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The closely linked fitness of the Epichloë symbiont and the host grass is presumed to align the coevolution of the species towards specialization and mutually beneficial cooperation. Ecological observations demonstrating that Epichloë-grass symbioses can modulate grassland ecosystems via both above- and belowground ecosystem processes support this. In many cases the detected ecological importance of Epichloë species is directly or indirectly linked to defensive mutualism attributable to alkaloids of fungal-origin. Now, modern genetic and molecular techniques enable the precise studies on evolutionary origin of endophytic Epichloë species, their coevolution with host grasses and identification the genetic variation that explains phenotypic diversity in ecologically relevant characteristics of Epichloë-grass associations. Here we briefly review the most recent findings in these areas of research using the present knowledge of the genetic variation that explains the biosynthetic pathways driving the diversity of alkaloids produced by the endophyte. These findings underscore the importance of genetic interplay between the fungus and the host in shaping their coevolution and ecological role in both natural grass ecosystems, and in the agricultural arena.

Structural features of genomes, including the three-dimensional arrangement of DNA in the nucleus, are increasingly seen as key contributors to the regulation of gene expression. However, studies on how genome structure and nuclear organisation influence transcription have so far been limited to a handful of model species. This narrow focus limits our ability to draw general conclusions about the ways in which three-dimensional structures are encoded, and to integrate information from three-dimensional data to address a broader gamut of biological questions. Here, we generate a complete and gapless genome sequence for the filamentous fungus, Epichloë festucae. We use Hi-C data to examine the three-dimensional organisation of the genome, and RNA-seq data to investigate how Epichloë genome structure contributes to the suite of transcriptional changes needed to maintain symbiotic relationships with the grass host. Our results reveal a genome in which very repeat-rich blocks of DNA with discrete boundaries are interspersed by gene-rich sequences that are almost repeat-free. In contrast to other species reported to date, the three-dimensional structure of the genome is anchored by these repeat blocks, which act to isolate transcription in neighbouring gene-rich regions. Genes that are differentially expressed in planta are enriched near the boundaries of these repeat-rich blocks, suggesting that their three-dimensional orientation partly encodes and regulates the symbiotic relationship formed by this organism.

A randomised, assessor- and participant-blind, sham-controlled trial was conducted to assess the safety and feasibility of adding transcranial direct current stimulation (tDCS) to quadriceps strengthening exercise in knee osteoarthritis (OA), and provide data to inform a fully powered trial. Participants were randomised to receive active tDCS+exercise (AT+EX) or sham tDCS+exercise (ST+EX) twice weekly for 8 weeks whilst completing home exercises twice per week. Feasibility, safety, patient-perceived response, pain, function, pressure pain thresholds (PPTs) and conditioned pain modulation (CPM) were assessed before and after treatment. Fifty-seven people were screened for eligibility. Thirty (52%) entered randomisation and 25 (84%) completed the trial. One episode of headache in the AT+EX group was reported. Pain reduced in both groups following treatment (AT+EX: p<0.001, partial η2 = 0.55; ST+EX: p = 0.026, partial η2 = 0.18) but no between-group differences were observed (p = 0.18, partial η2 = 0.08). Function improved in the AT+EX (p = 0.01, partial η2 = 0.22), but not the ST+EX (p = 0.16, partial η2 = 0.08) group, between-group differences did not reach significance (p = 0.28, partial η2 = 0.052). AT+EX produced greater improvements in PPTs than ST+EX (p<0.05) (superolateral knee: partial η2 = 0.17; superior knee: partial η2 = 0.3; superomedial knee: partial η2 = 0.26). CPM only improved in the AT+EX group but no between-group difference was observed (p = 0.054, partial η2 = 0.158). This study provides the first feasibility and safety data for the addition of tDCS to quadriceps strengthening exercise in knee OA. Our data suggest AT+EX may improve pain, function and pain mechanisms beyond that of ST+EX, and provides support for progression to a fully powered randomised controlled trial.

Introduction Reliable measurement of disability in multiple sclerosis (MS) using a comprehensive, patient self-reported scale, such as the World Health Organization Disability Assessment Schedule (WHODAS) 2.0, would be of clinical and research benefit. Methods In the Trajectories of Outcome in Neurological Conditions-MS study, WHODAS 2.0 (WHODAS-36 items for working, WHODAS-32 items if not working, WHODAS-12 items short-form) was examined using Rasch analysis in 5809 people with MS. Results The 36- and 32-item parallel forms, and the cognitive and physical domains, showed reliability consistent with individual or group use. The 12-item short-form is valid for group use only. Interval level measurement for parametric statistics can be derived from all three scales which showed medium to strong effect sizes for discrimination across characteristics such as age, subtype, and disease duration. Smallest detectable difference for each scale was < 6 on the standardised metric of 0–100 so < 6% of the total range. There was no substantial differential item functioning (DIF) by age, gender, education, working full/part-time, or disease duration; the finding of no DIF for time or sample supports the use of WHODAS 2.0 for longitudinal studies, with the 36- and 32-item versions and the physical and cognitive domains valid for individual patient follow-up. Conclusions Disability in MS can be comprehensively measured at interval level by the WHODAS 2.0, and validly monitored over time. Routine use of this self-reported measure in clinical and research practice would give valuable information on the trajectories of disability of individuals and groups.

Purpose Multiple sclerosis (MS) is a neurological disease that has different clinical presentations and illness trajectories. The aim of this study was to explore factors that are important for quality of life (QoL) of people with MS (pwMS), and to understand how they may differ across three subtypes. Methods Both convenience and purposive sampling were employed. Semi-structured interviews were conducted with people with relapsing–remitting MS ( n  = 16), secondary progressive MS ( n  = 14), and primary progressive MS ( n  = 13). All interviews were audio recorded and then transcribed verbatim for thematic analysis involving both inductive and deductive processes. A separate analysis for each subtype was made during the inductive process before examining for similarities and differences across the three subtypes in the deductive process. Findings Four factors were identified to have an important influence on QoL of pwMS: restricted and disrupted enjoyment, disturbed future, challenged sense of self, and well-being of significant others. The themes reflect how pwMS commonly perceived enjoyment as a purpose of life, while also illustrating how their QoL may be questioned because of new perspectives going forward with MS, challenges to their sense of self, and increased concerns for their significant others as a result of MS. Subtype differences were attributed to different illness trajectories: relapsing or progressive. Conclusions There are subtype differences in the negative impact of MS on QoL. Clinicians are encouraged to understand the challenges of different illness trajectories, in particular the traumatic nature of relapses and steady worsening of symptoms among those with progressive subtypes of MS.

Background Stigma is increasingly recognised as contributing to disability in MS. This systematic review aimed to answer the following question: To what extent is stigma associated with psychological and physical health outcomes in MS? Methods The inclusion criteria were: scientific publication of original quantitative research in adults with MS and/or Clinically Isolated Syndrome; outcome measures including a measurement of stigma and psychological and/or physical health; peer reviewed articles in the English language. Pubmed, PsycINFO and Science Direct were searched in November 2023. The Joanna Briggs Institute Critical Appraisal Tool was used to assess the methodological quality and risk of bias in all of the identified studies. The following data was extracted: (1) author and publication year, (2) country, (3) design, (4) sample size and demographics, (5) stigma measure, (6) psychological and/or physical health outcomes, 8) key findings. Results 18 Studies were identified, reporting in total 22,021 adult participants with multiple sclerosis, with individual sample sizes ranging from 33 to 6,670. The review consistently identified stigma to be significantly associated with adverse psychological and physical health outcomes in all 18 identified studies. Over half of all identified studies investigated depression and stigma and over half investigated quality of life and stigma, and a significant association was demonstrated for both of these variables with stigma in all of these studies. Discussion Limitations are that most studies were Western with primarily white participants. Only variables studied could be reported and therefore only a selective perspective of stigma in MS could be explored. A meta-analysis was not feasible, due to the variety of stigma definitions and measures employed. A model of stigma in MS is presented and possible interventions to manage stigma in MS are discussed. A need for international action to develop a consensus measure of MS stigma and determine the trajectory and causal dynamics of MS stigma is highlighted.

The epichloae (Epichloë and Neotyphodium species), a monophyletic group of fungi in the family Clavicipitaceae, are systemic symbionts of cool-season grasses (Poaceae subfamily Poöideae). Most epichloae are vertically transmitted in seeds (endophytes), and most produce alkaloids that attack nervous systems of potential herbivores. These protective metabolites include ergot alkaloids and indole-diterpenes (tremorgens), which are active in vertebrate systems, and lolines and peramine, which are more specific against invertebrates. Several Epichloë species have been described which are sexual and capable of horizontal transmission, and most are vertically transmissible also. Asexual epichloae are mainly or exclusively vertically transmitted, and many are interspecific hybrids with genomic contributions from two or three ancestral Epichloë species. Here we employ genome-scale analyses to investigate the origins of biosynthesis gene clusters for ergot alkaloids (EAS), indole-diterpenes (IDT), and lolines (LOL) in 12 hybrid species. In each hybrid, the alkaloid-gene and housekeeping-gene relationships were congruent. Interestingly, hybrids frequently had alkaloid clusters that were rare in their sexual ancestors. Also, in those hybrids that had multiple EAS, IDT or LOL clusters, one cluster lacked some genes, usually for late pathway steps. Possible implications of these findings for the alkaloid profiles and endophyte ecology are discussed.

Tall fescue ( Lolium arundinaceum ) is an important forage and turf grass that covers 35 million acres (140,000 square kilometers) in the transition zone of the southeastern United States. Most tall fescue in the US is infected with a symbiotic fungus, Epichloë coenophiala , which confers biotic and abiotic stress tolerance for the plant but also produces toxic alkaloids that harm livestock. Although there has been prior evidence that the grass host can influence alkaloid production levels, these have never been precisely quantified. Here, we report on testing alkaloid concentration and relative fungal biomass on > 1000 genetically distinct tall fescue plants. We find that these two traits are weakly correlated, and that both show evidence of moderate to high influence by the host genome. Genome-wide associations find only a single marginally significant hit, however, implying that any genetic control by the host is spread among a large number of genes. These results indicate that the host plant exerts moderate influence on these endophytic traits, that the two are largely independent of each other, and that the host’s influence is likely due to a large number of genes of small effect. These results have relevance for breeding tall fescue for forage and turf production, and especially for optimizing the endophyte relationship for tall fescue management.

Objectives The use of clinical staging in the fatal neurodegenerative disease amyotrophic lateral sclerosis would have value in optimising future therapeutic trials. We aimed to use previous clinical trial data to determine the length of time patients spend in each of four proposed stages, its range and transition patterns to subsequent stages. Methods Using databases from two multicentre clinical trials, patients were retrospectively staged through the trial course. At each stage we assessed whether patients then progressed to an earlier, consecutive or later stage or death. Duration spent in each stage before progression to a later stage was calculated. Results There were 725 patients. No patients moved to an earlier stage. More patients at stages 1, 2 and 3 progressed to the consecutive stage rather than skipping a stage. 59.3% of patients at Stage 1 progressed to Stage 2, 54.0% of patients at Stage 2 progressed to Stage 3, 42.3% of patients at Stage 3 progressed to Stage 4 and 47.0% of Stage 4 patients progressed to death. Transition times between stages had a median duration of 3 to 7 months for stages 2 to 4. Discussion We have shown using trial data that transition times between stages are short. Use of stage duration as an endpoint might allow a shorter trial duration. We have shown face validity in this system as most patients progress through consecutive stages, and none revert to earlier stages. Furthermore, we have shown the system is reliable across populations and therefore has content validity.

Self-splicing group I and II introns are selfish genetic elements that are widely yet patchily distributed across the tree of life. Their selfish behavior comes from super-Mendelian inheritance behaviors, collectively called “homing”, which allow them to rapidly spread within populations to the specific genomic sites they home into. Observations of self-splicing intron evolutionary dynamics have led to the formulation of an intron “lifecycle” model where, once fixed in a population, the introns lose selection for homing and undergo an extensive period of degradation until their eventual loss. Here, we find that self-splicing introns are common in the mitochondrial genomes of Epichloë species, endophytic fungi that live in symbioses with grasses. However, these introns show substantial intron presence–absence polymorphism, with our analyses suggesting that these result from a combination of vertical intron inheritance coupled with multiple invasion and loss events over the course of Epichloë evolution. Surprisingly, we find little evidence for the extensive intron degradation expected under the existing intron lifecycle model. Instead, these introns in Epichloë appear to be lost soon after fixation, suggesting that Epichloë self-splicing introns have a different lifecycle. However, rapid intron loss alone cannot explain our results, indicating that additional factors, such as the evolution of homing suppressors, also contribute to Epichloë self-splicing intron dynamics. This work shows that self-splicing introns have more diverse evolutionary dynamics than previously appreciated.