Imbalance of p75(NTR)/TrkB protein expression in Huntington's disease: Implication for neuroprotective therapies

Neuroprotective therapies based on brain-derived neurotrophic factor (BDNF) administration have been proposed for Huntington's disease (HD) treatment. However, our group has recently reported reduced levels of TrkB in HD mouse models and HD human brain suggesting that besides a decrease on BDNF levels a reduction of TrkB expression could also contribute to diminished neurotrophic support in HD. BDNF can also bind to p75 neurotrophin receptor (p75(NTR)) modulating TrkB signaling. Therefore, in this study we have analyzed the levels of p75(NTR) in several HD models, as well as in HD human brain. Our data demonstrates a p75(NTR)/TrkB imbalance in the striatum of two different HD mouse models, Hdh(Q111/111) homozygous knockin mice and R6/1 mice that was also manifested in the putamen of HD patients. The imbalance between TrkB and p75(NTR) levels in a HD cellular model did not affect BDNF-mediated TrkB activation of prosurvival pathways but induced activation of apoptotic cascades as demonstrated by increased JNK phosphorylation. Moreover, BDNF failed to protect mutant huntingtin striatal cells transfected with p75(NTR) against NMDA-mediated excitotoxicity, which was associated with decreased Akt phosphorylation. Interestingly, lack of Akt activation following BDNF and NMDA treatment correlated with increased PP1 levels. Accordingly, pharmacological inhibition of PP1 by okadaic acid (OA) prevented mutant huntingtin striatal cell death induced by NMDA and BDNF. Altogether, our findings demonstrate that the p75(NTR)/TrkB imbalance induced by mutant huntingtin in striatal cells associated with the aberrant activity of PP1 disturbs BDNF neuroprotection likely contributing to increasing striatal vulnerability in HD. On the basis of this data we hypothesize that normalization of p75(NTR) and/or TrkB expression or their signaling will improve BDNF neuroprotective therapies in HD. Cell Death and Disease (2013) 4, e595; doi:10.1038/cddis.2013.116; published online 18 April 201

Higher education and unemployment in Europe : an analysis of the academic subject and national effects

This paper examines the impact of an academic degree and field of study on short and long-term unemployment across Europe (EU15). Labour Force Survey (LFS) data on over half a million individuals are utilised for that purpose. The harmonized LFS classification of level of education and field of study overcomes past problems of comparability across Europe. The study analyses (i) the effect of an academic degree at a European level, (ii) the specific effect of 14 academic subjects and (iii) country specific effects. The results indicate that an academic degree is more effective on reducing the likelihood of short-term than long-term unemployment. This general pattern even though it is observed for most of the academic subjects its levels show significant variation across disciplines and countries

Improved prediction of mortality by combinations of inflammatory markers and standard clinical scores in patients with acute-on-chronic liver failure and acute decompensation

BACKGROUND AND AIM: Acute-on-chronic liver failure (ACLF) as a sinister prognosis and there is a need for accurate biomarkers and scoring systems to better characterize ACLF patients and predict prognosis. Systemic inflammation and renal failure are hallmarks in ACLF disease development and progression. We hypothesized that the combination of specific inflammatory markers in combination with clinical scores are better predictors of survival than the originally developed CLIF-C acute decompensation (AD) and CLIF-C ACLF scores. METHODS: We re-evaluated all previously measured inflammatory markers in 522 patients from the CANONIC study, 342 without and 180 with ACLF. We used the Harrell's C-index to determine the best marker alone or in combination with the original scores and calculated new scores for prediction of mortality in the original CANONIC cohort. RESULTS: The best markers to predict 90-day mortality in patients without ACLF were the plasma macrophage activation markers soluble (s)CD163 and mannose receptor (sMR). Urinary neutrophil gelatinase associated lipocalin (UNGAL) and sCD163 were predictors for 28-day mortality in patients with ACLF. The new developed CLIF-C AD+sMR score in patients without ACLF improved 90-days mortality prediction compared to the original CLIF-C AD score (C-index 0.82(0.78-0.86) vs. 0.74(0.70-0.78, P=0.004). Further, the new CLIF-C ACLF+sCD163+UNGAL improved the original CLIF-C ACLF score for 28-days mortality (0.85(0.79-0.91) vs. 0.75(0.70-0.80), P=0.039). CONCLUSIONS: The capability of these inflammatory markers to improve the original prognostic scores in cirrhosis patients without and with ACLF points to a key role of macrophage activation and inflammation in the development and progression of AD and ACLF

Interactions of treated municipal wastewater with native plant species

Potentially, the restoration of native ecosystems could be combined with the land application of treated municipal wastewater (TMW), reducing TMW discharge into waterbodies. High levels of nutrients, pathogens, and other contaminants from TMW can degrade water quality. The land application of TMW onto native vegetation reduces the nutrient load in water bodies and may create zones of ecological value. However, establishing native plants may be challenging if the species are not adapted to highly fertile environments, such as those resulting from TMW irrigation. There is a critical knowledge gap about the response of native plant species to irrigation with TMW. We aimed to determine the distribution and speciation of nutrients in the soil- plant system following application of TMW onto 11 species of native plants in a long-term field trial on Banks Peninsula, New Zealand (NZ). TMW was irrigated at a rate of 1000 mm per annum, equivalent to N, and P loading rates of 194 and 110 kg ha yr¯¹, respectively. We determined physicochemical properties from soil profiles (0–65 cm) under selected species as well as the growth and chemical composition of the plants. Despite the site receiving 950 kg ha¯¹ yr¯¹ of Na, there was no evidence of impaired soil structure following TMW irrigation. Nitrogen did not accumulate in the soil, and it is likely to have been taken up by plants or lost through denitrification and nitrate leaching. The accumulation rate of P indicated that soil P concentrations will remain within the range found in NZ agricultural soils for at least 50 years. TMW irrigation increased plant height by 10% compared to the control after 3.5 years of growth. Plant species significantly affected the concentrations of total C, total N, nitrate (NO‾₃), and Na in the soil. TMW application had negligible effects on the elemental composition of plant foliage. NZ native vegetation can facilitate the land application of TMW. Future work should elucidate the maximum rates that can be applied as well as the effect of TMW on the soil microbiota

Classification of Radiologically Isolated Syndrome and Clinically Isolated Syndrome with Machine-Learning Techniques

Background and purpose: The unanticipated detection by magnetic resonance imaging (MRI) in the brain of asymptomatic subjects of white matter lesions suggestive of multiple sclerosis (MS) has been named radiologically isolated syndrome (RIS). As the difference between early MS [i.e. clinically isolated syndrome (CIS)] and RIS is the occurrence of a clinical event, it is logical to improve detection of the subclinical form without interfering with MRI as there are radiological diagnostic criteria for that. Our objective was to use machine-learning classification methods to identify morphometric measures that help to discriminate patients with RIS from those with CIS. Methods: We used a multimodal 3-T MRI approach by combining MRI biomarkers (cortical thickness, cortical and subcortical grey matter volume, and white matter integrity) of a cohort of 17 patients with RIS and 17 patients with CIS for single-subject level classification. Results: The best proposed models to predict the diagnosis of CIS and RIS were based on the Naive Bayes, Bagging and Multilayer Perceptron classifiers using only three features: the left rostral middle frontal gyrus volume and the fractional anisotropy values in the right amygdala and right lingual gyrus. The Naive Bayes obtained the highest accuracy [overall classification, 0.765; area under the receiver operating characteristic (AUROC), 0.782]. Conclusions: A machine-learning approach applied to multimodal MRI data may differentiate between the earliest clinical expressions of MS (CIS and RIS) with an accuracy of 78%. Keywords: Bagging; Multilayer Perceptron; Naive Bayes classifier; clinically isolated syndrome; diffusion tensor imaging; machine-learning; magnetic resonance imaging; multiple sclerosis; radiologically isolated syndrome.Comment: 24 pages, 2 table

Synthetic routes, characterization and photophysical properties of luminescent, surface functionalized nanodiamonds

The functionalization of small diameter (ca. 50 nm) polycarboxylated nanodiamond particles using amide coupling methodologies in both water and acetonitrile solvent has been investigated. In this manner, the surfaces of nanodiamond particles were adorned with different luminescent moieties, including a green fluorescent 1,8-naphthalimide species (Nap-1), and a red emitting ruthenium(II) tris-bipyridine complex (Ru-1), as well as dual functionalization with both luminophores. Comprehensive characterization of the surface functionalized nanodiamonds has been achieved using a combination of dynamic light scattering, nanoparticle tracking analysis, transmission electron microscopy, X-ray photoelectron spectroscopy, zeta potential measurements, microwave plasma atomic emission spectroscopy and time-resolved photophysics. The tendency of the functionalized nanodiamonds to aggregate reflects the degree of surface substitution, yielding small aggregates with typical particle sizes ca. 150 nm. This is likely to be driven by the reduction of the zeta potential, concomitant with the conversion of surface charged carboxylate groups to neutral amide functions. The results show that luminescent nanodiamond materials can be synthesised with tuneable photophysical properties

Suppression of High-p_T Neutral Pion Production in Central Pb+Pb Collisions at sqrt{s_NN} = 17.3 GeV Relative to p+C and p+Pb Collisions

Neutral pion transverse momentum spectra were measured in p+C and p+Pb collisions at sqrt{s_NN} = 17.4 GeV at mid-rapidity 2.3 < eta_lab < 3.0 over the range 0.7< p_T < 3.5 GeV/c. The spectra are compared to pi0 spectra measured in Pb+Pb collisions at sqrt{s_NN} = 17.3 GeV in the same experiment. For a wide range of Pb+Pb centralities (N_part < 300) the yield of pi0's with p_T > 2 GeV/c is larger than or consistent with the p+C or p+Pb yields scaled with the number of nucleon-nucleon collisions (N_coll), while for central Pb+Pb collisions with N_part > 350 the pi0 yield is suppressed.Comment: 5 pages, 4 figure

Central Pb+Pb Collisions at 158 A GeV/c Studied by Pion-Pion Interferometry

Two-particle correlations have been measured for identified negative pions from central 158 AGeV Pb+Pb collisions and fitted radii of about 7 fm in all dimensions have been obtained. A multi-dimensional study of the radii as a function of kT is presented, including a full correction for the resolution effects of the apparatus. The cross term Rout-long of the standard fit in the Longitudinally CoMoving System (LCMS) and the vl parameter of the generalised Yano-Koonin fit are compatible with 0, suggesting that the source undergoes a boost invariant expansion. The shapes of the correlation functions in Qinv and Qspace have been analyzed in detail. They are not Gaussian but better represented by exponentials. As a consequence, fitting Gaussians to these correlation functions may produce different radii depending on the acceptance of the experimental setup used for the measurement.Comment: 13 pages including 10 figure

Stroke related mortality at different altitudes: A 17-year nationwide population-based analysis from Ecuador

Worldwide, more than 5.7% of the population reside above 1,500m of elevation. It has been hypothesized that acute short-term hypoxia exposure could increase the risk of developing a stroke. Studies assessing the effect of altitude on stroke have provided conflicting results, some analyses suggest that long-term chronic exposure could be associated with reduced mortality and lower stroke incidence rates. An ecological analysis of all stroke hospital admissions, mortality rates and disability-adjusted life years in Ecuador was performed from 2001-2017. The cases and population at risk were categorized in low (<1,500m), moderate (1,500m -2,500m), high (2,500m -3,500m) and very high altitude (3,500-5,500m) according to the place of residence. The derived crude and direct standardized age-sex adjusted mortality and hospital admission rates were calculated. A total of 38,201 deaths and 75,893 stroke-related hospital admissions were reported. High altitude populations (HAP) had lower stroke mortality in men (OR: 0.91 [0.88 - 0.95]) and women (OR: 0.83 [0.79 - 0.86]). In addition, HAP had a significant lower risk of getting admitted to the hospital when compared with the low altitude group in men (OR: 0.55 [CI95% 0.54 - 0.56]) and women (OR: 0.65 [CI95% [0.64 - 0.66]). This is the first epidemiological study that aims to elucidate the association between stroke and altitude using four different elevation ranges. Our findings suggest that living at higher elevations offers a reduction or the risk of dying due to stroke as well as a reduction in the probability of being admitted to the hospital. Nevertheless, this protective factor has a stronger effect between 2,000m to 3,500 m

Search for Disoriented Chiral Condensates in 158 AGeV Pb+Pb Collisions

The restoration of chiral symmetry and its subsequent breaking through a phase transition has been predicted to create regions of Disoriented Chiral Condensates (DCC). This phenomenon has been predicted to cause anomalous fluctuations in the relative production of charged and neutral pions in high-energy hadronic and nuclear collisions. The WA98 experiment has been used to measure charged and photon multiplicities in the central region of 158 AGeV Pb+Pb collisions at the CERN SPS. In a sample of 212646 events, no clear DCC signal can be distinguished. Using a simple DCC model, we have set a 90% C.L. upper limit on the maximum DCC production allowed by the data.Comment: 20 Pages, LaTeX, uses elsart.cls, 8 eps figures included, submitted to Physics Letters