The long non-coding RNA NEAT1 is increased in IUGR placentas, leading to potential new hypotheses of IUGR origin/development.

INTRODUCTION Intrauterine Growth Restriction (IUGR) is a multifactorial disease defined by an inability of the fetus to reach its growth potential. IUGR not only increases the risk of neonatal mortality/morbidity, but also the risk of metabolic syndrome during adulthood. Certain placental proteins have been shown to be implicated in IUGR development, such as proteins from the GH/IGF axis and angiogenesis/apoptosis processes. METHODS Twelve patients with term IUGR pregnancy (birth weight < 10th percentile) and 12 CTRLs were included. mRNA was extracted from the fetal part of the placenta and submitted to a subtraction method (Clontech PCR-Select cDNA Subtraction). RESULTS One candidate gene identified was the long non-coding RNA NEAT1 (nuclear paraspeckle assembly transcript 1). NEAT1 is the core component of a subnuclear structure called paraspeckle. This structure is responsible for the retention of hyperedited mRNAs in the nucleus. Overall, NEAT1 mRNA expression was 4.14 (±1.16)-fold increased in IUGR vs. CTRL placentas (P = 0.009). NEAT1 was exclusively localized in the nuclei of the villous trophoblasts and was expressed in more nuclei and with greater intensity in IUGR placentas than in CTRLs. PSPC1, one of the three main proteins of the paraspeckle, co-localized with NEAT1 in the villous trophoblasts. The expression of NEAT1_2 mRNA, the long isoform of NEAT1, was only modestly increased in IUGR vs. CTRL placentas. DISCUSSION/CONCLUSION The increase in NEAT1 and its co-localization with PSPC1 suggests an increase in paraspeckles in IUGR villous trophoblasts. This could lead to an increased retention of important mRNAs in villous trophoblasts nuclei. Given that the villous trophoblasts are crucial for the barrier function of the placenta, this could in part explain placental dysfunction in idiopathic IUGR fetuses.

Urinary leukotriene E4 concentrations as a potential marker of inflammation in dogs with inflammatory bowel disease

BACKGROUND: Inflammatory bowel disease (IBD) and food-responsive diarrhea (FRD) are chronic enteropathies of dogs (CCE) that currently can only be differentiated by their response to treatment after exclusion of other diseases. In humans, increased urinary concentrations of leukotriene E4 (LTE4) have been associated with active IBD. OBJECTIVES: To evaluate urinary LTE4 concentrations in dogs with IBD, FRD, and healthy controls, and to assess correlation of urinary LTE4 concentrations with the canine IBD activity index (CIBDAI) scores. ANIMALS: Eighteen dogs with IBD, 19 dogs with FRD, and 23 healthy control dogs. METHODS: In this prospective study, urine was collected and CIBDAI scores were calculated in client-owned dogs with IBD and those with FRD. Quantification of LTE4 in urine was performed by liquid chromatography-tandem mass spectrometry and corrected to creatinine. RESULTS: Urinary LTE4 concentrations were highest in dogs with IBD (median 85.2 pg/mg creatinine [10th-90th percentiles 10.9-372.6]) followed by those with FRD (median 31.2 pg/mg creatinine [10th-90th percentiles 6.2-114.5]) and control dogs (median 21.1 pg/mg creatinine [10th-90th percentiles 9.1-86.5]). Urinary LTE4 concentrations were higher in dogs with IBD than in control dogs (P = .011), but no significant difference between IBD and FRD was found. No correlation was found between urinary LTE4 concentrations and CIBDAI. CONCLUSIONS AND CLINICAL IMPORTANCE: The higher urinary LTE4 concentrations in dogs with IBD suggest that cysteinyl leukotriene pathway activation might be a component of the inflammatory process in canine IBD. Furthermore, urinary LTE4 concentrations are of potential use as a marker of inflammation in dogs with CCE.

Metabolomics Reveals Aging-associated Attenuation of Noninvasive Radiation Biomarkers in Mice: Potential Role of Polyamine Catabolism and Incoherent DNA Damage-repair

Development of methods for rapid screening and stratification of subjects after exposure is an integral part of countermeasures against radiation. The potential demographic and exposure history-related heterogeneity of exposed populations warrants robust biomarkers that withstand and reflect such differences. In this study, the effect of aging and repeated exposure on the metabolic response to sublethal irradiation was examined in mice using UPLC-ESI-QTOF mass spectrometry. Aging attenuated postexposure elevation in excretions of DNA damage biomarkers as well as N(1)-acetylspermidine. Although N(1)-acetylspermidine and 2'-deoxyuridine elevation was highly correlated in all age groups, xanthine and N(1)-acetylspermidine elevation was poorly correlated in older mice. These results may reflect the established decline in DNA damage-repair efficiency associated with aging and indicate a novel role for polyamine metabolism in the process. Although repeated irradiation at long intervals did not affect the elevation of N(1)-acetylspermidine, 2'-deoxyuridine, and xanthine, it did significantly attenuate the elevation of 2'-deoxycytidine and thymidine compared to a single exposure. However, these biomarkers were found to identify exposed subjects with accuracy ranging from 82% (xanthosine) to 98% (2'-deoxyuridine), irrespective of their age and exposure history. This indicates that metabolic biomarkers can act as robust noninvasive signatures of sublethal radiation exposure.

Honey - a potential agent against Porphyromonas gingivalis: an in vitro study.

BACKGROUND Honey has been discussed as a therapeutic option in wound healing since ancient time. It might be also an alternative to the commonly used antimicrobials in periodontitis treatment. The in-vitro study was aimed to determine the antimicrobial efficacy against Porphyromonas gingivalis as a major periodontopathogen. METHODS One Manuka and one domestic beekeeper honey have been selected for the study. As a screening, MICs of the honeys against 20 P. gingivalis strains were determined. Contents of methylglyoxal and hydrogen peroxide as the potential antimicrobial compounds were determined. These components (up to 100 mg/l), propolis (up to 200 mg/l) as well as the two honeys (up to 10% w/v) were tested against four P. gingivalis strains in planktonic growth and in a single-species biofilm. RESULTS 2% of Manuka honey inhibited the growth of 50% of the planktonic P. gingivalis, the respective MIC50 of the German beekeeper honey was 5%. Manuka honey contained 1.87 mg/kg hydrogen peroxide and the domestic honey 3.74 mg/kg. The amount of methylglyoxal was found to be 2 mg/kg in the domestic honey and 982 mg/kg in the Manuka honey. MICs for hydrogen peroxide were 10 mg/l - 100 mg/l, for methylglyoxal 5 - 20 mg/l, and for propolis 20 mg/l - 200 mg/l. 10% of both types of honey inhibited the formation of P. gingivalis biofilms and reduced the numbers of viable bacteria within 42 h-old biofilms. Neither a total prevention of biofilm formation nor a complete eradication of a 42 h-old biofilm by any of the tested compounds and the honeys were found. CONCLUSIONS Honey acts antibacterial against P. gingivalis. The observed pronounced effects of Manuka honey against planktonic bacteria but not within biofilm can be attributed to methylglyoxal as the characteristic antimicrobial component.

Improved methods for measuring forest landscape structure: LiDAR complements field-based habitat assessment

Conservation and monitoring of forest biodiversity requires reliable information about forest structure and composition at multiple spatial scales. However, detailed data about forest habitat characteristics across large areas are often incomplete due to difficulties associated with field sampling methods. To overcome this limitation we employed a nationally available light detection and ranging (LiDAR) remote sensing dataset to develop variables describing forest landscape structure across a large environmental gradient in Switzerland. Using a model species indicative of structurally rich mountain forests (hazel grouse Bonasa bonasia), we tested the potential of such variables to predict species occurrence and evaluated the additional benefit of LiDAR data when used in combination with traditional, sample plot-based field variables. We calibrated boosted regression trees (BRT) models for both variable sets separately and in combination, and compared the models’ accuracies. While both field-based and LiDAR models performed well, combining the two data sources improved the accuracy of the species’ habitat model. The variables retained from the two datasets held different types of information: field variables mostly quantified food resources and cover in the field and shrub layer, LiDAR variables characterized heterogeneity of vegetation structure which correlated with field variables describing the understory and ground vegetation. When combined with data on forest vegetation composition from field surveys, LiDAR provides valuable complementary information for encompassing species niches more comprehensively. Thus, LiDAR bridges the gap between precise, locally restricted field-data and coarse digital land cover information by reliably identifying habitat structure and quality across large areas.

Characterization of small ruminant lentivirus A4 subtype isolates and assessment of their pathogenic potential in naturally infected goats.

BACKGROUND Small ruminant lentiviruses escaping efficient serological detection are still circulating in Swiss goats in spite of a long eradication campaign that essentially eliminated clinical cases of caprine arthritis encephalitis in the country. This strongly suggests that the circulating viruses are avirulent for goats.To test this hypothesis, we isolated circulating viruses from naturally infected animals and tested the in vitro and in vivo characteristics of these field isolates. METHODS Viruses were isolated from primary macrophage cultures. The presence of lentiviruses in the culture supernatants was monitored by reverse transcriptase assay. Isolates were passaged in different cells and their cytopathogenic effects monitored by microscopy. Proviral load was quantified by real-time PCR using customized primer and probes. Statistical analysis comprised Analysis of Variance and Bonferroni Multiple Comparison Test. RESULTS The isolated viruses belonged to the small ruminant lentiviruses A4 subtype that appears to be prominent in Switzerland. The 4 isolates replicated very efficiently in macrophages, displaying heterogeneous phenotypes, with two isolates showing a pronounced cytopathogenicity for these cells. By contrast, all 4 isolates had a poor replication capacity in goat and sheep fibroblasts. The proviral loads in the peripheral blood and, in particular, in the mammary gland were surprisingly high compared to previous observations. Nevertheless, these viruses appear to be of low virulence for goats except for the mammary gland were histopathological changes were observed. CONCLUSIONS Small ruminant lentiviruses continue to circulate in Switzerland despite a long and expensive caprine arthritis encephalitis virus eradication campaign. We isolated 4 of these lentiviruses and confirmed their phylogenetic association with the prominent A4 subtype. The pathological and histopathological analysis of the infected animals supported the hypothesis that these A4 viruses are of low pathogenicity for goats, with, however, a caveat about the potentially detrimental effects on the mammary gland. Moreover, the high proviral load detected indicates that the immune system of the animals cannot control the infection and this, combined with the phenotypic plasticity observed in vitro, strongly argues in favour of a continuous and precise monitoring of these SRLV to avoid the risk of jeopardizing a long eradication campaign.

Prevalence of potential retrograde embolization pathways in the proximal descending aorta in stroke patients and controls.

BACKGROUND Retrograde diastolic blood flow in the proximal descending aorta (DAo) connecting complex plaques (≥4 mm thick) with brain-supplying supra-aortic arteries may constitute a source of stroke. Yet, data only from high-risk populations (cryptogenic stroke patients with aortic atheroma≥3 mm) regarding the prevalence of this potential stroke mechanism are available. We aimed to quantify the frequency of this mechanism in unselected patients with cryptogenic stroke after routine diagnostics and controls without a history of stroke. METHODS 88 patients (67 stroke patients, 21 cardiac controls) were prospectively included. 3D T1-weighted bright blood MRI of the aorta was applied for the detection of complex DAo atheroma. ECG-triggered and navigator-gated 4D flow MRI allowed measuring time-resolved 3D blood flow in vivo. Potential retrograde embolization pathways were defined as the co-occurrence of complex plaques and retrograde blood flow in the DAo reaching the outlet of (a) the left subclavian artery, (b) the left common carotid artery, or/and (c) the brachiocephalic trunk. The frequency of these pathways was analyzed by importing 2D plaque images into 3D blood flow visualization software. RESULTS Complex DAo plaques were more frequent in stroke patients (44 in 31/67 patients (46.3%) vs. 5 in 4/21 controls (19.1%); p=0.039), especially in older patients (29/46 (63.04%) patients≥60 years of age with 41 plaques vs. 2/21 (9.14%) patients<60 years of age with 3 plaques; p<0.001). Contrary to our assumption, retrograde diastolic blood flow at the DAo occurred in every patient irrespective of the existence of plaques with a similar extent in both groups (26±14 vs. 32±18 mm; p=0.114). Therefore, only the higher prevalence of complex DAo plaques in stroke patients resulted in a three times higher frequency of potential retrograde embolization pathways compared to controls (22/67 (32.8%) vs. 2/21 (9.5%) controls; p=0.048). CONCLUSIONS This study revealed that retrograde flow in the descending aorta is a common phenomenon not only in stroke patients. The existence of potential retrograde embolization pathways depends mainly on the occurrence of complex plaques in the area 0 to ∼30 mm behind the outlet of the left subclavian artery, which is exposed to flow reversal. In conclusion, we have shown that the frequency of potential retrograde embolization pathways was significantly higher in stroke patients suggesting that this mechanism may play a role in retrograde brain embolism.

Functionalization of PAMAM dendrimers with nitronyl nitroxide radicals as models for the outer-sphere relaxation in dentritic potential MRI contrast agents

PAMAM dendrimers functionalized with nitronyl nitroxide radicals were characterized. Quantitative determination of substitution with radicals was performed using EPR and electrochemical methods. The study of the 1H NMR relaxation of the surrounding water showed how the outer-sphere contribution to the relaxivity may be limited by the presence of the dendrimer core.

Complexity and non-linearity in earth surface processes - concepts, methods and applications

Complexity has long been recognized and is increasingly becoming mainstream in geomorphology. However, the relative novelty of various concepts and techniques associated to it means that ambiguity continues to surround complexity. In this commentary, we present and discuss a variety of recent contributions that have the potential to help clarify issues and advance the use of complexity in geomorphology.

Variation in life-history traits and their plasticities to elevational transplantation among seed families suggests potential for adaptative evolution of 15 tropical plant species to climate change

• Premise of the study: Because not all plant species will be able to move in response to global warming, adaptive evolution matters largely for plant persistence. As prerequisites for adaptive evolution, genetic variation in and selection on phenotypic traits are needed, but these aspects have not been studied in tropical species. We studied how plants respond to transplantation to different elevations on Mt. Kilimanjaro, Tanzania, and whether there is quantitative genetic (among-seed family) variation in and selection on life-history traits and their phenotypic plasticity to the different environments. • Methods: We reciprocally transplanted seed families of 15 common tropical, herbaceous species of the montane and savanna vegetation zone at Mt. Kilimanjaro to a watered experimental garden in the montane (1450 m) and in the savanna (880 m) zone at the mountain’s slope and measured performance, reproductive, and phenological traits. • Results: Plants generally performed worse in the savanna garden, indicating that the savanna climate was more stressful and thus that plants may suffer from future climate warming. We found significant quantitative genetic variation in all measured performance and reproductive traits in both gardens and for several measures of phenotypic plasticity in response to elevational transplantation. Moreover, we found positive selection on traits at low and intermediate trait values levelling to neutral or negative selection at high values. • Conclusions: We conclude that common plants at Mt. Kilimanjaro express quantitative genetic variation in fitness-relevant traits and in their plasticities, suggesting potential to adapt evolutionarily to future climate warming and increased temperature variability.

Spatial variability and potential impacts of climate change on flood and debris flow hazard zone mapping and implications for risk management

The main goals of this study were to identifythe alpine torrent catchments that are sensitive to climatic changes and to assess the robustness of the methods for the elaboration of flood and debris flow hazard zone maps to specific effects of climate changes. In this study, a procedure for the identification and localization of torrent catchments in which the climate scenarios will modify the hazard situation was developed. In two case studies, the impacts of a potential increase of precipitation intensities to the delimited hazard zones were studied. The identification and localization of the torrent and river catchments, where unfavourable changes in the hazard situation occur, could eliminate speculative and unnecessary measures against the impacts of climate changes like a general enlargement of hazard zones or a general over dimensioning of protection structures for the whole territory. The results showed a high spatial variability of the sensitivity of catchments to climate changes. In sensitive catchments, the sediment management in alpine torrents will meet future challenges due to a higher rate for sediment removal from retention basins. The case studies showed a remarkable increase of the areas affected by floods and debris flow when considering possible future precipitation intensities in hazard mapping. But, the calculated increase in extent of future hazard zones lay within the uncertainty of the methods used today for the delimitation of the hazard zones. Thus, the consideration of the uncertainties laying in the methods for the elaboration of hazard zone maps in the torrent and river catchments sensitive to climate changes would provide a useful instrument for the consideration of potential future climate conditions. The study demonstrated that weak points in protection structures in future will become more important in risk management activities.

Extratropical fronts in the lower troposphere-global perspectives obtained from two automated methods

In this study two commonly used automated methods to detect atmospheric fronts in the lower troposphere are compared in various synoptic situations. The first method is a thermal approach, relying on the gradient of equivalent potential temperature (TH), while the second method is based on temporal changes in the 10 m wind (WND). For a comprehensive objective comparison of the outputs of these methods of frontal identification, both schemes are firstly applied to an idealised strong baroclinic wave simulation in the absence of topography. Then, two case-studies (one in the Northern Hemisphere (NH) and one in the Southern Hemisphere (SH)) were conducted to contrast fronts detected by the methods. Finally, we obtain global winter and summer frontal occurrence climatologies (derived from ERA-Interim for 1979–2012) and compare the structure of these. TH is able to identify cold and warm fronts in strong baroclinic cases that are in good agreement with manual analyses. WND is particularly suited for the detection of strongly elongated, meridionally oriented moving fronts, but has very limited ability to identify zonally oriented warm fronts. We note that the areas of the main TH frontal activity are shifted equatorwards compared to the WND patterns and are located upstream of regions of main WND front activity. The number of WND fronts in the NH shows more interseasonal variations than TH fronts, decreasing by more than 50% from winter to summer. In the SH there is a weaker seasonal variation of the number of observed WND fronts, however TH front activity reduces from summer (DJF) to winter (JJA). The main motivation is to give an overview of the performance of these methods, such that researchers can choose the appropriate one for their particular interest.

Itineraries of pottery: a mixed methods approach to mobility

Neolithic wetland sites in the Swiss Plateau provide an extraordinary database for the study of mobilities, entanglements and transformations in material culture. Based on dendrochronologically dated settlements between 3900 and 3500 BC, two regional pottery styles and their local variations are well known, Pfyn and Cortaillod. The vessels share the same habitus and were made of local raw materials. However, some vessels specific to other pottery styles are also present in the sites. By focusing on itineraries of vessels and shifts in pottery knowledge, their appropriation in different contexts and the resulting material entanglements, we want to approach the multiple regimes of mobility: At Lake Constance - known for Pfyn pottery - specific Michelsberg vessels like tulip beakers and lugged jars occur in small numbers. These travelling objects were produced with exogenous raw materials and transported to the sites from Southern Germany. At Concise (Lake Neuchâtel) besides the local Cortaillod pottery the whole repertoire of NMB pottery, characteristic for Eastern France, was also produced. Further cases from the same space-time frame point to other regimes of mobility. In our two PhD-projects we compare pottery practices - styles, techniques, raw materials - from over 20 key sites in the region. Based on Bourdieu’s reflexive anthropology, we apply different qualitative and quantitative archaeological and archaeometrical methods, thus striving for a deeper understanding of habitus and the transformative potential of moving people, objects and ideas on local and regional scales and related social contexts.

Effect sizes and standardization in neighbourhood models of forest stands: potential biases and misinterpretations

Effects of conspecific neighbours on survival and growth of trees have been found to be related to species abundance. Both positive and negative relationships may explain observed abundance patterns. Surprisingly, it is rarely tested whether such relationships could be biased or even spurious due to transforming neighbourhood variables or influences of spatial aggregation, distance decay of neighbour effects and standardization of effect sizes. To investigate potential biases, communities of 20 identical species were simulated with log-series abundances but without species-specific interactions. No relationship of conspecific neighbour effects on survival or growth with species abundance was expected. Survival and growth of individuals was simulated in random and aggregated spatial patterns using no, linear, or squared distance decay of neighbour effects. Regression coefficients of statistical neighbourhood models were unbiased and unrelated to species abundance. However, variation in the number of conspecific neighbours was positively or negatively related to species abundance depending on transformations of neighbourhood variables, spatial pattern and distance decay. Consequently, effect sizes and standardized regression coefficients, often used in model fitting across large numbers of species, were also positively or negatively related to species abundance depending on transformation of neighbourhood variables, spatial pattern and distance decay. Tests using randomized tree positions and identities provide the best benchmarks by which to critically evaluate relationships of effect sizes or standardized regression coefficients with tree species abundance. This will better guard against potential misinterpretations.

Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics.

BACKGROUND Endometriosis, the growth of endometrial tissue outside the uterine cavity, is associated with chronic pelvic pain, subfertility and an increased risk of ovarian cancer. Current treatments include the surgical removal of the lesions or the induction of a hypoestrogenic state. However, a reappearance of the lesion after surgery is common and a hypoestrogenic state is less than optimal for women of reproductive age. Additional approaches are required. Endometriosis lesions exist in a unique microenvironment characterized by increased concentrations of hormones, inflammation, oxidative stress and iron. This environment influences cell survival through the binding of membrane receptors and a subsequent cascading activation of intracellular kinases that stimulate a cellular response. Many of these kinase signalling pathways are constitutively activated in endometriosis. These pathways are being investigated as therapeutic targets in other diseases and thus may also represent a target for endometriosis treatment. METHODS To identify relevant English language studies published up to 2015 on kinase signalling pathways in endometriosis, we searched the Pubmed database using the following search terms in various combinations; 'endometriosis', 'inflammation', 'oxidative stress', 'iron', 'kinase', 'NF kappa', 'mTOR', 'MAPK' 'p38', 'JNK', 'ERK' 'estrogen' and progesterone'. Further citing references were identified using the Scopus database and finally current clinical trials were searched on the clinicaltrials.gov trial registry. RESULTS The current literature on intracellular kinases activated by the endometriotic environment can be summarized into three main pathways that could be targeted for treatments: the canonical IKKβ/NFκB pathway, the MAPK pathways (ERK1/2, p38 and JNK) and the PI3K/AKT/mTOR pathway. A number of pharmaceutical compounds that target these pathways have been successfully trialled in in vitro and animal models of endometriosis, although they have not yet proceeded to clinical trials. The current generation of kinase inhibitors carry a potential for adverse side effects. CONCLUSIONS Kinase signalling pathways represent viable targets for endometriosis treatment. At present, however, further improvements in clinical efficacy and the profile of adverse effects are required before these compounds can be useful for long-term endometriosis treatment. A better understanding of the molecular activity of these kinases, including the specific extracellular compounds that lead to their activation in endometriotic cells specifically should facilitate their improvement and could potentially lead to new, non-hormonal treatments of endometriosis.