Concurrent self-regulated autonomous synthesis and functionalization of pH-responsive giant vesicles by a chemical pH oscillator.

The semibatch BrO3--SO32- pH oscillator serves as the radical source for the in situ polymerization of the pH-responsive 2-(diisopropylamino)-ethyl methacrylate monomer on poly(ethylene-glycol)-macroCTA chain and generates an amphiphilic block copolymer. These building blocks concurrently self-assemble to micelles and then transforms to vesicles as the chain length of the hydrophobic block growths. Large amplitude oscillations in the concentration of H+ by the semibatch BrO3--SO32- are provoked when the conditions in the system are favorable. The oscillations control the protonation state of the tertiary amine group in the core segment of the block copolymer. Rhythmic assembly-disassembly of the polymer structures is observed. All processes, from the time- regulated autonomous formation of the building blocks, their self-assembly and the rhythmic disassembly-reassembly are governed by the same simple chemical system, in the same reaction vessel, without complicated multi step procedures and are fueled and kept out of equilibrium by the uniform inflow of SO32-.

Revisiting Panda 100, the first archaeological chimpanzee nut-cracking site.

Archaeological recovery of chimpanzee Panda oleosa nut cracking tools at the Panda 100 (P100) and Noulo sites in the Taï Forest, Côte d'Ivoire, showed that this behavior is over 4000 years old, making it the oldest known evidence of non-human tool use. In 2002, the first report on the lithic material from P100 was directly compared to early hominin stone tools, highlighting their similarities and proposing the name 'Pandan' for the chimpanzee material. Here we present an expanded and comprehensive technological, microscopic, and refit analysis of the late twentieth century lithic assemblage from P100. Our re-analysis provides new data and perspectives on the applicability of chimpanzee nut cracking tools to our understanding of the percussive behaviors of early hominins. We identify several new refit sets, including the longest (>17 m) hammerstone transport seen in the chimpanzee archaeological record. We provide detailed evidence of the fragmentation sequences of Panda nut hammerstones, and characterize the percussive damage on fragmented material from P100. Finally, we emphasize that the chimpanzee lithic archaeological record is dynamic, with the preservation of actual hammerstones being rare, and the preservation of small broken pieces more common. P100 - the first archaeological chimpanzee nut cracking lithic assemblage - provides a valuable comparative sample by which to identify past chimpanzee behavior elsewhere, as well as similar hominin percussive behavior in the Early Stone Age.

Multitrait genome association analysis identifies new susceptibility genes for human anthropometric variation in the GCAT cohort.

BACKGROUND: Heritability estimates have revealed an important contribution of SNP variants for most common traits; however, SNP analysis by single-trait genome-wide association studies (GWAS) has failed to uncover their impact. In this study, we applied a multitrait GWAS approach to discover additional factor of the missing heritability of human anthropometric variation. METHODS: We analysed 205 traits, including diseases identified at baseline in the GCAT cohort (Genomes For Life- Cohort study of the Genomes of Catalonia) (n=4988), a Mediterranean adult population-based cohort study from the south of Europe. We estimated SNP heritability contribution and single-trait GWAS for all traits from 15 million SNP variants. Then, we applied a multitrait-related approach to study genome-wide association to anthropometric measures in a two-stage meta-analysis with the UK Biobank cohort (n=336 107). RESULTS: Heritability estimates (eg, skin colour, alcohol consumption, smoking habit, body mass index, educational level or height) revealed an important contribution of SNP variants, ranging from 18% to 77%. Single-trait analysis identified 1785 SNPs with genome-wide significance threshold. From these, several previously reported single-trait hits were confirmed in our sample with LINC01432 (p=1.9×10-9) variants associated with male baldness, LDLR variants with hyperlipidaemia (ICD-9:272) (p=9.4×10-10) and variants in IRF4 (p=2.8×10-57), SLC45A2 (p=2.2×10-130), HERC2 (p=2.8×10-176), OCA2 (p=2.4×10-121) and MC1R (p=7.7×10-22) associated with hair, eye and skin colour, freckling, tanning capacity and sun burning sensitivity and the Fitzpatrick phototype score, all highly correlated cross-phenotypes. Multitrait meta-analysis of anthropometric variation validated 27 loci in a two-stage meta-analysis with a large British ancestry cohort, six of which are newly reported here (p value threshold <5×10-9) at ZRANB2-AS2, PIK3R1, EPHA7, MAD1L1, CACUL1 and MAP3K9. CONCLUSION: Considering multiple-related genetic phenotypes improve associated genome signal detection. These results indicate the potential value of data-driven multivariate phenotyping for genetic studies in large population-based cohorts to contribute to knowledge of complex traits.

A class-selective immunoassay for simultaneous analysis of anilinopyrimidine fungicides using a rationally designed hapten.

The development of multianalyte immunoassays constitutes a main research issue in the field of bioanalytical techniques. In the present study, class-specific antibodies against the three members of the anilinopyrimidine family of fungicides (pyrimethanil, cyprodinil and mepanipyrim) were raised by using a bioconjugate of a rationally designed hapten [5-(6-methyl-2-(phenylamino)pyrimidin-4-yl)pentanoic acid]. Highly sensitive immunoassays were developed for the generic determination of these compounds, using the competitive enzyme-linked immunosorbent assay (ELISA). Particularly, a direct antibody-coated competitive ELISA afforded identical sensitivity for the three anilinopyrimidines, with IC50 values of 0.26, 0.27 and 0.25 µg L-1 for pyrimethanil, cyprodinil and mepanipyrim, respectively. This immunoassay was fully characterized and applied to the multianalyte determination of anilinopyrimidine fungicides in white and red wines, with a limit of quantification of 1 µg L-1, average recoveries from 93.1 to 114.4%, and relative standard deviations lower than 20%. Commercial wine samples were analyzed and those containing detectable anilinopyrimide residues were verified by a reference chromatographic technique.

Decreased lipid metabolism but increased FA biosynthesis are coupled with changes in liver microRNAs in obese subjects with NAFLD.

BACKGROUND/OBJECTIVE: Many controversies regarding the association of liver miRNAs with obesity and nonalcoholic fatty liver diseases (NAFLD) call for additional validations. This study sought to investigate variations in genes and hepatic miRNAs in a sample of obese patients with or without NAFLD and human hepatocytes (HH). SUBJECTS/METHODS: A total of 60 non-consecutive obese women following bariatric surgery were recruited. Subjects were classified as NAFLD (n=17), borderline (n=24) and controls (n=19) with normal enzymatic profile, liver histology and ultrasound assessments. Profiling of 744 miRNAs was performed in 8 obese women with no sign of hepatic disease and 11 NAFLD patients. Additional validation and expression of genes related to de novo fatty acid (FA) biosynthesis, uptake, transport and ß-oxidation; glucose metabolism, and inflammation was tested in the extended sample. Induction of NAFLD-related genes and miRNAs was examined in HepG2 cells and primary HH treated with palmitic acid (PA), a combination of palmitate and oleic acid, or high glucose, and insulin (HG) mimicking insulin resistance in NAFLD. RESULTS: In the discovery sample, 14 miRNAs were associated with NAFLD. Analyses in the extended sample confirmed decreased miR-139-5p, miR-30b-5p, miR-122-5p and miR-422a, and increased miR-146b-5p in obese subjects with NAFLD. Multiple linear regression analyses disclosed that NAFLD contributed independently to explain miR-139-5p (P=0.005), miR-30b-5p (P=0.005), miR-122-5p (P=0.021), miR-422a (P=0.007) and miR-146a (P=0.033) expression variance after controlling for confounders. Decreased miR-122-5p in liver was associated with impaired FA usage. Expression of inflammatory and macrophage-related genes was opposite to decreased miR-30b-5p, miR-139-5p and miR-422a, whereas increased miR-146b-5p was associated with FABP4 and decreased glucose metabolism and FA mobilization. In partial agreement, PA (but not HG) led to decreased miR-139-5p, miR-30b-5p, miR-422a and miR-146a in vitro, in parallel with increased lipogenesis and FA transport, decreased glucose metabolism and diminished FA oxidation. CONCLUSION: This study confirms decreased liver glucose and lipid metabolism but increased FA biosynthesis coupled with changes in five unique miRNAs in obese patients with NAFLD.

Combination of low dose of the anti-adipogenic agents resveratrol and phenelzine in drinking water is not sufficient to prevent obesity in very-high-fat diet-fed mice.

PURPOSE: Resveratrol inhibits lipid accumulation but suffers from limited bioavailability. The anti-depressive agent phenelzine limits adipogenesis in various models of cultured preadipocytes, and this hydrazine derivative also inhibits de novo lipogenesis in mature adipocytes. It was therefore tested whether resveratrol effects on adiposity reduction and glucose tolerance improvement could be reinforced by co-administration with phenelzine. METHODS: Mice fed a very-high-fat diet (VHFD, 60% calories as fat) were subjected to drinking solution containing low dose of resveratrol (0.003%) and/or 0.02% phenelzine for 12 weeks. Body fat content, glucose tolerance, food and water consumption were checked during treatment while fat depot mass was determined at the end of supplementation. Direct influence of the agents on lipogenesis and glucose uptake was tested in adipocytes. RESULTS: Epididymal fat depots were reduced in mice drinking phenelzine alone or with resveratrol. No limitation of body weight gain or body fat content was observed in the groups drinking resveratrol or phenelzine, separately or in combination. The altered glucose tolerance and the increased fat body composition of VHFD-fed mice were not reversed by resveratrol and/or phenelzine. Such lack of potentiation between resveratrol and phenelzine prompted us to verify in vitro their direct effects on mouse adipocytes. Both molecules inhibited de novo lipogenesis, but did not potentiate each other at 10 or 100 µM. Only resveratrol inhibited hexose uptake in a manner that was not improved by phenelzine. CONCLUSIONS: Phenelzine has no interest to be combined with low doses of resveratrol for treating/preventing obesity, when considering the VHFD mouse model.

Nuevo dispositivo para el aislamiento de la fracción estromal vascular a partir de lipoaspirados humanos: método de obtención y análisis de calidad celular / New device for stromal vascular fraction isolation from human lipoaspirates: method and cell quality analysis

El tejido adiposo obtenido mediante liposucción es una fuente idónea para aislar células con potencial terapéutico, las denominadas células de la fracción estromal vascular (FEV), que incluyen células madre mesenquimales. Estas células se han convertido en una de las principales herramientas de terapia celular autóloga para diversas aplicaciones médicas, y en los últimos años se han ido desarrollando diversas tecnologías para su aislamiento y uso clínico. En este trabajo presentamos un nuevo método rápido, sencillo y eficiente para el aislamiento de células de la FEV mediante un dispositivo médico cerrado que permite recoger y procesar lipoaspirados humanos en el mismo procedimiento quirúrgico de manera coste-efectiva. Además describimos los métodos llevados a cabo para cuantificar la calidad, seguridad y eficacia del inóculo celular obtenido (AU)

The adipose tissue obtained by liposuction is an abundant source to isolate regenerative cells, the stromal vascular fractions cells (SVF), including adipose mesenchymal stem cells. These cells have became an excellent tool for autologous cell therapy in different clinical applications, and several platforms for adipose tissue processing have been developed for SVF isolation. In this study we describe a new medical device for SVF isolation from human lipoaspirates, using a fast, efficient and user-friendly procedure in the same surgical act in a cost-effective way. Additionally, we present different methods to guarantee the quality, safety and potency of the cell inoculum obtained (AU)

Thyroid hormone receptor alpha gene variants increase the risk of developing obesity and show gene-diet interactions.

OBJECTIVE: Thyroid hormone receptor-beta resistance has been associated with metabolic traits. THRA gene sequencing of an obese woman (index case) who presented as empirical thyroid hormone receptor-α (THRA) resistance, disclosed a polymorphism (rs12939700) in a critical region involved in TRα alternative processing. DESIGN AND SUBJECTS: THRA gene variants were evaluated in three independent europid populations (i) in two population cohorts at baseline (n=3417 and n=2265), 6 years later (n=2139) and (ii) in 4734 high cardiovascular risk subjects (HCVR, PREDIMED trial). RESULTS: The minor allele of the index case polymorphism (rs12939700), despite having a very low frequency (4%), was significantly associated with higher body mass index (BMI) (P=0.042) in HCVR subjects. A more frequent THRA polymorphism (rs1568400) was associated with higher BMI in subjects from the population (P=0.00008 and P=0.05) after adjusting for several confounders. Rs1568400 was also strongly associated with fasting triglycerides (P dominant=3.99 × 10(-5)). In the same sample, 6 years later, age and sex-adjusted risk of developing obesity was significantly increased in GG homozygotes (odds ratio 2.93 (95% confidence interval, 1.05-6.95)). In contrast, no association between rs1568400 and BMI was observed in HCVR subjects, in whom obesity was highly prevalent. This might be explained by the presence of an interaction (P <0.001) among the rs1568400 variant, BMI and saturated fat intake. Only when saturated fat intake was high (>24.5 g d(-1)), GG carriers showed a significantly higher BMI than A carriers after controlling for energy intake and physical activity. CONCLUSIONS: THRA gene polymorphisms are associated with obesity development. This is a novel observation linking the THRA locus to metabolic phenotypes.

Direct surface plasmon resonance immunosensing of pyraclostrobin residues in untreated fruit juices.

A surface plasmon resonance (SPR) immunoassay for on-line detection of the strobilurin fungicide pyraclostrobin in untreated fruit juices is presented. The analysis of pyraclostrobin residues is accomplished in apple, grape, and cranberry samples by monitoring the recognition events occurring separately in a two-channel home-made SPR biosensor. Covalent coupling of the analyte derivative results in a reversible method, enabling more than 80 measurements on the same sensor surface. Optimization of the immunoassay conditions provides limits of detection as low as 0.16 µg L(-1). The selectivity and reproducibility of the analysis is ensured by studying both non-specific interactions with unrelated compounds and inter-assay coefficients of variation. Excellent recovery ranging from 98 to 103% was achieved by a simple 1:5 dilution of fruit juice with assay buffer before the analysis. The lack of previous cleaning and homogenization procedures reduces the analysis time of a single food sample to only 25 min, including the regeneration cycle.

Long-term activation of semicarbazide-sensitive amine oxidase lowers circulating levels of uric acid in diabetic conditions.

Uric acid is involved in nitrogenous waste in animals, together with ammonia and urea. Uric acid has also antioxidant properties and is a surrogate marker of metabolic syndrome. We observed that the elevated plasma uric acid of high-fat fed mice was normalized by benzylamine treatment. Indeed, benzylamine is the reference substrate of semicarbazide-sensitive amine oxidase (SSAO), an enzyme highly expressed in fat depots and vessels, which generates ammonia when catalysing oxidative deamination. Ammonia interferes with uric acid metabolism/solubility. Our aim was therefore to investigate whether the lowering action of benzylamine on uric acid was related to an improvement of diabetic complications, or was connected with SSAO-dependent ammonia production. First, we observed that benzylamine administration lowered plasma uric acid in diabetic db/db mice while it did not modify uric acid levels in normoglycemic and lean mice. In parallel, benzylamine improved the glycemic control in diabetic but not in normoglycemic mice, while plasma urea remained unaltered. Then, uric acid plasma levels were measured in mice invalidated for AOC3 gene, encoding for SSAO. These mice were unable to oxidize benzylamine but were not diabetic and exhibited unaltered plasma uric levels. Therefore, activated or abolished ammonia production by SSAO was without influence on uric acid in the context of normoglycemia. Our observations confirm that plasma uric acid increases with diabetes and can be normalized when glucose tolerance is improved. They also show that uric acid, a multifunctional metabolite at the crossroads of nitrogen waste and of antioxidant defences, can be influenced by SSAO, in a manner apparently related to changes in glucose homeostasis.

Correlation of BDNF blood levels with interoceptive awareness and maturity fears in anorexia and bulimia nervosa patients.

Association studies and rodent models suggest a major role for BDNF (brain-derived neurotrophic factor) in feeding regulation. Altered BDNF blood levels have been associated with eating disorders (ED) and their related psychopathological traits. Since the influence of BDNF on self-reported eating disorder inventory scores (EDI) has not been tested, we investigated the correlation of EDI scales with BDNF plasma levels. BDNF levels were measured by (ELISA), and the EDI questionnaire was administered in a total of 81 ED patients. The relationship between BDNF levels and EDI scores was calculated using a general linear model. After correcting for multiple testing, BDNF plasma levels negatively correlated with the EDI total score (R (2) = 0.26; p = 4.09 x 10(-4)), interoceptive awareness (R (2) = 0.26; p = 1.96 x 10(-4)), and maturity fears (R (2) = 0.13; p = 6.92 x 10(-4)). When subdividing according to the main diagnoses, interoceptive awareness presented significant correlations with BDNF blood levels in both the anorexia nervosa (R (2) = 0.33, p = 0.0026) and bulimia nervosa groups (R (2) = 0.10; p = 0.008). Our data suggest that BDNF levels may influence the severity of the ED by modulating the associated psychopathology, in particular through the impairment of interoceptive awareness.

Retinol-binding protein 4 and nicotinamide phosphoribosyltransferase/visfatin in rat obesity models.

Retinol-binding protein 4 (RBP4) and nicotinamide phosphoribosyltransferase/visfatin (Nampt/visfatin) are adipocyte-secreted proteins (adipokines) whose relevance to the metabolic syndrome and regulation in obesity remain controversial. Here, we tested the hypothesis that adipose tissue expression and circulating levels of these two adipokines are elevated in obesity by analyzing their changes in both a genetic and a diet-induced model of obesity in the rat (obese FA/ FA Zucker rats and Wistar rats fed a cafeteria diet, respectively). Compared with lean controls, obese FA/ FA rats were hyperleptinemic, hyperinsulinemic, and insulin resistant and had reduced RBP4 serum levels and mRNA levels in adipose depots, unchanged Nampt/visfatin serum levels, and reduced Nampt/visfatin mRNA levels selectively in the inguinal adipose depot. Cafeteria diet-induced obesity resulted in increased fed blood glucose levels, a variable degree of insulin resistance, unchanged serum Nampt/visfatin and RBP4 levels, and reduced mRNA levels of both adipokines in several adipose depots. Hence, increases in RBP4 or Nampt/visfatin do not accompany obesity and insulin resistance in the models examined.

Altered brain-derived neurotrophic factor blood levels and gene variability are associated with anorexia and bulimia.

Murine models and association studies in eating disorder (ED) patients have shown a role for the brain-derived neurotrophic factor (BDNF) in eating behavior. Some studies have shown association of BDNF -270C/T single-nucleotide polymorphism (SNP) with bulimia nervosa (BN), while BDNF Val66Met variant has been shown to be associated with both BN and anorexia nervosa (AN). To further test the role of this neurotrophin in humans, we screened 36 SNPs in the BDNF gene and tested for their association with ED and plasma BDNF levels as a quantitative trait. We performed a family-based association study in 106 ED nuclear families and analyzed BDNF blood levels in 110 ED patients and in 50 sib pairs discordant for ED. The rs7124442T/rs11030102C/rs11030119G haplotype was found associated with high BDNF levels (mean BDNF TCG haplotype carriers = 43.6 ng/ml vs. mean others 23.0 ng/ml, P = 0.016) and BN (Z = 2.64; P recessive = 0.008), and the rs7934165A/270T haplotype was associated with AN (Z =-2.64; P additive = 0.008). The comparison of BDNF levels in 50 ED discordant sib pairs showed elevated plasma BDNF levels for the ED group (mean controls = 41.0 vs. mean ED = 52.7; P = 0.004). Our data strongly suggest that altered BDNF levels modulated by BDNF gene variability are associated with the susceptibility to ED, providing physiological evidence that BDNF plays a role in the development of AN and BN, and strongly arguing for its involvement in eating behavior and body weight regulation.

Increased cerebral activity in Parkinson's disease patients carrying the DRD2 TaqIA A1 allele during a demanding motor task: a compensatory mechanism?

Previous studies suggest that neuroimaging techniques are useful for detecting the effects of functional genetic polymorphisms on brain function in healthy subjects or in patients presenting with psychiatric or neurodegenerative conditions. Former evidence showed that individuals carrying risk alleles displayed broader patterns of brain activity during behavioural and cognitive tasks, despite being clinically comparable to non-carriers. This suggests the presence of compensatory brain mechanisms. In the present study, we investigated this effect in Parkinson's disease (PD) patients carrying the DRD2 TaqIA A1 allelic variant. This variant may confer an increased risk of developing the disease and/or influence the clinical presentation. During a complex sequential motor task, we evidenced by functional magnetic resonance imaging that A1 allele carriers activated a larger network of bilateral cerebral areas than non-carriers, including cerebellar and premotor regions. Both groups had similar clinical and demographic measures. In addition, their motor performance during the functional magnetic resonance experiment was comparable. Therefore, our conclusions, pending replication in a larger sample, seem to reflect the recruitment of compensatory cerebral resources during motor processing in PD patients carrying the A1 allele.

Abnormal orbitofrontal development due to prematurity.

OBJECTIVE: To investigate the effects of prematurity on sulcal formation. METHODS: We evaluated the depth and volume of the primary olfactory sulcus (developed at 16 weeks' gestation) and the secondary orbital sulci (which start to develop at 28 weeks' gestation) in a sample of 22 adolescents with history of very-preterm birth (VPTB). We compared this preterm sample with a sample of subjects born at term and matched by age, gender, and sociocultural status. The Anatomist/BrainVISA 3.0.1 package was used to identify and quantify the sulci. In addition, voxel-based morphometry (VBM) was used to analyze possible reductions of gray and white matter in the orbitofrontal area. RESULTS: Compared with controls, we found a significant reduction in the secondary sulci depth but not in the primary sulcus in the VPTB. VBM analysis showed reduced gray-matter volume in VPTB in the orbital region. CONCLUSIONS: Premature birth affects cerebral gyrification, and this impairment is not reversible during childhood. Identification of the specific factors involved in abnormal brain maturation may lead to effective interventions.

Cistoadenoma gigante de páncreas. Una entidad poco frecuente / Giant pancreatic cystadenoma. A very rare entity

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Valor del diagnóstico de malabsorción de lactosa en pacientes con síndrome de intestino irritable / Value of the diagnosis of malabsorption of lactose in patients with syndrome or irritable intestine

Fundamento: En ocasiones se aconseja suprimirlos lácteos a pacientes con Síndrome de Intestino Irritable (SII) sin evidencia de malabsorción. El objetivo es estudiar la frecuencia de malabsorción de lactosa en pacientes diagnosticados de SII. Método: Se estudia la frecuencia de malabsorción de lactosa a 50 pacientes con SII y 25controles sanos, se realiza test de hidrógeno espirado para evaluar dicha malabsorción. Resultados: Se observó malabsorción de lactosa en 12/50 (24%) pacientes con SII y 5/25(20%) sujetos control. Tras retirar la leche durante seis meses en aquellos pacientes diagnosticados de SII y que dieron positivo para malabsorción de lactosa, sólo mejoraron su sintomatología 1/12 (8,33%) pacientes. Conclusiones: La identificación de malabsorción de lactosa en pacientes con diagnóstico de SII presenta escasas ventajas. No se aprecia una frecuencia significativamente mayor de malabsorción en pacientes con SII que en controles sanos, además en nuestro estudio los casos con malabsorción diagnosticados de SII, mejoran en una pequeña proporción cuando se suprime la leche de la dieta (AU)

Basis: In occasions one advises to suppress the lacteal products to patients with Irritable Bowel Syndrome (IBS) without evidence of malabsorption. The aim is to study the frequency of malabsorption of lactose in patients diagnosed of IBS. Method: The frequency is studied of malabsorption of lactose to 50 patients with IBS and25 healthy controls, test of hydrogen is realized exhaled to evaluate malabsorption. Results: It was observed malabsorption of lactose in 12/50 (24%) patients with IBS and5/25 (20%) controls. After removing the milk for six months in those patients diagnosed of IBS and that gave alone positive, 1/12 (8,33%) patients improved of his symptomatology of partial form. Conclusions: The identification of the malabsorption of lactose in patients with diagnosis of syndrome of irritable intestine not presents advantages. A significantly major frequency does not estimate of malabsorption in patients with IBS that in healthy controls, in addition in our study the cases with malabsorption diagnosed of IBS, the improvement is low when the milk of the diet is suppressed (AU)

Síndrome de la persona rígida: manifestación de afectación inmunológica específica del sistema nervioso central / Stiff man syndrome: a specific immunological condition affecting the central nervous system

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