Latitudinal variation in ecological opportunity and intraspecific competition indicates differences in niche variability and diet specialization of Arctic marine predators

Individual specialization (IS), where individuals within populations irrespective of age, sex, and body size are either specialized or generalized in terms of resource use, has implications on ecological niches and food web structure. Niche size and degree of IS of near-top trophic-level marine predators have been little studied in polar regions or with latitude. We quantified the largescale latitudinal variation of population- and individual-level niche size and IS in ringed seals (Pusa hispida) and beluga whales (Delphinapterus leucas) using stable carbon and nitrogen isotope analysis on 379 paired ringed seal liver and muscle samples and 124 paired beluga skin and muscle samples from eight locations ranging from the low to high Arctic. We characterized both withinand between-individual variation in predator niche size at each location as well as accounting for spatial differences in the isotopic ranges of potential prey. Total isotopic niche width (TINW) for populations of ringed seals and beluga decreased with increasing latitude. Higher TINW values were associated with greater ecological opportunity (i.e., prey diversity) in the prey fish community which mainly consists of Capelin (Mallotus villosus) and Sand lance (Ammodytes sp.) at lower latitudes and Arctic cod (Boreogadus saida) at high latitudes. In beluga, their dietary consistency between tissues also known as the within-individual component (WIC) increased in a near 1:1 ratio with TINW (slope = 0.84), suggesting dietary generalization, whereas the slope (0.18) of WIC relative to TINW in ringed seals indicated a high degree of individual specialization in ringed seal populations with higher TINWs. Our findings highlight the differences in TINW and level of IS for ringed seals and beluga relative to latitude as a likely response to large-scale spatial variation in ecological opportunity, suggesting species-specific variation in dietary plasticity to spatial differences in prey resources and environmental conditions in a rapidly changing ecosystem

Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy

Background: Preclinical studies have documented antitumor activity of PARP inhibition both in vitro and in vivo, against Ewing sarcoma cells. This study aimed to translate that observation into a clinical trial to assess the efficacy and tolerability of olaparib, a PARP inhibitor, in patients with advanced Ewing sarcoma (EWS) progressing after prior chemotherapy. Methods: In this nonrandomized phase II trial, adult participants with radiographically measureable metastatic EWS received olaparib tablets, 400 mg orally twice daily, until disease progression or drug intolerance. Tumor measurements were determined by CT or MRI at 6 and 12 weeks after starting olaparib administration, and then every 8 weeks thereafter. Tumor response determinations were made according to RECIST 1.1, and adverse event determinations were made according to CTCAE, version 4.0. A total of 22 participants were planned to be enrolled using a conventional 2-step phase II study design. If no objective responses were observed after 12 participants had been followed for at least 3 months, further accrual would be stopped. Results: 12 participants were enrolled, and all were evaluable. There were no objective responses (PR/CR), 4 SD (duration 10.9, 11.4, 11.9, and 17.9 wks), and 8 PD as best response. Of the SD, 2 had minor responses (−9% and −11.7% by RECIST 1.1). The median time to disease progression was 5.7 weeks. Further enrollment was therefore discontinued. No significant or unexpected toxicities were observed with olaparib, with only a single case each of grade 3 anemia and grade 3 thrombocytopenia observed. Conclusions: This study is the first report of a prospective phase II trial to evaluate the safety and efficacy of a PARP inhibitor in patients with advanced Ewing sarcoma after failure of standard chemotherapy. Olaparib administration was safe and well tolerated when administered to this small heavily pre-treated cohort at the 400 mg BID dose, although the median duration of dosing was for only 5.7 weeks. No significant responses or durable disease control was seen, and the short average interval to disease progression underscores the aggressiveness of this disease. Other studies to combine cytotoxic chemotherapy with PARP inhibition in EWS are actively ongoing. Trial registration ClinicalTrials.gov Identifier: NCT0158354

Reduced epithelial suppressor of cytokine signalling 1 in severe eosinophilic asthma

Severe asthma represents a major unmet clinical need. Eosinophilic inflammation persists in the airways of many patients with uncontrolled asthma, despite high-dose inhaled corticosteroid therapy. Suppressors of cytokine signalling (SOCS) are a family of molecules involved in the regulation of cytokine signalling via inhibition of the Janus kinase–signal transducers and activators of transcription pathway. We examined SOCS expression in the airways of asthma patients and investigated whether this is associated with persistent eosinophilia.Healthy controls, mild/moderate asthmatics and severe asthmatics were studied. Whole genome expression profiling, quantitative PCR and immunohistochemical analysis were used to examine expression of SOCS1, SOCS2 and SOCS3 in bronchial biopsies. Bronchial epithelial cells were utilised to examine the role of SOCS1 in regulating interleukin (IL)-13 signalling in vitro.SOCS1 gene expression was significantly lower in the airways of severe asthmatics compared with mild/moderate asthmatics, and was inversely associated with airway eosinophilia and other measures of T-helper type 2 (Th2) inflammation. Immunohistochemistry demonstrated SOCS1 was predominantly localised to the bronchial epithelium. SOCS1 overexpression inhibited IL-13-mediated chemokine ligand (CCL) 26 (eotaxin-3) mRNA expression in bronchial epithelial cells.Severe asthma patients with persistent airway eosinophilia and Th2 inflammation have reduced airway epithelial SOCS1 expression. SOCS1 inhibits epithelial IL-13 signalling, supporting its key role in regulating Th2-driven eosinophilia in severe asthma.</jats:p

Latitudinal variation in ecological opportunity and intraspecific competition indicates differences in niche variability and diet specialization of Arctic marine predators

Individual specialization (IS), where individuals within populations irrespective of age, sex, and body size are either specialized or generalized in terms of resource use, has implications on ecological niches and food web structure. Niche size and degree of IS of near‐top trophic‐level marine predators have been little studied in polar regions or with latitude. We quantified the large‐scale latitudinal variation of population‐ and individual‐level niche size and IS in ringed seals (Pusa hispida) and beluga whales (Delphinapterus leucas) using stable carbon and nitrogen isotope analysis on 379 paired ringed seal liver and muscle samples and 124 paired beluga skin and muscle samples from eight locations ranging from the low to high Arctic. We characterized both within‐ and between‐individual variation in predator niche size at each location as well as accounting for spatial differences in the isotopic ranges of potential prey. Total isotopic niche width (TINW) for populations of ringed seals and beluga decreased with increasing latitude. Higher TINW values were associated with greater ecological opportunity (i.e., prey diversity) in the prey fish community which mainly consists of Capelin (Mallotus villosus) and Sand lance (Ammodytes sp.) at lower latitudes and Arctic cod (Boreogadus saida) at high latitudes. In beluga, their dietary consistency between tissues also known as the within‐individual component (WIC) increased in a near 1:1 ratio with TINW (slope = 0.84), suggesting dietary generalization, whereas the slope (0.18) of WIC relative to TINW in ringed seals indicated a high degree of individual specialization in ringed seal populations with higher TINWs. Our findings highlight the differences in TINW and level of IS for ringed seals and beluga relative to latitude as a likely response to large‐scale spatial variation in ecological opportunity, suggesting species‐specific variation in dietary plasticity to spatial differences in prey resources and environmental conditions in a rapidly changing ecosystem

Latitudinal variation in ecological opportunity and intraspecific competition indicates differences in niche variability and diet specialization of Arctic marine predators

Individual specialization (IS), where individuals within populations irrespective of age, sex, and body size are either specialized or generalized in terms of resource use, has implications on ecological niches and food web structure. Niche size and degree of IS of near‐top trophic‐level marine predators have been little studied in polar regions or with latitude. We quantified the large‐scale latitudinal variation of population‐ and individual‐level niche size and IS in ringed seals (Pusa hispida) and beluga whales (Delphinapterus leucas) using stable carbon and nitrogen isotope analysis on 379 paired ringed seal liver and muscle samples and 124 paired beluga skin and muscle samples from eight locations ranging from the low to high Arctic. We characterized both within‐ and between‐individual variation in predator niche size at each location as well as accounting for spatial differences in the isotopic ranges of potential prey. Total isotopic niche width (TINW) for populations of ringed seals and beluga decreased with increasing latitude. Higher TINW values were associated with greater ecological opportunity (i.e., prey diversity) in the prey fish community which mainly consists of Capelin (Mallotus villosus) and Sand lance (Ammodytes sp.) at lower latitudes and Arctic cod (Boreogadus saida) at high latitudes. In beluga, their dietary consistency between tissues also known as the within‐individual component (WIC) increased in a near 1:1 ratio with TINW (slope = 0.84), suggesting dietary generalization, whereas the slope (0.18) of WIC relative to TINW in ringed seals indicated a high degree of individual specialization in ringed seal populations with higher TINWs. Our findings highlight the differences in TINW and level of IS for ringed seals and beluga relative to latitude as a likely response to large‐scale spatial variation in ecological opportunity, suggesting species‐specific variation in dietary plasticity to spatial differences in prey resources and environmental conditions in a rapidly changing ecosystem

Increased autophagy-related 5 gene expression is associated with collagen expression in the airways of refractory asthmatics

Background: Fibrosis, particularly excessive collagen deposition, presents a challenge for treating asthmatic individuals. At present, no drugs can remove or reduce excessive collagen in asthmatic airways. Hence, the identification of pathways involved in collagen deposition would help to generate therapeutic targets to interfere with the airway remodeling process. Autophagy, a cellular degradation process, has been shown to be dysregulated in various fibrotic diseases, and genetic association studies in independent human populations have identified autophagy-related 5 (ATG5) to be associated with asthma pathogenesis. Hence, the dysregulation of autophagy may contribute to fibrosis in asthmatic airways. Objective: This study aimed to determine if (1) collagen deposition in asthmatic airways is associated with ATG5 expression and (2) ATG5 protein expression is associated with asthma per se and severity. Methods: Gene expression of transforming growth factor beta 1, various asthma-related collagen types [collagen, type I, alpha 1; collagen, type II, alpha 1; collagen, type III, alpha 1; collagen, type V, alpha 1 (COL5A1) and collagen, type V, alpha 2], and ATG5 were measured using mRNA isolated from bronchial biopsies of refractory asthmatic subjects and assessed for pairwise associations. Protein expression of ATG5 in the airways was measured and associations were assessed for asthma per se, severity, and lung function. Main results: In refractory asthmatic individuals, gene expression of ATG5 was positively associated with COL5A1 in the airways. No association was detected between ATG5 protein expression and asthma per se, severity, and lung function. Conclusion and clinical relevance: Positive correlation between the gene expression patterns of ATG5 and COL5A1 suggests that dysregulated autophagy may contribute to subepithelial fibrosis in the airways of refractory asthmatic individuals. This finding highlights the therapeutic potential of ATG5 in ameliorating airway remodeling in the difficult-to-treat refractory asthmatic individuals

Repeated, Long-Distance Migrations by a Philopatric Predator Targeting Highly Contrasting Ecosystems

Long-distance movements of animals are an important driver of population spatial dynamics and determine the extent of overlap with area-focused human activities, such as fishing. Despite global concerns of declining shark populations, a major limitation in assessments of population trends or spatial management options is the lack of information on their long-term migratory behaviour. For a large marine predator, the tiger shark Galeocerdo cuvier, we show from individuals satellite-tracked for multiple years (up to 1101 days) that adult males undertake annually repeated, round-trip migrations of over 7,500 km in the northwest Atlantic. Notably, these migrations occurred between the highly disparate ecosystems of Caribbean coral reef regions in winter and high latitude oceanic areas in summer, with strong, repeated philopatry to specific overwintering insular habitat. Partial migration also occurred, with smaller, immature individuals displaying reduced migration propensity. Foraging may be a putative motivation for these oceanic migrations, with summer behaviour showing higher path tortuosity at the oceanic range extremes. The predictable migratory patterns and use of highly divergent ecosystems shown by male tiger sharks appear broadly similar to migrations seen in birds, reptiles and mammals, and highlight opportunities for dynamic spatial management and conservation measures of highly mobile sharks

Ontogenetic Partial Migration Is Associated with Environmental Drivers and Influences Fisheries Interactions in a Marine Predator

The ability to predict animal movement based on environmental change is essential for understanding the dynamic nature of their spatial ecology, and in turn the effectiveness of conservation strategies. We used a large marine predator that displays partial migration (the tiger shark Galeocerdo cuvier) as a model to test the role of oceanic conditions in predicting the space-use of different size classes. By using generalized additive mixed models (GAMMs), we revealed that environmental variables (sea surface temperature, primary productivity, thermal fronts, and bathymetry) had much greater predictive power for the movements of large, migratory tiger sharks than for small, resident individuals. We also found that coverage of tiger shark movements within “shark sanctuaries” (protected areas specifically for sharks) in the northwest Atlantic could be increased from 12 to 52% through inclusion of Bermuda’s waters. However, as large tiger sharks are migratory, over 80% of potential longline fisheries interactions would still occur outside the boundaries of even the expanded protected areas. This emphasises that management of highly migratory species needs to be dynamic and account for changing interactions with fisheries over time, which in a changing climate may rely on predicting movements based on oceanic conditions to be effective

Anosmin-1 contributes to brain tumor malignancy through integrin signal pathways

Anosmin-1, encoded by the KAL1 gene, is an extracellular matrix (ECM)-associated protein which plays essential roles in the establishment of olfactory and GNRH neurons during early brain development. Loss-of-function mutations of KAL1 results in Kallmann syndrome with delayed puberty and anosmia. There is, however, little comprehension of its role in the developed brain. As reactivation of developmental signal pathways often takes part in tumorigenesis, we investigated if anosmin-1-mediated cellular mechanisms associated with brain tumors. Our meta-analysis of gene expression profiles of patients' samples and public microarray datasets indicated that KAL1 mRNA was significantly upregulated in high-grade primary brain tumors compared with the normal brain and low-grade tumors. The tumor-promoting capacity of anosmin-1 was demonstrated in the glioblastoma cell lines, where anosmin-1 enhanced cell motility and proliferation. Notably, anosmin-1 formed a part of active β1 integrin complex, inducing downstream signaling pathways. ShRNA-mediated knockdown of anosmin-1 attenuated motility and growth of tumor cells and induced apoptosis. Anosmin-1 may also enhance the invasion of tumor cells within the ECM by modulating cell adhesion and activating extracellular proteases. In a mouse xenograft model, anosmin-1-expressing tumors grew faster, indicating the role of anosmin-1 in tumor microenvironment in vivo. Combined, these data suggest that anosmin-1 can facilitate tumor cell proliferation, migration, invasion, and survival. Therefore, although the normal function of anosmin-1 is required in the proper development of GNRH neurons, overexpression of anosmin-1 in the developed brain may be an underlying mechanism for some brain tumors