Male testosterone (T) decreases in response to childbirth. Longitudinal support for this has come from samples across cultures. In this study, we look at individual differences in this phenomenon. Utilizing a sample of U.S. fathers, we employ life history theory to investigate the influence of a father's early experience on his neuroendocrine response to fatherhood. We conducted three home visits (n = 226 fathers) from the third trimester of pregnancy to when infants were 10 months old. In this sample, T declined from the third trimester of (a partner's) pregnancy to the early months of the postnatal period. T recovered to pre-birth levels by the time infants reached 10 months old. We did not find any evidence that one's subjective experience of their early environment could account for any meaningful variability in T calibration. Objective, “event” measures of early harshness (i.e., death of a sibling/friend) and unpredictability (i.e., parent upheaval) each uniquely predicted a younger age of sexual debut. Neither harshness nor unpredictability had any (direct or indirect) effects on T calibration. Age of sexual debut did predict the rate of T recovery from 3 to 10 months postnatal. The younger one's sexual debut, the more accelerated their T ascent during this period. We discuss the potential reasons for, and implications of our mixed results.

The immense geologic and ecological complexity of the Caribbean has created a natural laboratory for interpreting when and how organisms disperse through time and space. However, competing hypotheses compounded with this complexity have resulted in a lack of unifying principles of biogeography for the region. Though new data concerning the timing of geologic events and dispersal events are emerging, powerful new analytical tools now allow for explicit hypothesis testing. Arthropods, with varying dispersal ability and high levels of endemism in the Caribbean, are an important, albeit understudied, biogeographic model system. Herein, we include a comprehensive analysis of every publicly available genetic dataset (at the time of writing) of terrestrial Caribbean arthropod groups using a statistically robust pipeline to explicitly test the current extent of biogeographic hypotheses for the region. Our findings indicate several important biogeographic generalizations for the region: the South American continent is the predominant origin of Caribbean arthropod fauna; GAARlandia played a role for some taxa in aiding dispersal from South America to the Greater Antilles; founder event dispersal explains the majority of dispersal events by terrestrial arthropods, and distance between landmasses is important for dispersal; most dispersal events occurred via island hopping; there is evidence of ‘reverse’ dispersal from islands to the mainland; dispersal across the present-day Isthmus of Panama generally occurred prior to 3 mya; the Greater Antilles harbor more lineage diversity than the Lesser Antilles, and the larger Greater Antilles typically have greater lineage diversity than the smaller islands; basal Caribbean taxa are primarily distributed in the Greater Antilles, the basal-most being from Cuba, and derived taxa are mostly distributed in the Lesser Antilles; Jamaican taxa are usually endemic and monophyletic. Given the diversity and deep history of terrestrial arthropods, incongruence of biogeographic patterns is expected, but focusing on both similarities and differences among divergent taxa with disparate life histories emphasizes the importance of particular qualities responsible for resulting diversification patterns. Furthermore, this study provides an analytical toolkit that can be used to guide researchers interested in answering questions pertaining to Caribbean biogeography using explicit hypothesis testing.

Similar to other types of neuronal degeneration, Parkinson’s disease (PD) is characterized by the aggregation of a pathological protein, α-synuclein. The endoplasmic reticulum (ER) is the principal site of protein synthesis, quality control and degradation. Genetic mutants, environmental insults and other factors disturb ER balance and induce the accumulation of misfolded/unfolded proteins, which initiate ER stress and disturb normal cell function. ER stress perturbs Ca2+ homeostasis and initiates the activation of autophagy and inflammasomes, which have been identified as risk factors for the development of PD. However, the mechanisms by which ER stress contributes to the processed of PD pathogenesis and development remain unclear. This review summarizes current knowledge of ER stress and highlights the principal role of ER stress in PD pathogenesis which may help reveal novel sight to illustrate the pathomechanism of PD.

Abstract Seasonality exerts strong pressures on biodiversity patterns. Yet, temporal beta-diversity is poorly studied in tropical systems, and the drivers of variability in amphibian activity and seasonality remain largely unknown. We quantified intra- and interannual variation in temporal beta-diversity relying on a nine-year, year-round survey (51 species, n > 23,000) performed in a protected area (Betampona, Madagascar). We assessed the dependence on climate of beta-diversity and abundance using a distance-based redundancy analysis and generalised linear mixed models, respectively. Despite the majority of species being preferentially active during one specific period, beta-diversity and abundance were more variable between years than within years. Temporal variation in beta-diversity was best explained by temperature (but climate accounted for only 2% of variation). Species abundance was best explained by temperature (for 32% of the tested species), monthly humidity (30%) and monthly rainfall (24%). We found no climatic dependence for 24% of the species. Our results suggest that studies focusing on species phenology can be misleading when based on single-year surveys even in seasonal systems. The high interannual variability in diversity may be due to an adaptive responses to an important regime of stochastic events. Given the direction of the relationships between weather and abundances, we predict that a large proportion of amphibians would suffer from climate change in Madagascar. We emphasise the need to account for multiple temporal scales in studies of tropical species composition and abundance to better understand species phenology and their response to climate change, and make targeted conservation actions more effective.

Abstract Miocene, Pliocene and Pleistocene changes to the geomorphology, climate and vegetation of southern Africa are considered responsible for radical differences between southwest and northeast dung beetle assemblages (Coleoptera: Scarabaeidae: Scarabaeinae) leading to current endemism in Namibia, Botswana and South Africa. This bias is supported by distributional analysis of 437 species across vegetation regions and 2° × 2° squares of latitude and longitude using non-metric multidimensional scaling (NMDS) and minimum spanning trees (MST). The ordinal values for six NMDS dimensions showed significant correlations with annual rainfall, annual temperature, rainfall seasonality and altitude. Significant climatic differences were also shown between six regional centres defined and modelled for the subcontinent: winter/bimodal rainfall, southwest arid, southeast highlands, savanna, sandy savanna and east coast. Twenty-one, principal, subregional centres defined from further NMDS and MST analyses of regional data showed significant intra-regional differences in climatic attributes although published data suggest that soil, vegetation and dung type associations were frequent additional influences. Species showing the smallest ranges were centred primarily around the coast and bordering escarpments, which coincide with regions and subregions showing unique environmental conditions characterized by many endemic genera and species. Published land use data indicate that large parts of these regions are highly transformed or degraded, so that some species are facing strong current threats. Furthermore, published global climatic change data suggest that many endemic species could be further threatened, especially to the southwest where the late Cenozoic trend to unique climatic and environmental conditions could, potentially, be reversed in the future.

Abstract Grasslands and grassy woodlands worldwide have experienced declines in extent and condition, with substantial changes to their ground-layer biodiversity. In Australia, this decline has coincided with the extinction of many digging mammals that may have once created regeneration niches for native ground layer plants. These digging mammals are widely recognised as ‘ecosystem engineers’, due to their influence on biopedturbation and resultant soil functions. Yet there is uncertainty as to the benefits of digging in restoring grassland diversity with current levels of modification and the presence of exotic plants. We investigated the effect of digging by the reintroduced eastern bettong (Bettongia gaimardi) on seedling germination in a temperate grassy woodland in south-eastern Australia. We marked fresh bettong foraging pits and undisturbed control plots in dense and open grassland. We added seeds of seven native forb species and monitored germination and establishment over 2 years. We found significantly more seedlings in bettong pits than controls, particularly in dense grassland. This effect persisted beyond 1 year, suggesting that pits may have increased seedling survival in dry conditions. Surprisingly, native species displayed a stronger positive response to pits than exotic species, particularly in a wet year. There was an initial reduction in exotic species, but this was followed by their increase in 1-year-old pits, suggesting that the disturbance created by digging could eventually lead to an increase in weed abundance. Our results demonstrate that while bettong pits provide a germination niche for native forbs, reintroducing digging animals will not necessarily result in the desired restoration outcomes. Ongoing persistence of exotic species is to be expected, and seed addition may be required for species that are seed-limited.

Abstract Although it is well known that the increasing size of the human population has a negative effect on freshwater biodiversity, the subject of whether or how the intersection of roads and streams (hereafter road crossings) influence the diversity of stream macro-invertebrates is under-researched. To fill this gap in our knowledge, we collected stream macro-invertebrates from road crossings (bridges and culverts) and compared their diversity with upstream and downstream sections. We found that road crossings had negative effects on the richness and abundance of native macro-invertebrates, as well as on the number of protected taxa. Our results showed also that alien individuals were more abundant at road crossings. These findings support the assumption that road crossings contribute to the spread of alien species. The assessment of environmental variables indicated that road crossings caused habitat modifications, and based on these it can be assumed that habitat modifications and associated phenomena (e.g. pollutants and storm events) were the major drivers of the observed patterns in biodiversity. Our results fill a knowledge gap and contribute to the deeper understanding of the effect of road crossings on freshwater biodiversity.

Abstract Fossorial rodents are recognized as diversity drivers in grassland ecosystems and are therefore considered ecosystem engineers and keystone species. However, there is a lack of evidence regarding this function for species in temperate grasslands, especially one of the most threatened, the European ground squirrel. We examined the effect of the European ground squirrel on plant species composition and diversity along the disturbance gradient mediated by their different population density and subsequently different disturbance intensity. We evaluated the effect of ground squirrel disturbance on plant diversity patterns in two plant communities with different species richness to determine whether the same pattern exists in contrasting habitats. In each plant community, we established transect of 25 × 250 m composed of 10 quadrats with different disturbance intensities of the ground squirrels. Vascular plant species were recorded in 320 plots of 1 m2. The distribution of individual species along the ground squirrel-mediated disturbance gradient was analysed using redundancy analysis. Diversity measures were calculated and modelled as a function of disturbances using generalized additive models. We observed significant compositional changes in plant communities accompanied by a reduction in dominant graminoid cover and a non-decreasing trend in forb cover along the disturbance gradient in both types of communities. We found that increasing disturbance activity leads to an increase in diversity at coarse spatial scale (625 m2) and spatial heterogeneity in species composition of both species-poor and species-rich plant community. The fine-scale (1 m2) diversity increased significantly only in species-poor community. Our results demonstrate that the European ground squirrel can be deservedly labelled as an important ecosystem engineer and keystone species promoting the diversity and heterogeneity of European temperate grasslands.

Abstract Spring ecosystems are exceptionally threatened and their conservation is often emphasized due to high levels of endemism among the groups inhabiting these ecosystems. This study includes gastropod assemblages of 36 springs situated in the northwestern part of Bosnia and Herzegovina. The aims of this paper were: to determine key factors for distribution of gastropod species on microspatial scale; to define the environmental preferences of gastropod species with respect to the physicochemical properties of water, the hydrological characteristics and the sediment structure; to determine species tolerance ranges and species optimums, with special emphasis on new and endemic species. Moreover the aim was to identify the species with highest extinction risk. The contribution of endangered and rare species to the total density was extremely high (64.6%). Species Response Curves were used to predict the distribution of gastropod species along the environmental gradient in the spring environments for the first time. The most important factors in structuring gastropod spring assemblages were oxygen and temperature. HOF (Huisman–Olff–Fresco) models may determine differences in range of environmental tolerance of species with similar ecological requirements. Our results have shown that two species: Ancylus fluviatilis and A. recurvus may be distinguished by their species response curves. Although there are no data on conservation status of A. recurvus, the extinction risk should be inferred as high, suggesting that IUCN status for this species should be updated to the category Vulnerable. Our study using HOF models revealed the potential gastropod species useful as indicators of karstic springs.

Abstract This paper reports the results of a survey carried out in the Foggia province (Puglia Region, Italy) with the aims of: (1) assessing the level of diversity and distribution of the on-farm vegetable landraces, (2) identifying vegetable landrace-rich areas, and (3) analysing the main agro-ecological, socio-economic factors affecting their maintenance. Several territorial surveys were performed over four years and a total of 163 vegetable crop landraces were found at 52 sites, mostly cultivated on small farms or home gardens by elderly farmers. The surveyed landraces belong to nine botanical families and 34 species, with the highest number for Solanaceae, Cucurbitaceae, Brassicaceae, Liliaceae and Leguminosae. The diversity status of the landraces was evaluated by adopting a landscape scale approach considering the provincial landscape types (LT) (3) and, within each LT, the landscape units (LU) accounting for the incidence of high-productive and marginal agricultural systems and of natural/seminatural systems. Principal component analysis clearly separated one landscape unit for each LT for their higher abundance of landraces and higher diversity, richness and evenness of species. These LUs are characterized by high-ecological and agricultural marginal land where the low fertility of soil seems conducive to landraces maintenance. Additionally, the preservation of vegetable diversity may be linked to the distance of the surveyed sites from the most important urban centres along with the commitment of local people and/or tourists to traditional products and their related cultural aspects.

Abstract Ruderal plant species typically occur and prevail in frequently disturbed areas especially in sites with pronounced direct or indirect human activity. In Greece ruderal taxa (both exclusive and non-exclusive) account for 23.9% of all recorded plant taxa. This study presents an analysis of the ruderal plant diversity patterns in the 13 floristic regions of Greece and different aspects of ruderal diversity related to alien taxa and to taxa of conservation interest. Although many ruderal plant taxa are common and widespread, their contribution to the diversity of each floristic region ranges between 27.8% in the North Central and 41.6% in the Cyclades region. Spatial distribution analysis revealed that the ruderal flora presents higher frequency of occurrence in major urban areas, in coastal and low to medium elevation mainland and island areas. The total number of ruderal taxa per floristic region is strongly correlated with the total number of taxa per region. The richness in exclusive ruderal taxa is highly correlated with surface area proportions of settlements and other built-up areas, as well as with artificial land, wetlands, sparsely vegetated land and shrublands. Ruderals account for a greater proportion of taxa in species-poor regions than in species-rich ones. Patterns of ruderal taxa diversity proved to be rather complicated and different spatial scales must be considered if ruderal biodiversity of the cultural landscapes in Greece is to be preserved.

Abstract Understanding the drivers of species’ geographic distribution and assembly of communities is one of the most intriguing questions in ecology and has become extremely important in face of global changes. This study aims to assess broad-scale patterns of tree species diversity and compare the importance of environmental correlates relative to purely spatial factors in structuring communities in the Brazilian Atlantic Forest. We compiled abundance data from 2948 species in 117 localities across the entire biome and obtained climatic and soil variables that we hypothesized to be environmental filters. We constructed correlograms for species richness and composition and assessed the relative importance of correlates using spatially explicit generalized additive models coupled with information-theoretic analyses. Variation partitioning was used to infer the relative importance of environmental- and spatial-based hypotheses. Species richness presented positive spatial correlation of ~ 435 km beyond which it became negative and again positive at the furthest distances, whereas compositional turnover showed positive correlation of ~ 435–555 km with decreasing similarity in increasing distances. Climatic variables were important factors correlating with richness patterns, with soil being less important. Species composition was significantly correlated with environmental variables and spatial constraints. The spatial component showed similar amount of explanation in statistical models compared to the environmental component. Our results suggest a combined contribution of environment, stochasticity, and historical-dispersion processes in patterns of biodiversity. More interestingly, a similar set of variables was the better correlates of species richness and composition, indicating convergence of driving factors for both descriptors of plant communities.

Abstract Based on data from three surveys of the vascular flora of the province of Scania, southernmost Sweden, conducted 1938–1971, 1987–2006 and 2008–2015, we analyse the change in frequency of individual species and groups of species associated with particular vegetation types. A majority of all species have experienced a change in frequency since 1938, and this turnover has continued in recent decades. The species showing the most dramatic declines since 1987 represent a mixture of arable weeds, grassland species and ruderals, but excludes forest species. In contrast, a majority of the most increasing species are escapes from cultivation that thrive under shaded conditions. The vegetation types showing the largest decreases since 1987 are all open seminatural grasslands and wetlands, while the vegetation types performing best are wooded. All vegetation types increasing since 1987 also increased during the 1900s; however, species of wooded types performed relatively better in recent decades, as opposed to the minimal increase observed for species of vegetation strongly influenced by human activities. Among decreasing vegetation types, those that have received much attention from conservationists, e.g. sand-steppe and calcareous fens tend to perform relatively better now than during the 1900s, while those that have received less attention, e.g. poor fens, oligotrophic waters and heaths, now comprise the most rapidly declining vegetation types. A majority of the species that decreased 1938–1996 also decreased 1987–2015, but, in general, species shown to have increased during the 1900s have not continued to increase.

The emergence of novel diseases represents a major hurdle for the recovery of endangered populations, and in some cases may even present the threat of extinction. In recent years, epizootics of infectious diseases have emerged as a major threat to marine mammal populations, particularly group-living odontocetes. However, little research has explored the potential consequences of novel pathogens in endangered cetacean populations. Here, we present the first study predicting the spread of infectious disease over the social network of an entire free-ranging cetacean population, the southern resident killer whale community (SRKW). Utilizing 5 years of detailed data on close contacts between individuals, we build a fine-scale social network describing potential transmission pathways in this population. We then simulate the spread of cetacean morbillivirus (CeMV) over this network. Our analysis suggests that the SRKW population is highly vulnerable to CeMV. The majority of simulations resulted in unusual mortality events (UMEs), with mortality rates predicted to be at least twice the recorded maximum annual mortality. We find only limited evidence that this population's social structure inhibits disease spread. Vaccination is not likely to be an efficient strategy for reducing the likelihood of UMEs, with over 40 vaccinated individuals (>50% of the population) required to reduce the likelihood of UMEs below 5%. This analysis highlights the importance of modelling efforts in designing strategies to mitigate disease, and suggests that populations with strong social preferences and distinct social units may still be highly vulnerable to disease outbreaks.

The environmental light changing, such as light spectrum (LS), influences the balance of energy metabolism and sex allocation based on plant species. However, the molecular mechanism underlying systems energy responses (SERs) linked to sex differentiation of Drynaria roosii gametophytes in response to LS remains the enigma. Here, we used Red-LED-Light (RLL), Blue-LED-Light (BLL) and Fluorescent-Light (FL) regimes to treat D. roosii gametophytes to achieve the knowledge of global expression database. Compared with FL, transcriptional changes showed that RLL reduced mRNA levels of photosynthetic genes and improved mRNA levels of respiratory genes. Obviously, RLL decreased PSII/PSI activities with lower Y(II), Fv/Fm, Y(I) and ETR(I) values, and promoted mitochondria activity with higher respiratory rate. Combined with severer ROS stress, we suggested that RLL caused the energy deficit to gametophytes. However, the impacts of BLL were contrary to RLL. Exactly, 63.75% of males was induced under RLL vs 12.70% under FL, whilst 64.50% of females under BLL vs 48.08% under FL. Moreover, we applied the WGCNA to cluster LS-induced DEGs into eleven modules, and DEGs in five significant sample-specific modules mainly fell in energy metabolism categorization through KEGG pathway analysis. Networks proved the complicated ‘cross-talk’ between SER- and TF-associated genes, and revealed hub genes in response to LS. Based on previous experimental evidence, we supposed a link between LS-induced energy metabolism responses and sex differentiation in D. roosii gametophytes, showing that RLL contributed to male-biased sex ratios for less energy production than BLL and FL, while BLL contributed to a female-biased trend. Our work firstly shed light on SERs to LS in D. roosii gametophytes, and provided new insights for understanding the sex differentiation in ferns.

Assessing the impact of increasing carbon dioxide (CO2) on nutrient cycling requires understanding of the relationship between the concentration of CO2 and litter dynamics. It is, therefore necessary to understand leaf litter traits in response to increased atmospheric CO2. Variations in plant litter chemistry under elevated carbon dioxide (e-CO2) are the critical factors in ecosystem feedback. Litter fall, litter substrate quality, nutrient flux and decay rate in two tropical tree of Tectona grandis (Teak) and Butea monosperma (Butea) were examined. Saplings were exposed to elevated CO2 treatment (e-CO2 -550 ppm) and ambient CO2 (a-CO2; - 395 ppm) in the FACE (Free air CO2 enrichment) facility in CSIR- National Botanical Research Institute in Indo-Gangetic plain region. Litter was analysed for concentrations of carbon (C), nitrogen (N), soluble sugars (SS), lipids, lignin, cellulose, hemi-cellulose (HC) and C-based defensive compounds; soluble phenolics (SP). Nutrient concentration in naturally senesced litter for Butea and Teak was significantly different in elevated and ambient rings. Elevated CO2 significantly increased C/N (+8.27% and +21.94%), lowered mean litter N concentration (–3.27% and -12.15%), and affected the concentrations of soluble sugars, soluble phenolic and lipids in leaf litter of Butea and Teak plantations, respectively. Increase in litter biomass production (+19.75% and 22.84%) for both the plants under e-CO2, resulted in significant increase in the flux of N, SS, SP and lipid in to the soil. Elevated CO2 increased cellulose (+18.21%; 12.30%), hemicellulose (+8.48%; +10.18%) and lignin inputs to soils (+35.22; +43.36%) in Butea and Teak plantation respectively. The study indicated that changes in litter biomass production and litter substrate quality during exposure to e-CO2 could significantly alter the input of nitrogen, soluble phenolic, soluble sugars, lipids, cellulose, and lignin to soils, and so also the biogeochemical cycle of the prevailing ecosystem.

Plants under combined stresses exhibit a prominent shift in molecular responses compared with plants exposed to the same stresses independently. Profiling responses to individual and combined stressors at the gene expression level have identified several genes with intersecting responses to these stressors. However, the upstream regulators at the intersection of plant responses to individual and combined stresses are not known. Here, using the transcriptome of Arabidopsis thaliana under individual and combined drought and Pseudomonas syringae infection, we identified several genes whose expression overlaps between individual and combined stresses. To study the key regulator of such an overlapping gene, we predicted that the expression of 1-Pyrroline-5-carboxylate synthase 1 (AtP5CS1) is regulated by ath-miR164c at post-transcriptional level. Our results from the stem-loop RT-PCR based expression analysis revealed significant downregulation of ath-miR164c in response to P. syringae infection under both well-irrigated (pathogen only) and drought stress (combined stress) conditions. Furthermore, an Arabidopsis loss-of-function mutant of the miRNA ath-miR164c exhibited resistance to pathogen infection under combined stress, unlike the wild-type plants, implicating the role of ath-miR164c in regulating plant immunity. AtP5CS1 gene expression and proline accumulation were enhanced in the ath-miR164c mutant plants relative to the wild-type plants, demonstrating that ath-miR164c regulates AtP5CS1 of the proline biosynthesis pathway, which was also validated by 5’RLM-RACE results. This miRNA-mediated modulation of AtP5CS1 gene expression under combined stress fills crucial gaps in identifying the key convergent players in the current understanding of plant stress responses.

Rising atmospheric CO2 concentrations and global warming can alter how plants partition their resources. This is important for food crops through changes in resource allocation to edible tissues and toxic defence compounds. While research suggests elevated temperature and [CO2] independently drive changes in plant metabolism and stress levels, and photosynthetic rates, respectively, it is less clear how these environmental changes impact plants when combined. Cassava is an important dietary staple for many developing nations. However, the safety of cassava depends on cyanogenic glucoside concentrations. In a climate-controlled greenhouse, the effects of elevated temperature in the presence and absence of elevated [CO2] on the growth, physiology and chemical defence of cassava at two growth stages were examined. Growth in cassava was initially increased by elevated temperature. However, across time, simultaneous elevated [CO2] led to an increasing biomass advantage over plants grown at ambient [CO2]. Elevated temperature and [CO2] significantly increased tuber initiation and early tuber expansion. Tuber and leaf cyanide concentrations were significantly reduced under elevated temperature, while elevated temperature and [CO2] produced tuber cyanide concentrations similar to the higher levels found in plants grown at ambient conditions. The findings highlight how future climate change may impact cassava production and quality.

Background Redirecting glucose from skeletal muscle and adipose tissue, likely benefits the tumor’s energy demand to support tumor growth, as cancer patients with type 2 diabetes have 30% increased mortality rates. The aim of this study was to elucidate tissue-specific contributions and molecular mechanisms underlying cancer-induced metabolic perturbations. Methods Glucose uptake in skeletal muscle and white adipose tissue (WAT), as well as hepatic glucose production, were determined in control and Lewis lung carcinoma (LLC) tumor-bearing C57BL/6 mice using isotopic tracers. Skeletal muscle microvascular perfusion was analyzed via a real-time contrast-enhanced ultrasound technique. Finally, the role of fatty acid turnover on glycemic control was determined by treating tumor-bearing insulin-resistant mice with nicotinic acid or etomoxir. Results LLC tumor-bearing mice displayed reduced insulin-induced blood-glucose-lowering and glucose intolerance, which was restored by etomoxir or nicotinic acid. Insulin-stimulated glucose uptake was 30-40% reduced in skeletal muscle and WAT of mice carrying large tumors. Despite compromised glucose uptake, tumor-bearing mice displayed upregulated insulin-stimulated phosphorylation of TBC1D4Thr642 (+18%), AKTSer474 (+65%), and AKTThr309 (+86%) in muscle. Insulin caused a 70% increase in muscle microvascular perfusion in control mice, which was abolished in tumor-bearing mice. Additionally, tumor-bearing mice displayed increased (+45%) basal (not insulin-stimulated) hepatic glucose production. Conclusions Cancer can result in marked perturbations on at least six metabolically essential functions; i) insulin’s blood-glucose-lowering effect, ii) glucose tolerance, iii) skeletal muscle and WAT insulin-stimulated glucose uptake, iv) intramyocellular insulin signaling, v) muscle microvascular perfusion, and vi) basal hepatic glucose production in mice. The mechanism causing cancer-induced insulin resistance may relate to fatty acid metabolism.

Phenylketonuria (PKU) is a rare autosomal recessive condition affecting about 1 in 10,000 people in the Europe, with a higher rate in some countries, like Ireland and Italy. In Italy, newborn screening (NBS) by MS/MS allows the diagnostic suspicion of PKU and its variants (Hyperphenylalaninemia (HPA), Tetrahydrobiopterin (BH4) synthesis deficiency, and Tetrahydrobiopterin (BH4) recycling deficiency) through the quantification of Phenylalanine (Phe) and the Phenylalanine/Tyrosine (Phe/Tyr) ratio in dried blood Spot (DBS) samples. Here, we report a case of an HPA whose suspicion was possible with expanded NBS, even if the normal-weight newborn was in total parenteral nutrition (TPN). It is known that TPN may present metabolic alterations, mainly for amino acids at NBS in MS/MS, frequently causing false positives. Actually, TPN is considered a special protocol in NBS, requiring several sample collections. In particular, a DBS sample is required before TPN, at basal time point (48 h after birth) and 72 h after the end of the procedure. In the case we report, even if the first DBS sample (before TPN) resulted negative, the repeated NBS tests revealed increased levels of Phe and dramatically high Phe/Tyr ratio. Thus, the newborn was recalled, and the NBS test was repeated several times before that HPA suspicion was confirmed by other specific biochemical tests. This case highlights the importance of Phe/Tyr ratio, only detectable by MS/MS analysis, in supporting the diagnostic suspicion during amino acids administration in the neonatal period.

Cryptosporidiosis is a significant diarrhoeal disease in both people and animals across the world and is caused by several species of the protozoan parasite Cryptosporidium. Recent research has highlighted the longer-term consequences of the disease for malnourished children, involving growth stunting and cognitive deficits, and significant growth and production losses for livestock. There are no vaccines currently available to prevent the disease and few treatment options in either humans or animals, which has been a significant limiting factor in disease control to date. A One Health approach to tackle zoonotic cryptosporidiosis looking at new advances in veterinary, public, and environmental health research may offer several advantages and new options to help control the disease.

Polarization‐resolved second‐harmonic generation (P‐SHG) microscopy is a technique capable of characterizing nonlinear optical properties of non‐centrosymmetric biomaterials by extracting the nonlinear susceptibility tensor components ratio , with z‐axis parallel and x‐axis perpendicular to the C6 symmetry axis of molecular fiber, such as a myofibril or a collagen fiber. In this paper, we present two P‐SHG techniques based on incoming and outgoing circular polarization states for a fast extraction of : A dual‐shot configuration where the SHG circular anisotropy generated using incident right‐ and left‐handed circularly‐polarized light is measured; and a single‐shot configuration for which the SHG circular anisotropy is measured using only one incident circular polarization state. These techniques are used to extract the of myosin fibrils in the body wall muscles of Drosophila melanogaster larva. The results are in good agreement with values obtained from the double Stokes‐Mueller polarimetry. The dual‐ and single‐shot circular anisotropy measurements can be used for fast imaging that is independent of the in‐plane orientation of the sample. They can be used for imaging of contracting muscles, or for high throughput imaging of large sample areas.

Hair follicles (HF) represent a drug delivery reservoir for improved treatment of skin disorders. Although various particulate systems play an important role in HF‐targeting, their optical monitoring in skin is challenging due to strong light scattering. Optical clearing is an effective approach allowing the increasing of particle detection depth in skin. The enhancement of optical probing depth (OPD) and optical detection depth (ODD) of particle localization using optical coherence tomography (OCT) was evaluated under application of various optical clearing agents (OCAs) together with skin permeability enhancers ex vivo in rats. Efficient OPD increasing was demonstrated for all investigated OCAs. However, skin dehydration under action of hyperosmotic agents led to the worsening of OCT‐contrast in dermis decreasing the ODD. Lipophilic agents provided optical clearing of epidermis without its dehydration. The highest ODD was obtained at application of a PEG‐400/oleic acid mixture. This OCA was tested in vivo showing beneficial ODD and OPD enhancement.

Many populations of freshwater fishes are threatened with losses, and increasingly, the release of hatchery individuals is one strategy being implemented to support wild populations. However, stocking of hatchery individuals may pose long‐term threats to wild populations, particularly if genetic interactions occur between wild and hatchery individuals. One highly prized sport fish that has been heavily stocked throughout its range is the brook trout (Salvelinus fontinalis). In Nova Scotia, Canada, hatchery brook trout have been stocked since the early 1900s, and despite continued stocking efforts, populations have suffered declines in recent decades. Before this study, the genetic structure of brook trout populations in the province was unknown; however, given the potential negative consequences associated with hatchery stocking, it is possible that hatchery programs have adversely affected the genetic integrity of wild populations. To assess the influence of hatchery supplementation on wild populations, we genotyped wild brook trout from 12 river systems and hatchery brook trout from two major hatcheries using 100 microsatellite loci. Genetic analyses of wild trout revealed extensive population genetic structure among and within river systems and significant isolation‐by‐distance. Hatchery stocks were genetically distinct from wild populations, and most populations showed limited to no evidence of hatchery introgression (<5% hatchery ancestry). Only a single location had a substantial number of hatchery‐derived trout and was located in the only river where a local strain is used for supplementation. The amount of hatchery stocking within a watershed did not influence the level of hatchery introgression. Neutral genetic structure of wild populations was influenced by geography with some influence of climate and stocking indices. Overall, our study suggests that long‐term stocking has not significantly affected the genetic integrity of wild trout populations, highlighting the variable outcomes of stocking and the need to evaluate the consequences on a case‐by‐case basis.

The variance in phenotypic trait values is a product of environmental and genetic variation. The sensitivity of traits to environmental variation has a genetic component and is likely to be under selection. However, there are few studies investigating the evolution of this sensitivity, in part due to the challenges of estimating the environmental variance. The livestock literature provides a wealth of studies that accurately partition components of phenotypic variance, including the environmental variance, in well‐defined environments. These studies involve breeds that have been under strong selection on mean phenotype in optimal environments for many generations, and therefore represent an opportunity to study the potential evolution of trait sensitivity to environmental conditions. Here we use literature on domestic cattle to examine the evolution of micro‐environmental variance (CVR – the coefficient of residual variance) by testing for differences in expression of CVR in animals from the same breed reared in different environments. Traits that have been under strong selection did not follow a null‐expectation of an increase in CVR in heterogenous environments (e.g. grazing), a pattern that may reflect evolution of increased uniformity in heterogeneous environments. When comparing CVR across environments of different levels of optimality, here measured by trait mean, we found a reduction in CVR in the more optimal environments for both life‐history and growth traits. Selection aimed at increasing trait means in livestock breeds typically occurs in the more optimal environments, and we therefore suspect that the decreased CVR is a consequence of evolution of the expression of micro‐environmental variance in this environment. Our results highlight the heterogeneity in micro‐environmental variance across environments and point to possible connections to the intensity of selection on trait means.

The resiliency of populations and species to environmental change is dependent on the maintenance of genetic diversity, and as such quantifying diversity is central to combatting ongoing wide spread reductions in biodiversity. With the advent of next‐generation sequencing, several methods now exist for resolving fine‐scale population structure, but the comparative performance of these methods for genetic assignment has rarely been tested. Here we evaluate the performance of sequenced microsatellites and a single nucleotide polymorphism (SNP) array to resolve fine‐scale population structure in a critically important salmonid in northeastern Canada, Arctic charr (Salvelinus alpinus). We also assess the utility of sequenced microsatellites for fisheries applications by quantifying the spatial scales of movement and exploitation through genetic assignment of fishery samples to rivers of origin and comparing these results with a 29‐year tagging dataset. Self‐assignment and simulation‐based analyses of 111 genome‐wide microsatellite loci and 500 informative SNPs from 28 populations of Arctic charr in northeastern Canada identified largely river‐specific genetic structure. Despite large differences (~4X) in the number of loci surveyed between panels, mean self‐assignment accuracy was similar with the SNP panel and with the microsatellite loci (>90%). Subsequent analysis of 996 fishery‐collected samples using the microsatellite panel revealed that larger rivers contribute greater numbers of individuals to the fishery, and that coastal fisheries largely exploit individuals originating from nearby rivers, corroborating results from traditional tagging experiments. Our results demonstrate the efficacy of sequence‐based microsatellite genotyping to advance understanding of fine‐scale population structure and harvest composition in northern and understudied species.

Abstract Introduction Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder. Hyperandrogenism (HA) and insulin resistance (IR) are two important pathogenic factors. Objective We aimed to investigate the inherent disturbed metabolic profiles for women with HA or IR in PCOS as well as discover diagnostic biomarkers. Methods A total of 286 subjects were recruited for the study. They constituted the following groups: healthy women (C), those with HA (B1), those with IR but not obese (B2) and obese women with IR (B3) in PCOS. Nine cross-comparisons with PCOS were performed to characterize metabolic disturbances. Serum metabolomic profiles were determined by gas chromatography–mass spectrometry. Results and conclusion We found a total of 59 differential metabolites. 28 metabolites for B1 vs C, 32 for B2 vs C and 25 for B3 vs C were discovered. Among them, palmitic acid, cholesterol, myo-inositol, d-allose, 1,5-anhydro-d-sorbitol, 1-monopalmitin, 1-monostearin, glycerol 1-phosphate, malic acid and citric acid, were the common differential metabolites among B1 vs C, B2 vs C and B3 vs C, which related to biosynthesis of unsaturated fatty acids, citrate cycle etc. Besides, 9-biomarker panel can diagnose well between HA and IR in PCOS. They provided areas under the receiver operating characteristic curve of 0.8511 to 1.000 in the discovery phase, and predictive values of 90% to 92% in the validation set. The result indicated that the differential metabolites can reflect the underlying mechanism of PCOS and serve as biomarkers for complementary diagnosis of HA and IR in PCOS.

Abstract Introduction The metabolic shift induced by hypoxia in cancer cells has not been explored at volatilomic level so far. The volatile organic metabolites (VOMs) constitute an important part of the metabolome and their investigation could provide us crucial aspects of hypoxia driven metabolic reconfiguration in cancer cells. Objective To identify the altered volatilomic response induced by hypoxia in metastatic/aggressive breast cancer (BC) cells. Methods BC cells were cultured under normoxic and hypoxic conditions and VOMs were extracted using HS-SPME approach and profiled by standard GC–MS system. Univariate and multivariate statistical approaches (p < 0.05, Log2 FC ≥ 0.58/≤ − 0.58, PC1 > 0.13/< − 0.13) were applied to select the VOMs differentially altered after hypoxic treatment. Metabolic pathway analysis was also carried out in order to identify altered metabolic pathways induced by the hypoxia in the selected BC cells. Results Overall, 20 VOMs were found to be significantly altered (p < 0.05, PC1 > 0.13/< − 0.13) upon hypoxic exposure to BC cells. Further, cell line specific volatilomic alterations were extracted by comparative metabolic analysis of aggressive (MDA-MB-231) vs. non-aggressive (MCF-7) cells incubated under hypoxia and normoxia. In this case, 15 and 12 VOMs each were found to be significantly altered in aggressive cells when exposed to hypoxic and normoxic condition respectively. Out of these, 9 VOMs were found to be uniquely associated with hypoxia, 6 were specific to normoxia and 6 were found common to both the conditions. Formic acid was identified as the most prominent molecule with higher abundance levels in aggressive as compared to non-aggressive cells in both conditions. Furthermore, metabolic pathway analyses revealed that fatty acid biosynthesis and nicotinate and nicotinamide metabolism were significantly altered in aggressive as compared to non-aggressive cells in normoxia and hypoxia respectively. Conclusions Higher formate overflow was observed in aggressive cells compared to non-aggressive cells incubated under both the conditions, reinforcing its correlation with aggressive and invasive cancer type. Moreover, under hypoxia, aggressive cells preferred to be bioenergetically more efficient whereas, under normoxia, fatty acid biosynthesis was favoured when compared to non-aggressive cells. Graphic Abstract

Abstract Introduction Preterm birth (PTB) is defined as birth occurring before 37 weeks’ gestation, affects 5–9% of all pregnancies in developed countries, and is the leading cause of perinatal mortality. Spontaneous preterm birth (sPTB) accounts for 31–50% of all PTB, but the underlying pathophysiology is poorly understood. Objective This study aimed to decipher the lipidomics pathways involved in pathophysiology of sPTB. Methods Blood samples were taken from SCreening fOr Pregnancy Endpoints (SCOPE), an international study that recruited 5628 nulliparous women, with a singleton low-risk pregnancy. Our analysis focused on plasma from SCOPE in Cork. Discovery profiling of the samples was undertaken using liquid chromatography-mass spectrometry Lipidomics, and features significantly altered between sPTB (n = 16) and Control (n = 32) groups were identified using empirical Bayes testing, adjusting for multiple comparisons. Results Twenty-six lipids showed lower levels in plasma of sPTB compared to controls (adjusted p < 0.05), including 20 glycerophospholipids (12 phosphatidylcholines, 7 phosphatidylethanolamines, 1 phosphatidylinositol) and 6 sphingolipids (2 ceramides and 4 sphingomyelines). In addition, a diaglyceride, DG (34:4), was detected in higher levels in sPTB compared to controls. Conclusions We report reduced levels of plasma phospholipids in sPTB. Phospholipid integrity is linked to biological membrane stability and inflammation, while storage and breakdown of lipids have previously been implicated in pregnancy complications. The contribution of phospholipids to sPTB as a cause or effect is still unclear; however, our results of differential plasma phospholipid expression represent another step in advancing our understanding of the aetiology of sPTB. Further work is needed to validate these findings in independent pregnancy cohorts.

Nitrous oxide (N2O) is an air pollutant of major environmental concern, with agriculture representing 60% of anthropogenic global N2O emissions. Much of the N2O emissions from livestock production systems result from transformation of N deposited to soil within animal excreta. There exists a substantial body of literature on urine patch N2O dynamics, we aimed to identify key controlling factors influencing N2O emissions and to aid understanding of knowledge gaps to improve GHG reporting and prioritise future research. We conducted an extensive literature review and random effect meta‐analysis (using REML) of results to identify key relationships between multiple potential independent factors and global N2O emissions factors (EFs) from urine patches. Mean air temperature, soil pH and ruminant animal species (sheep or cow) were significant factors influencing the EFs reviewed. However, several factors that are known to influence N2O emissions, such as animal diet and urine composition, could not be considered due to the lack of reported data. The review highlighted a widespread tendency for inadequate metadata and uncertainty reporting in the published studies, as well as the limited geographical extent of investigations, which are more often conducted in temperate regions thus far. Therefore, here we give recommendations for factors that are likely to affect the EFs and should be included in all future studies, these include: soil pH and texture; experimental set‐up; direct measurement of soil moisture and temperature during the study period; amount and composition of urine applied; animal type and diet; N2O emissions with a measure of uncertainty; data from a control with zero‐N application and meteorological data.

In plants and green algae, light-harvesting complexes (LHCs) are a large family of chlorophyll binding proteins functioning as antennae, collecting solar photons and transferring the absorbed energy to the photosynthetic reaction centers, where light to chemical energy conversion begins. Although LHCs are all highly homologous in their structure and display a variety of common features, each complex finds a specific location and task in the energy transport. One example is CP29, which occupies a pivotal position in Photosystem II, bridging the peripheral antennae to the core. The design principles behind this specificity, however, are still unclear. Here, a synergetic approach combining steady-state and ultrafast spectroscopy, mutational analysis and structure-based exciton modeling allows uncovering the energy landscape of the chlorophylls bound to this complex. We found that, although displaying an overall highly conserved exciton structure very similar to that of other LHCs, CP29 possesses an additional terminal emitter domain. The simultaneous presence of two low energy sites facing the peripheral antennae and the core, allows CP29 to efficiently work as a conduit in the energy flux. Our results show that the LHCs share a common solid architecture but have finely tuned their structure to carry out specific functions.

Recent analyses of genomic sequence data suggest cross-species gene flow is common in both plants and animals, posing challenges to species tree estimation. We examine the levels of gene flow needed to mislead species tree estimation with three species and either episodic introgressive hybridization or continuous migration between an outgroup and one ingroup species. Several species tree estimation methods are examined, including the majority-vote method based on the most common gene tree topology (with either the true or reconstructed gene trees used), the UPGMA method based on the average sequence distances (or average coalescent times) between species, and the full-likelihood method based on multi-locus sequence data. Our results suggest that the majority-vote method based on gene tree topologies is more robust to gene flow than the UPGMA method based on coalescent times and both are more robust than likelihood assuming a multispecies coalescent (MSC) model with no cross-species gene flow. Comparison of the continuous migration model with the episodic introgression model suggests that a small amount of gene flow per generation can cause drastic changes to the genetic history of the species and mislead species tree methods, especially if the species diverged through radiative speciation events. Estimates of parameters under the MSC with gene flow suggest that African mosquito species in the Anopheles gambia species complex constitute such an example of extreme impact of gene flow on species phylogeny.

MotivationGene sets over-representation analysis (GSOA) is a common technique of enrichment analysis that measures the overlap between a gene set and selected instances (e.g., pathways). Despite its popularity, there is currently no established standard for visualisation of GSOA results. ResultsHere, we propose a visual exploration of the GSOA results by showing the relationships among the enriched instances; while highlighting important instance attributes, such as significance, closeness (centrality) and clustering. AvailabilityGSOAP is implemented as an R package and is available at https://github.com/tomastokar/gsoap.

Maternal obesity has become a growing global health concern that may predispose the offspring to medical conditions later in life. However, the metabolic link between maternal pre-pregnant obesity and healthy offspring has not yet been fully elucidated. In this study, we conducted a case-control study using coupled untargeted and targeted metabolomics approach, from the newborn cord blood metabolomes associated with a matched maternal pre-pregnant obesity cohort of 28 cases and 29 controls. The subjects were recruited from multi-ethnic populations in Hawaii, including rarely reported Native Hawaiian and other Pacific Islanders (NHPI). We found that maternal obesity was the most important factor contributing to differences in cord blood metabolomics. Using elastic net regularization based logistic regression model, we identified 29 metabolites as potential early-life biomarkers manifesting intrauterine effect of maternal obesity, with accuracy as high as 0.947 after adjusting for clinical confounding (maternal and paternal age and ethnicity, parity and gravidity). We validated the model results in a subsequent set of samples (N=30) with an accuracy of 0.822. Among the metabolites, six metabolites (galactonic acid, butenylcarnitine, 2-hydroxy-3-methylbutyric acid, phosphatidylcholine diacyl C40:3, 1,5-anhydrosorbitol, and phosphatidylcholine acyl-alkyl 40:3) were individually and significantly different between the maternal obese vs. norm-weight groups. Interestingly, Hydroxy-3-methylbutyric acid showed significnatly higher levels in cord blood from the NHPI group, compared to asian and caucasian groups. In summary, significant associations were observed between maternal pre-pregnant obesity and offspring metabolomics alternation at birth, revealing the inter-generational impact of maternal obesity.

Accurate protein inference under the presence of shared peptides is still one of the key problems in bottom-up proteomics. Most protein inference tools employing simple heuristic inference strategies are efficient, but exhibit reduced accuracy. More advanced probabilistic methods often exhibit better inference quality but tend to be too slow for large data sets. Here we present a novel protein inference method, EPIFANY, combining a loopy belief propagation algorithm with convolution trees for efficient processing of Bayesian networks. We demonstrate that EPIFANY combines the reliable protein inference of Bayesian methods with significantly shorter runtimes. On the 2016 iPRG protein inference benchmark data EPIFANY is the only tested method which finds all true-positive proteins at a 5% protein FDR without strict pre-filtering on PSM level, yielding an increase in identification performance (+10% in the number of true positives and +14% in partial AUC) compared to previous approaches. Even very large data sets with hundreds of thousands of spectra (which are intractable with other Bayesian and some non-Bayesian tools) can be processed with EPIFANY within minutes. The increased inference quality including shared peptides results in better protein inference results and thus increased robustness of the biological hypotheses generated. EPIFANY is available as open-source software for all major platforms at https://OpenMS.de/epifany.

Phosphorylation-driven cell signaling governs most biological functions and is widely studied using mass spectrometry-based phosphoproteomics. Identifying the peptides and localizing the phosphorylation sites within them from the raw data is challenging and can be performed by several algorithms that return scores that are not directly comparable. This increases the heterogeneity among published phosphoproteomics data sets and prevents their direct integration. Here, we compare 22 pipelines implemented in the main software tools used for bottom-up phosphoproteomics analysis (MaxQuant, Proteome Discoverer, PeptideShaker). We test six search engines (Andromeda, Comet, Mascot, MS Amanda, SequestHT, and X!Tandem) in combination with several localization scoring algorithms (delta score, D-score, PTM-score, phosphoRS, and Ascore). We show that these follow very different score distributions, which can lead to different false localization rates for the same threshold. We provide a strategy to discriminate correctly from incorrectly localized phosphorylation sites in a consistent manner across the tested pipelines. The results presented here can help users choose the most appropriate pipeline and cutoffs for their phosphoproteomics analysis.

Metabolomics may identify biomarkers in blood that differentiate pregnant from open embryo recipients. Fresh and vitrified/warmed, in-vitro produced embryos, were transferred to Holstein recipients (discovery group). Recipient blood plasma collected on Day-0 (estrus) and Day-7 (before embryo transfer) was analysed by nuclear magnetic resonance, (N=36 metabolites quantified). Metabolites whose concentrations differed between open and pregnant recipients were analysed [(P<0.05); FDR (P<0.05)]. Biomarkers were identified in Day-7 plasma (ROC-AUC>0.650; T-Test P<0.05; Random Forests, mean decrease accuracy) and cross-validated in independent Holstein, beef and crossbred recipients (overall classification accuracy –OCA-; P<0.05). Recipients with fresh embryos showed N=6 biomarkers consistently on Day-40, Day-62 and at birth. Recipients with vitrified embryos showed N=5 biomarkers on Day-40 and Day-62 but only one biomarker at birth. The most predictive biomarkers identified at birth within fresh embryos were Oxoglutaric acid (ROC-AUC=0.709; OCA=0.812) and Ornithine (ROC-AUC=0.731; OCA=0.727), while L-Glycine was identified in vitrified embryos (ROC-AUC=0.796; OCA=0.667) together with other predictive biomarkers not identified at birth (Day-62: L-Glutamine ROC-AUC= 0.757; OCA=0.767) and L-Lysine (Day-62: ROC-AUC=0.680; OCA=0.767). Pathway enrichment analysis distinguished between pregnant recipients for fresh (enriched energy oxidative metabolism from fat) and vitrified embryos (lower lipid metabolism). Metabolomics can select individuals which will become pregnant in a defined cycle.

Mitochondria are involved in many crucial cellular processes. Maintaining healthy mitochondria is essential for cellular homeostasis. Parkin-dependent mitophagy plays an important role in selectively eliminating damaged mitochondria in mammalian cells. However, mechanisms of Parkin-dependent mitophagy remain elusive. In this research, we performed data-independent acquisition (DIA)-based quantitative mitochondrial proteomics to study the proteomic alterations of carbonyl cyanide m-chlorophenylhydrazone (CCCP)-induced Parkin-mediated mitophagy. We identified 222 differentially expressed proteins, with 76 up-regulations and 146 down-regulations, which were potentially involved in mitophagy. We then demonstrated that annexin A7 (ANXA7), a calcium-dependent phospholipid-binding protein, can translocate to impaired mitochondria upon CCCP treatment, where it played a pivotal part in the process of Parkin-dependent mitophagy via interacting with BASP1. As a mitochondrial uncoupling agent, CCCP indirectly regulated ANXA7 and BASP1 to induce Parkin-dependent mitophagy. Keywords: mitochondrial proteomics, mitophagy, ANXA7

Reliable in silico approaches to replace animal testing for the evaluation of potential acute toxic effects are highly demanded by regulatory agencies. In particular, quantitative structure-activity relationships (QSAR) models have been used to rapidly assess chemical induced toxicity using either continuous (regression) or discrete (classification) predictions. However, it is often unclear how those different types of models can complement and potentially help each other to afford the best prediction accuracy for a given chemical. This paper presents a novel, dual-layer hierarchical modeling method to fully integrate regression and classification QSAR models for assessing rat acute oral systemic toxicity, with respect to regulatory classifications of concern. The first layer of independent regression, binary and multiclass models (base models) were solely built using computed chemical descriptors/fingerprints. Then, a second layer of models (hierarchical models) were built by stacking all the cross-validated out-of-fold predictions from the base models. All models were validated using an external test set and we found that the hierarchical models did outperform the base models for all the three endpoints. The H-QSAR modeling method represents a promising approach for chemical toxicity prediction and more generally for stacking and blending individual QSAR models into more predictive ensemble models.

Changes to neonatal nutrition result in long-lasting impairments in energy balance, which may be described as metabolic programing. Astrocytes, which are interconnected by gap junctions, have emerged as important players in the hypothalamic control of food intake. In order to study the effects of nutritional programming on glial morphology and protein expression, cross-fostered male Wistar rats at postnatal day 3 were assigned to three groups based on litter size: small litter (3 pups per dam, SL), normal litter (10 pups per dam, NL), and large litter (16 pups per dam, LL). Rats from the SL group exhibited higher body weight throughout the study and hyperphagia after weaning. LL animals exhibited hyperphagia, high energy efficiency and catch-up of body weight after weaning. Both the SL and LL groups at postnatal day 60 (PN60) exhibited increased levels of plasma leptin, the Lee index (as an index of obesity), adiposity content, immunoreactivity toward T-cell protein tyrosine phosphatase (TCPTP), and glial fibrillary acidic protein (GFAP) in the arcuate nucleus (ARC) of the hypothalamus. Astrocyte morphology was altered in the ARC of SL and LL animals, and this effect occurred in parallel with a reduction in immunoreactivity toward connexin 30 (CX30). The data obtained demonstrate that both neonatal over- and underfeeding promote not only alterations in the metabolic status but also morphological changes in glial cells in parallel with increasing TCPTP and changes in connexin expression.

Chloropicrin is a volatile and reactive chemical that has been utilized as a warfare agent and a pesticide to fumigate soil against insects, fungi and nematodes. It poses a health risk to humans and animals if inhaled. The main source of chloropicrin exposure is occupational and occurs during its manufacture, transport and fumigation. Chloropicrin is toxic via all routes of exposure but the main route of systemic exposure is inhalation of the ambient air. Thus, the toxicity mainly affects the respiratory system. After a low level exposure, the first sign is irritation of the upper respiratory tract and eyes. Irritation is mediated by the sensory nerve fibers, which coordinate further activation of various protective reflexes. Chloropicrin-induced irritation is generally reversible but can alter airway responsiveness to other inhalation toxicants. Severe exposures cause injuries in the respiratory tract, inflammation, and even life-threatening edema. Much of the chloropicrin-caused symptoms and toxicity in the respiratory system displays similarities with those evoked by chlorine, which is also a breakdown product of chloropicrin. This review summarizes the latest information on chloropicrin with emphasis on the toxicity in the respiratory system. The data indicates that oxidative stress, modification of macromolecules, mutations, dysfunctions of cell organelles and cell death are involved in acute chloropicrin-induced toxicity in the respiratory system.

Justification for lethal control in conservation is often presumed to be shaped by human attitudes toward different species and whether these species are regarded as native or introduced to a particular system. Conservation researchers and practitioners attitudes often differ in this regard, so different conservation frameworks have evolved such as traditional compositionalist conservation, ‘new’ functionalist conservation, and compassionate conservation. Yet, there is limited research on how the public perceives and values native versus introduced species and thus how public perceptions align with these different and somewhat conflicting definitions of conservation. We conducted an online public survey (N = 811) in Australia to explore how perceptions of species are related to each other and to the approval of lethal control. We focused on native kangaroos, the long-established dingo, and more recently introduced red foxes and wild horses. Perceptions of species' ‘nativeness’ varied and did not always align with policy definitions or reality, with 18.4% and 17.9% considering horses and foxes, respectively, to be native to Australia. The perception that a species was not native and was a pest were linked, and correlated positively with approval for lethal control. The results reveal the conflicting perceptions of conservation among conservationists, the public, and policy definitions. This highlights the difficulty of developing a set of agreed upon conservation goals which would help promote conservation practices supported by stakeholder values.

Aims/hypothesis Brown adipose tissue (BAT) improves energy metabolism by combusting glucose and lipids into heat. Agonism of the glucagon-like peptide-1 receptor (GLP-1R) within the central nervous system activates BAT in mice. Moreover, in patients with type 2 diabetes, GLP-1R agonism lowers body weight and improves glucose and lipid levels, possibly involving BAT activation. Interestingly, people from South Asian descent are prone to develop cardiometabolic disease. We studied the effect of GLP-1R agonism on BAT in humans, specifically in South Asians and Europids without obesity or type 2 diabetes. Methods Twelve Dutch South Asian and 12 age- and BMI-matched Europid nondiabetic men received 12 weeks extended-release exenatide (Bydureon) in this single-arm prospective study. Before and after treatment, BAT was visualized by a cold-induced [18F]FDG-PET/CT scan and a thermoneutral MRI scan, and resting energy expenditure (REE), substrate oxidation, body composition and fasting plasma glucose and serum lipids were determined. Appetite was rated using a visual analogue scale. Results Since the effect of exenatide on metabolic parameters did not evidently differ between ethnicities, data of all participants were pooled. Exenatide decreased body weight (−1.5 ± 0.4 kg, p < .01), without affecting REE or substrate oxidation, and transiently decreased appetite ratings during the first weeks. Exenatide also lowered triglycerides (−15%, p < .05) and total cholesterol (−5%, p < .05), and tended to lower glucose levels. Notably, exenatide increased BAT metabolic volume (+28%, p < .05) and mean standardized uptake value (+11%, p < .05) ([18F]FDG-PET/CT), without affecting supraclavicular adipose tissue fat fraction (MRI). Conclusions/interpretation We show for the first time that GLP-1R agonism increases [18F]FDG uptake by BAT in South Asian and Europid men without obesity or type 2 diabetes. Trial registry. Clinicaltrials.gov NCT03002675

Background There is no consensus in the field regarding the optimal method for the expression of metabolic flux data, such as glucose disposal rates during hyperinsulinemic-euglycemic clamp experiments. Several normalization methods are in use today, but their impact on study outcomes is rarely discussed. Methods We illustrate this issue using clamp data from 92 lean and 66 obese subjects. Glucose kinetics and insulin sensitivity were determined during hyperinsulinemic-euglycemic clamp studies using [6,6-2H2]glucose. From this single dataset, we calculated 21 expression methods for the glucose disposal rate during hyperinsulinemic conditions. Results and discussion With most normalization methods, the obese subjects demonstrated reduced insulin-stimulated glucose disposal as compared to the lean subjects. However, depending on the normalization method, glucose disposal rates in obese subjects ranged from 26 ± 1% to 207 ± 10% of glucose disposal rates in lean subjects. We conclude that data normalization methods greatly impacted metabolic flux outcomes in our dataset of lean and obese subjects. There is no compelling evidence to select one method over the other, but we encourage authors in the metabolic arena to think about, and provide a rationale for, the best normalization method for their specific research questions.