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1.  Management of primary achalasia: The role of endoscopy 
Achalasia is an oesophageal motor disorder which leads to the functional obstruction of the lower oesophageal sphincter (LES) and is currently incurable. The main objective of all existing therapies is to achieve a reduction in the obstruction of the distal oesophagus in order to improve oesophageal transit, relieve the symptomatology, and prevent long-term complications. The most common treatments used are pneumatic dilation (PD) and laparoscopic Heller myotomy, which involves partial fundoplication with comparable short-term success rates. The most economic non-surgical therapy is PD, with botulinum toxin injections reserved for patients with a higher surgical risk for whom the former treatment option is unsuitable. A new technology is peroral endoscopic myotomy, postulated as a possible non-invasive alternative to surgical myotomy. Other endoluminal treatments subject to research more recently include injecting ethanolamine into the LES and using a temporary self-expanding metallic stent. At present, there is not enough evidence permitting a routine recommendation of any of these three novel methods. Patients must undergo follow-up after treatment to guarantee that their symptoms are under control and to prevent complications. Most experts are in favour of some form of endoscopic follow-up, however no established guidelines exist in this respect. The prognosis for patients with achalasia is good, although a recurrence after treatment using any method requires new treatment.
doi:10.4253/wjge.v7.i6.593
PMCID: PMC4461934  PMID: 26078828
Achalasia; Endoscopic treatment; Dilation; Botulinum toxin; Myotomy
2.  Ortho-methylated 3-hydroxypyridines hinder hen egg-white lysozyme fibrillogenesis 
Scientific Reports  2015;5:12052.
Protein aggregation with the concomitant formation of amyloid fibrils is related to several neurodegenerative diseases, but also to non-neuropathic amyloidogenic diseases and non-neurophatic systemic amyloidosis. Lysozyme is the protein involved in the latter, and it is widely used as a model system to study the mechanisms underlying fibril formation and its inhibition. Several phenolic compounds have been reported as inhibitors of fibril formation. However, the anti-aggregating capacity of other heteroaromatic compounds has not been studied in any depth. We have screened the capacity of eleven different hydroxypyridines to affect the acid-induced fibrillization of hen lysozyme. Although most of the tested hydroxypyridines alter the fibrillation kinetics of HEWL, only 3-hydroxy-2-methylpyridine, 3-hydroxy-6-methylpyridine and 3-hydroxy-2,6-dimethylpyridine completely abolish fibril formation. Different biophysical techniques and several theoretical approaches are combined to elucidate their mechanism of action. O-methylated 3-hydroxypyridines bind non-cooperatively to two distinct but amyloidogenic regions of monomeric lysozyme. This stabilises the protein structure, as evidenced by enhanced thermal stability, and results in the inhibition of the conformational transition that precedes fibril assembly. Our results point to o-methylated 3-hydroxypyridines as a promising molecular scaffold for the future development of novel fibrillization inhibitors.
doi:10.1038/srep12052
PMCID: PMC4500996  PMID: 26169912
3.  Effects of allopurinol on exercise-induced muscle damage: new therapeutic approaches? 
Cell Stress & Chaperones  2014;20(1):3-13.
Intensive muscular activity can trigger oxidative stress, and free radicals may hence be generated by working skeletal muscle. The role of the enzyme xanthine oxidase as a generating source of free radicals is well documented and therefore is involved in the skeletal muscle damage as well as in the potential transient cardiovascular damage induced by high-intensity physical exercise. Allopurinol is a purine hypoxanthine-based structural analog and a well-known inhibitor of xanthine oxidase. The administration of the xanthine oxidase inhibitor allopurinol may hence be regarded as promising, safe, and an economic strategy to decrease transient skeletal muscle damage (as well as heart damage, when occurring) in top-level athletes when administered before a competition or a particularly high-intensity training session. Although continuous administration of allopurinol in high-level athletes is not recommended due to its possible role in hampering training-induced adaptations, the drug might be useful in non-athletes. Exertional rhabdomyolysis is the most common form of rhabdomyolysis and affects individuals participating in a type of intense exercise to which they are not accustomed. This condition can cause exercise-related myoglobinuria, thus increasing the risk of acute renal failure and is also associated with sickle cell trait. In this manuscript, we have reviewed the recent evidence about the effects of allopurinol on exercise-induced muscle damage. More research is needed to determine whether allopurinol may be useful for preventing not only exertional rhabdomyolysis and acute renal damage but also skeletal muscle wasting in critical illness as well as in immobilized, bedridden, sarcopenic or cachectic patients.
doi:10.1007/s12192-014-0543-2
PMCID: PMC4255256  PMID: 25181966
Xanthine oxidase; Free radicals; Muscle injury; Rhabdomyolysis; Sarcopenia; Cachexy
4.  Executioner Caspase-3 and 7 Deficiency Reduces Myocyte Number in the Developing Mouse Heart 
PLoS ONE  2015;10(6):e0131411.
Executioner caspase-3 and -7 are proteases promoting cell death but non-apoptotic roles are being discovered. The heart expresses caspases only during development, suggesting they contribute to the organ maturation process. Therefore, we aimed at identifying novel functions of caspases in heart development. We induced simultaneous deletion of executioner caspase-3 and -7 in the mouse myocardium and studied its effects. Caspase knockout hearts are hypoplastic at birth, reaching normal weight progressively through myocyte hypertrophy. To identify the molecular pathways involved in these effects, we used microarray-based transcriptomics and multiplexed quantitative proteomics to compare wild type and executioner caspase-deficient myocardium at different developmental stages. Transcriptomics showed reduced expression of genes promoting DNA replication and cell cycle progression in the neonatal caspase-deficient heart suggesting reduced myocyte proliferation, and expression of non-cardiac isoforms of structural proteins in the adult null myocardium. Proteomics showed reduced abundance of proteins involved in oxidative phosphorylation accompanied by increased abundance of glycolytic enzymes underscoring retarded metabolic maturation of the caspase-null myocardium. Correlation between mRNA expression and protein abundance of relevant genes was confirmed, but transcriptomics and proteomics indentified complementary molecular pathways influenced by caspases in the developing heart. Forced expression of wild type or proteolytically inactive caspases in cultured cardiomyocytes induced expression of genes promoting cell division. The results reveal that executioner caspases can modulate heart’s cellularity and maturation during development, contributing novel information about caspase biology and heart development.
doi:10.1371/journal.pone.0131411
PMCID: PMC4487935  PMID: 26121671
5.  Primary Cutaneous Mucormycosis Produced by the New Species Apophysomyces mexicanus 
Journal of Clinical Microbiology  2014;52(12):4428-4431.
A case of fungal necrotizing fasciitis that appeared in an immunocompetent Mexican woman after a car accident is described. The patient did not respond to antifungal treatment and died 4 days later. The fungus was molecularly identified as a new species of Apophysomyces, namely, Apophysomyces mexicanus.
doi:10.1128/JCM.02138-14
PMCID: PMC4313335  PMID: 25297328
6.  Babelomics 5.0: functional interpretation for new generations of genomic data 
Nucleic Acids Research  2015;43(Web Server issue):W117-W121.
Babelomics has been running for more than one decade offering a user-friendly interface for the functional analysis of gene expression and genomic data. Here we present its fifth release, which includes support for Next Generation Sequencing data including gene expression (RNA-seq), exome or genome resequencing. Babelomics has simplified its interface, being now more intuitive. Improved visualization options, such as a genome viewer as well as an interactive network viewer, have been implemented. New technical enhancements at both, client and server sides, makes the user experience faster and more dynamic. Babelomics offers user-friendly access to a full range of methods that cover: (i) primary data analysis, (ii) a variety of tests for different experimental designs and (iii) different enrichment and network analysis algorithms for the interpretation of the results of such tests in the proper functional context. In addition to the public server, local copies of Babelomics can be downloaded and installed. Babelomics is freely available at: http://www.babelomics.org.
doi:10.1093/nar/gkv384
PMCID: PMC4489263  PMID: 25897133
7.  Prognostic Value of the Interaction between Galectin-3 and Antigen Carbohydrate 125 in Acute Heart Failure 
PLoS ONE  2015;10(4):e0122360.
Aims
Galectin-3 (Gal-3) and carbohydrate antigen 125 (CA125) have emerged as robust prognostic biomarkers in heart failure. Experimental data have also suggested a potential molecular interaction between CA125 and Gal-3; however, the biological and clinical relevance of this interaction is still uncertain. We sought to evaluate, in patients admitted for acute heart failure, the association between plasma Gal-3 with all-cause mortality and the risk for rehospitalizations among high and low levels of CA125.
Methods and Results
We included 264 consecutive patients admitted for acute heart failure to the Cardiology Department in a third-level center. Both biomarkers were measured on admission. Negative binomial and Cox regression models were used to evaluate the prognostic effect of the interaction between Gal-3 and CA125 (dichotomized by its median) with hospital readmission and all-cause mortality, respectively. During a median follow-up of 2 years (IQR = 1-2.8), 108 (40.9%) patients deaths and 365 rehospitalizations in 171 (69.5%) patients were registered. In a multivariable setting, the effect of Gal-3 on mortality and rehospitalization was differentially mediated by CA125 (p = 0.007 and p<0.001, respectively). Indeed, in patients with CA125 above median (>67 U/ml), values across the continuum of Gal-3 showed a positive and almost linear relationship with either the risk of death or rehospitalization. Conversely, when CA125 was below median (≤67 U/ml), Gal-3 lacked any prognostic effect on both endpoints.
Conclusion
In patients with acute heart failure, Gal-3 was strongly associated with higher risk of long-term mortality and repeated rehospitalizations, but only in those patients exhibiting higher values of CA125 (above 67 U/ml).
doi:10.1371/journal.pone.0122360
PMCID: PMC4395409  PMID: 25875367
8.  Experimental Therapy with Azoles against Candida guilliermondii 
Antimicrobial Agents and Chemotherapy  2014;58(10):6255-6257.
We evaluated the in vitro killing activity of voriconazole (VRC) and posaconazole (PSC) against two clinical isolates of Candida guilliermondii. The two drugs showed fungistatic activity against both isolates and were effective in reducing kidney fungal burden in a neutropenic murine model of disseminated candidiasis in infected mice. PSC was significantly more effective than VRC against one of the strains. The serum levels of PSC and VRC were above the corresponding MICs for these isolates.
doi:10.1128/AAC.03051-14
PMCID: PMC4187986  PMID: 25049245
9.  Changes in nerve-mediated contractility of the lower urinary tract in a mouse model of premature ageing 
British Journal of Pharmacology  2014;171(7):1687-1705.
Background and Purpose
A high incidence of lower urinary tract disorders is associated with ageing. In the senescent-accelerated prone (SAMP8) mouse strain and the senescent-accelerated resistant (SAMR1) strain, we compared smooth muscle contractility in responses to intrinsic neurotransmitters, both in the bladder and urethra.
Experimental Approach
We analysed micturition frequency, the changes in muscle tension induced by electrical field stimulation or agonist administration, the density of nerves (adrenergic, cholinergic and nitrergic) and interstitial cells (ICs), as well as cGMP accumulation in bladder and urethral preparations.
Key Results
Senescent mice of the SAMP8 strain displayed increased micturition frequency and excitatory contractility of neurogenic origin in the bladder. While cholinergic nerve density remained unchanged, there was a mild sensitization to ACh in male mice. Potentiation in the detrusor may be also provoked by the stronger contribution of ATP, together with reduced adrenergic innervation in males and COX-derived prostanoid production in females. The greater excitatory contractility in the urethra was probably due to the sensitization to noradrenaline, in conjunction with attenuated nitrergic relaxation. There were also fewer neuronal NOS immunoreactive (ir) nerves and vimentin-positive ICs, although the sildenafil-and diethylamine-NONOate-induced relaxations and cGMP-ir remained unchanged.
Conclusions and Implications
Premature senescent mice exhibit bladder and urethral hyperexcitability, coupled with reduced urethral relaxation of neurogenic origin, which could model the impaired urinary function in elderly humans. We propose that senescence-accelerated mice provide a useful tool to analyse the basic mechanisms of age-related changes in bladder and urethral function.
doi:10.1111/bph.12567
PMCID: PMC3966749  PMID: 24372152
ageing; SAMP8 mouse; bladder; urethra; cholinergic; adrenergic; nitrergic; nerve-mediated contractility; bladder hyperactivity
10.  Factors Associated With Scoliosis in Schoolchildren: a Cross-Sectional Population-Based Study 
Journal of Epidemiology  2015;25(3):212-220.
Background
The present study aimed to investigate the prevalence of scoliosis and to analyze the factors associated with scoliosis in schoolchildren aged between 7 and 17 years.
Methods
This is a cross-sectional and quantitative study with stratified random selection of public school students in the city of Santa Cruz, Brazil. The presence of scoliosis was examined, as well as the flexibility of the posterior muscle chain, socioeconomic characteristics, anthropometry, lifestyle habits, sexual maturation, and ergonomics of school furniture. In order to identify factors associated with scoliosis, the variables were divided in biological, socioeconomic, lifestyle, and ergonomic factors, and crude and adjusted prevalence ratios (PRs) were estimated by means of Poisson regression analysis.
Results
Two hundred and twelve pupils participated in this study (mean age 11.61 years, 58% female). The prevalence of scoliosis was 58.1% (n = 123) and associated with female sex (PR 2.54; 95% CI, 1.33–4.86) and age between 13 and 15 years (PR 5.35; 95% CI, 2.17–13.21). Sleeping in a hammock was inversely associated with scoliosis (PR 0.44; 95% CI, 0.23–0.81).
Conclusions
Scoliosis seems to be positively associated with female sex and age between 13 and 15 years, whereas the habit of sleeping in a hammock is negatively associated with the onset of scoliosis.
doi:10.2188/jea.JE20140061
PMCID: PMC4340998  PMID: 25716134
scoliosis; children; risk factors
11.  Exceptional longevity and muscle and fitness related genotypes: a functional in vitro analysis and case-control association replication study with SNPs THRH rs7832552, IL6 rs1800795, and ACSL1 rs6552828 
There are several gene variants that are candidates to influence functional capacity in long-lived individuals. As such, their potential association with exceptional longevity (EL, i.e., reaching 100+ years) deserves analysis. Among them are rs7832552 in the thyrotropin-releasing hormone receptor (TRHR) gene, rs1800795 in the interleukin-6 (IL6) gene and rs6552828 in the coenzyme A synthetase long-chain 1 (ACSL1) gene. To gain insight into their functionality (which is yet unknown), here we determined for the first time luciferase gene reporter activity at the muscle tissue level in rs7832552 and rs6552828. We then compared allele/genotype frequencies of the 3 abovementioned variants among centenarians [n = 138, age range 100–111 years (114 women)] and healthy controls [n = 334, 20–50 years (141 women)] of the same ethnic and geographic origin (Spain). We also studied healthy centenarians [n = 79, 100–104 years (40 women)] and controls [n = 316, 27–81 years (156 women)] from Italy, and centenarians [n = 742, 100–116 years (623 women)] and healthy controls [n = 499, 23–59 years (356 women)] from Japan. The THRH rs7832552 T-allele and ACSL1 rs6552828 A-allele up-regulated luciferase activity compared to the C and G-allele, respectively (P = 0.001). Yet we found no significant association of EL with rs7832552, rs1800795 or rs6552828 in any of the 3 cohorts. Further research is needed with larger cohorts of centenarians of different origin as well as with younger old people.
doi:10.3389/fnagi.2015.00059
PMCID: PMC4422078  PMID: 25999849
centenarians; polymorphisms; luciferase reporter; gene association study; muscle and sarcopenia
14.  Histone deacetylase inhibitors promote glioma cell death by G2 checkpoint abrogation leading to mitotic catastrophe 
Cell Death & Disease  2014;5(10):e1435-.
Glioblastoma multiforme is resistant to conventional anti-tumoral treatments due to its infiltrative nature and capability of relapse; therefore, research efforts focus on characterizing gliomagenesis and identifying molecular targets useful on therapy. New therapeutic strategies are being tested in patients, such as Histone deacetylase inhibitors (HDACi) either alone or in combination with other therapies. Here two HDACi included in clinical trials have been tested, suberanilohydroxamic acid (SAHA) and valproic acid (VPA), to characterize their effects on glioma cell growth in vitro and to determine the molecular changes that promote cancer cell death. We found that both HDACi reduce glioma cell viability, proliferation and clonogenicity. They have multiple effects, such as inducing the production of reactive oxygen species (ROS) and activating the mitochondrial apoptotic pathway, nevertheless cell death is not prevented by the pan-caspase inhibitor Q-VD-OPh. Importantly, we found that HDACi alter cell cycle progression by decreasing the expression of G2 checkpoint kinases Wee1 and checkpoint kinase 1 (Chk1). In addition, HDACi reduce the expression of proteins involved in DNA repair (Rad51), mitotic spindle formation (TPX2) and chromosome segregation (Survivin) in glioma cells and in human glioblastoma multiforme primary cultures. Therefore, HDACi treatment causes glioma cell entry into mitosis before DNA damage could be repaired and to the formation of an aberrant mitotic spindle that results in glioma cell death through mitotic catastrophe-induced apoptosis.
doi:10.1038/cddis.2014.412
PMCID: PMC4237242  PMID: 25275596
15.  Land Snails as a Diet Diversification Proxy during the Early Upper Palaeolithic in Europe 
PLoS ONE  2014;9(8):e104898.
Despite the ubiquity of terrestrial gastropods in the Late Pleistocene and Holocene archaeological record, it is still unknown when and how this type of invertebrate resource was incorporated into human diets. In this paper, we report the oldest evidence of land snail exploitation as a food resource in Europe dated to 31.3-26.9 ka yr cal BP from the recently discovered site of Cova de la Barriada (eastern Iberian Peninsula). Mono-specific accumulations of large Iberus alonensis land snails (Ferussac 1821) were found in three different archaeological levels in association with combustion structures, along with lithic and faunal assemblages. Using a new analytical protocol based on taphonomic, microX-Ray Diffractometer (DXR) and biometric analyses, we investigated the patterns of selection, consumption and accumulation of land snails at the site. The results display a strong mono-specific gathering of adult individuals, most of them older than 55 weeks, which were roasted in ambers of pine and juniper under 375°C. This case study uncovers new patterns of invertebrate exploitation during the Gravettian in southwestern Europe without known precedents in the Middle Palaeolithic nor the Aurignacian. In the Mediterranean context, such an early occurrence contrasts with the neighbouring areas of Morocco, France, Italy and the Balkans, where the systematic nutritional use of land snails appears approximately 10,000 years later during the Iberomaurisian and the Late Epigravettian. The appearance of this new subsistence activity in the eastern and southern regions of Spain was coeval to other demographically driven transformations in the archaeological record, suggesting different chronological patterns of resource intensification and diet broadening along the Upper Palaeolithic in the Mediterranean basin.
doi:10.1371/journal.pone.0104898
PMCID: PMC4139308  PMID: 25141047
16.  Human XCR1+ Dendritic Cells Derived In Vitro from CD34+ Progenitors Closely Resemble Blood Dendritic Cells, Including Their Adjuvant Responsiveness, Contrary to Monocyte-Derived Dendritic Cells 
Human monocyte-derived dendritic cell (MoDC) have been used in the clinic with moderately encouraging results. Mouse XCR1+ DC excel at cross-presentation, can be targeted in vivo to induce protective immunity, and share characteristics with XCR1+ human DC. Assessment of the immunoactivation potential of XCR1+ human DC is hindered by their paucity in vivo and by their lack of a well-defined in vitro counterpart. We report in this study a protocol generating both XCR1+ and XCR1− human DC in CD34+ progenitor cultures (CD34-DC). Gene expression profiling, phenotypic characterization, and functional studies demonstrated that XCR1− CD34-DC are similar to canonical MoDC, whereas XCR1+ CD34-DC resemble XCR1+ blood DC (bDC). XCR1+ DC were strongly activated by polyinosinic-polycytidylic acid but not LPS, and conversely for MoDC. XCR1+ DC and MoDC expressed strikingly different patterns of molecules involved in inflammation and in cross-talk with NK or T cells. XCR1+ CD34-DC but not MoDC efficiently cross-presented a cell-associated Ag upon stimulation by polyinosinic-polycytidylic acid or R848, likewise to what was reported for XCR1+ bDC. Hence, it is feasible to generate high numbers of bona fide XCR1+ human DC in vitro as a model to decipher the functions of XCR1+ bDC and as a potential source of XCR1+ DC for clinical use.
doi:10.4049/jimmunol.1401243
PMCID: PMC4120898  PMID: 25009205
17.  Protective effect of trehalose-loaded liposomes against UVB-induced photodamage in human keratinocytes 
Biomedical Reports  2014;2(5):755-759.
Trehalose, a naturally occurring non-reducing disaccharide, is known to act as a major protein stabilizer that can reduce ultraviolet B (UVB)-induced corneal damage when topically applied to the eye. However, due to the low skin permeability of trehalose, which makes the development of topical formulations difficult, its use as a skin photoprotective agent has been limited. Previous findings demonstrated that liposomes may significantly improve the intracellular delivery of trehalose. Therefore, the present study aimed to assess the protective effects of trehalose-loaded liposomes against UVB-induced photodamage using the immortalized human keratinocyte cell line, HaCaT. The effects were also compared to those of the common skin photoprotective compounds, including L-carnosine, L-(+)-ergothioneine, L-ascorbic acid and DL-α-tocopherol. The levels of cyclobutane pyrimidine dimers, 8-hydroxy-2′-deoxyguanosine and protein carbonylation in HaCaT cells were used as biological markers of UVB-induced damage. Compared to other compounds, trehalose-loaded liposomes showed the highest efficacy in reducing the levels of the three markers following UVB irradiation of HaCaT cells (all P<0.001 when compared to each of the four other photoprotective compounds). Therefore, these findings indicate that there may be a clinical application for trehalose-loaded liposomes, and further studies should be performed to assess the potential usefulness in skin photoprotection and the prevention of non-melanoma skin cancer.
doi:10.3892/br.2014.310
PMCID: PMC4106593  PMID: 25054023
ultraviolet radiation; keratinocytes; trehalose; cyclobutane pyrimidine dimers; 8-hydroxy-2′-deoxyguanosine; protein carbonylation
18.  Geonic black holes and remnants in Eddington-inspired Born–Infeld gravity 
We show that electrically charged solutions within the Eddington-inspired Born–Infeld theory of gravity replace the central singularity by a wormhole supported by the electric field. As a result, the total energy associated with the electric field is finite and similar to that found in the Born–Infeld electromagnetic theory. When a certain charge-to-mass ratio is satisfied, in the lowest part of the mass and charge spectrum the event horizon disappears, yielding stable remnants. We argue that quantum effects in the matter sector can lower the mass of these remnants from the Planck scale down to the TeV scale.
doi:10.1140/epjc/s10052-014-2804-8
PMCID: PMC4371069  PMID: 25814883
19.  Physical activity - an important preanalytical variable 
Biochemia Medica  2014;24(1):68-79.
The concentration of several biochemical and hematological biomarkers is strongly influenced by a number of preanalytical variables. Several lines of evidence attest that short, middle, and long-term exercise, as well as the relative intensity of physical effort (from mild to strenuous), may influence a broad array of laboratory variables. The amount of extracellular release and clearance from blood of most of these biomarkers is markedly influenced by the biological characteristics of the molecule(s), level of training, type, intensity and duration of exercise, and time of recovery after training. It is hence noteworthy that test results that fall outside the conventional reference ranges in athletes not only may reflect the presence of a given disease, but may frequently mirror an adaptation to regular training or changes that have occurred during and/or following strenuous exercise, and which should be clearly acknowledged to prevent misinterpretation of laboratory data. The aim of this narrative review is to provide an update about the most significant changes of some biochemical and hematological biomarkers in response to physical exercise, for appropriate interpretation of these changes in the context of physically active subjects.
doi:10.11613/BM.2014.009
PMCID: PMC3936967  PMID: 24627716
biomarkers; training; plasma volume; metabolism; cellular damage
20.  New Molecular Targets and Lifestyle Interventions to Delay Aging Sarcopenia 
doi:10.3389/fnagi.2014.00156
PMCID: PMC4078253  PMID: 25071565
muscle atrophy; senescence factors; signaling pathways; frailty; pharmaceutical targets
21.  Neurobiological foundations of multisensory integration in people with autism spectrum disorders: the role of the medial prefrontal cortex 
This review aims to relate the sensory processing problems in people with autism spectrum disorders (ASD), especially multisensory integration (MSI), to the role of the medial prefrontal cortex (mPFC) by exploring neuroanatomical findings; brain connectivity and Default Network (DN); global or locally directed attention; and temporal multisensory binding. The mPFC is part of the brain’s DN, which is deactivated when attention is focused on a particular task and activated on rest when spontaneous cognition emerges. In those with ASD, it is hypoactive and the higher the social impairment the greater the atypical activity. With an immature DN, cross-modal integration is impaired, resulting in a collection of disconnected fragments instead of a coherent global perception. The deficit in MSI may lie in the temporal synchronization of neural networks. The time interval in which the stimulation of one sensory channel could influence another would be higher, preventing integration in the typical shorter time range. Thus, the underconnectivity between distant brain areas would be involved in top-down information processes (relying on global integration of data from different sources) and would enhance low level perception processes such as over focused attention to sensory details.
doi:10.3389/fnhum.2014.00970
PMCID: PMC4255523  PMID: 25538597
autism spectrum disorders (ASD); multisensory integration; medial prefrontal cortex (mPFC); default network; temporal multisensory binding
22.  Effects of nitrogen nutrition on the synthesis and deposition of the ω-gliadins of wheat 
Annals of Botany  2013;113(4):607-615.
Background and Aims
The ω-gliadin storage proteins of wheat are of interest in relation to their impact on grain processing properties and their role in food allergy, particularly the ω-5 sub-group and wheat-dependent exercise-induced anaphylaxis. The ω-gliadins are also known to be responsive to nitrogen application. This study therefore compares the effects of cultivar and nitrogen availability on the synthesis and deposition of ω-gliadins in wheat grown under field conditions in the UK, including temporal and spatial analyses at the protein and transcript levels.
Methods
SDS–PAGE, western blotting and N-terminal amino acid sequencing were used to compare the patterns of ω-gliadin components in mature grain of six British wheat (Triticum aestivum) cultivars and their accumulation during the development of grain grown in field plots with varying nitrogen supply. Changes in gene expression during development were determined using real-time reverse transcription–PCR (RT–PCR). Spatial patterns of gene expression and protein accumulation were determined by in situ hybridization and immunofluorescence microscopy, respectively.
Key Results
Two patterns of ω-gliadins were identified in the six cultivars, including both monomeric ‘gliadin’ proteins and subunits present in polymeric ‘glutenin’ fractions. Increasing the level of nitrogen fertilizer in field plots resulted in increased expression of ω-gliadin transcripts and increased proportions of ω-5 gliadins. Nitrogen supply also affected the spatial patterns of ω-gliadin synthesis and deposition, which were differentially increased in the outer layers of the starchy endosperm with high levels of nitrogen.
Conclusions
Wheat ω-gliadins vary in amount and composition between cultivars, and in their response to nitrogen supply. Their spatial distribution is also affected by nitrogen supply, being most highly concentrated in the sub-aleurone cells of the starchy endosperm under higher nitrogen availability.
doi:10.1093/aob/mct291
PMCID: PMC3936585  PMID: 24344140
Wheat; Triticum aestivum; storage protein; nitrogen; ω-gliadin; RNA in situ hybridization; immunolocalization; protein bodies; wheat allergy
23.  The p38–PGC-1α–irisin–betatrophin axis 
Adipocyte  2013;3(1):67-68.
The discovery of irisin as a novel and promising peptidic hormone has raised hopes regarding the hypothesis that irisin may provide additional benefits, not only for obesity and diabetes, but also for a wide range of pathological conditions since this hormone may prove to be therapeutically and clinically beneficial. In addition, a new hormone, betatrophin, has recently been identified by Yi and coworkers. Both hormones are connected by a new pathway clearly involved in insulin resistance. We hypothesize here how these hormones may be linked and their possible implications in both aged-reduced restricted regenerative capacity and dedifferentiated β cells of diabetic patients.
doi:10.4161/adip.27370
PMCID: PMC3917937  PMID: 24575373
diabetes; metabolism; obesity; oxidative stress; β cells
24.  Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel 
Biomaterials  2011;32(15):10.1016/j.biomaterials.2011.01.073.
Angiogenesis plays a prominent role in cancer progression. Anti-angiogenic therapy therefore, either alone or in combination with conventional cytotoxic therapy, offers a promising therapeutic approach. Paclitaxel (PTX) is a widely-used potent cytotoxic drug that also exhibits anti-angiogenic effects at low doses. However, its use, at its full potential, is limited by severe side effects. Here we designed and synthesized a targeted conjugate of PTX, a polymer and an integrin-targeted moiety resulting in a polyglutamic acid (PGA)-PTX-E-[c(RGDfK)2] nano-scaled conjugate. Polymer conjugation converted PTX to a macromolecule, which passively targets the tumor tissue exploiting the enhanced permeability and retention effect, while extravasating via the leaky tumor neovasculature. The cyclic RGD peptidomimetic enhanced the effects previously seen for PGA-PTX alone, utilizing the additional active targeting to the αvβ3 integrin overexpressed on tumor endothelial and epithelial cells. This strategy is particularly valuable when tumors are well-vascularized, but they present poor vascular permeability. We show that PGA is enzymatically-degradable leading to PTX release under lysosomal acidic pH. PGA-PTX-E-[c(RGDfK)2] inhibited the growth of proliferating αvβ3-expressing endothelial cells and several cancer cells. We also showed that PGA-PTX-E-[c(RGDfK)2] blocked endothelial cells migration towards vascular endothelial growth factor; blocked capillary-like tube formation; and inhibited endothelial cells attachment to fibrinogen. Orthotopic studies in mice demonstrated preferential tumor accumulation of the RGD-bearing conjugate, leading to enhanced antitumor efficacy and a marked decrease in toxicity as compared with free PTX-treated mice.
doi:10.1016/j.biomaterials.2011.01.073
PMCID: PMC3857101  PMID: 21376390
Angiogenesis; polymer therapeutics; Polyglutamic acid; paclitaxel; RGD peptidomimetic; integrin
25.  Vitamin C Supplementation Does not Improve Hypoxia-Induced Erythropoiesis 
High Altitude Medicine & Biology  2012;13(4):269-274.
Abstract
Martinez-Bello,Vladimir E., Fabian Sanchis-Gomar, Daniel Martinez-Bello, Gloria Olaso-Gonzalez, Mari Carmen Gomez-Cabrera, and Jose Viña. Vitamin C Supplementation Does Not Improve Hypoxia-Induced Erythropoiesis. High Alt Med Biol 13:269–274, 2012.—Hypoxia induces reactive oxygen species production. Supplements with antioxidant mixtures can compensate for the decline in red cell membrane stability following intermittent hypobaric hypoxia by decreasing protein and lipid oxidation. We aimed to determine whether supplementation with vitamin C is implicated in the regulation of erythropoiesis and in the oxygen-carrying capacity of the blood, and also whether antioxidant supplementation prevents the oxidative stress associated to intermittent hypoxia. Twenty-four male Wistar rats were randomly divided into four experimental groups: normoxia control (n=6), normoxia + vitamin C (n=6), hypoxia control (12 h pO2 12%/12 h pO2 21%) (n=6), and hypoxia + vitamin C (n=6). Animals were supplemented with vitamin C at a dose of 250 mg·kg−1·day−1 for 21 days. Red blood cell count, hemoglobin, hematocrit, reticulocytes, erythropoietin, and oxidative stress parameters such as malondialdehyde and protein oxidation in plasma were analyzed at two different time points: basal sample (day zero) and final sample (day 21). Similar RBC, Hb, Hct, and Epo increments were observed in both hypoxic groups regardless of the vitamin C supplementation. There was no change on MDA levels after intermittent hypoxic exposure in any experimental group. However, we found an increase in plasma protein oxidation in both hypoxic groups. Vitamin C does not affect erythropoiesis and protein oxidation in rats submitted to intermittent hypoxic exposure.
doi:10.1089/ham.2012.1028
PMCID: PMC3533831  PMID: 23270444
hematocrit; hemoglobin; red blood cells; oxidative stress; antioxidants

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