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Primary progressive multiple sclerosis (PPMS) shows a highly variable disease progression with poor prognosis and a characteristic accumulation of disabilities in patients. These hallmarks of PPMS make it difficult to diagnose and currently impossible to efficiently treat. This study aimed to identify plasma metabolite profiles that allow diagnosis of PPMS and its differentiation from the relapsing-remitting subtype (RRMS), primary neurodegenerative disease (Parkinson's disease, PD), and healthy controls (HCs) and that significantly change during the disease course and could serve as surrogate markers of multiple sclerosis (MS)-associated neurodegeneration over time. We applied untargeted high-resolution metabolomics to plasma samples to identify PPMS-specific signatures, validated our findings in independent sex- and age-matched PPMS and HC cohorts and built discriminatory models by partial least square discriminant analysis (PLS-DA). This signature was compared to sex- and age-matched RRMS patients, to patients with PD and HC. Finally, we investigated these metabolites in a longitudinal cohort of PPMS patients over a 24-month period. PLS-DA yielded predictive models for classification along with a set of 20 PPMS-specific informative metabolite markers. These metabolites suggest disease-specific alterations in glycerophospholipid and linoleic acid pathways. Notably, the glycerophospholipid LysoPC(20:0) significantly decreased during the observation period. These findings show potential for diagnosis and disease course monitoring, and might serve as biomarkers to assess treatment efficacy in future clinical trials for neuroprotective MS therapies.

Climate change poses a significant threat to species with temperature-dependent sex determination, such as sea turtles. Their conservation often involves relocating nests to hatcheries, which is also crucial on the Pacific coast of Guatemala, where virtually no hatchlings emerge from natural nests. Populations there rely heavily on hatcheries, yet nest temperature monitoring in relation to environmental and management factors is rarely conducted. Research is needed to improve artificial nest management and hatchery design. This study investigated how distance to the hatchery wall, number of eggs, position in the nest, development period, season, and weather conditions influenced temperature variation in Olive Ridley Turtle (Lepidochelys olivacea) nests. We generally found nest temperatures within viable ranges and near the pivotal temperature for Olive Ridleys. The pivotal temperature of Olive Ridley was exceeded 6%–21% of the time during the thermosensitive period of all nests (starting days 9–15 and ending days 33–37 of incubation), and the upper thermal tolerance limit was rarely reached. However, nests closer to concrete walls were up to 1°C warmer than those farther away, and 30–40 more eggs per nest raised average temperatures by 0.7°C. These findings suggest that distance to hatchery walls and egg numbers per nest can be tools to manipulate nest temperatures and sex ratios. The sex ratios in this study were slightly female-biased. However, optimal sex ratios remain poorly understood, and reliance on ex situ incubation may reduce population adaptability to environmental changes. Ex situ nest conditions in our study displayed lower temperatures than potential in situ conditions, which exceeded the lethal threshold in 86% (z-test, p < 0.001) of the measurements. Our study emphasizes the need for careful hatchery management to safeguard sea turtles against the effects of climate change but also to avoid the consequences of overcompensation due to mismanagement.

Global warming is expected to affect movement‐related thermoregulation in ectotherms, but the likely effects on thermoconforming lizards, which spend little energy in thermoregulation behavior, are unclear. We used the Guatemalan beaded lizard (Heloderma charlesbogerti) as a model thermoconforming species to investigate the effects of ambient temperature and barometric pressure (a cue for rain in the study area) on activity intensity and the structure of movement paths. We tracked 12 individuals over a total of 148 animal days during the wet season of 2019 using Global Positioning System tags and triaxial accelerometry. We found a clear positive effect of ambient temperature on activity (using vectorial dynamic body acceleration [VeDBA]) and step length of lizard movements. The movement also became more directional (longer step lengths and smaller turning angles) with increasing ambient temperatures. There was a small negative effect of barometric pressure on VeDBA. We propose that our patterns are indicative of internal state changes in the animals, as they move from a state of hunger, eliciting foraging, which is enhanced by lower temperatures and rainfall to a thermally stressed state, which initiates shelter‐seeking. Our findings highlight the sensitivity of this species to temperature change, show that not all thermoconforming lizards are thermal generalists, and indicate that predicted regional increases in temperature and reduction in rainfall are likely to negatively impact this species by reducing the width of their operational thermal window.

Background: Semi-aquatic mammals exploit resources both on land and in water and may require both to meet their habitat requirements including food- and building resources, refuges, and for social interactions with conspecifics. Within this, the specific availability of both terrestrial and aquatic resources is expected to impact individual fitness. Beavers are highly dependent on water for movement and protection from predators. They are central place foragers and mostly forage on woody vegetation near water although aquatic vegetation may also be an important food resource. However, little is known about their use of aquatic habitats. We aimed to address this knowledge gap by dead-reckoning fine-scale movement tracks and classifying fine-scale diving events, which we then related to the spatial distribution of aquatic vegetation and habitat components within the territory. Results: Overall, there was a statistically clear decrease in probability that diving would occur at dawn and with increasing distance from territory borders. In addition, the distance from the lodge at which animals dived decreased through the night and during the spring/early summer. There was strong selection for diving habitats located closer to the riverbank, with stronger selection for these areas being observed in individuals with larger home ranges. We saw a higher selection for diving above clay sediment, and within 150 m from the lodge, presumably because mud and clay sediment tended to be located closer to the lodge than sand and rock sediment. Furthermore, we found a clear selection for diving in the presence of quillwort (Isoetes spp.), shoreweed (Littorella uniflora), and stonewort (Nitella spp.). Selection for these focal species was stronger among subordinate individuals. Individuals with lower body condition dived closer to the beaver lodge, and dives located further from the lodge were associated with high densities of aquatic vegetation. Conclusion: We provide new knowledge on the aquatic habitat use in a semi-aquatic mammal and show how energetic constraints may shape how beavers spatially use the aquatic environment, whereby short and shallow dives appear most beneficial. We show how aquatic habitats may have great importance for both foraging, building materials and safety, and discuss to how they may affect the fitness of individuals.

Lichen heaths are declining in abundance in alpine and Arctic areas partly due to an increasing competition with shrubs. This shift in vegetation types might have important consequences for the microclimate and climate on a larger scale. The aim of our study is to measure the difference in microclimatic conditions between lichen heaths and shrub vegetation during the growing season. With a paired plot design, we measured the net radiation, soil heat flux, soil temperature and soil moisture on an alpine mountain area in southern Norway during the summer of 2018 and 2019. We determined that the daily net radiation of lichens was on average 3.15 MJ (26 %) lower than for shrubs during the growing season. This was mainly due to a higher albedo of the lichen heaths but also due to a larger longwave radiation loss. Subsequently, we estimate that a shift from a lichen heath to shrub vegetation leads to an average increase in atmospheric heating of 3.35 MJ d−1 during the growing season. Surprisingly, the soil heat flux and soil temperature were higher below lichens than below shrubs during days with high air temperatures. This implies that the relatively high albedo of lichens does not lead to a cooler soil compared to shrubs during the growing season. We predict that the thicker litter layer, the presence of soil shading and a higher evapotranspiration rate at shrub vegetation are far more important factors in explaining the variation in soil temperature between lichens and shrubs. Our study shows that a shift from lichen heaths to shrub vegetation in alpine and Arctic areas will lead to atmospheric heating, but it has a cooling effect on the subsurface during the growing season, especially when air temperatures are relatively high.

Animals balance foraging with other activities, and activity patterns may differ between sexes due to differing physical requirements and reproductive investments. Sex-specific behavioural differences are common in sexually dimorphic mammals, but have received limited research attention in monomorphic mammals where the sexes are similar in body size. Eurasian beavers (Castor fiber) are obligate monogamous and monomorphic mammals and a good model species to study sex-specific differences. As females increase energy expenditure during reproduction, we hypothesized differing seasonal activity budgets, circadian activity rhythms and foraging patterns between male and reproducing female beavers. To test this hypothesis, we equipped adult beavers with VHF transmitters (N=41; 16 female, 25 male) and observed them throughout their active period at night from spring to late summer. Occurrence of their main activities (foraging, travelling and being in lodge) and use of food items (trees/shrubs, aquatic vegetation and herbs/grasses) were modelled to investigate sex-specific seasonal activity budgets and circadian activity rhythms. The sexes did not differ in time spent foraging across the season or night, but during spring, females resided more in the lodge and travelled less. Males and females both foraged on aquatic vegetation during spring, but females used this food source also during late summer, whereas males mostly foraged on trees/shrubs throughout the year. We conclude that seasonal activity budgets and foraging differ subtly between the sexes, which may relate to different energy budgets associated with reproduction and nutritional requirements. Such subtle seasonal behavioural adaptions may be vital for survival and reproduction of monomorphic species.

Animals balance foraging with other activities, and activity patterns may differ between sexes due to differing physical requirements and reproductive investments. Sex-specific behavioural differences are common in sexually dimorphic mammals, but have received limited research attention in monomorphic mammals where the sexes are similar in body size. Eurasian beavers (Castor fiber) are obligate monogamous and monomorphic mammals and a good model species to study sex-specific differences. As females increase energy expenditure during reproduction, we hypothesized differing seasonal activity budgets, circadian activity rhythms and foraging patterns between male and reproducing female beavers. To test this hypothesis, we equipped adult beavers with VHF transmitters (N=41; 16 female, 25 male) and observed them throughout their active period at night from spring to late summer. Occurrence of their main activities (foraging, travelling and being in lodge) and use of food items (trees/shrubs, aquatic vegetation and herbs/grasses) were modelled to investigate sex-specific seasonal activity budgets and circadian activity rhythms. The sexes did not differ in time spent foraging across the season or night, but during spring, females resided more in the lodge and travelled less. Males and females both foraged on aquatic vegetation during spring, but females used this food source also during late summer, whereas males mostly foraged on trees/shrubs throughout the year. We conclude that seasonal activity budgets and foraging differ subtly between the sexes, which may relate to different energy budgets associated with reproduction and nutritional requirements. Such subtle seasonal behavioural adaptions may be vital for survival and reproduction of monomorphic species.

Neurodegeneration in multiple sclerosis (MS) affects the visual system but dynamics and pathomechanisms over several years especially in primary progressive MS (PPMS) are not fully understood. We assessed longitudinal changes in visual function, retinal neurodegeneration using optical coherence tomography, MRI and serum NfL (sNfL) levels in a prospective PPMS cohort and matched healthy controls. We investigated the changes over time, correlations between outcomes and with loss of visual function. We followed 81 patients with PPMS (mean disease duration 5.9 years) over 2.7 years on average. Retinal nerve fibre layer thickness (RNFL) was reduced in comparison with controls (90.1 vs 97.8 µm; p<0.001). Visual function quantified by the area under the log contrast sensitivity function (AULCSF) remained stable over a continuous loss of RNFL (0.46 µm/year, 95% CI 0.10 to 0.82; p=0.015) up until a mean turning point of 91 µm from which the AULCSF deteriorated. Intereye RNFL asymmetry above 6 µm, suggestive of subclinical optic neuritis, occurred in 15 patients and was related to lower AULCSF but occurred also in 5 out of 44 controls. Patients with an AULCSF progression had a faster increase in Expanded Disability Status Scale (beta=0.17/year, p=0.043). sNfL levels were elevated in patients (12.2 pg/mL vs 8.0 pg/mL, p<0.001), but remained stable during follow-up (beta=-0.14 pg/mL/year, p=0.291) and were not associated with other outcomes. Whereas neurodegeneration in the anterior visual system is already present at onset, visual function is not impaired until a certain turning point. sNfL is not correlated with structural or functional impairment in the visual system.

ObjectiveTo investigate whether oral administration of a standardised frankincense extract (SFE) is safe and reduces disease activity in patients with relapsing-remitting multiple sclerosis (RRMS).MethodsWe performed an investigator-initiated, bicentric phase IIa, open-label, baseline-to-treatment pilot study with an oral SFE in patients with RRMS (NCT01450124). After a 4-month baseline observation phase, patients were treated for 8 months with an option to extend treatment for up to 36 months. The primary outcome measures were the number and volume of contrast-enhancing lesions (CEL) measured in MRI during the 4-month treatment period compared with the 4-month baseline period. Eighty patients were screened at two centres, 38 patients were included in the trial, 28 completed the 8-month treatment period and 18 of these participated in the extension period.ResultsThe SFE significantly reduced the median number of monthly CELs from 1.00 (IQR 0.75–3.38) to 0.50 (IQR 0.00–1.13; difference −0.625, 95% CI −1.25 to −0.50; P<0.0001) at months 5–8. We observed significantly less brain atrophy as assessed by parenchymal brain volume change (P=0.0081). Adverse events were generally mild (57.7%) or moderate (38.6%) and comprised mainly gastrointestinal symptoms and minor infections. Mechanistic studies showed a significant increase in regulatory CD4+ T cell markers and a significant decrease in interleukin-17A-producing CD8+ T cells indicating a distinct mechanism of action of the study drug.InterpretationThe oral SFE was safe, tolerated well and exhibited beneficial effects on RRMS disease activity warranting further investigation in a controlled phase IIb or III trial.Clinical trial registrationNCT01450124; Results.