Structural changes induced by daily music listening in the recovering brain after middle cerebral artery stroke: a voxel-based morphometry study

Music is a highly complex and versatile stimulus for the brain that engages many temporal, frontal, parietal, cerebellar, and subcortical areas involved in auditory, cognitive, emotional, and motor processing. Regular musical activities have been shown to effectively enhance the structure and function of many brain areas, making music a potential tool also in neurological rehabilitation. In our previous randomized controlled study, we found that listening to music on a daily basis can improve cognitive recovery and improve mood after an acute middle cerebral artery stroke. Extending this study, a voxel-based morphometry (VBM) analysis utilizing cost function masking was performed on the acute and 6-month post-stroke stage structural magnetic resonance imaging data of the patients (n = 49) who either listened to their favorite music [music group (MG), n = 16] or verbal material [audio book group (ABG), n = 18] or did not receive any listening material [control group (CG), n = 15] during the 6-month recovery period. Although all groups showed significant gray matter volume (GMV) increases from the acute to the 6-month stage, there was a specific network of frontal areas [left and right superior frontal gyrus (SFG), right medial SFG] and limbic areas [left ventral/subgenual anterior cingulate cortex (SACC) and right ventral striatum (VS)] in patients with left hemisphere damage in which the GMV increases were larger in the MG than in the ABG and in the CG. Moreover, the GM reorganization in the frontal areas correlated with enhanced recovery of verbal memory, focused attention, and language skills, whereas the GM reorganization in the SACC correlated with reduced negative mood. This study adds on previous results, showing that music listening after stroke not only enhances behavioral recovery, but also induces fine-grained neuroanatomical changes in the recovering brain.

An update of the mechanisms of resistance to EGFR-tyrosine kinase inhibitors in breast cancer: gefitinib (Iressatrade mark)-induced changes in the expression and nucleo-cytoplasmic trafficking of HER-ligands (Review)

Intrinsic resistance to the epidermal growth factor receptor (EGFR; HER1) tyrosine kinase inhibitor (TKI) gefitinib, and more generally to EGFR TKIs, is a common phenomenon in breast cancer. The availability of molecular criteria for predicting sensitivity to EGFR-TKIs is, therefore, the most relevant issue for their correct use and for planning future research. Though it appears that in non-small-cell lung cancer (NSCLC) response to gefitinib is directly related to the occurrence of specific mutations in the EGFR TK domain, breast cancer patients cannot be selected for treatment with gefitinib on the same basis as such EGFR mutations have beenreported neither in primary breast carcinomas nor in several breast cancer cell lines. Alternatively, there is a generalagreement on the hypothesis that the occurrence of molecular alterations that activate transduction pathways downstreamof EGFR (i.e., MEK1/MEK2 - ERK1/2 MAPK and PI-3'K - AKT growth/survival signaling cascades) significantly affect the response to EGFR TKIs in breast carcinomas. However,there are no studies so far addressing a role of EGF-related ligands as intrinsic breast cancer cell modulators of EGFR TKIefficacy. We recently monitored gene expression profiles andsub-cellular localization of HER-1/-2/-3/-4 related ligands (i.e., EGF, amphiregulin, transforming growth factor-α, ß-cellulin,epiregulin and neuregulins) prior to and after gefitinib treatment in a panel of human breast cancer cell lines. First, gefitinibinduced changes in the endogenous levels of EGF-related ligands correlated with the natural degree of breast cancer cellsensitivity to gefitinib. While breast cancer cells intrinsically resistant to gefitinib (IC50 ≥15 μM) markedly up-regulated(up to 600 times) the expression of genes codifying for HERspecific ligands, a significant down-regulation (up to 106 times)of HER ligand gene transcription was found in breast cancer cells intrinsically sensitive to gefitinib (IC50 ≤1 μM). Second,loss of HER1 function differentially regulated the nuclear trafficking of HER-related ligands. While gefitinib treatment induced an active import and nuclear accumulation of the HER ligand NRG in intrinsically gefitinib-resistant breastcancer cells, an active export and nuclear loss of NRG was observed in intrinsically gefitinib-sensitive breast cancer cells.In summary, through in vitro and pharmacodynamic studies we have learned that, besides mutations in the HER1 gene,oncogenic changes downstream of HER1 are the key players regulating gefitinib efficacy in breast cancer cells. It now appears that pharmacological inhibition of HER1 functionalso leads to striking changes in both the gene expression and the nucleo-cytoplasmic trafficking of HER-specific ligands,and that this response correlates with the intrinsic degree of breast cancer sensitivity to the EGFR TKI gefitinib. Therelevance of this previously unrecognized intracrine feedback to gefitinib warrants further studies as cancer cells could bypassthe antiproliferative effects of HER1-targeted therapeutics without a need for the overexpression and/or activation of other HER family members and/or the activation of HER-driven downstream signaling cascades

Minimization of biosynthetic costs in adaptive gene expression responses of yeast to environmental changes

Yeast successfully adapts to an environmental stress by altering physiology and fine-tuning metabolism. This fine-tuning is achieved through regulation of both gene expression and protein activity, and it is shaped by various physiological requirements. Such requirements impose a sustained evolutionary pressure that ultimately selects a specific gene expression profile, generating a suitable adaptive response to each environmental change. Although some of the requirements are stress specific, it is likely that others are common to various situations. We hypothesize that an evolutionary pressure for minimizing biosynthetic costs might have left signatures in the physicochemical properties of proteins whose gene expression is fine-tuned during adaptive responses. To test this hypothesis we analyze existing yeast transcriptomic data for such responses and investigate how several properties of proteins correlate to changes in gene expression. Our results reveal signatures that are consistent with a selective pressure for economy in protein synthesis during adaptive response of yeast to various types of stress. These signatures differentiate two groups of adaptive responses with respect to how cells manage expenditure in protein biosynthesis. In one group, significant trends towards downregulation of large proteins and upregulation of small ones are observed. In the other group we find no such trends. These results are consistent with resource limitation being important in the evolution of the first group of stress responses.

Heat shock response in yeast involves changes in both transcription rates and mRNA stabilities

We have analyzed the heat stress response in the yeast Saccharomyces cerevisiae by determining mRNA levels and transcription rates for the whole transcriptome after a shift from 25uC to 37uC. Using an established mathematical algorithm, theoretical mRNA decay rates have also been calculated from the experimental data. We have verified the mathematical predictions for selected genes by determining their mRNA decay rates at different times during heat stress response using the regulatable tetO promoter. This study indicates that the yeast response to heat shock is not only due to changes in transcription rates, but also to changes in the mRNA stabilities. mRNA stability is affected in 62% of the yeast genes and it is particularly important in shaping the mRNA profile of the genes belonging to the environmental stress response. In most cases, changes in transcription rates and mRNA stabilities are homodirectional for both parameters, although some interesting cases of antagonist behavior are found. The statistical analysis of gene targets and sequence motifs within the clusters of genes with similar behaviors shows that both transcriptional and post-transcriptional regulons apparently contribute to the general heat stress response by means of transcriptional factors and RNA binding proteins.

Phosphorous and nitrogen changes in compost-amended schist soils in vineyards in the D.O. Priorat wine-producing area (NE Spain)

The impact, on nitrogen and phosphorous dynamics, of applying compost at different rates was investigated in soils developed on schist in new terraced vineyards (NTV) and in undisturbed areas (NC). Repacked soil columns amended with 0 (control), 50 t ha –1 (T1) and 100 t ha–1 (T2) of compost were studied under laboratory conditions simulating both situations. The columns were maintained for 1 year, during which time a total of 300 mm of simulated rainfall was applied in ten 30 mm applications. Soil organic matter (OM), nitrogen and phosphorous contents were analysed at the end of the study period and leachates were analysed after each simulated rainfall event. Significant differences in nitrate leaching were observed between the control and the treated soils and these differences were greater in the NC (control = 1.368 g, T1 = 1.526 g and T2 = 1.686 g) than in the NTV soils (control = 0.61 g, T1 = = 1.068 g and T2 = 1.283 g). The relative effect was greater in the NTV soils (T1/control = 1.11 vs. 1.75 and T2/control = 1.23 vs. 2.1 for NC and NTV, respectively). The nitrate concentration in the leached water reached up to 400 mg L–1, which implied a risk of groundwater pollution. Phosphorous losses through leaching were very low with concentrations of < 0.15 mg L–1, without any significant differences between treatments. The phosphorous concentrations in the surface horizon increased by 50.8% in T1 and by 66.8% in T2 in the NC soils, compared with increases of 20.3% and 38%, respectively, in the NTV soils. Due to the high infiltration capacity of the study soils, leaching effects must be considered in order to prevent groundwater pollution.

Concentrative nucleoside transporter 1 (hCNT1) promotes phenotypic changes relevant to tumor biology in a translocation independent manner

Nucleoside transporters (NTs) mediate the uptake of nucleosides and nucleobases across the plasma membrane, mostly for salvage purposes. The canonical NTs belong to two gene families, SLC29 and SLC28. The former encode equilibrative nucleoside transporter proteins (ENTs), which mediate the facilitative diffusion of natural nucleosides with broad selectivity, whereas the latter encode concentrative nucleoside transporters (CNTs), which are sodium-coupled and show high affinity for substrates with variable selectivity. These proteins are expressed in most cell types, exhibiting apparent functional redundancy. This might indicate that CNTs play specific roles in the physiology of the cell beyond nucleoside salvage. Here, we addressed this possibility using adenoviral vectors to restore tumor cell expression of hCNT1 or a polymorphic variant (hCNT1S546P) lacking nucleoside translocation ability. We found that hCNT1 restoration in pancreatic cancer cells significantly altered cell-cycle progression and phosphorylation status of key signal-transducing kinases, promoted poly-(ADP ribose) polymerase hyperactivation and cell death, and reduced tumor growth and cell migration. Importantly, the translocation-defective transporter triggered these same effects on cell physiology. These data predict a novel and totally unexpected biological role for the nucleoside transporter protein hCNT1 that appears to be independent of its role as mediator of nucleoside uptake by cells, thereby suggesting a transceptor function. Cell Death & Disease Anastasis Stephanou Receiving Editor Cell Death & Disease 19th Apr 2013 Dr Perez-Torras Av/ Diagonal 643. Edif. Prevosti, Pl -1 Barcelona 08028 Spain RE: Manuscript CDDIS-13-0136R, 'CDDIS-13-0136R' Dear Dr Perez-Torras, It is a pleasure to inform you that your manuscript has been evaluated at the editorial level and has now been officially accepted for publication in Cell Death & Disease, pending you meet the following editorial requirements: 1) the list of the abbreviations is missing please include Could you send us the revised text as word file via e-mail and we will proceed and transfer the paper onto our typesetters. Please download, print, sign, and return the Licence to Publish Form using the link below. This must be returned via FAX to ++ 39 06 7259 6977 before your manuscript can be published:

APOE status modulates the changes in network connectivity induced by brain stimulation in non-demented elders.

Behavioral consequences of a brain insult represent an interaction between the injury and the capacity of the rest of the brain to adapt to it. We provide experimental support for the notion that genetic factors play a critical role in such adaptation. We induced a controlled brain disruption using repetitive transcranial magnetic stimulation (rTMS) and show that APOE status determines its impact on distributed brain networks as assessed by functional MRI (fMRI).Twenty non-demented elders exhibiting mild memory dysfunction underwent two fMRI studies during face-name encoding tasks (before and after rTMS). Baseline task performance was associated with activation of a network of brain regions in prefrontal, parietal, medial temporal and visual associative areas. APOE ε4 bearers exhibited this pattern in two separate independent components, whereas ε4-non carriers presented a single partially overlapping network. Following rTMS all subjects showed slight ameliorations in memory performance, regardless of APOE status. However, after rTMS APOE ε4-carriers showed significant changes in brain network activation, expressing strikingly similar spatial configuration as the one observed in the non-carrier group prior to stimulation. Similarly, activity in areas of the default-mode network (DMN) was found in a single component among the ε4-non bearers, whereas among carriers it appeared disaggregated in three distinct spatiotemporal components that changed to an integrated single component after rTMS. Our findings demonstrate that genetic background play a fundamental role in the brain responses to focal insults, conditioning expression of distinct brain networks to sustain similar cognitive performance.

Assessment of the water chemistry and the macroinvertebrate community changes produced during the creation of the new Llobregat river mouth (Barcelona, NE Spain)

In 1999, a set of coordinated projects and investments whose principal objective was to transform Barcelona into one of the main distribution points of southern Europe resulted in the relocation of the Llobregat River mouth. The mouth was relocated by draining the old river mouth and constructing a new one. The aim of this study was to characterise the physico-chemical properties and the aquatic macroinvertebrate communities of the new river mouth and to monitor the changes experienced by the estuarine environment during its creation. A sampling point was established in the river 1.8 km upstream from its connection with the new mouth, and two sampling points were established in the new mouth. Samples of water and macroinvertebrates were collected every two months from May 2004 to June 2005, covering the periods before (from May to September 2004) and after (from September 2004 to June 2005) the new mouth was connected to the river and the sea. During the period before its connection to the river and the sea, the new mouth was functionally similar to a lagoon, with clear waters, charophytes and a rich invertebrate community. After the connection was completed, seawater penetrated the river mouth and extended to the connection point with the river (approximately 3.9 km upstream). An increase in conductivity from 4-6 mS cm 1 to 24-30 mS cm 1 caused important changes in the macroinvertebrate community of the new mouth. An initial defaunation was followed by a colonisation of the new mouth by brackish-water and marine invertebrate species. Due to its design (which allows the penetration of the sea) and the decreased discharge from the lower part of the Llobregat River, the new mouth has become an arm of the sea

Inversion polymorphism in two Serbian natural populations of Drosophila subobscura: Analysis of long-term changes

To study whether inversions (or arrangements) by themselves or karyotypes are the main global warming adaptive target of natural selection, two Drosophila subobscura Serbian populations (Apatin and Petnica) were re analyzed using different statistical approaches. Both populations were sampled in an approximately 15 years period: Apatin in 1994 and 2008 + 2009 and Petnica in 1995 and 2010. For all chromosomes, the four collections studied were in Hardy-Weinberg equilibrium. Thus, it seems that inversions (or arrangements) combined at random to constitute populations" karyotypes. However, there were differences in karyotypic fre quencies along the years, although they were significant only for Apatin population. It is possible to conclude that inversions (or arrangements) are likely the target of natural selection, because they presented long term changes, but combine at random to generate the corresponding karyotypic combinations. As a consequence, the frequencies of karyotypes also change along time.

Assessing changes in Cd phytoavailability to tomato in amended calcareous soils.

A plot study was conducted to assess changes in Cd phytoavailability to a tomato cultivar in an agricultural soil in Southeastern Spain amended in two different ways (A and B), under controlled conditions. The experimental soil corresponded to a fine-loamy carbonatic thermic Calcidic Haploxeroll (Soil Survey Staff, 1998). A) Soil was amended with a single application of sewage sludge from a municipal source that had a total Cd concentration of 0.5 mg kg-1 at a rate that represented a final average concentration in the mixture of soil and sludge of less than 50 µg Cd kg-1. B) The amendment consisted of the addition of a mineral fertiliser with the same amount of NPK as in the sewage sludge application. The final levels of Cd were supposed to be negligible. A plot series without amendments was also performed (C). DTPA plus triethanolamine, and ammonium acetate extractable fractions in soils were analysed for all the plots. The time-dependent Cd accumulation in different parts of the tomato plants was studied by means of a Cd salt treatment. For each block (A, B, and C) four levels of Cd (0, 3, 30, 100 mg kg-1) were added as CdCl2. There was a significant increase in plant Cd after the initial cropping. Tomato stems, leaves and fruits were analysed separately for Cd determination. Differential Cd distribution and accumulation in tomato parts was detected.

Land use changes, landscape ecology and their socioeconomic driving forces in the Spanish Mediterranean coast (the Maresme County, 1850-2005)

[cat] Utilitzem un conjunt de mètriques del paisatge per estudiar l'evolució a llarg termini seguida en una típica zona costanera del Mediterrani des de 1850 fins a 2005, que mostren una greu deterioració del medi ambient entre 1950 i 2005. Les principals forces motores d'aquesta degradació del paisatge han estat el creixement urbà experimentat a les antigues zones agrícoles situades a les planes litorals, juntament amb l'abandonament i la reforestació dels vessants dels pujols interceptats per àrees residencials de baixa densitat, carreteres i altres infraestructures lineals. Duem a terme una anàlisi estadística de redundància (RDA) amb la finalitat d'identificar els que considerem com alguns agents rectors socioeconòmics i polítics d'última instància d'aquests impactes ambientals. Els resultats confirmen les nostres hipòtesis interpretatives, que són que: 1) els canvis en les cobertes i usos del sòl determinen canvis en les propietats dels paisatge, tant estructurals com funcionals; 2) aquests canvis no es produeixen per atzar, sinó que estan relacionats amb factors geogràfics i forces socioeconòmiques i polítiques.

Land use changes, landscape ecology and their socioeconomic driving forces in the Spanish Mediterranean coast (the Maresme County, 1850-2005)

[cat] Utilitzem un conjunt de mètriques del paisatge per estudiar l'evolució a llarg termini seguida en una típica zona costanera del Mediterrani des de 1850 fins a 2005, que mostren una greu deterioració del medi ambient entre 1950 i 2005. Les principals forces motores d'aquesta degradació del paisatge han estat el creixement urbà experimentat a les antigues zones agrícoles situades a les planes litorals, juntament amb l'abandonament i la reforestació dels vessants dels pujols interceptats per àrees residencials de baixa densitat, carreteres i altres infraestructures lineals. Duem a terme una anàlisi estadística de redundància (RDA) amb la finalitat d'identificar els que considerem com alguns agents rectors socioeconòmics i polítics d'última instància d'aquests impactes ambientals. Els resultats confirmen les nostres hipòtesis interpretatives, que són que: 1) els canvis en les cobertes i usos del sòl determinen canvis en les propietats dels paisatge, tant estructurals com funcionals; 2) aquests canvis no es produeixen per atzar, sinó que estan relacionats amb factors geogràfics i forces socioeconòmiques i polítiques.

Ultra-Deep Pyrosequencing Detects Conserved Genomic Sites and Quantifies Linkage of Drug-Resistant Amino Acid Changes in the Hepatitis B Virus Genome

Selection of amino acid substitutions associated with resistance to nucleos(t)ide-analog (NA) therapy in the hepatitis B virus (HBV) reverse transcriptase (RT) and their combination in a single viral genome complicates treatment of chronic HBV infection and may affect the overlapping surface coding region. In this study, the variability of an overlapping polymerase-surface region, critical for NA resistance, is investigated before treatment and under antiviral therapy, with assessment of NA-resistant amino acid changes simultaneously occurring in the same genome (linkage analysis) and their influence on the surface coding region.

Changes in the phenolic content of low density lipoprotein after olive oil consumption in men. A randomized crossover controlled trial

Olive oil decreases the risk of CVD. This effect may be due to the fatty acid profile of the oil, but it may also be due to its antioxidant content which differs depending on the type of olive oil. In this study, the concentrations of oleic acid and antioxidants (phenolic compounds and vitamin E) in plasma and LDL were compared after consumption of three similar olive oils, but with differences in their phenolic content. Thirty healthy volunteers participated in a placebo-controlled, double-blind, crossover, randomized supplementation trial. Virgin, common, and refined olive oils were administered during three periods of 3 weeks separated by a 2-week washout period. Participants were requested to ingest a daily dose of 25 ml raw olive oil, distributed over the three meals of the day, during intervention periods. All three olive oils caused an increase in plasma and LDL oleic acid (P,0·05) content. Olive oils rich in phenolic compounds led to an increase in phenolic compounds in LDL (P,0·005). The concentration of phenolic compounds in LDL was directly correlated with the phenolic concentration in the olive oils. The increase in the phenolic content of LDL could account for the increase of the resistance of LDL to oxidation, and the decrease of the in vivo oxidized LDL, observed in the frame of this trial. Our results support the hypothesis that a daily intake of virgin olive oil promotes protective LDL changes ahead of its oxidation.

Botulinum neurotoxin type A blocks the morphological changes induced by chemical stimulation on the presynaptic membrane of Torpedo synaptosomes.

The action of botulinum neurotoxin on acetylcholine release, and on the structural changes at the presynaptic membrane associated with the transmitter release,was studied by using a subcellular fraction of cholinergic nerve terminals (synaptosomes) isolated from the Torpedo electric organ. Acetylcholine and ATP release were continuously monitored by chemiluminescent methods.To catch the membrane morphological changes, the quick-freezing method was applied. Our results show that botulinum neurotoxin inhibits the release of acetylcholine from these isolated nerve terminals in a dose-dependent manner, whereas ATP release is not affected. The maximal inhibition (70%) is achieved at neurotoxin concentrations as low as 125 pM with an incubation time of 6 min. This effect is not linked to an alteration of the integrity of the synaptosomes since, after poisoning by botulinum neurotoxin type A, they show a nonmodified occluded lactate dehydrogenase activity. Moreover, membrane potential is not altered by the toxin with respect to the control, either in resting condition or after potassium depolarization. In addition to acetylcholine release inhibition, botulinum neurotoxin blocks the rearrangement of the presynaptic intramembrane particles induced by potassium stimulation. The action of botulinum neurotoxin suggests that the intramembrane particle rearrangement is related to the acetylcholine secretion induced by potassium stimulation in synaptosomes isolated from the electric organ of Torpedo marmorata.