Opposite Roles of NMDA Receptors in Relapsing and Primary Progressive Multiple Sclerosis

Synaptic transmission and plasticity mediated by NMDA receptors (NMDARs) could modulate the severity of multiple sclerosis (MS). Here the role of NMDARs in MS was first explored in 691 subjects carrying specific allelic variants of the NR1 subunit gene or of the NR2B subunit gene of this glutamate receptor. The analysis was replicated for significant SNPs in an independent sample of 1548 MS subjects. The C allele of rs4880213 was found to be associated with reduced NMDAR-mediated cortical excitability, and with increased probability of having more disability than the CT/TT MS subjects. MS severity was higher in the CC group among relapsing-remitting MS (RR-MS) patients, while primary progressive MS (PP-MS) subjects homozygous for the T allele had more pronounced clinical worsening. Mean time to first relapse, but not to an active MRI scan, was lower in the CC group of RR-MS patients, and the number of subjects with two or more clinical relapses in the first two years of the disease was higher in CC compared to CT/TT group. Furthermore, the percentage of relapses associated with residual disability was lower in subjects carrying the T allele. Lesion load at the MRI was conversely unaffected by the C or T allele of this SNP in RR-MS patients. Axonal and neuronal degeneration at the optical coherence tomography was more severe in the TT group of PP-MS patients, while reduced retinal nerve fiber thickness had less consequences on visual acuity in RR-MS patients bearing the T allele. Finally, the T allele was associated with preserved cognitive abilities at the Rao’s brief repeatable neuropsychological battery in RR-MS. Signaling through glutamate NMDARs enhances both compensatory synaptic plasticity and excitotoxic neurodegeneration, impacting in opposite ways on RR-MS and PP-MS pathophysiological mechanisms.     

Evaluation of Relapse-Free Survival in T3N0 Colon Cancer: The Role of Chemotherapy,a Multicentric Retrospective Analysis

Background

Adjuvant chemotherapy (AC) in Stage II Colon Cancer (CC) is still under debate. Choice should be based on patients and disease characteristics. According to guidelines AC should be considered in high-risk T3N0 patients. No data are available for better option in low-risk patients. The aim of the study is to retrospectively evaluate relapse-free survival (RFS) and disease-free survival (DFS) according to treatment received in T3N0 CC.

Methods

RFS and DFS are evaluated with Kaplan-Meier method. Multivariate Cox proportional hazard model was developed using stepwise regression, enter limit and remove limit were p = 0.10 and p = 0.15, respectively.

Results

834 patients with T3N0 CC were recruited. Median age was 69 (29–93), M/F 463/371, 335 low-risk patients (40.2%), 387 high-risk (46.4%), 112 unknown (13.4%); 127 (15.2%) patients showed symptoms at diagnosis. Median sampled lymph nodes were 15 (1–76); 353 (42.3%) patients were treated with AC. Median follow up was 5 years (range 3–24). The 5-years RFS was 78.4% and the 5-years DFS was 76.7%. At multivariate analysis symptoms, lymph nodes, and adjuvant chemotherapy were prognostic factors for RFS. AC is prognostic factor for all endpoints.In low-risk group 5-years RFS was 87.3% in treated patients and 74.7% in non-treated patients (p 0.03); in high-risk group was respectively 82.7% and 71.4% (p 0.005).

Conclusions

Data confirmed the role of known prognostic factors and suggest the relevance of adjuvant chemotherapy also in low-risk stage II T3N0 CC patients. However, the highest risk in low-risk subgroup should be identified to be submitted to AC.     

Selenium improves photosynthesis and induces ultrastructural changes but does not alleviate cadmium-stress damages in tomato plants

Protoplasma - The application of Se to plants growing under Cd contamination may become an alternative strategy to minimize Cd damage. However, there is no specific information available regarding...     

When size does matter: organelle size influences the properties of transport mediated by molecular motors

Background

Organelle transport is driven by the action of molecular motors. In this work, we studied the dynamics of organelles of different sizes with the aim of understanding the complex relation between organelle motion and microenvironment.

Methods

We used single particle tracking to obtain trajectories of melanosomes (pigmented organelles in Xenopus laevis melanophores). In response to certain hormones, melanosomes disperse in the cytoplasm or aggregate in the perinuclear region by the combined action of microtubule and actin motors.

Results and conclusions

Melanosome trajectories followed an anomalous diffusion model in which the anomalous diffusion exponent (α) provided information regarding the trajectories' topography and thus of the processes causing it. During aggregation, the directionality of big organelles was higher than that of small organelles and did not depend on the presence of either actin or intermediate filaments (IF). Depolymerization of IF significantly reduced α values of small organelles during aggregation but slightly affect their directionality during dispersion.

General significance

Our results could be interpreted considering that the number of copies of active motors increases with organelle size. Transport of big organelles was not influenced by actin or IF during aggregation showing that these organelles are moved processively by the collective action of dynein motors. Also, we found that intermediate filaments enhance the directionality of small organelles suggesting that this network keeps organelles close to the tracks allowing their efficient reattachment. The higher directionality of small organelles during dispersion could be explained considering the better performance of kinesin-2 vs. dynein at the single molecule level.     

Biochemical modifications of gliadins induced by microbial transglutaminase on wheat flour

Background

Celiac disease (CD) is an immune-mediated disorder caused by the ingestion of wheat gluten. A lifelong, gluten-free diet is required to normalize the intestinal mucosa. We previously found that transamidation by microbial transglutaminase (mTGase) suppressed the gliadin-specific immune response in intestinal T-cell lines from CD patients and in models of gluten sensitivity.

Methods

SDS-PAGE, Western blot, ELISA, tissue transglutaminase (tTGase) assay and nano-HPLC–ESI-MS/MS experiments were used to analyze prolamins isolated from treated wheat flour.

Results

Gliadin and glutenin yields decreased to 7.6 ± 0.5% and 7.5 ± 0.3%, respectively, after a two-step transamidation reaction that produced a water-soluble protein fraction (spf). SDS-PAGE, Western blot and ELISA analyses confirmed the loss of immune cross-reactivity with anti-native gliadin antibodies in residual transamidated gliadins (K-gliadins) and spf as well as the occurrence of neo-epitopes. Nano-HPLC–ESI-MS/MS experiments identified some native and transamidated forms of celiacogenic peptides including p31–49 and confirmed that mTGase had similar stereo-specificity of tTGase. Those peptides resulted to be 100% and 57% modified in spf and K-gliadins, respectively. In particular, following transamidation p31–49 lost its ability to increase tTGase activity in Caco-2 cells. Finally, bread manufactured with transamidated flour had only minor changes in baking characteristics.

Conclusions

The two-step transamidation reaction modified the analyzed gliadin peptides, which are known to trigger CD, without influencing main technological properties.

General significance

Our data shed further light on a detoxification strategy alternative to the gluten free diet and may have important implications for the management of CD patients.     

Probing antioxidant activity of 2′-hydroxychalcones: Crystal and molecular structures, in vitro antiproliferative studies and in vivo effects on glucose regulation

In order to better understand the antioxidant behavior of a series of polyphenolic 2′-hydroxychalcones, we describe the results of several chemical and biological studies, in vitro and in vivo. Single crystal X-ray methods elucidated their molecular structures and important intermolecular interactions such as H-bonding and molecular stacking in the crystal structures that contribute to our knowledge in explaining antioxidant activity. The results of experiments using the 1,1-diphenyl-2-dipicrylhydrazyl (DPPH) UV–vis spectroscopic method indicate that a hydroxyl group in position 5′ induces the highest antioxidant activity. Consequently, 2,2′,5′-trihydroxychalcone was selected for further study in vitro towards ROS scavenging in L-6 myoblasts and THP-1 human monocytes, where it shows an excellent antioxidant activity in a concentration range lower than that reported by most studies of related molecules. In addition, this chalcone shows a very selective activity: it inhibits the proliferation of leukemic cells, but it does not affect the normal L-6 myoblasts and human fibroblasts. In studying 2,2′,5′-trihydroxychalcone's effect on weight gain and serum glucose and insulin levels in Zucker fatty (fa⁻/fa⁻) rats we found that supplementing the diet with a 10 mg/kg dose of this chalcone (3 times weekly) blunted the increase in glucose that co-occurs with weight gain over the 6-week treatment period. It is concluded that 2,2′,5′-trihydroxychalcone has the potential to serve as a protective agent for some debilitating diseases.     

Annual and monthly carbon balance in an intensively managed Mediterranean olive orchard

At present, research activities on the role of orchard systems in sequestering atmospheric CO₂ remain scarce. This paper aimed to contribute to assessing the carbon balance of a Mediterranean olive (Olea europea) orchard. The net ecosystem exchange, the ecosystem respiration and the gross primary production were computed for two consecutive years through eddy covariance, and the different biomass accumulation terms were also inferred in the same period through an inventorial method. The net carbon exchange ranged from 13.45 t(C) ha^?1 year^?1 to 11.60 t(C) ha^?1 year^?1. Very similar values [12.2 and 11.5 t(C) ha^?1 year^?1] were found with the direct carbon accumulation inventory. The intensive farming management (irrigation included) and the young age of the plants (12–16 years old), still in an active growing phase, led the olive plantation to be a higher carbon sink with respect to other evergreen orchards reported in the literature.     

Models of the pharmacophoric pattern and affinity trend of methyl 2-(aminomethyl)-1-phenylcyclopropane-1-carboxylate derivatives as σ1 ligands

Sigma-1 (σ₁) affinities of methyl 2-(aminomethyl)-1-phenylcyclopropane-1-carboxylate (MAPCC) derivatives were modelled by the genetic algorithm with linear assignment of hypermolecular alignment of datasets (GALAHAD) and the comparative molecular field analysis (CoMFA)/comparative molecular similarity indices analysis (CoMSIA) methods. GALAHAD was used for deriving the 3D pharmacophore pattern that encompasses the most potent σ₁ ligands within this series. Five MAPCC derivatives with a high σ₁ affinity were used for deriving this model. The obtained model included a nitrogen atom, the hydrophobes and the hydrogen bond acceptor features; it was able to identify other potent σ₁ ligands. On the other hand, CoMFA and CoMSIA methods were used for deriving quantitative structure–activity relationship (QSAR) models. All QSAR models were trained with 17 compounds, after which they were evaluated for predictive ability with additional five compounds. The best QSAR model was obtained by using CoMSIA, including steric, electrostatic and hydrophobic fields, and had a good predictive quality according to both internal and external validation criteria. In general, the models described herein provide meaningful information relevant for the rational design of new σ₁ ligands.     

Tree-ring wood anatomy and stable isotopes show structural and functional adjustments in olive trees under different water availability

Background and Aims

Olive tree (Olea europaea L.) is a drought-tolerant tree species cultivated in Mediterranean-type environments. Although it is tolerant to drought, dry conditions decrease its productivity. A thorough analysis of the hydraulic architecture and wood anatomical plasticity, as well as of their physiological significance, is needed to understand how olive trees will adapt to the predicted increase in frequency and severity of drought in the Mediterranean region.

Methods

Dendrochronological, stable isotopic (δ¹³C, δ¹⁸O) and wood anatomical analyses were applied to understand how different water availability can affect wood stem structure and function, in rainfed and irrigated at 100 % of crop evapotranspiration (ETc) olive trees in an experimental orchard close to Benevento (Italy) from 1992 to 2009.

Results

Dendrochronological data indicate that cross-dating and synchronization of ring-width time series in olive tree is possible. After the start of irrigation, significantly more negative δ¹³C and lower δ¹⁸O values were recorded in irrigated trees indicating higher stomatal conductance and transpiration rates. Increased water balance induced the formation of a higher number of vessels with higher diameter.

Conclusions

Water balance variations affected wood anatomy and isotopic composition. Anatomical analyses detected structural and functional adjustments in rainfed trees that produced more vessels with lower diameter to prevent cavitation. Isotopic analyses confirmed that irrigated trees continuously showed enhanced transpiration rates.     

Habitat selection in translocated gregarious ungulate species: An interplay between sociality and ecological requirements

The adaptation of translocated organisms to a new environment in the first years after their release is crucial in translocation programs because it may affect survival and reproductive success. Therefore, identifying the factors determining resource selection by the relocated animals is essential to improve the planning and the outcome of such programs. Using data collected in 2006–2009 in the framework of a restocking program, we studied the temporal variation of habitat selection in 14 translocated Alpine ibex (Capra ibex) during the year of their release and the following 3 years. We hypothesized a progressive adaptation of the translocated individuals, highlighted by a gradual decrease in the dissimilarities between translocated and resident individuals in ecological characteristics and social behavior. We tested the differences in habitat selection and home range size between the translocated and resident individuals and compared the spatial overlap between the groups. As expected, the dissimilarities decreased annually. The translocated and resident ibex almost immediately selected the same habitat resources, but the translocated individuals required 3 years to become fully socially assimilated. Our results indicated that habitat selection by gregarious species in a new environment is primarily driven by specific ecological requirements and that sociality plays a significant role. The translocated individuals tended to colonize areas already occupied by residents, either to fulfill social requirements and/or because the location of resident individuals may indicate high-quality habitat. This pattern of behavior must be considered in the planning of translocation programs because habitat selection can affect the outcomes of the programs. © 2013 The Wildlife Society.