A disease similarity approach identifies short-lived Niemann-Pick type C disease mice with accelerated brain aging as a novel mouse model for Alzheimer's disease and aging research.

Since its first description in 1906 by Dr. Alois Alzheimer, Alzheimer's disease (AD) has been the most common type of dementia. Initially thought to be caused by age-associated accumulation of plaques, in recent years, research has increasingly associated AD with lysosomal storage and metabolic disorders, and the explanation of its pathogenesis has shifted from amyloid and tau accumulation to oxidative stress and impaired lipid and glucose metabolism aggravated by hypoxic conditions. However, the underlying mechanisms linking those cellular processes and conditions to disease progression have yet to be defined. Here, we applied a disease similarity approach to identify unknown molecular targets of AD by using transcriptomic data from congenital diseases known to increase AD risk, namely Down Syndrome, Niemann Pick Disease Type C (NPC), and Mucopolysaccharidoses I. We uncovered common pathways, hub genes, and miRNAs across in vitro and in vivo models of these diseases as potential molecular targets for neuroprotection and amelioration of AD pathology, many of which have never been associated with AD. We then investigated common molecular alterations in brain samples from an NPC disease mouse model by juxtaposing them with brain samples of both human and mouse models of AD. Detailed phenotypic and molecular analyses revealed NPC mut mouse as a novel, short-lived in vivo model of AD characterized by accelerated brain aging, concluding that NPC mut mouse model can serve as a potential short-lived in vivo model for AD research and for understanding molecular factors affecting brain aging. This research represents the first comprehensive approach to congenital disease association with neurodegeneration and a new perspective on AD research while highlighting shortcomings and lack of correlation in diverse in vitro models. Our findings provide a foundation for future animal and clinical studies and will lead to a better understanding of the molecular mechanisms underpinning the observed association between neurological congenital diseases and AD, thus has the potential to accelerate diagnostic and therapeutic applications against common types of dementia.

Human habitat modification, not apex scavenger decline, drives isotopic niche variation in a carnivore community.

Top carnivores can influence the structure of ecological communities, primarily through competition and predation; however, communities are also influenced by bottom-up forces such as anthropogenic habitat disturbance. Top carnivore declines will likely alter competitive dynamics within and amongst sympatric carnivore species. Increasing intraspecific competition is generally predicted to drive niche expansion and/or individual specialisation, while interspecific competition tends to constrain niches. Using stable isotope analysis of whiskers, we studied the effects of Tasmanian devil Sarcophilus harrisii declines upon the population- and individual-level isotopic niches of Tasmanian devils and sympatric spotted-tailed quolls Dasyurus maculatus subsp. maculatus. We investigated whether time since the onset of devil decline (a proxy for severity of decline) and landscape characteristics affected the isotopic niche breadth and overlap of devil and quoll populations. We quantified individual isotopic niche breadth for a subset of Tasmanian devils and spotted-tailed quolls and assessed whether between-site population niche variation was driven by individual-level specialisation. Tasmanian devils and spotted-tailed quolls demonstrated smaller population-level isotopic niche breadths with increasing human-modified habitat, while time since the onset of devil decline had no effect on population-level niche breadth or interspecific niche overlap. Individual isotopic niche breadths of Tasmanian devils and spotted-tailed quolls were narrower in human-modified landscapes, likely driving population isotopic niche contraction, however, the degree of individuals' specialisation relative to one another remained constant. Our results suggest that across varied landscapes, mammalian carnivore niches can be more sensitive to the bottom-up forces of anthropogenic habitat disturbance than to the top-down effects of top carnivore decline.

Using sulfur stable isotope ratios (δ34 S) for animal geolocation: Estimating the delay mechanisms between diet ingestion and isotope incorporation in tail hair.

RATIONALE: Metabolism and diet quality play an important role in determining delay mechanisms between an animal ingesting an element and depositing the associated isotope signal in tissue. While many isotope mixing models assume instantaneous reflection of diet in an animal- tissue, this is rarely the case. Here we use data from wildebeest to measure the lag time between ingestion of 34 S and its detection in tail hair. METHODS: We use time-lagged regression analysis of δ34 S data from GPS-collared blue wildebeest from the Serengeti ecosystem in combination with δ34 S isoscape data to estimate the lag time between an animal ingesting and depositing 34 S in tail hair. RESULTS: The best fitting regression model of δ34 S in tail hair and an individual- position on the δ34 S isoscape is generated assuming an average time delay of 78 days between ingestion and detection in tail hair. This suggests that sulfur may undergo multiple metabolic transitions before being deposited in tissue. CONCLUSION: Our findings help to unravel the underlying complexities associated with sulfur metabolism and are broadly consistent with results from other species. These findings will help to inform research aiming to apply the variation of δ34 S in inert biological material for geolocation or understanding dietary changes, especially for fast moving migratory ungulates such as wildebeest.

High spatial resolution assessment of air quality in urban centres using lichen carbon, nitrogen and sulfur contents and stable-isotope-ratio signatures.

Air pollution and poor air quality is impacting human health globally and is a major cause of respiratory and cardiovascular disease and damage to human organ systems. Automated air quality monitoring stations continuously record airborne pollutant concentrations, but are restricted in number, costly to maintain and cannot document all spatial variability of airborne pollutants. Biomonitors, such as lichens, are commonly used as an inexpensive alternative to assess the degree of pollution and monitor air quality. However, only a few studies combined lichen carbon, nitrogen and sulfur contents, with their stable-isotope-ratio signatures (δ13C, δ15N and δ34S values) to assess spatial variability of air quality and to 'fingerprint' potential pollution sources. In this study, a high-spatial resolution lichen biomonitoring approach (using Xanthoria parietina and Physcia spp.) was applied to the City of Manchester (UK), the centre of the urban conurbation Greater Manchester, including considerations of its urban characteristics (e.g., building heights and traffic statistics), to investigate finer spatial detail urban air quality. Lichen wt% N and δ15N signatures, combined with lichen nitrate (NO3-) and ammonium (NH4+) concentrations, suggest a complex mixture of airborne NOx and NHx compounds across Manchester. In contrast, lichen S wt%, combined with δ34S strongly suggest anthropogenic sulfur sources, whereas C wt% and δ13C signatures were not considered reliable indicators of atmospheric carbon emissions. Manchester's urban attributes were found to influence lichen pollutant loadings, suggesting deteriorated air quality in proximity to highly trafficked roads and densely built-up areas. Lichen elemental contents and stable-isotope-ratio signatures can be used to identify areas of poor air quality, particularly at locations not covered by automated air quality measurement stations. Therefore, lichen biomonitoring approaches provide a beneficial method to supplement automated monitoring stations and also to assess finer spatial variability of urban air quality.

Geolocator-tracking seabird migration and moult reveal large-scale, temperature-driven isoscapes in the NE Atlantic.

RATIONALE: By combining precision satellite-tracking with blood sampling, seabirds can be used to validate marine carbon and nitrogen isoscapes, but it is unclear whether a comparable approach using low-precision light-level geolocators (GLS) and feather sampling can be similarly effective. METHODS: Here we used GLS to identify wintering areas of northern gannets (Morus bassanus) and sampled winter grown feathers (confirmed from image analysis of non-breeding birds) to test for spatial gradients in δ13 C and δ15 N in the NE Atlantic. RESULTS: By matching winter-grown feathers with the non-breeding location of tracked birds we found latitudinal gradients in δ13 C and δ15 N in neritic waters. Moreover, isotopic patterns were best explained by sea surface temperature. Similar isotope gradients were found in fish muscle sampled at local ports. CONCLUSIONS: Our study reveals the potential of using seabird GLS and feathers to reconstruct large-scale isotopic patterns.

Tracking the British agricultural revolution through the isotopic analysis of dated parchment.

Between the sixteenth and nineteenth century, British agriculture underwent a 'revolutionary' transformation. Yet despite over a century of research and the recognised centrality of agricultural developments to industrialisation and population growth, the character or chronology of any 'revolution' during this period remains contentious. Enquiry has been hampered by the fragmented and locally specific nature of historic accounts and the broad dating of early-modern zooarchaeological assemblages. To address this, we conducted stable isotope analysis on 658 legal documents written on sheepskin parchment; a unique biological resource that records the day, month and year of use (AD 1499 to 1969). We find these provide a high temporal resolution analysis of changing agricultural practices and episodes of disease. Most significantly, they suggest that if an 'Agricultural Revolution' occurred in livestock management, it did so from the mid-nineteenth century, in the aftermath of the Napoleonic Wars.

Can diet niche partitioning enhance sexual dimorphism?

Classic evolutionary theory suggests that sexual dimorphism evolves primarily via sexual and fecundity selection. However, theory and evidence are beginning to accumulate suggesting that resource competition can drive the evolution of sexual dimorphism, via ecological character displacement between sexes. A key prediction of this hypothesis is that the extent of ecological divergence between sexes will be associated with the extent of sexual dimorphism. As the stable isotope ratios of animal tissues provide a quantitative measure of various aspects of ecology, we carried out a meta-analysis examining associations between the extent of isotopic divergence between sexes and the extent of body size dimorphism. Our models demonstrate that large amounts of between-study variation in isotopic (ecological) divergence between sexes is nonrandom and may be associated with the traits of study subjects. We, therefore, completed meta-regressions to examine whether the extent of isotopic divergence between sexes is associated with the extent of sexual size dimorphism. We found modest but significantly positive associations across species between size dimorphism and ecological differences between sexes, that increased in strength when the ecological opportunity for dietary divergence between sexes was greatest. Our results, therefore, provide further evidence that ecologically mediated selection, not directly related to reproduction, can contribute to the evolution of sexual dimorphism.

Comment on "Evidence of prehistoric human activity in the Falkland Islands".

Stable isotopes from archaic Falkland Islands wolves (Dusicyon australis) indicate a high trophic, marine diet. Hamley et al. argue that this is consistent with mutualism with Yaghan people. However, most D. australis had similar isotopic signatures in the European era, despite human persecution. These data therefore neither support nor refute human-mediated introduction of D. australis to the Falklands.

Mercury speciation in Scottish raptors reveals high proportions of inorganic mercury in Scottish golden eagles (Aquila chrysaetos): Potential occurrence of mercury selenide nanoparticles.

Knowledge of the uptake and fate of mercury (Hg) compounds in biota is important in understanding the global cycling of Hg and its transfer pathways through food chains. In this study, we analysed total mercury (T-Hg) and methylmercury (MeHg) concentrations in 117 livers of Scottish birds of prey that were found across Scotland and submitted for post-mortem examination through the Raptor Health Scotland project between 2009 and 2019. Statistical comparisons focussed on six species (barn owl, Tyto alba; Eurasian common buzzard, Buteo buteo; golden eagle, Aquila chrysaetos; hen harrier, Circus cyaneus; Eurasian sparrowhawk, Accipiter nisus; and tawny owl, Strix aluco) and showed that golden eagles had a statistically lower fraction of MeHg compared to other raptor species. Further investigation using stable carbon and stable nitrogen isotope ratio measurements carried out for the golden eagles (n = 15) indicated that the increased presence of inorganic mercury (iHg) correlated with a marine influence on the primarily terrestrial diet. Additional bioimaging (n = 1) with laser ablation - inductively coupled plasma - mass spectrometry indicated the co-location of Hg and selenium (Se) within the liver tissue and transmission electron microscopy showed evidence of nanoparticles within the range of 10-20 nm. Further analysis using single particle - inductively coupled plasma - mass spectrometry (n = 4) confirmed the presence of Hg nanoparticles. Together, the evidence suggests the presence of mercury selenide (HgSe) nanoparticles in the liver of some golden eagles that, to our knowledge, has never been directly observed in terrestrial birds of prey. This study points to two alternative hypotheses: these golden eagles may be efficient at breaking down MeHg and form HgSe nanoparticles as a detoxification mechanism (as previously observed in cetaceans), or some golden eagles with elevated iHg may have accumulated these nanoparticles by foraging on stranded cetaceans or seabirds.

A modern baseline for the paired isotopic analysis of skin and bone in terrestrial mammals.

We present the isotopic discrimination between paired skin and bone collagen from animals of known life history, providing a modern baseline for the interpretation of archaeological isotopic data. At present, the interpretation of inter-tissue variation (Δ(skin-bone)) in mummified remains is based on comparisons with other archaeological material, which have attributed divergence to their contrasting turnover rates, with rapidly remodelling skin collagen incorporating alterations in environmental, cultural and physiological conditions in the months prior to death. While plausible, the lack of baseline data from individuals with known life histories has hindered evaluation of the explanations presented. Our analysis of a range of animals raised under a variety of management practices showed a population-wide trend for skin collagen to be depleted in 13C by -0.7‰ and enriched in 15N by +1.0‰ relative to bone collagen, even in stillborn animals. These results are intriguing and difficult to explain using current knowledge; however, on the basis of the findings reported here, we caution any results which interpret simply on differing turnover rates. We hypothesize that there may be a consistent difference in the routing of dietary protein and lipids between skin and bone, with potentially on-site synthesis of non-essential amino acids using carbon and nitrogen that have been sourced via different biochemical pathways.

We are what we eat, plus some per mill: Using stable isotopes to estimate diet composition in Gyps vultures over space and time.

Dietary studies in birds of prey involve direct observation and examination of food remains at resting and nesting sites. Although these methods accurately identify diet in raptors, they are time-consuming, resource-intensive, and associated with biases from the feeding ecology of raptors like Gyps vultures. Our study set out to estimate diet composition in Gyps vultures informed by stable isotopes that provide a good representation of assimilated diet from local systems.We hypothesized that differences in Gyps vulture diet composition is a function of sampling location and that these vultures move between Serengeti National Park and Selous Game Reserve to forage. We also theorized that grazing ungulates are the principal items in Gyps vulture diet.Through combined linear and Bayesian modeling, diet derived from δ13C in Gyps vultures consisted of grazing herbivores across sites, with those in Serengeti National Park consuming higher proportions of grazing herbivores (>87%). δ13C differences in vulture feather subsets did not indicate shifts in vulture diet and combined with blood δ13C, vultures fed largely on grazers for ~159 days before they were sampled. Similarly, δ15N values indicated Gyps vultures fed largely on herbivores. δ34S ratios separated where vultures fed when the two sites were compared. δ34S variation in vultures across sites resulted from baseline differences in plant δ34S values, though it is not possible to match δ34S to specific locations.Our findings highlight the relevance of repeated sampling that considers tissues with varying isotopic turnover and emerging Bayesian techniques for dietary studies using stable isotopes. Findings also suggested limited vulture movement between the two local systems. However, more sampling coupled with environmental data is required to fully comprehend this observation and its implications to Gyps vulture ecology and conservation.

Diacylglycerol Lipase-ß Knockout Mice Display a Sex-Dependent Attenuation of Traumatic Brain Injury-Induced Mortality with No Impact on Memory or Other Functional Consequences.

Background: The endogenous cannabinoid system modulates inflammatory signaling in a variety of pathological states, including traumatic brain injury (TBI). The selective expression of diacylglycerol lipase-ß (DAGL-ß), the 2-arachidonylglycerol biosynthetic enzyme, on resident immune cells of the brain (microglia) and the role of this pathway in neuroinflammation, suggest that this enzyme may contribute to TBI-induced neuroinflammation. Accordingly, we tested whether DAGL-ß-/- mice would show a protective phenotype from the deleterious consequences of TBI on cognitive and neurological motor functions. Materials and Methods: DAGL-ß-/- and -ß+/+ mice were subjected to the lateral fluid percussion model of TBI and assessed for learning and memory in the Morris water maze (MWM) Fixed Platform (reference memory) and Reversal (cognitive flexibility) tasks, as well as in a cued MWM task to infer potential sensorimotor/motivational deficits. In addition, subjects were assessed for motor behavior (Rotarod and the Neurological Severity Score assays) and in the light/dark box and the elevated plus maze to infer whether these manipulations affected anxiety-like behavior. Finally, we also examined whether brain injury disrupts the ceramide/sphingolipid lipid signaling system and if DAGL-ß deletion offers protection. Results: TBI disrupted all measures of neurological motor function and reduced body weight, but did not affect body temperature or performance in common assays used to infer anxiety. TBI also impaired performance in MWM Fixed Platform and Reversal tasks, but did not affect cued MWM performance. Although no differences were found between DAGL-ß-/- and -ß+/+ mice in any of these measures, male DAGL-ß-/- mice displayed an unexpected survival-protective phenotype, which persisted at increased injury severities. In contrast, TBI did not elicit mortality in female mice regardless of genotype. TBI also produced significant changes in sphingolipid profiles (a family of lipids, members of which have been linked to both apoptotic and antiapoptotic pathways), in which DAGL-ß deletion modestly altered levels of select species. Conclusions: These findings indicate that although DAGL-ß does not play a necessary role in TBI-induced cognitive and neurological function, it appears to contribute to the increased vulnerability of male mice to TBI-induced mortality, whereas female mice show high survival rates irrespective of DAGL-ß expression.

CRISPR/Cas9 deletion of ORMDLs reveals complexity in sphingolipid metabolism.

The serine palmitoyltransferase (SPT) complex catalyzes the rate-limiting step in the de novo biosynthesis of ceramides, the precursors of sphingolipids. The mammalian ORMDL isoforms (ORMDL1-3) are negative regulators of SPT. However, the roles of individual ORMDL isoforms are unclear. Using siRNA against individual ORMDLs, only single siORMDL3 had modest effects on dihydroceramide and ceramide levels, whereas downregulation of all three ORMDLs induced more pronounced increases. With the CRISPR/Cas9-based genome-editing strategy, we established stable single ORMDL3 KO (ORMDL3-KO) and ORMDL1/2/3 triple-KO (ORMDL-TKO) cell lines to further understand the roles of ORMDL proteins in sphingolipid biosynthesis. While ORMDL3-KO modestly increased dihydroceramide and ceramide levels, ORMDL-TKO cells had dramatic increases in the accumulation of these sphingolipid precursors. SPT activity was increased only in ORMDL-TKO cells. In addition, ORMDL-TKO but not ORMDL3-KO dramatically increased levels of galactosylceramides, glucosylceramides, and lactosylceramides, the elevated N-acyl chain distributions of which broadly correlated with the increases in ceramide species. Surprisingly, although C16:0 is the major sphingomyelin species, it was only increased in ORMDL3-KO, whereas all other N-acyl chain sphingomyelin species were significantly increased in ORMDL-TKO cells. Analysis of sphingoid bases revealed that although sphingosine was only increased 2-fold in ORMDL-TKO cells, levels of dihydrosphingosine, dihydrosphingosine-1-phosphate, and sphingosine-1-phosphate were hugely increased in ORMDL-TKO cells and not in ORMDL3-KO cells. Thus, ORMDL proteins may have a complex, multifaceted role in the biosynthesis and regulation of cellular sphingolipids.

An insect isoscape of UK and Ireland.

RATIONALE: The study of insect migration is problematic due to the small size of insects. Stable isotope analysis can be used to elucidate movement, either by geographic assignment of location of a species, or by simply distinguishing migrant from resident populations. There are few isoscapes of any kind in the UK/Ireland available for interrogation. Thus, I have measured stable isotope ratios (of H, C, N and S) of 299 individuals of the non-migratory Brimstone moth (Opisthograptis luteolata) collected from 93 locations around the UK and Ireland by citizen scientists. METHODS: After removing lipids, stable isotope ratios were measured by continuous flow isotope ratio mass spectrometry, using either a conventional elemental analyser (C, N and S) or a high-temperature, thermal conversion elemental analyser in reductive mode. RESULTS: Maps (isoscapes) were constructed that illustrate the stable isotope spatial distribution of this insect. These are the first isoscapes of H, C, N and S of biological samples covering both UK and Ireland. CONCLUSIONS: The insect isoscape patterns can be explained from what we know of moth diet, climate and geology. Sulfur isotopes may be of particular use for distinguishing individuals from areas of unique geology. Isoscape patterns may (with care) predict isotope compositions of other, herbivorous, non-aquatic, chitinous taxa. Such isoscapes, when extended beyond the UK and Ireland, would provide a useful tool to elucidate insect migration.

Ceramide in apoptosis and oxidative stress in allergic inflammation and asthma.

BACKGROUND: Nothing is known about the mechanisms by which increased ceramide levels in the lung contribute to allergic responses and asthma severity. OBJECTIVE: We sought to investigate the functional role of ceramide in mouse models of allergic airway disease that recapitulate the cardinal clinical features of human allergic asthma. METHODS: Allergic airway disease was induced in mice by repeated intranasal administration of house dust mite or the fungal allergen Alternaria alternata. Processes that can be regulated by ceramide and are important for severity of allergic asthma were correlated with ceramide levels measured by mass spectrometry. RESULTS: Both allergens induced massive pulmonary apoptosis and also significantly increased reactive oxygen species in the lung. Prevention of increases in lung ceramide levels mitigated allergen-induced apoptosis, reactive oxygen species, and neutrophil infiltration. In contrast, dietary supplementation of the antioxidant α-tocopherol decreased reactive oxygen species but had no significant effects on elevation of ceramide level or apoptosis, indicating that the increases in lung ceramide levels in allergen-challenged mice are not mediated by oxidative stress. Moreover, specific ceramide species were altered in bronchoalveolar lavage fluid from patients with severe asthma compared with in bronchoalveolar lavage fluid from individuals without asthma. CONCLUSION: Our data suggest that elevation of ceramide level after allergen challenge contributes to the apoptosis, reactive oxygen species generation, and neutrophilic infiltrate that characterize the severe asthmatic phenotype. Ceramide might be the trigger of formation of Creola bodies found in the sputum of patients with severe asthma and could be a biomarker to optimize diagnosis and to monitor and improve clinical outcomes in this disease.

Hydrogen isotopes reveal evidence of migration of Miniopterus schreibersii in Europe.

BACKGROUND: The Schreiber's bat, Miniopterus schreibersii, is adapted to long-distance flight, yet long distance movements have only been recorded sporadically using capture-mark-recapture. In this study, we used the hydrogen isotopic composition of 208 wing and 335 fur specimens from across the species' European range to test the hypothesis that the species migrates over long distances. RESULTS: After obtaining the hydrogen isotopic composition (δ2H) of each sample, we performed geographic assignment tests by comparing the δ2H of samples with the δ2H of sampling sites. We found that 95 bats out of 325 showed evidence of long-distance movement, based on the analysis of either fur or wing samples. The eastern European part of the species range (Greece, Bulgaria and Serbia) had the highest numbers of bats that had moved. The assignment tests also helped identify possible migratory routes, such as movement between the Alps and the Balkans. CONCLUSIONS: This is the first continental-scale study to provide evidence of migratory behaviour of M. schreibersii throughout its European range. The work highlights the need for further investigation of this behaviour to provide appropriate conservation strategies.

Tracking animal movements using biomarkers in tail hairs: a novel approach for animal geolocating from sulfur isoscapes.

BACKGROUND: Current animal tracking studies are most often based on the application of external geolocators such as GPS and radio transmitters. While these technologies provide detailed movement data, they are costly to acquire and maintain, which often restricts sample sizes. Furthermore, deploying external geolocators requires physically capturing and recapturing of animals, which poses an additional welfare concern. Natural biomarkers provide an alternative, non-invasive approach for addressing a range of geolocation questions and can, because of relatively low cost, be collected from many individuals thereby broadening the scope for population-wide inference. METHODS: We developed a low-cost, minimally invasive method for distinguishing between local versus non-local movements of cattle using sulfur isotope ratios (δ34S) in cattle tail hair collected in the Greater Serengeti Ecosystem, Tanzania. RESULTS: We used a Generalized Additive Model to generate a predicted δ34S isoscape across the study area. This isoscape was constructed using spatial smoothers and underpinned by the positive relationship between δ34S values and lithology. We then established a strong relationship between δ34S from recent sections of cattle tail hair and the δ34S from grasses sampled in the immediate vicinity of an individual's location, suggesting δ34S in the hair reflects the δ34S in the environment. By combining uncertainty in estimation of the isoscape, with predictions of tail hair δ34S given an animal's position in the isoscape we estimated the anisotropic distribution of travel distances across the Serengeti ecosystem sufficient to detect movement using sulfur stable isotopes. CONCLUSIONS: While the focus of our study was on cattle, this approach can be modified to understand movements in other mobile organisms where the sulfur isoscape is sufficiently heterogeneous relative to the spatial scale of animal movements and where tracking with traditional methods is difficult.

Targeting defective sphingosine kinase 1 in Niemann-Pick type C disease with an activator mitigates cholesterol accumulation.

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder arising from mutations in the cholesterol-trafficking protein NPC1 (95%) or NPC2 (5%). These mutations result in accumulation of low-density lipoprotein-derived cholesterol in late endosomes/lysosomes, disruption of endocytic trafficking, and stalled autophagic flux. Additionally, NPC disease results in sphingolipid accumulation, yet it is unique among the sphingolipidoses because of the absence of mutations in the enzymes responsible for sphingolipid degradation. In this work, we examined the cause for sphingosine and sphingolipid accumulation in multiple cellular models of NPC disease and observed that the activity of sphingosine kinase 1 (SphK1), one of the two isoenzymes that phosphorylate sphingoid bases, was markedly reduced in both NPC1 mutant and NPC1 knockout cells. Conversely, SphK1 inhibition with the isotype-specific inhibitor SK1-I in WT cells induced accumulation of cholesterol and reduced cholesterol esterification. Of note, a novel SphK1 activator (SK1-A) that we have characterized decreased sphingoid base and complex sphingolipid accumulation and ameliorated autophagic defects in both NPC1 mutant and NPC1 knockout cells. Remarkably, in these cells, SK1-A also reduced cholesterol accumulation and increased cholesterol ester formation. Our results indicate that a SphK1 activator rescues aberrant cholesterol and sphingolipid storage and trafficking in NPC1 mutant cells. These observations highlight a previously unknown link between SphK1 activity, NPC1, and cholesterol trafficking and metabolism.

Stable isotopes reveal the importance of seabirds and marine foods in the diet of St Kilda field mice.

Introduced mammals have devastated island nesting seabird populations worldwide. Declines in breeding seabirds on St Kilda, UK, have been linked to climate change and predation from great skuas Stercorarius skuas, but the introduced St Kilda field mouse Apodemus sylvaticus hirtensis may also play a role by feeding on adults, chicks or eggs. Here, we use stable isotopes in St Kilda mouse blood and potential dietary items to investigate their foraging ecology, specifically focussing on the importance of seabirds and marine foods in their diet. Mice were seasonally sampled at three sites on Hirta, St Kilda over three consecutive years (2010-2012). The δ13C and δ15N ratios were used in analyses, including isotope niche and dietary source mixing models, to examine foraging behaviour among locations and between seabird breeding seasons. Mice sampled in Carn Mor - where the majority of the island's seabirds nest - had consistently higher δ13C than other locations throughout the year, with δ15N also being significantly higher for all but one comparison. The isotopic niche width (SEAs) of Carn Mor mice in each season were distinct from the other locations, and became smaller during the seabird breeding season. Dietary mixing models revealed that seabirds made up a large proportion of the diet for mice from Carn Mor, particularly during the seabird breeding season. In conclusion, our work reveals that seabird-derived foods are likely to form a significant part of the diet of St Kilda mice populations located in and around breeding colonies. It is unclear however, whether this is from scavenging or predation of seabirds, or through their discarded food items. Given that mice have had significant effects on seabird populations elsewhere, it is important to carry out further work to determine whether mice are a significant cause of seabird mortality in this island ecosystem.

Carbon burial over the last four millennia is regulated by both climatic and land use change.

Carbon sequestration by sediments and vegetated marine systems contributes to atmospheric carbon drawdown, but little empirical evidence is available to help separate the effects of climate change and other anthropogenic activities on carbon burial over centennial timescales. We used marine sediment organic carbon to determine the role of historic climate variability and human habitation in carbon burial over the past 5,071 years. There was centennial-scale sensitivity of carbon supply and burial to climatic variability, with Little Ice Age cooling causing an abrupt ecosystem shift and an increase in marine carbon contributions compared to terrestrial carbon. Although land use changes during the late 1800s did not cause marked alteration in average carbon burial, they did lead to marked increases in the spatial variability of carbon burial. Thus, while carbon burial by vegetated systems is expected to increase with projected climate warming over the coming century, ecosystem restructuring caused by abrupt climate change may produce unexpected change in carbon burial whose variability is also modulated by land use change.