Toxic Tau Oligomers Modulated by Novel Curcumin Derivatives

The pathological aggregation and accumulation of tau, a microtubule-associated protein, is a common feature amongst more than 18 different neurodegenerative diseases that are collectively known as tauopathies. Recently, it has been demonstrated that the soluble and hydrophobic tau oligomers are highly toxic in vitro due to their capacity towards seeding tau misfolding, thereby propagating the tau pathology seen across different neurodegenerative diseases. Modulating the aggregation state of tau oligomers through the use of small molecules could be a useful therapeutic strategy to target their toxicity, regardless of other factors involved in their formation. In this study, we screened and tested a small library of newly synthesized curcumin derivatives against preformed recombinant tau oligomers. Our results show that the curcumin derivatives affect and modulate the tau oligomer aggregation pathways, converting to a more aggregated non-toxic state as assessed in the human neuroblastoma SH-SY5Y cell line and primary cortical neuron cultures. These results provide insight into tau aggregation and may become a basis for the discovery of new therapeutic agents, as well as advance the diagnostic field for the detection of toxic tau oligomers

Are chlorophyll concentrations and nitrogen across the vertical canopy profile affected by elevated CO2 in mature Quercus trees?

Key message: In mature Q. robur, chlorophyll varied with season and canopy height, whilst eCO2-driven changes were consistent with Marea, highlighting key factors for consideration when scaling photosynthetic processes and canopy N-use. Nitrogen-rich chlorophyll and carotenoid pigments are important in photosynthetic functioning. Photosynthetic pigments have been found to decrease with elevated CO2 (eCO2), but few such studies have been done in aged forest trees. This study aimed to assess the effects of eCO2 (150 μmol mol−1 above ambient) and canopy position on chlorophyll content in mature Quercus robur (Q. robur). Over 5000 in situ chlorophyll absorbance measurements, alongside laboratory chlorophyll extractions, were collected on canopy-dominant Q. robur in the 3rd and 4th season of CO2 fumigation of a free-air CO2 enrichment (FACE) study in central England. Mass-based chlorophyll concentration (Chlmass, mg g−1) was significantly higher in the lower canopy compared to upper canopy foliage (P < 0.05). In contrast, significantly higher chlorophyll content (Chlarea, mg m−2) was observed in the upper canopy. ECO2 did not affect Chlmass but Chlarea significantly increased, attributable to increased leaf mass per unit area (Marea, g m−2). We found no effect of eCO2 on mass-based or area-based nitrogen (Nmass, mg g−1 or Narea g m−2); however, Narea significantly increased with canopy height, again attributable to Marea. The parallel relationships between Marea, Narea and Chlarea suggest the allocation of N to light harvesting is maintained with eCO2 exposure as well as in the upper canopy, and that increased photosynthetic mass may help regulate the eCO2 variation. An understanding of changes in the light-harvesting machinery with eCO2 will be useful to assess canopy processes and, at larger scales, changes in biogeochemical cycles in future climate scenarios

Efficacy and safety of fluticasone furoate 100 μg and 200 μg once daily in the treatment of moderate-severe asthma in adults and adolescents: a 24-week randomised study

Background: Inhaled corticosteroids are a mainstay of therapy for persistent asthma, but suboptimal adherence with twice-daily use is widespread. Fluticasone furoate (FF) is a new inhaled corticosteroid (ICS) suitable for once-daily dosing in asthma. This study was performed to descriptively assess the efficacy and safety of two doses of FF, with no planned formal statistical hypothesis testing. Methods: This was a 24-week double-blind, multicentre, parallel-group study (NCT01431950). Patients aged ≥ 12 years with moderate-severe persistent asthma and uncontrolled on mid-high dose ICS were stratified by baseline FEV1 and randomised (1:1) to treatment with FF 100 μg or 200 μg once daily in the evening. The primary endpoint was change from baseline trough FEV1 after 24 weeks; secondary and other endpoints included peak expiratory flow (PEF) and rescue-free and symptom-free 24-hour periods over Weeks 1–24, and Asthma Control Test™ (ACT) score at Week 24. A pre-specified subgroup analysis of patients by randomisation strata was performed for the primary and selected secondary and other endpoints. Safety assessments included adverse events, laboratory and vital sign measurements, and change from baseline in 24-hour urinary cortisol at Week 24. Results: With FF 100 μg and 200 μg, least squares mean trough FEV1 improved from baseline by 208 mL and 284 mL, respectively, at Week 24; treatment difference: 77 mL (95% CI: –39, 192). Similar improvements from baseline in rescue- and symptom-free periods, and morning and evening PEF were observed in both groups. Patients were 42% more likely to be well-controlled (ACT score ≥ 20) with FF 200 μg than with FF 100 μg. Slightly more patients receiving FF 200 μg vs. FF 100 μg reported adverse events (63% vs. 59%) and events deemed treatment related (5% vs. <1%). Seven serious adverse events (FF 200 μg 4; FF 100 μg 3) were reported, none of which were deemed treatment related. No clinically relevant effects of either dose on 24-hour urinary cortisol were observed. Conclusion: Improvements from baseline in trough FEV1 were observed after 24 weeks of treatment with both doses of FF, with a numerically greater improvement in FEV1 observed in patients receiving FF 200 μg. Secondary endpoint findings were similar between groups. No safety concerns were identified during the study

The CIN4 chromosomal instability qPCR classifier defines tumor aneuploidy and stratifies outcome in grade 2 breast cancer.

Purpose: Quantifying chromosomal instability (CIN) has both prognostic and predictive clinical utility in breast cancer. In order to establish a robust and clinically applicable gene expression-based measure of CIN, we assessed the ability of four qPCR quantified genes selected from the 70-gene Chromosomal Instability (CIN70) expression signature to stratify outcome in patients with grade 2 breast cancer. Methods: AURKA, FOXM1, TOP2A and TPX2 (CIN4), were selected from the CIN70 signature due to their high level of correlation with histological grade and mean CIN70 signature expression in silico. We assessed the ability of CIN4 to stratify outcome in an independent cohort of patients diagnosed between 1999 and 2002. 185 formalin-fixed, paraffin-embedded (FFPE) samples were included in the qPCR measurement of CIN4 expression. In parallel, ploidy status of tumors was assessed by flow cytometry. We investigated whether the categorical CIN4 score derived from the CIN4 signature was correlated with recurrence-free survival (RFS) and ploidy status in this cohort. Results: We observed a significant association of tumor proliferation, defined by Ki67 and mitotic index (MI), with both CIN4 expression and aneuploidy. The CIN4 score stratified grade 2 carcinomas into good and poor prognostic cohorts (mean RFS: 83.864.9 and 69.4 +- 8.2 months, respectively, p = 0.016) and its predictive power was confirmed by multivariate analysis outperforming MI and Ki67 expression. Conclusions: The first clinically applicable qPCR derived measure of tumor aneuploidy from FFPE tissue, stratifies grade 2 tumors into good and poor prognosis groups

Asymmetrical effects of mesophyll conductance on fundamental photosynthetic parameters and their relationships estimated from leaf gas exchange measurements

Worldwide measurements of nearly 130C3 species covering all major plant functional types are analysed in conjunction with model simulations to determine the effects of mesophyll conductance (gm) on photosynthetic parameters and their relationships estimated from A/Ci curves. We find that an assumption of infinite gm results in up to 75% underestimation for maximum carboxylation rate Vcmax, 60% for maximum electron transport rate Jmax, and 40% for triose phosphate utilization rate Tu.Vcmax is most sensitive, Jmax is less sensitive, and Tu has the least sensitivity to the variation of gm. Because of this asymmetrical effect of gm, the ratios of Jmax to Vcmax, Tu to Vcmax and Tu to Jmax are all overestimated. An infinite gm assumption also limits the freedom of variation of estimated parameters and artificially constrains parameter relationships to stronger shapes. These findings suggest the importance of quantifying gm for understanding in situ photosynthetic machinery functioning.We show that a nonzero resistance to CO2 movement in chloroplasts has small effects on estimated parameters. A non-linear function with gm as input is developed to convert the parameters estimated under an assumption of infinite gm to proper values. This function will facilitate gm representation in global carbon cycle models.This is the publisher’s final pdf. The published article is copyrighted by John Wiley & Sons Ltd. and can be found at: http://onlinelibrary.wiley.com/journal/10.1111/%28ISSN%291365-304

Diffractive Pedagogies- dancing across new materialist imaginaries

This paper outlines the affirmative potential of diffractive pedagogies, presenting learning through dance as its central empirical focus. Drawing on data from the university classroom and new materialist scholarship, we consider the problem of learning through the body for university students. We argue that embodied creative processes within pedagogical contexts can liberate those who learn from reproducing, or being reproduced, as the finite set of reductive yet historically determined and governed images, figures or metaphors assigned to them. Building on a feminist investment in the agency of materiality we think through the problem of the body as a site of learning in the university. Learning in higher education is popularly thought as pertaining to the transfer of abstract knowledge, and this process typically occurs in ways that largely ignore the physicality of learning. A pedagogical system which presents repeated structures and patterns of discourse as more valued vehicles for learning than experimentation and creation recognises only preconceived, representational models of thought and expression. This philosophical imaginary therefore requires reconfiguring, to allow for embodied and creative learning processes that are open-ended, nomadic and affirmative

Combined dark matter searches towards dwarf spheroidal galaxies with Fermi-LAT, HAWC, H.E.S.S., MAGIC, and VERITAS

Cosmological and astrophysical observations suggest that 85% of the total matter of the Universe is made of Dark Matter (DM). However, its nature remains one of the most challenging and fundamental open questions of particle physics. Assuming particle DM, this exotic form of matter cannot consist of Standard Model (SM) particles. Many models have been developed to attempt unraveling the nature of DM such as Weakly Interacting Massive Particles (WIMPs), the most favored particle candidates. WIMP annihilations and decay could produce SM particles which in turn hadronize and decay to give SM secondaries such as high energy \u1d6fe rays. In the framework of indirect DM search, observations of promising targets are used to search for signatures of DM annihilation. Among these, the dwarf spheroidal galaxies (dSphs) are commonly favored owing to their expected high DM content and negligible astrophysical background. In this work, we present the very first combination of 20 dSph observations, performed by the Fermi-LAT, HAWC, H.E.S.S., MAGIC, and VERITAS collaborations in order to maximize the sensitivity of DM searches and improve the current results. We use a joint maximum likelihood approach combining each experiment’s individual analysis to derive more constraining upper limits on the WIMP DM self-annihilation cross-section as a function of DM particle mass. We present new DM constraints over the widest mass range ever reported, extending from 5 GeV to 100 TeV thanks to the combination of these five different \u1d6fe-ray instruments

Non-structural carbohydrates in woody plants compared among laboratories

Non-structural carbohydrates (NSC) in plant tissue are frequently quantified to make inferences about plant responses to environmental conditions. Laboratories publishing estimates of NSC of woody plants use many different methods to evaluate NSC. We asked whether NSC estimates in the recent literature could be quantitatively compared among studies. We also asked whether any differences among laboratories were related to the extraction and quantification methods used to determine starch and sugar concentrations. These questions were addressed by sending sub-samples collected from five woody plant tissues, which varied in NSC content and chemical composition, to 29 laboratories. Each laboratory analyzed the samples with their laboratory-specific protocols, based on recent publications, to determine concentrations of soluble sugars, starch and their sum, total NSC. Laboratory estimates differed substantially for all samples. For example, estimates for Eucalyptus globulus leaves (EGL) varied from 23 to 116 (mean = 56) mg g⁻¹ for soluble sugars, 6–533 (mean = 94) mg g⁻¹ for starch and 53–649 (mean = 153) mg g⁻¹ for total NSC. Mixed model analysis of variance showed that much of the variability among laboratories was unrelated to the categories we used for extraction and quantification methods (method category R² = 0.05–0.12 for soluble sugars, 0.10–0.33 for starch and 0.01–0.09 for total NSC). For EGL, the difference between the highest and lowest least squares means for categories in the mixed model analysis was 33 mg g⁻¹ for total NSC, compared with the range of laboratory estimates of 596 mg g⁻¹. Laboratories were reasonably consistent in their ranks of estimates among tissues for starch (r = 0.41–0.91), but less so for total NSC (r = 0.45–0.84) and soluble sugars (r = 0.11–0.83). Our results show that NSC estimates for woody plant tissues cannot be compared among laboratories. The relative changes in NSC between treatments measured within a laboratory may be comparable within and between laboratories, especially for starch. To obtain comparable NSC estimates, we suggest that users can either adopt the reference method given in this publication, or report estimates for a portion of samples using the reference method, and report estimates for a standard reference material. Researchers interested in NSC estimates should work to identify and adopt standard methods.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Oxford University Press. The published article can be found at: http://treephys.oxfordjournals.org/Keywords: soluble sugars, starch, particle size, reference method, standardization, non-structural carbohydrate chemical analysis, extraction and quantification consistenc