IHG-1 amplifies TGF-beta1 signaling and is increased in renal fibrosis

Induced in high glucose-1 (IHG-1) is an evolutionarily conserved gene transcript upregulated by high extracellular glucose concentrations, but its function is unknown. Here, it is reported that the abundance of IHG-1 mRNA is nearly 10-fold higher in microdissected, tubule-rich renal biopsies from patients with diabetic nephropathy compared with control subjects. In the diabetic nephropathy specimens, in situ hybridization localized IHG-1 to tubular epithelial cells along with TGF-beta1 and activated Smad3, suggesting a possible role in the development of tubulointerstitial fibrosis. Supporting this possibility, IHG-1 mRNA and protein expression also increased with unilateral ureteral obstruction. In the HK-2 proximal tubule cell line, overexpression of IHG-1 increased TGF-beta1-stimulated expression of connective tissue growth factor and fibronectin. IHG-1 was found to amplify TGF-beta1-mediated transcriptional activity by increasing and prolonging phosphorylation of Smad3. Conversely, inhibition of endogenous IHG-1 with small interference RNA suppressed transcriptional responses to TGF-beta1. In summary, IHG-1, which increases in diabetic nephropathy, may enhance the actions of TGF-beta1 and contribute to the development of tubulointerstitial fibrosis.

EXPRESSION OF THE INFLAMMATORY REGULATOR A20 CORRELATES WITH LUNG FUNCTION IN PATIENTS WITH CYSTIC FIBROSIS

Abstract: Background: A20 and TAX1BP1 interact to negatively regulate NF-
-driven inflammation. A20 expression is altered in F508del/F508del
patients. Here we explore the effect of CFTR and CFTR genotype on A20 and
TAX1BP1expression. The relationship with lung function is also assessed.
Methods: Primary Nasal Epithelial cells (NECs) from CF patients
(F508del/F508del, n=8, R117H/F508del, n=6) and Controls (age-matched,
n=8), and 16HBE14o- cells were investigated. A20 and TAX1BP1 gene
expression was determined by qPCR.
Results: Silencing of CFTR reduced basal A20 expression. Following LPS
stimulation A20 and TAX1BP1 expression was induced in control NECs and
reduced in CF NECs, broadly reflecting the CF genotype: F508del/F508del
had lower expression than R117H/F508del. A20, but not TAX1BP1 expression,
was proportional to FEV1 in all CF patients (r=0.968, p<0.001).
Conclusions: A20 expression is reduced in CF and is proportional to FEV1.
Pending confirmation in a larger study, A20 may prove a novel predictor
of CF inflammation/disease severity.

The Adult Cystic Fibrosis Airway Microbiota Is Stable over Time and Infection Type, and Highly Resilient to Antibiotic Treatment of Exacerbations

Cystic fibrosis (CF) is characterized by defective mucociliary clearance and chronic airway infection by a complex microbiota. Infection, persistent inflammation and periodic episodes of acute pulmonary exacerbation contribute to an irreversible decline in CF lung function. While the factors leading to acute exacerbations are poorly understood, antibiotic treatment can temporarily resolve pulmonary symptoms and partially restore lung function. Previous studies indicated that exacerbations may be associated with changes in microbial densities and the acquisition of new microbial species. Given the complexity of the CF microbiota, we applied massively parallel pyrosequencing to identify changes in airway microbial community structure in 23 adult CF patients during acute pulmonary exacerbation, after antibiotic treatment and during periods of stable disease. Over 350,000 sequences were generated, representing nearly 170 distinct microbial taxa. Approximately 60% of sequences obtained were from the recognized CF pathogens Pseudomonas and Burkholderia, which were detected in largely non-overlapping patient subsets. In contrast, other taxa including Prevotella, Streptococcus, Rothia and Veillonella were abundant in nearly all patient samples. Although antibiotic treatment was associated with a small decrease in species richness, there was minimal change in overall microbial community structure. Furthermore, microbial community composition was highly similar in patients during an exacerbation and when clinically stable, suggesting that exacerbations may represent intrapulmonary spread of infection rather than a change in microbial community composition. Mouthwash samples, obtained from a subset of patients, showed a nearly identical distribution of taxa as expectorated sputum, indicating that aspiration may contribute to colonization of the lower airways. Finally, we observed a strong correlation between low species richness and poor lung function. Taken together, these results indicate that the adult CF lung microbiome is largely stable through periods of exacerbation and antibiotic treatment and that short-term compositional changes in the airway microbiota do not account for CF pulmonary exacerbations.

Oxidative-nitrosative stress and systemic vascular function in highlanders with and without exaggerated hypoxemia

ABSTRACT BACKGROUND: Acute exposure to high-altitude stimulates free radical formation in lowlanders yet whether this persists during chronic exposure in healthy well-adapted and maladapted highlanders suffering from chronic mountain sickness (CMS) remains to be established. METHODS: Oxidative-nitrosative stress [ascorbate radical (A•-), electron paramagnetic resonance spectroscopy and nitrite (NO2-), ozone-based chemiluminescence] was assessed in venous blood of 25 male highlanders living at 3,600 m with (n = 13, CMS+) and without (n = 12, CMS-) CMS. Twelve age and activity-matched healthy male lowlanders were examined at sea-level and during acute hypoxia. We also measured flow-mediated dilatation (FMD), arterial stiffness (AIx-75) and carotid intima-media thickness (IMT). RESULTS: Compared to normoxic lowlanders, oxidative-nitrosative stress was moderately increased in CMS- (P < 0.05) as indicated by elevated A•- (3,191 ± 457 vs. 2,640 ± 445 arbitrary units (AU)] and lower NO2- (206 ± 55 vs. 420 ± 128 nmol/L) whereas vascular function remained preserved. This was comparable to that observed during acute hypoxia in lowlanders in whom vascular dysfunction is typically observed. In contrast, this response was markedly exaggerated in CMS+ (A•-: 3,765 ± 429 AU and NO2- : 148 ± 50 nmol/L) compared to both CMS- and lowlanders (P < 0.05). This was associated with systemic vascular dysfunction as indicated by lower (P < 0.05 vs. CMS-) FMD (4.2 ± 0.7 vs. 7.6 ± 1.7 %) and increased AIx-75 (23 ± 8 vs. 12 ± 7 %) and carotid IMT (714 ± 127 vs. 588 ± 94 µM). CONCLUSIONS: Healthy highlanders display a moderate sustained elevation in oxidative-nitrosative stress that unlike the equivalent increase evoked by acute hypoxia in healthy lowlanders, failed to affect vascular function. Its more marked elevation in patients with CMS may contribute to systemic vascular dysfunction.Clinical Trials Gov Registration # NCT011827921Neurovascular Research Laboratory, Faculty of Health, Science and Sport, University of Glamorgan, Wales, UK;2Sondes Moléculaires en Biologie et Stress Oxydant, Institut de Chimie Radicalaire, CNRS UMR 7273, Aix-Marseille University, France;3Department of Cardiology, University Hospital of Bern, Bern, Switzerland;4Institute of Clinical Physiology, CNR, Pisa, Italy;5Instituto Bolivano de Biologia de Altura, La Paz, Bolivia;6Centre for Clinical and Population Sciences, Queen's University Belfast, Belfast, Northern Ireland,7Botnar Center for Clinical Research, Hirslanden Group, Lausanne, Switzerland;8Facultad de Ciencias, Departamento de Biología, Universidad de Tarapacá, Arica, Chile and9Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland*Drs Bailey, Rimoldi, Scherrer and Sartori contributed equally to this workCorrespondence: Damian Miles Bailey, Neurovascular Research Laboratory, Faculty of Health, Science and Sport, University of Glamorgan, UK CF37 4AT email: dbailey1@glam.ac.uk.

Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial:a double-blind, active and placebo-controlled study

The treatment of ischaemic stroke with neuroprotective drugs has been unsuccessful, and whether these compounds can be used to reduce disability after recurrent stroke is unknown. The putative neuroprotective effects of antiplatelet compounds and the angiotensin II receptor antagonist telmisartan were investigated in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial.

Decreased serum retinol is associated with increased mortality in renal transplant recipients

Vitamin A plays a central role in epithelial integrity and immune function. Given the risk of infection after transplantation, adequate vitamin A concentrations may be important in patients with a transplant. We assessed whether there was an association between retinol concentration and all-cause mortality in renal transplant recipients.

A test for psychometric function shift

A nonparametric, small-sample-size test for the homogeneity of two psychometric functions against the left- and right-shift alternatives has been developed. The test is designed to determine whether it is safe to amalgamate psychometric functions obtained in different experimental sessions. The sum of the lower and upper p-values of the exact (conditional) Fisher test for several 2 × 2 contingency tables (one for each point of the psychometric function) is employed as the test statistic. The probability distribution of the statistic under the null (homogeneity) hypothesis is evaluated to obtain corresponding p-values. Power functions of the test have been computed by randomly generating samples from Weibull psychometric functions. The test is free of any assumptions about the shape of the psychometric function; it requires only that all observations are statistically independent. © 2011 Psychonomic Society, Inc.

Effect of fruit and vegetable consumption on immune function in older people: A randomized controlled trial

Background: Fruit and vegetable (FV) intake, which is often low in older people, is associated with reduced chronic disease risk. Objective: We determined whether increased FV intake improves measures of immune function. Design: We conducted a randomized controlled trial (The Ageing and Dietary Intervention Trial) in 83 healthy volunteers aged 65-85 y with low FV intakes (=2 portions/d); 82 subjects completed the intervention. Participants were assigned to continue their normal diets or to consume =5 FV portions/d for 16 wk. At 12 wk, tetanus toxoid (0.5 mL intramuscular) and Pneumovax II vaccine (0.5 mL intramuscular; both vaccines from Sanofi Pasteur) were administered. FV intake was monitored by using diet histories, and biomarkers of nutritional status were assessed. The primary endpoint was the antibody response to vaccination. Specific antibodies binding to tetanus toxoid (total IgG) and pneumococcal capsular polysaccharide (total IgG and IgG2) were assessed at baseline and 16 wk. Participants were recruited between October 2006 and June 2008. Results: The change in FV consumption differed significantly between groups [mean change in number of portions (95% CI): in the 2-portion/d group, 0.4 portions/d (0.2, 0.7 portions/d); in the 5-portion/d group, 4.6 portions/d (4.1, 5.0 portions/d); P < 0.001)] and also in micronutrient status. Antibody binding to pneumococcal capsular polysaccharide (total IgG) increased more in the 5-portion/d group than in the 2-portion/d group [geometric mean (95% CI) of the week 16:baseline ratio: 3.1 (2.1, 4.4) and 1.7 (1.3, 2.1), respectively; P = 0.005)]. There was no significant difference in the increases in antibody binding to tetanus toxoid. Conclusion: Increased FV intake improves the Pneumovax II vaccination antibody response in older people, which links an achievable dietary goal with improved immune function. This trial was registered at clinicaltrials.gov as NCT00858728. © 2012 American Society for Nutrition.

The importance of pH in regulating the function of the Fasciola hepatica cathepsin L1 cysteine protease

The helminth parasite Fasciola hepatica secretes cathepsin L cysteine proteases to invade its host, migrate through tissues and digest haemoglobin, its main source of amino acids. Here we investigated the importance of pH in regulating the activity and functions of the major cathepsin L protease FheCL1. The slightly acidic pH of the parasite gut facilitates the auto-catalytic activation of FheCL1 from its inactive proFheCL1 zymogen; this process was approximately 40-fold faster at pH 4.5 than at pH 7.0. Active mature FheCL1 is very stable at acidic and neutral conditions (the enzyme retained approximately 45% activity when incubated at 37 degrees C and pH 4.5 for 10 days) and displayed a broad pH range for activity peptide substrates and the protein ovalbumin, peaking between pH 5.5 and pH 7.0. This pH profile likely reflects the need for FheCL1 to function both in the parasite gut and in the host tissues. FheCL1, however, could not cleave its natural substrate Hb in the pH range pH 5.5 and pH 7.0; digestion occurred only at pH

Corpus callosum size and inter-hemispheric function in schizophrenia

We studied the relationship between corpus callosum area and both inter-hemispheric facilitation and interference in schizophrenics and controls. Mid-sagittal sections through the corpus callosum were measured using structural magnetic resonance imaging on 42 patients and 43 normal controls, along with symptom profiles. In a sub-sample, a modified version of the Stroop Test was also performed (27 patients and 29 controls) to assess inter-hemispheric facilitation and interference of colour naming. In the larger sample (total subjects, n=85), there were no significant differences between patients and controls in CC area but a trend towards smaller values in patients in all but the posterior segment. In the sub-sample, bilateral facilitation was greater, and interference, less in schizophrenics compared with controls. There was a positive correlation between facilitation and posterior CC area, parallelled by a negative correlation between interference and posterior CC area, in both patients and controls, which only reached statistical significance when both groups were combined. These findings suggest that the link, between CC size and neuropsychological processes involving inter-hemispheric transfer of information, is common to both schizophrenics and normal controls. There were significant negative correlations between anterior CC area and psychomotor poverty (avolition, anhedonia and affective flattening), and a suggestion that the negative correlation between age and CC size in controls was not present in patients.

Prediction of ionic liquid properties. II. Volumetric properties as a function of temperature and pressure

The density of ionic liquids (ILs) as a function of pressure and temperature has been modeled using a group contribution model. This model extends the calculations previously reported (Jacquemin et al. J. Chem. Eng. Data 2008) which used 4000 IL densities at 298.15 K and 600 IL densities as a function of temperature up to 423 K at 0.1 MPa to pressures up to 207 MPa by using described data in the literature and presented in this study. The densities of two different ionic liquids (butyltrimethylammonium bis(trifluoromethylsulfonyl)imide, [N][NTf], and 1-butyl-l-methyl-pyrrolidiniumbis(trifluoromethylsulfonyl)imide, [C mPyrro]-[NTf]) were measured as a function of temperature from (293 to 415) K and over an extended pressure range from (0.1 to 40) MPa using a vibrating-tube densimeter. The model is able to predict the ionic liquid densities of over 5080 experimental data points to within 0.36%. In addition, this methodology allows the calculation of the mechanical coefficients using the calculated density as a function of temperature and pressure with an estimated uncertainty of ± 20%. © 2008 American Chemical Society.

Low pressure carbon dioxide solubility in lithium-ion batteries based electrolytes as a function of temperature. Measurement and prediction

We present in this study the effect of nature and concentration of lithium salt, such as the lithium hexafluorophosphate, LiPF6; lithium tris(pentafluoroethane)-trifluorurophosphate LiFAP; lithium bis(trifluoromethylsulfonyl)imide, LiTFSI, on the CO2 solubility in four electrolytes for lithium ion batteries based on pure solvent that include ethylene carbonate (EC), dimethyl carbonate (DMC), ethyl methyl carbonate (EMC), diethyl carbonate (DEC), as well as, in the EC:DMC, EC:EMC and EC:DEC (50:50) wt.% binary mixtures as a function of temperature from (283 to 353) K and atmospheric pressure. Based on experimental solubility values, the Henry’s law constant of the carbon dioxide in these solutions with the presence or absence of lithium salt was then deduced and compared with reported values from the literature, as well as with those predicted by using COSMO-RS methodology within COSMOThermX software. From this study, it appears that the addition of 1 mol · dm-3 LiPF6 salt in alkylcarbonate solvents decreases their CO2 capture capacity. By using the same experimental conditions, an opposite CO2 solubility trend was generally observed in the case of the addition of LiFAP or LiTFSI salts in these solutions. Additionally, in all solutions investigated during this work, the CO2 solubility is greater in electrolytes containing the LiFAP salt, followed by those based on the LiTFSI case. The precision and accuracy of the experimental data reported therein, which are close to (1 and 15)%, respectively. From the variation of the Henry’s law constant with temperature, the partial molar thermodynamic functions of dissolution such as the standard Gibbs energy, the enthalpy, and the entropy, as well as the mixing enthalpy of the solvent with CO2 in its hypothetical liquid state were calculated. Finally, a quantitative analysis of the CO2 solubility evolution was carried out in the EC:DMC (50:50) wt.% binary mixture as the function of the LiPF6 or LiTFSI concentration in solution to elucidate how ionic species modify the CO2 solubility in alkylcarbonates-based Li-ion electrolytes by investigating the salting effects at T = 298.15 K and atmospheric pressure.

Living is Information Processing: From Molecules to Global Systems

We extend the concept that life is an informational phenomenon, at every level of organisation, from molecules to the global ecological system. According to this thesis: (a) living is information processing, in which memory is maintained by both molecular states and ecological states as well as the more obvious nucleic acid coding; (b) this information processing has one overall function-to perpetuate itself; and (c) the processing method is filtration (cognition) of, and synthesis of, information at lower levels to appear at higher levels in complex systems (emergence). We show how information patterns, are united by the creation of mutual context, generating persistent consequences, to result in 'functional information'. This constructive process forms arbitrarily large complexes of information, the combined effects of which include the functions of life. Molecules and simple organisms have already been measured in terms of functional information content; we show how quantification may be extended to each level of organisation up to the ecological. In terms of a computer analogy, life is both the data and the program and its biochemical structure is the way the information is embodied. This idea supports the seamless integration of life at all scales with the physical universe. The innovation reported here is essentially to integrate these ideas, basing information on the 'general definition' of information, rather than simply the statistics of information, thereby explaining how functional information operates throughout life. © 2013 Springer Science+Business Media Dordrecht.

Exchange potential from the common energy denominator approximation for the Kohn-Sham Green's function: Application to (hyper)polarizabilities of molecular chains

An approximate Kohn-Sham (KS) exchange potential v(xsigma)(CEDA) is developed, based on the common energy denominator approximation (CEDA) for the static orbital Green's function, which preserves the essential structure of the density response function. v(xsigma)(CEDA) is an explicit functional of the occupied KS orbitals, which has the Slater v(Ssigma) and response v(respsigma)(CEDA) potentials as its components. The latter exhibits the characteristic step structure with "diagonal" contributions from the orbital densities \psi(isigma)\(2), as well as "off-diagonal" ones from the occupied-occupied orbital products psi(isigma)psi(j(not equal1)sigma). Comparison of the results of atomic and molecular ground-state CEDA calculations with those of the Krieger-Li-Iafrate (KLI), exact exchange (EXX), and Hartree-Fock (HF) methods show, that both KLI and CEDA potentials can be considered as very good analytical "closure approximations" to the exact KS exchange potential. The total CEDA and KLI energies nearly coincide with the EXX ones and the corresponding orbital energies epsilon(isigma) are rather close to each other for the light atoms and small molecules considered. The CEDA, KLI, EXX-epsilon(isigma) values provide the qualitatively correct order of ionizations and they give an estimate of VIPs comparable to that of the HF Koopmans' theorem. However, the additional off-diagonal orbital structure of v(xsigma)(CEDA) appears to be essential for the calculated response properties of molecular chains. KLI already considerably improves the calculated (hyper)polarizabilities of the prototype hydrogen chains H-n over local density approximation (LDA) and standard generalized gradient approximations (GGAs), while the CEDA results are definitely an improvement over the KLI ones. The reasons of this success are the specific orbital structures of the CEDA and KLI response potentials, which produce in an external field an ultranonlocal field-counteracting exchange potential. (C) 2002 American Institute of Physics.

Hypothalamic-pituitary-adrenal (HPA) axis function in 3-month old infants with prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure

Prenatal exposure to stress and selective serotonin reuptake inhibitors (SSRIs) alter hypothalamic-pituitary-adrenal (HPA) stress reactivity in offspring, however, the effects of combined exposure to HPA activity in human infants is unknown.