Molecular Characterisation of Faecal Bacterial Assemblages Among Four Species of Syntopic Odonates.

Factors such as host species, phylogeny, diet, and both timing and location of sampling are thought to influence the composition of gut-associated bacteria in insects. In this study, we compared the faecal-associated bacterial taxa for three Coenagrion and one Enallagma damselfly species. We expected high overlap in representation of bacterial taxa due to the shared ecology and diet of these species. Using metabarcoding based on the 16S rRNA gene, we identified 1513 sequence variants, representing distinct bacterial 'taxa'. Intriguingly, the damselfly species showed somewhat different magnitudes of richness of ZOTUs, ranging from 480 to 914 ZOTUs. In total, 921 (or 60.8% of the 1513) distinct ZOTUs were non-shared, each found only in one species, and then most often in only a single individual. There was a surfeit of these non-shared incidental ZOTUs in the Enallagma species accounting for it showing the highest bacterial richness and accounting for a sample-wide pattern of more single-species ZOTUs than expected, based on comparisons to the null model. Future studies should address the extent to which faecal bacteria represent non-incidental gut bacteria and whether abundant and shared taxa are true gut symbionts. Pictures of odonates adopted from Norske Art databank under Creative Commons License (CC BY 4.0).

Interrelationships and properties of parasite aggregation measures: a user's guide.

Aggregation of macroparasites among hosts is nearly universal among parasite-host associations. Researchers testing hypotheses on origins of parasite aggregation and its importance to parasite and host population ecology have used different measures of aggregation that are not necessarily measuring the same thing, potentially clouding our understanding of underlying epidemiological processes. We highlight these differences in meanings by exploring properties and interrelationships of six common measures of parasite aggregation, and provide a "user's guide" to inform researchers' decisions regarding their application. We compared the mathematical expressions of the different measures of aggregation, and ran two series of simulations and analyses. The first simulations tested the effect of random removals of parasites on aggregation levels under different conditions, while the second explored interrelationships between the measures, as well as between other individual parasitological sample measures (i.e. mean abundance, prevalence) and aggregation. Results of simulations and analyses showed that the six measures of aggregation could be separated readily into three groups: the variance-to-mean ratio (VMR) together with mean crowding, patchiness with k of the negative binomial, and Poulin's D with Hoover's index. These three pairs of measures showed differing responses to random parasite removals and differing relations with mean abundance and/or prevalence, highlighting that metrics capture different variation in other sample measures and different attributes of aggregation. We used results of our simulations and analyses, and a literature review, to list the properties, advantages, and disadvantages of each aggregation metric. We provide a comprehensive exploration of what is assessed by each metric, as a guide to metric choice. We implore researchers to provide enough information such that aggregation measures from each group are reported or can be readily calculated. Such steps are needed to allow large-scale analyses of variation in degrees of aggregation within and among parasite-host associations, to uncover epidemiological processes shaping parasite distributions.

Circulating Immune Bioenergetic, Metabolic, and Genetic Signatures Predict Melanoma Patients' Response to Anti-PD-1 Immune Checkpoint Blockade.

PURPOSE: Immunotherapy with checkpoint inhibitors is improving the outcomes of several cancers. However, only a subset of patients respond. Therefore, predictive biomarkers are critically needed to guide treatment decisions and develop approaches to the treatment of therapeutic resistance. EXPERIMENTAL DESIGN: We compared bioenergetics of circulating immune cells and metabolomic profiles of plasma obtained at baseline from patients with melanoma treated with anti-PD-1 therapy. We also performed single-cell RNA sequencing (scRNAseq) to correlate transcriptional changes associated with metabolic changes observed in peripheral blood mononuclear cells (PBMC) and patient plasma. RESULTS: Pretreatment PBMC from responders had a higher reserve respiratory capacity and higher basal glycolytic activity compared with nonresponders. Metabolomic analysis revealed that responder and nonresponder patient samples cluster differently, suggesting differences in metabolic signatures at baseline. Differential levels of specific lipid, amino acid, and glycolytic pathway metabolites were observed by response. Further, scRNAseq analysis revealed upregulation of T-cell genes regulating glycolysis. Our analysis showed that SLC2A14 (Glut-14; a glucose transporter) was the most significant gene upregulated in responder patients' T-cell population. Flow cytometry analysis confirmed significantly elevated cell surface expression of the Glut-14 in CD3+, CD8+, and CD4+ circulating populations in responder patients. Moreover, LDHC was also upregulated in the responder population. CONCLUSIONS: Our results suggest a glycolytic signature characterizes checkpoint inhibitor responders; consistently, both ECAR and lactate-to-pyruvate ratio were significantly associated with overall survival. Together, these findings support the use of blood bioenergetics and metabolomics as predictive biomarkers of patient response to immune checkpoint inhibitor therapy.

HSP90-CDC37 functions as a chaperone for the oncogenic FGFR3-TACC3 fusion.

The FGFR3-TACC3 (F3-T3) fusion gene was discovered as an oncogenic molecule in glioblastoma and bladder cancers, and has subsequently been found in many cancer types. Notably, F3-T3 was found to be highly expressed in both untreated and matched recurrence glioblastoma under the concurrent radiotherapy and temozolomide (TMZ) treatment, suggesting that targeting F3-T3 is a valid strategy for treatment. Here, we show that the F3-T3 protein is a client of heat shock protein 90 (HSP90), forming a ternary complex with the cell division cycle 37 (CDC37). Deprivation of HSP90 or CDC37 disrupts the formation of the ternary complex, which destabilizes glycosylated F3-T3, and thereby suppresses F3-T3 oncogenic activity. Gliomas harboring F3-T3 are resistant to TMZ chemotherapy. HSP90 inhibitors sensitized F3-T3 glioma cells to TMZ via the inhibition of F3-T3 activation and potentiated TMZ-induced DNA damage. These results demonstrate that F3-T3 oncogenic function is dependent on the HSP90 chaperone system and suggests a new clinical option for targeting this genetic aberration in cancer.

Trematodes coupled with neonicotinoids: effects on blood cell profiles of a model amphibian.

Habitat loss, climate change, environmental contaminants, and parasites and pathogens are among the main factors thought to act singly or together in causing amphibian declines. We tested for combined effects of neonicotinoid pesticides and parasites (versus parasites-only) on mortality, growth, and white blood cell profiles of a model amphibian: the northern leopard frog (Rana pipiens). We first exposed infectious stages of frog trematodes (cercariae of Echinostoma spp.) to low and high concentrations of thiamethoxam or clothianidin versus water-only controls. There were no differences in survival of trematode cercariae between treatments. For the main experiment, we exposed tadpoles to clean water versus high concentrations of clothianidin or thiamethoxam for 2 weeks and added trematode cercariae to all tanks after 1 week. Exposure of tadpoles and parasites to high concentrations of thiamethoxam or clothianidin did not affect parasite infection success. Tadpole survival was not different between treatments before or after parasite addition and there were no significant differences in tadpole snout-to-vent lengths or developmental stages between treatments. Tadpoles exposed to thiamethoxam + parasites had smaller widths than parasite-only tadpoles, whereas tadpoles exposed to clothianidin + parasites had higher eosinophil to leukocyte ratios compared to parasite-only tadpoles. Tadpoles of both neonicotinoid + parasite treatments had significantly lower monocyte to leukocyte ratios relative to parasite-only tadpoles. High concentrations of neonicotinoid combined with parasites appear to influence tadpole immune function important for further defense against parasites and pathogens. This work highlights the need for more holistic approaches to ecotoxicity studies, using multiple stressors.

Seaduck engineers in the Arctic Archipelago: nesting eiders deliver marine nutrients and transform the chemistry of island soils, plants, and ponds.

Seabirds are thought to provide ecological services such as the movement of nutrients between marine and terrestrial ecosystems, which may be especially critical to productivity and diversity in nutrient-poor environments. Most Arctic ecosystems are unaffected by local human impacts and are naturally nutrient poor and especially sensitive to warming. Here, we assessed the effects of nesting common eider ducks (Somateria mollissima) on soil, vegetation, and pond sediments on island archipelagoes in Hudson Strait between Nunavut and Québec, Canada. Soil, moss, and pond sediments were significantly higher in nitrogen on islands with large numbers of nesting eiders compared to sites with no nesting birds. The highest concentrations of nitrogen in soils and moss occurred at the margins of ponds on eider islands, which correspond to the areas of highest eider use. δ15N and δ34S values in soils, moss, and sediments indicated substantial marine-derived organic matter inputs at the higher nutrient sites. We propose that by foraging on coastal marine benthic invertebrates and returning to islands to nest, eider ducks bio-transport and concentrate marine-derived nutrients to their colony islands, fertilizing Arctic island ecosystems in the process. As common eiders nest on thousands of low to mid-latitude islands throughout the circumpolar Arctic, these nutrient inputs likely dramatically affect biota and ecosystem functioning throughout the tundra biome.

IGFBP2: integrative hub of developmental and oncogenic signaling network.

Insulin-like growth factor (IGF) binding protein 2 (IGFBP2) was discovered and identified as an IGF system regulator, controlling the distribution, function, and activity of IGFs in the pericellular space. IGFBP2 is a developmentally regulated gene that is highly expressed in embryonic and fetal tissues and markedly decreases after birth. Studies over the last decades have shown that in solid tumors, IGFBP2 is upregulated and promotes several key oncogenic processes, such as epithelial-to-mesenchymal transition, cellular migration, invasion, angiogenesis, stemness, transcriptional activation, and epigenetic programming via signaling that is often independent of IGFs. Growing evidence indicates that aberrant expression of IGFBP2 in cancer acts as a hub of an oncogenic network, integrating multiple cancer signaling pathways and serving as a potential therapeutic target for cancer treatment.

Anti-parasite treatment results in decreased estimated survival with increasing lead (Pb) levels in the common eider Somateria mollissima.

Field experiments where parasites are removed through treatment and contaminant levels in host tissues are recorded can provide insight into the combined effects of parasitism and contaminants in wild populations. In 2013 and 2014, we treated northern common eider ducks (Somateria mollissima) arriving at a breeding colony with either a broad-spectrum antihelminthic (PANACUR®) or distilled water, and measured their blood lead (Pb) levels. Breeding propensity and clutch sizes were inversely related to Pb in both treatment groups. In comparison, a negative effect of Pb on resight probability the following year was observed only in the anti-parasitic treatment (APT) group. These contrasting patterns suggest a long-term benefit to survival of intestinal parasitism in eiders experiencing Pb exposure. The arrival date of hens explained some, but not all, of the effects of Pb. We weigh the merits of different hypotheses in explaining our results, including protective bioaccumulation of Pb by parasites, condition-linked thresholds to costly reproduction and the direct effects of APT on eider health. We conclude that variation in helminth parasitism influences survival in this migratory bird in counterintuitive ways.

Sub-chronic exposure to a neonicotinoid does not affect susceptibility of larval leopard frogs to infection by trematode parasites, via either depressed cercarial performance or host immunity.

Little information is available on the effects of neonicotinoid insecticides on vertebrates. Previous work using amphibians found chronic exposure to some neonicotinoids had no detrimental effects on fitness-relevant traits. However, there is some evidence of more subtle effects of neonicotinoids on immune traits and evidence that other pesticides can suppress tadpole immunity resulting in elevated levels of parasitism in the exposed tadpoles. The objective of our study was to assess whether neonicotinoid exposure affected tadpole immunometrics and susceptibility to parasitic helminths. We assessed northern leopard frog tadpole (Lithobates pipiens) levels of parasitism and leukocyte profiles following exposure to environmentally relevant concentrations of clothianidin and free-living infective cercariae of a helminth parasite, an Echinostoma sp. trematode. When comparing tadpoles from controls to either 1 or 100 µg/L clothianidin treatments, we found similar measures of parasitism (i.e. prevalence, abundance and intensity of echinostome cysts) and similar leukocyte profiles. We also confirmed that clothianidin was not lethal for cercariae; however, slight reductions in swimming activity were detected at the lowest exposure concentration of 0.23 µg/L. Our results show that exposure to clothianidin during the larval amphibian stage does not affect leukocyte profiles or susceptibility to parasitism by larval trematodes in northern leopard frogs although other aspects such as length of host exposure require further study.

The Moderating Role of Sleep in the Relationship Between Social Isolation and Internalising Problems in Early Adolescence.

Social isolation may be a unique risk factor for depression and anxiety in early adolescence. However, optimal sleep may protect adolescents from the emotional sequela of social isolation. The present study aimed to investigate whether sleep moderates the relationship between social isolation and symptoms of anxiety and depression in early adolescence. Five hundred and twenty eight early adolescents (M = 11.18 years, SD = 0.56, range 10-12 years, 51% male) completed online questionnaires assessing social isolation, sleep duration, daytime sleepiness and symptoms of generalised anxiety, social anxiety, separation anxiety and depression. Sleep duration moderated the effect of social isolation on symptoms of generalised anxiety, social anxiety and depression, but not separation anxiety. Daytime sleepiness emerged as an additional sleep-related risk factor in the relationship between social isolation and depressive symptoms. Therefore, sleep may be an important modifiable risk or protective factor to target, in the prevention of depression and anxiety in adolescence.

Incorporating blood-based liquid biopsy information into cancer staging: time for a TNMB system?

Tissue biopsy is the standard diagnostic procedure for cancer. Biopsy may also provide material for genotyping, which can assist in the diagnosis and selection of targeted therapies but may fall short in cases of inadequate sampling, particularly from highly heterogeneous tumors. Traditional tissue biopsy suffers greater limitations in its prognostic capability over the course of disease, most obviously as an invasive procedure with potential complications, but also with respect to probable tumor clonal evolution and metastasis over time from initial biopsy evaluation. Recent work highlights circulating tumor DNA (ctDNA) present in the blood as a supplemental, or perhaps an alternative, source of DNA to identify the clinically relevant cancer mutational landscape. Indeed, this noninvasive approach may facilitate repeated monitoring of disease progression and treatment response, serving as a means to guide targeted therapies based on detected actionable mutations in patients with advanced or metastatic solid tumors. Notably, ctDNA is heralding a revolution in the range of genomic profiling and molecular mechanisms to be utilized in the battle against cancer. This review will discuss the biology of ctDNA, current methods of detection and potential applications of this information in tumor diagnosis, treatment, and disease prognosis. Conventional classification of tumors to describe cancer stage follow the TNM notation system, heavily weighting local tumor extent (T), lymph node invasion (N), and detectable metastasis (M). With recent advancements in genomics and bioinformatics, it is conceivable that routine analysis of ctDNA from liquid biopsy (B) may make cancer diagnosis, treatment, and prognosis more accurate for individual patients. We put forward the futuristic concept of TNMB tumor classification, opening a new horizon for precision medicine with the hope of creating better outcomes for cancer patients.

Anti-parasite treatment, but not mercury burdens, influence nesting propensity dependent on arrival time or body condition in a marine bird.

Arctic wildlife can be exposed to high mercury (Hg) levels, and are also naturally exposed to gastrointestinal parasites that can reduce condition and negatively affect reproductive output and/or survival in similar ways. Importantly, both Hg and parasites are increasing in wildlife in some Arctic regions. We studied the northern common eider duck (Somateria mollissima) to explore how Hg in association with both natural levels and experimentally reduced parasitic infections, affect reproduction and survival. Female eiders were measured, banded, and blood sampled to determine blood Hg burdens, prior to breeding. Propensity to nest, clutch size, nest survival, nest attendance, and return rates were assessed in relation to both Hg burden and parasite treatment. Neither reproduction nor return rates of females varied with Hg concentrations, but females arriving late to the colony, or in low body condition, showed increased nesting propensity when given the anti-parasite treatment as compared to placebo treatment. Our results suggest that parasites can play a critical role in decisions to invest in avian breeding annually, particularly among individuals with a late onset to breeding, and in poor condition.

Perceived needs for mental health care and barriers to treatment across age groups.

PURPOSE: This study aimed to assess responses to a structured measure of perceived need for treatment to understand whether differences in treatment uptake across age groups are related to differences in: (1) perceived need for mental health care; (2) perceptions of treatment needs being met; and/or (3) perceived attitudinal and structural treatment barriers. METHODS: Data from a nationally representative sample of the Australian population (2007 National Survey of Mental Health and Wellbeing) were analysed using logistic and multinomial regression. All participants potentially benefiting from mental health services were included in analyses; including those reporting symptoms of mental disorders, using mental health services, or self-reporting significant mental health problems in the past 12 months (n = 5733). All regression analyses were adjusted for gender, the presence of chronic physical health conditions, disorder type, and disorder severity. RESULTS: Older adults were the least likely to report any perceived need for mental health care, and specifically reported lower needs for psychotherapy, information about available services, and support improving their ability to work. Older adults perceiving a need for mental health care were also the most likely to report having these needs met. There were no differences in attitudinal and structural barriers to treatment across age groups. CONCLUSIONS: These results highlight that age needs to be considered in strategies for improving engagement and efficacy of mental health services, as well as the need for further research to understand what drives age differences in perceived need for mental health care.

Implications of mercury and lead concentrations on breeding physiology and phenology in an Arctic bird.

Although physiological traits and phenology are thought to be evolved traits, they often show marked variation within populations, which may be related to extrinsic factors. For example, trace elements such as mercury (Hg) and lead (Pb) alter biochemical processes within wildlife that may affect migration and breeding. While there is a growing understanding of how contaminants may influence wildlife physiology, studies addressing these interactions in free-living species are still limited. We examined how four non-essential trace elements (cadmium, Hg, Pb and selenium) interacted with physiological and breeding measures known to influence breeding in a free-living population of common eider ducks (Somateria mollissima). We collected blood from female eiders as they arrived at a breeding colony in northern Canada. Blood was subsequently assessed for baseline corticosterone (CORT), immunoglobulin Y (IgY), and the four trace elements. We used model selection to identify which elements varied most with CORT, IgY, arrival condition, and arrival timing. We then used path analysis to assess how the top two elements from the model selection process (Hg and Pb) varied with metrics known to influence reproduction. We found that arrival date, blood Hg, CORT, and IgY showed significant inter-annual variation. While blood Pb concentrations were low, blood Pb levels significantly increased with later arrival date of the birds, and varied negatively with eider body condition, suggesting that even at low blood concentrations, Pb may be related to lower investment in reproduction in eiders. In contrast, blood Hg concentrations were positively correlated with eider body condition, indicating that fatter birds also had higher Hg burdens. Overall, our results suggest that although blood Hg and Pb concentrations were below no-effect levels, these low level concentrations of known toxic metals show significant relationships with breeding onset and condition in female eider ducks, factors that could influence reproductive success in this species.

Direct and indirect causes of sex differences in mercury concentrations and parasitic infections in a marine bird.

In many animal species, males and females differ in their levels of contaminants and/or parasitic infections. Most contaminants and gastro-intestinal parasites are obtained through prey ingestion, and thus the causes of sex differences in the distribution of these factors might follow similar pathways. We studied the northern common eider duck (Somateria molissima borealis) as an avian model, and used directed separation path analysis to explore the causes of sex differences in mercury (Hg) and gastro-intestinal helminths. Two trophically transmitted helminths were examined: a cestode (Lateriporus sp.) and an acanthocephalan (Polymorphus sp). We found that the number of Lateriporus sp. varied positively with stable isotope signature (as indicated by δ(15)N in eider breast muscle tissue), and negatively with crustaceans being present in the short term diet. We also found that Polymorphus sp. varied positively with eider tissue stable isotope signature. However, Polymorphus sp. varied negatively with sex indirectly through condition and liver mass. Similarly, Hg concentrations also varied negatively with sex indirectly through condition and liver mass, with both Polymorphus sp. intensity and Hg concentrations significantly higher in males. We found that model fit increased when a negative relationship between the two helminth species was included, suggesting a yet unknown causal mechanism linking these parasites. Our findings suggest that although Hg and gastro-intestinal parasites are both trophically transmitted through the eider's prey items, the factors that contribute towards bioaccumulation of these two burdens differ in source, likely caused by several different factors and may potentially influence each other.

A population of mitochondrion-rich cells in the pars recta of mouse kidney.

Following perfusion of adult mouse kidney with a solution of nitroblue tetrazolium (NBT), certain epithelial cells in the pars recta (S3) segments of proximal tubules react to form cytoplasmic deposits of blue diformazan particles. Such cells are characterized by dark cytoplasm, small and often elliptical nuclei, elaborate, process-bearing profiles, and abundant mitochondria. The atypical epithelial cells display the additional characteristic of immunoreactivity for a wide spectrum of antigens, including mesenchymal proteins such as vimentin. Though present in kidneys of untreated or sham-operated animals, they are particularly evident under experimental conditions such as unilateral ureteral obstruction (UUO), appearing in both contralateral and obstructed kidneys over the course of a week's duration, but disappearing from the obstructed kidney as it undergoes the profound atrophy attributable to deterioration of the population of its proximal tubules. The cells do not appear in neonatal kidneys, even those undergoing UUO, but begin to be recognizable soon after weaning (28 days). It is possible that diformazan-positive cells in the mouse S3 tubular segment constitute a resident population of cells that can replenish or augment the tubule. Although somewhat similar cells, with dark cytoplasm and vimentin expression, have been described in human, rat, and transgenic mouse kidney (Smeets et al. in J Pathol 229: 645-659, 2013; Berger et al. in Proc Natl Acad Sci U S A 111: 1533-1538, 2014), those cells-known as "scattered tubule cells" or "proximal tubule rare cells"- differ from the S3-specific cells in that they are present throughout the entire proximal tubule, often lack a brush border, and have only a few mitochondria.