Sclerostin does not play a major role in the pathogenesis of skeletal complications in type 2 diabetes mellitus

In contrast to previously reported elevations in serum sclerostin levels in diabetic patients, the present study shows that the impaired bone microarchitecture and cellular turnover associated with type 2 diabetes mellitus (T2DM)-like conditions in ZDF rats are not correlated with changes in serum and bone sclerostin expression. INTRODUCTION: T2DM is associated with impaired skeletal structure and a higher prevalence of bone fractures. Sclerostin, a negative regulator of bone formation, is elevated in serum of diabetic patients. We aimed to relate changes in bone architecture and cellular activities to sclerostin production in the Zucker diabetic fatty (ZDF) rat. METHODS: Bone density and architecture were measured by micro-CT and bone remodelling by histomorphometry in tibiae and femurs of 14-week-old male ZDF rats and lean Zucker controls (n = 6/group). RESULTS: ZDF rats showed lower trabecular bone mineral density and bone mass compared to controls, due to decreases in bone volume and thickness, along with impaired bone connectivity and cortical bone geometry. Bone remodelling was impaired in diabetic rats, demonstrated by decreased bone formation rate and increased percentage of tartrate-resistant acid phosphatase-positive osteoclastic surfaces. Serum sclerostin levels (ELISA) were higher in ZDF compared to lean rats at 9 weeks (+40 %, p < 0.01), but this difference disappeared as their glucose control deteriorated and by week 14, ZDF rats had lower sclerostin levels than control rats (-44 %, p < 0.0001). Bone sclerostin mRNA (qPCR) and protein (immunohistochemistry) were similar in ZDF, and lean rats at 14 weeks and genotype did not affect the number of empty osteocytic lacunae in cortical and trabecular bone. CONCLUSION: T2DM results in impaired skeletal architecture through altered remodelling pathways, but despite altered serum levels, it does not appear that sclerostin contributes to the deleterious effect of T2DM in rat bone

Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

Some anti-diabetic therapies can have adverse effects on bone health and increase fracture risk. In this study, we tested the skeletal effects of chronic administration of two Glucagon-like peptide-1 receptor agonists (GLP-1RA), increasingly used for type 2 diabetes treatment, in a model of osteoporosis associated bone loss and examined the expression and activation of GLP-1R in bone cells. Mice were ovariectomised (OVX) to induce bone loss and four weeks later they were treated with Liraglutide (LIR) 0.3 mg/kg/day, Exenatide (Ex-4) 10 μg/kg/day or saline for four weeks. Mice were injected with calcein and alizarin red prior to euthanasia, to label bone-mineralising surfaces. Tibial micro-architecture was determined by micro-CT and bone formation and resorption parameters measured by histomorphometric analysis. Serum was collected to measure calcitonin and sclerostin levels, inhibitors of bone resorption and formation, respectively. GLP-1R mRNA and protein expression were evaluated in the bone, bone marrow and bone cells using RT-PCR and immunohistochemistry. Primary osteoclasts and osteoblasts were cultured to evaluate the effect of GLP-1RA on bone resorption and formation in vitro. GLP-1RA significantly increased trabecular bone mass, connectivity and structure parameters but had no effect on cortical bone. There was no effect of GLP-1RA on bone formation in vivo but an increase in osteoclast number and osteoclast surfaces was observed with Ex-4. GLP-1R was expressed in bone marrow cells, primary osteoclasts and osteoblasts and in late osteocytic cell line. Both Ex-4 and LIR stimulated osteoclastic differentiation in vitro but slightly reduced the area resorbed per osteoclast. They had no effect on bone nodule formation in vitro. Serum calcitonin levels were increased and sclerostin levels decreased by Ex-4 but not by LIR. Thus, GLP-1RA can have beneficial effects on bone and the expression of GLP-1R in bone cells may imply that these effects are exerted directly on the tissue

Measures of oxidative state are primarily driven by extrinsic factors in a long-distance migrant

This is the author accepted manuscript. The final version is available from the Royal Society via the DOI in this recordData accessibility: Data are available from the Dryad Digital Repository: https://doi.org/10.5061/dryad.j4k3t6f/1 [20].Oxidative stress is a likely consequence of hard physical exertion and thus a potential mediator of life-history trade-offs in migratory animals. However, little is known about the relative importance of intrinsic and extrinsic stressors on the oxidative state of individuals in wild populations. We quantified the relationships between air temperature, sex, body condition and three markers of oxidative state (malondialdehyde, superoxide dismutase and total antioxidant capacity) across hundreds of individuals of a long-distance migrant (the brent goose Branta bernicla hrota) during wintering and spring staging. We found that air temperature and migratory stage were the strongest predictors of oxidative state. This emphasizes the importance of extrinsic factors in regulating the oxidative state of migrating birds, with differential effects across the migration. The significance of abiotic effects demonstrates an additional mechanism by which changing climates may affect migratory costs.European Commissio

Passerine Birds Breeding under Chronic Noise Experience Reduced Fitness

Background Fitness in birds has been shown to be negatively associated with anthropogenic noise, but the underlying mechanisms remain obscure. It is however crucial to understand the mechanisms of how urban noise impinges on fitness to obtain a better understanding of the role of chronic noise in urban ecology. Here, we examine three hypotheses on how noise might reduce reproductive output in passerine birds: (H1) by impairing mate choice, (H2) by reducing territory quality and (H3) by impeding chick development. Methodology/Principal Findings We used long-term data from an island population of house sparrows, Passer domesticus, in which we can precisely estimate fitness. We found that nests in an area affected by the noise from large generators produced fewer young, of lower body mass, and fewer recruits, even when we corrected statistically for parental genetic quality using a cross-fostering set-up, supporting H3. Also, individual females provided their young with food less often when they bred in the noisy area compared to breeding attempts by the same females elsewhere. Furthermore, we show that females reacted flexibly to increased noise levels by adjusting their provisioning rate in the short term, which suggests that noise may be a causal factor that reduces reproductive output. We rejected H1 and H2 because nestbox occupancy, parental body mass, age and reproductive investment did not differ significantly between noisy and quiet areas. Conclusions/Significance Our results suggest a previously undescribed mechanism to explain how environmental noise can reduce fitness in passerine birds: by acoustically masking parent–offspring communication. More importantly, using a cross-fostering set-up, our results demonstrate that birds breeding in a noisy environment experience significant fitness costs. Chronic noise is omnipresent around human habitation and may produces similar fitness consequences in a wide range of urban bird species

Frequency and consequences of individual dietary specialisation in a wide-ranging marine predator, the northern gannet

Individual specialisations in animals are important contributors to a wide range of ecological and evolutionary processes, and have been particularly documented in relation to multiple aspects of foraging behaviours. Central-place foragers, such as seabirds, frequently exhibit pronounced specialisations and individual differences in a variety of foraging traits. In particular, the availability of fisheries discards alongside natural prey resources provides additional potential for differentiation and specialisation for opportunistically scavenging seabird species. However, the consequences of such specialisations for at-sea distributions and intraspecific interactions are not well known. Here, we investigated the links between the degree of dietary specialisation on natural or discarded prey and the foraging movements and spatial occupancy of northern gannets Morus bassanus in relation to differing intraspecific competition at 6 colonies of differing sizes. We found that, at most colonies, individuals with different dietary strategies concentrated foraging at differing levels of intraspecific competition. In addition, individuals pursuing different strategies were frequently, but not consistently, spatially separated, distinctions that were most acutely seen in females. However, this variation in individual strategy had no significant impact on current body condition. These analyses demonstrate how foraging-associated metrics need not covary within an unconstrained system. They also reveal that specialisation can have important consequences for the competitive regimes individuals experience, highlighting the complexity of examining interacting consequences at large spatial scales

A metabolite-derived protein modification integrates glycolysis with KEAP1-NRF2 signalling.

Mechanisms that integrate the metabolic state of a cell with regulatory pathways are necessary to maintain cellular homeostasis. Endogenous, intrinsically reactive metabolites can form functional, covalent modifications on proteins without the aid of enzymes1,2, and regulate cellular functions such as metabolism3-5 and transcription6. An important 'sensor' protein that captures specific metabolic information and transforms it into an appropriate response is KEAP1, which contains reactive cysteine residues that collectively act as an electrophile sensor tuned to respond to reactive species resulting from endogenous and xenobiotic molecules. Covalent modification of KEAP1 results in reduced ubiquitination and the accumulation of NRF27,8, which then initiates the transcription of cytoprotective genes at antioxidant-response element loci. Here we identify a small-molecule inhibitor of the glycolytic enzyme PGK1, and reveal a direct link between glycolysis and NRF2 signalling. Inhibition of PGK1 results in accumulation of the reactive metabolite methylglyoxal, which selectively modifies KEAP1 to form a methylimidazole crosslink between proximal cysteine and arginine residues (MICA). This posttranslational modification results in the dimerization of KEAP1, the accumulation of NRF2 and activation of the NRF2 transcriptional program. These results demonstrate the existence of direct inter-pathway communication between glycolysis and the KEAP1-NRF2 transcriptional axis, provide insight into the metabolic regulation of the cellular stress response, and suggest a therapeutic strategy for controlling the cytoprotective antioxidant response in several human diseases

The feasibility of milkfish (Chanos chanos) aquaculture in Solomon Islands

Fish is crucial to food and nutrition security in Solomon Islands, and demand is expected to increase due to a growing population. However, it is projected that current capture fisheries production will not meet this growing demand. Aquaculture has the potential to mitigate the capture fishery shortfall, and the Government of Solomon Islands is prioritizing aquaculture as a solution to meet future food and income needs. Aquaculture in Solomon Islands is still in early development. Mozambique tilapia (Oreochromis mossambicus) is farmed for household consumption, but its prolific reproductive rate and resulting slow growth limit its potential as a commercial aquaculture species. More productive fish species that are not indigenous to Solomon Islands but are successfully farmed overseas could be introduced; however, such a decision needs to take into account the potential ecological or social impacts. For land-based pond aquaculture, the only indigenous species that has been farmed extensively elsewhere is milkfish (Chanos chanos). This report presents a feasibility assessment for milkfish farming in Solomon Islands. It synthesizes the current knowledge about milkfish farming and presents results of a 4-year study on the potential for milkfish aquaculture in Solomon Islands

ESCRT-III is necessary for the integrity of the nuclear envelope in micronuclei but is aberrant at ruptured micronuclear envelopes generating damage

Micronuclei represent the cellular attempt to compartmentalize DNA to maintain genomic integrity threatened by mitotic errors and genotoxic events. Some micronuclei show aberrant nuclear envelopes (NEs) that collapse, generating damaged DNA that can promote complex genome alterations. However, ruptured micronuclei also provide a pool of cytosolic DNA that can stimulate antitumor immunity, revealing the complexity of micronuclear impact on tumor progression. The ESCRT-III (Endosomal Sorting Complex Required for Transport-III) complex ensures NE reseals during late mitosis and is repaired in interphase. Therefore, ESCRT-III activity maybe crucial for maintaining the integrity of other genomic structures enclosed by a NE. ESCRT-III activity at the NE is coordinated by the subunit CHMP7. We show that CHMP7 and ESCRT-III protect against the genomic instability associated with micronuclei formation. Loss of ESCRT-III activity increases the population of micronuclei with ruptured NEs, revealing that its NE repair activity is also necessary to maintain micronuclei integrity. Surprisingly, aberrant accumulation of ESCRT-III are found at the envelope of most acentric collapsed micronuclei, suggesting that ESCRT-III is not recycled efficiently from these structures. Moreover, CHMP7 depletion relieves micronuclei from the aberrant accumulations of ESCRT-III. CHMP7-depleted cells display a reduction in micronuclei containing the DNA damage marker RPA and a sensor of cytosolic DNA. Thus, ESCRT-III activity appears to protect from the consequence of genomic instability in a dichotomous fashion: ESCRT-III membrane repair activity prevents the occurrence of micronuclei with weak envelopes, but the aberrant accumulation of ESCRT-III on a subset of micronuclei appears to exacerbate DNA damage and sustain proinflammatory pathways

Sexual Size Dimorphism and Body Condition in the Australasian Gannet

Funding: The research was financially supported by the Holsworth Wildlife Research Endowment. Acknowledgments We thank the Victorian Marine Science Consortium, Sea All Dolphin Swim, Parks Victoria, and the Point Danger Management Committee for logistical support. We are grateful for the assistance of the many field volunteers involved in the study.Peer reviewedPublisher PD