these conditions. Fieldwork was carried out at Totternhoe Quarry Reserve, a chalk grassland site in Bedfordshire, UK. Confirming previous research, we found that large Primula plants in dense patches were chosen for oviposition, but that once chosen there was no preference to lay eggs on a plant’s largest leaf. Chosen foodplants were also more sheltered and in closer proximity to scrub than their controls. However, at a finer scale, we found little evidence for any preference based on differences in microclimate, or vegetation height immediately surrounding the plants. This suggests features that alter microclimatic conditions at a larger scale are relatively more important for determining the suitability of oviposition sites. Nearly all preferences remained consistent over time and did not vary between years. Management of scrub on the reserve was able to reproduce some preferred habitat features (high plant density), but not others (large plant size). Implications for insect conservation: The consistency of findings across years, despite inter-annual variation in temperature, rainfall and number of adults, indicates that the Duke of Burgundy is conservative in its foodplant choice, highlighting its need for specific habitat management. Targeted management for foodplants could form part of a tractable set of tools to support Duke of Burgundy numbers on reserves, but a careful balance is needed to avoid scrub clearance leaving plants in sub-optimal conditions