Endothelin Receptor A Antagonism Attenuates Renal Medullary Blood Flow Impairment in Endotoxemic Pigs

BACKGROUND: Endothelin-1 is a potent endogenous vasoconstrictor that contributes to renal microcirculatory impairment during endotoxemia and sepsis. Here we investigated if the renal circulatory and metabolic effects of endothelin during endotoxemia are mediated through activation of endothelin-A receptors. METHODS AND FINDINGS: A randomized experimental study was performed with anesthetized and mechanically ventilated pigs subjected to Escherichia coli endotoxin infusion for five hours. After two hours the animals were treated with the selective endothelin receptor type A antagonist TBC 3711 (2 mg⋅kg(-1), n = 8) or served as endotoxin-treated controls (n = 8). Renal artery blood flow, diuresis and creatinine clearance decreased in response to endotoxemia. Perfusion in the cortex, as measured by laser doppler flowmetry, was reduced in both groups, but TBC 3711 attenuated the decrease in the medulla (p = 0.002). Compared to control, TBC 3711 reduced renal oxygen extraction as well as cortical and medullary lactate/pyruvate ratios (p<0.05) measured by microdialysis. Furthermore, TBC 3711 attenuated the decline in renal cortical interstitial glucose levels (p = 0.02) and increased medullary pyruvate levels (p = 0.03). Decreased creatinine clearance and oliguria were present in both groups without any significant difference. CONCLUSIONS: These results suggest that endothelin released during endotoxemia acts via endothelin A receptors to impair renal medullary blood flow causing ischemia. Reduced renal oxygen extraction and cortical levels of lactate by TBC 3711, without effects on cortical blood flow, further suggest additional metabolic effects of endothelin type A receptor activation in this model of endotoxin induced acute kidney injury

Profiling Circulating and Urinary Bile Acids in Patients with Biliary Obstruction before and after Biliary Stenting

Bile acids are considered as extremely toxic at the high concentrations reached during bile duct obstruction, but each acid displays variable cytotoxic properties. This study investigates how biliary obstruction and restoration of bile flow interferes with urinary and circulating levels of 17 common bile acids. Bile acids (conjugated and unconjugated) were quantified by liquid chromatography coupled with tandem mass spectrometry in serum and urine samples from 17 patients (8 men and 9 women) with biliary obstruction, before and after biliary stenting. Results were compared with serum concentrations measured in 40 age- and sex-paired control donors (20 men and 20 women). The total circulating bile acid concentration increases from 2.7 µM in control donors to 156.9 µM in untreated patients with biliary stenosis. Serum taurocholic and glycocholic acids exhibit 304- and 241-fold accumulations in patients with biliary obstruction compared to controls. The enrichment in chenodeoxycholic acid species reached a maximum of only 39-fold, while all secondary and 6α-hydroxylated species –except taurolithocholic acids – were either unchanged or significantly reduced. Stenting was efficient in restoring an almost normal circulating profile and in reducing urinary bile acids

Large-Scale Candidate Gene Analysis of HDL Particle Features

Background: HDL cholesterol (HDL-C) is an established marker of cardiovascular risk with significant genetic determination. However, HDL particles are not homogenous, and refined HDL phenotyping may improve insight into regulation of HDL metabolism. We therefore assessed HDL particles by NMR spectroscopy and conducted a large-scale candidate gene association analysis. Methodology/Principal Findings: We measured plasma HDL-C and determined mean HDL particle size and particle number by NMR spectroscopy in 2024 individuals from 512 British Caucasian families. Genotypes were 49,094 SNPs in >2,100 cardiometabolic candidate genes/loci as represented on the HumanCVD BeadChip version 2. False discovery rates (FDR) were calculated to account for multiple testing. Analyses on classical HDL-C revealed significant associations (FDR<0.05) only for CETP (cholesteryl ester transfer protein; lead SNP rs3764261: p = 5.6*10(-15)) and SGCD (sarcoglycan delta; rs6877118: p = 8.6*10(-6)). In contrast, analysis with HDL mean particle size yielded additional associations in LIPC (hepatic lipase; rs261332: p = 6.1*10(-9)), PLTP (phospholipid transfer protein, rs4810479: p = 1.7*10(-8)) and FBLN5 (fibulin-5; rs2246416: p = 6.2*10(-6)). The associations of SGCD and Fibulin-5 with HDL particle size could not be replicated in PROCARDIS (n = 3,078) and/or the Women's Genome Health Study (n = 23,170). Conclusions: We show that refined HDL phenotyping by NMR spectroscopy can detect known genes of HDL metabolism better than analyses on HDL-C

Anterior Thalamic High Frequency Band Activity Is Coupled with Theta Oscillations at Rest

Cross-frequency coupling (CFC) between slow and fast brain rhythms, in the form of phase–amplitude coupling (PAC), is proposed to enable the coordination of neural oscillatory activity required for cognitive processing. PAC has been identified in the neocortex and mesial temporal regions, varying according to the cognitive task being performed and also at rest. PAC has also been observed in the anterior thalamic nucleus (ATN) during memory processing. The thalamus is active during the resting state and has been proposed to be involved in switching between task-free cognitive states such as rest, in which attention is internally-focused, and externally-focused cognitive states, in which an individual engages with environmental stimuli. It is unknown whether PAC is an ongoing phenomenon during the resting state in the ATN, which is modulated during different cognitive states, or whether it only arises during the performance of specific tasks. We analyzed electrophysiological recordings of ATN activity during rest from seven patients who received thalamic electrodes implanted for treatment of pharmacoresistant focal epilepsy. PAC was identified between theta (4–6 Hz) phase and high frequency band (80–150 Hz) amplitude during rest in all seven patients, which diminished during engagement in tasks involving an external focus of attention. The findings are consistent with the proposal that theta–gamma coupling in the ATN is an ongoing phenomenon, which is modulated by task performance

Time-Course of Changes in Inflammatory Response after Whole-Body Cryotherapy Multi Exposures following Severe Exercise

The objectives of the present investigation was to analyze the effect of two different recovery modalities on classical markers of exercise-induced muscle damage (EIMD) and inflammation obtained after a simulated trail running race. Endurance trained males (n = 11) completed two experimental trials separated by 1 month in a randomized crossover design; one trial involved passive recovery (PAS), the other a specific whole body cryotherapy (WBC) for 96 h post-exercise (repeated each day). For each trial, subjects performed a 48 min running treadmill exercise followed by PAS or WBC. The Interleukin (IL) -1 (IL-1), IL-6, IL-10, tumor necrosis factor alpha (TNF-α), protein C-reactive (CRP) and white blood cells count were measured at rest, immediately post-exercise, and at 24, 48, 72, 96 h in post-exercise recovery. A significant time effect was observed to characterize an inflammatory state (Pre vs. Post) following the exercise bout in all conditions (p<0.05). Indeed, IL-1β (Post 1 h) and CRP (Post 24 h) levels decreased and IL-1ra (Post 1 h) increased following WBC when compared to PAS. In WBC condition (p<0.05), TNF-α, IL-10 and IL-6 remain unchanged compared to PAS condition. Overall, the results indicated that the WBC was effective in reducing the inflammatory process. These results may be explained by vasoconstriction at muscular level, and both the decrease in cytokines activity pro-inflammatory, and increase in cytokines anti-inflammatory

Inhibition of Toxic Shock by Human Monoclonal Antibodies against Staphylococcal Enterotoxin B

BACKGROUND: Staphylococcus aureus is implicated in many opportunistic bacterial infections around the world. Rising antibiotic resistance and few alternative methods of treatment are just two looming problems associated with clinical management of S. aureus. Among numerous virulence factors produced by S. aureus, staphylococcal enterotoxin (SE) B is a secreted protein that binds T-cell receptor and major histocompatibility complex class II, potentially causing toxic shock mediated by pathological activation of T cells. Recombinant monoclonal antibodies that target SEB and block receptor interactions can be of therapeutic value. METHODOLOGY/PRINCIPAL FINDINGS: The inhibitory and biophysical properties of ten human monoclonal antibodies, isolated from a recombinant library by panning against SEB vaccine (STEBVax), were examined as bivalent Fabs and native full-length IgG (Mab). The best performing Fabs had binding affinities equal to polyclonal IgG, low nanomolar IC(50)s against SEB in cell culture assays, and protected mice from SEB-induced toxic shock. The orthologous staphylococcal proteins, SEC1 and SEC2, as well as streptococcal pyrogenic exotoxin C were recognized by several Fabs. Four Fabs against SEB, with the lowest IC(50)s, were converted into native full-length Mabs. Although SEB-binding kinetics were identical between each Fab and respective Mab, a 250-fold greater inhibition of SEB-induced T-cell activation was observed with two Mabs. CONCLUSIONS/SIGNIFICANCE: Results suggest that these human monoclonal antibodies possess high affinity, target specificity, and toxin neutralization qualities essential for any therapeutic agent

Precise Measurement of the Neutrino Mixing Parameter theta(23) from Muon Neutrino Disappearance in an Off-Axis Beam

New data from the T2K neutrino oscillation experiment produce the most precise measurement of the neutrino mixing parameter theta_{23}. Using an off-axis neutrino beam with a peak energy of 0.6 GeV and a data set corresponding to 6.57 x 10^{20} protons on target, T2K has fit the energy-dependent nu_mu oscillation probability to determine oscillation parameters. Marginalizing over the values of other oscillation parameters yields sin^2 (theta_{23}) = 0.514 +0.055/-0.056 (0.511 +- 0.055), assuming normal (inverted) mass hierarchy. The best-fit mass-squared splitting for normal hierarchy is Delta m^2_{32} = (2.51 +- 0.10) x 10^{-3} eV^2/c^4 (inverted hierarchy: Delta m^2_{13} = (2.48 +- 0.10) x 10^{-3} eV^2/c^4). Adding a model of multinucleon interactions that affect neutrino energy reconstruction is found to produce only small biases in neutrino oscillation parameter extraction at current levels of statistical uncertainty

Measurement of the intrinsic electron neutrino component in the T2K neutrino beam with the ND280 detector

The T2K experiment has reported the first observation of the appearance of electron neutrinos in a muon neutrino beam. The main and irreducible background to the appearance signal comes from the presence in the neutrino beam of a small intrinsic component of electron neutrinos originating from muon and kaon decays. In T2K, this component is expected to represent 1.2% of the total neutrino flux. A measurement of this component using the near detector (ND280), located 280 m from the target, is presented. The charged current interactions of electron neutrinos are selected by combining the particle identification capabilities of both the time projection chambers and electromagnetic calorimeters of ND280. The measured ratio between the observed electron neutrino beam component and the prediction is 1.01 +/- 0.10 providing a direct confirmation of the neutrino fluxes and neutrino cross section modeling used for T2K neutrino oscillation analyses. Electron neutrinos coming from muons and kaons decay are also separately measured, resulting in a ratio with respect to the prediction of 0.68 +/- 0.30 and 1.10 +/- 0.14, respectively

The Molecular Evolution of the p120-Catenin Subfamily and Its Functional Associations

p120-catenin (p120) is the prototypical member of a subclass of armadillo-related proteins that includes δ-catenin/NPRAP, ARVCF, p0071, and the more distantly related plakophilins 1–3. In vertebrates, p120 is essential in regulating surface expression and stability of all classical cadherins, and directly interacts with Kaiso, a BTB/ZF family transcription factor.To clarify functional relationships between these proteins and how they relate to the classical cadherins, we have examined the proteomes of 14 diverse vertebrate and metazoan species. The data reveal a single ancient δ-catenin-like p120 family member present in the earliest metazoans and conserved throughout metazoan evolution. This single p120 family protein is present in all protostomes, and in certain early-branching chordate lineages. Phylogenetic analyses suggest that gene duplication and functional diversification into “p120-like” and “δ-catenin-like” proteins occurred in the urochordate-vertebrate ancestor. Additional gene duplications during early vertebrate evolution gave rise to the seven vertebrate p120 family members. Kaiso family members (i.e., Kaiso, ZBTB38 and ZBTB4) are found only in vertebrates, their origin following that of the p120-like gene lineage and coinciding with the evolution of vertebrate-specific mechanisms of epigenetic gene regulation by CpG island methylation.The p120 protein family evolved from a common δ-catenin-like ancestor present in all metazoans. Through several rounds of gene duplication and diversification, however, p120 evolved in vertebrates into an essential, ubiquitously expressed protein, whereas loss of the more selectively expressed δ-catenin, p0071 and ARVCF are tolerated in most species. Together with phylogenetic studies of the vertebrate cadherins, our data suggest that the p120-like and δ-catenin-like genes co-evolved separately with non-neural (E- and P-cadherin) and neural (N- and R-cadherin) cadherin lineages, respectively. The expansion of p120 relative to δ-catenin during vertebrate evolution may reflect the pivotal and largely disproportionate role of the non-neural cadherins with respect to evolution of the wide range of somatic morphology present in vertebrates today

Measurement of the neutrino-oxygen neutral-current interaction cross section by observing nuclear deexcitation gamma rays

We report the first measurement of the neutrino-oxygen neutral-current quasielastic (NCQE) cross section gamma It is obtained by observing nuclear deexcitation. rays which follow neutrino-oxygen interactions at the Super-Kamiokande water Cherenkov detector. We use T2K data corresponding to 3.01 x 10(20) protons on target. By selecting only events during the T2K beam window and with well-reconstructed vertices in the fiducial volume, the large background rate from natural radioactivity is dramatically reduced. We observe 43 events in the 4-30 MeV reconstructed energy window, compared with an expectation of 51.0, which includes an estimated 16.2 background events. The background is primarily nonquasielastic neutral-current interactions and has only 1.2 events from natural radioactivity. The flux-averaged NCQE cross section we measure is 1.55 x 10(-38) cm(2) with a 68% confidence interval of (1.22, 2.20) x 10(-38) cm(2) at a median neutrino energy of 630 MeV, compared with the theoretical prediction of 2.01 x 10(-38) cm(2)