Characterization of Two Novel Missense Mutations in the AQP2 Gene Causing Nephrogenic Diabetes Insipidus

Here, we report the aquaporin 2 (AQP2) mutational analysis of a patient with nephrogenic diabetes insipidus heterozygote due to two novel missense mutations. Direct sequencing of DNA in the male patient revealed that he was compound heterozygote for two mutations in the AQP2 gene: a thymine-to-adenine transversion at position 450 (c.450T>A) in exon 2 and a guanine-to-thymine at nucleotide position 643 (c.643G>T) in exon 4. The double heterozygous 450T>A and 643G>T transversion causes the amino acid substitution D150E and G215C. Direct sequencing of exons 2 and 4 of the AQP2 gene from each of the parents revealed that the c.450T>A mutation was inherited from the father while the c.643G>T mutation was inherited from the mother. Analysis of AQP2 excretion demonstrated that no AQP2 was detectable in the urine of the proband, whereas normal AQP2 levels were measured in both parents. When expressed in renal cells, both proteins were retarded in the endoplasmic reticulum and no redistribution was observed after forskolin stimulation. Of note, homology modeling revealed that the two mutations involve two highly conserved residues providing important clues about the role of the wt residues in AQP2 stability and function

Study of the impact of the post-MS evolution of the host star on the orbits of close-in planets. I. Sample definition and physical properties

Context: To date, more than 30 planets have been discovered around giant stars, but only one of them has been found to be orbiting within 0.6 AU from the host star, in direct contrast to what is observed for FGK dwarfs. This result suggests that evolved stars destroy/engulf close-in planets during the red giant phase. Aims: We are conducting a radial velocity survey of 164 bright G and K giant stars in the southern hemisphere with the aim of studying the effect of the host star evolution on the inner structure of planetary systems. In this paper we present the spectroscopic atmospheric parameters (\Teff, \logg, $\xi$, [Fe/H]) and the physical properties (mass, radius, evolutionary status) of the program stars. In addition, rotational velocities for all of our targets were derived. Methods: We used high resolution and high S/N spectra to measure the equivalent widths of many Fe{\sc\,i} and Fe{\sc\,ii} lines, which were used to derive the atmospheric parameters by imposing local thermodynamic and ionization equilibrium. The effective temperatures and metallicities were used, along with stellar evolutionary tracks to determine the physical properties and evolutionary status of each star. Results: We found that our targets are on average metal rich and they have masses between $\sim$\,1.0\,M$_\odot$ and 3.5\,M$_\odot$. In addition, we found that 122 of our targets are ascending the RGB, while 42 of them are on the HB phase.Comment: Accepted for publication in A&

Exploring the social cognition network in young adults with autism spectrum disorder using graph analysis

Background: Autism spectrum disorder (ASD) is characterized by an impairment in social cognition (SC). SC is a cognitive construct that refers to the capacity to process information about social situations. It is a complex network that includes distinct components. Exploring how SC components work together leads to a better understanding of how their interactions promote adequate social functioning. Our main goal was to use a novel statistical method, graph theory, to analyze SC relationships in ASD and Typically Developing (TD) individuals. Methods: We applied graph theory to SC measures to verify how the SC components interact and to establish which of them are important within the interacting SC network for TD and ASD groups. Results: The results showed that, in the TD group, the SC nodes are connected; their network showed increased betweenness among nodes, especially for the Theory of Mind. By contrast, in the SC network in the ASD group the nodes are highly disconnected, and the efficient connection among the components is absent. Conclusion: ASD adults do not show SC competencies and functional communication among these skills. Under this regard, specific components are crucial, suggesting they could represent critical domains for ASD SC

Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

Tumor-derived exosomes confer antigen-specific immunosuppression in a murine delayed-type hypersensitivity model

Exosomes are endosome-derived small membrane vesicles that are secreted by most cell types including tumor cells. Tumor-derived exosomes usually contain tumor antigens and have been used as a source of tumor antigens to stimulate anti-tumor immune responses. However, many reports also suggest that tumor-derived exosomes can facilitate tumor immune evasion through different mechanisms, most of which are antigen-independent. In the present study we used a mouse model of delayed-type hypersensitivity (DTH) and demonstrated that local administration of tumor-derived exosomes carrying the model antigen chicken ovalbumin (OVA) resulted in the suppression of DTH response in an antigen-specific manner. Analysis of exosome trafficking demonstrated that following local injection, tumor-derived exosomes were internalized by CD11c+ cells and transported to the draining LN. Exosome-mediated DTH suppression is associated with increased mRNA levels of TGF-β1 and IL-4 in the draining LN. The tumor-derived exosomes examined were also found to inhibit DC maturation. Taken together, our results suggest a role for tumor-derived exosomes in inducing tumor antigen-specific immunosuppression, possibly by modulating the function of APCs. © 2011 Yang et al

Register-based cumulative prevalence of Autism Spectrum Disorders during childhood and adolescence in Central Italy

Background: Studies have evaluated the prevalence of Autism Spectrum Disorders (ASD), focusing on different ages during childhood and adolescence. How cumulative prevalence increases before adulthood remains unclear. Methods: We used data from the Autism Register of the Regional Reference Centre for Autism in L'Aquila, Central Italy, to retrieve information on individuals born in 2001-2012 with any of the inclusion diagnoses of ASD (DSM criteria) for the period 2001 to 2018. Cumulative prevalence on L'Aquila district population data was calculated as percentages for three-year age strata. Results: All prevalence data were estimated at December 31st, 2018. The overall crude prevalence was 0.95% (352 cases over 36938 population). Cumulative prevalence was 1.19% among those born in 2001-2003 (15 to 17 years of follow up), 1.15% among those born in 2004-2006 (12 to 14 years of follow up), 1.04% among those born in 2007-2009 (9 to 11 years of follow up), 0.80% among those born in 2010-2012 (6 to 8 years of follow up), and 0.57% among those born in 2013-2015 (3 to 5 years of follow up). The proportion of ASD diagnoses until the age of 5 years, compared to the group diagnosed 6 to 8 years of age, showed a significant increasing trend over calendar time (53.6% for those born in 2001-2003, to 77.0% for those born in 2010-2012). Conclusions: Cumulative prevalence by time period provides a better understanding of ASD occurrence than a point prevalence. We did not find any difference in frequency of diagnosis comparing age strata and year of birth, suggesting that frequencies of ASD diagnosis remained roughly constant from 2001 to 2015. Results show that cumulative prevalence of autism diagnosis does not substantially change over time; instead, diagnosis of ASD is more likely at earliest ages over time, although new cases of ASD are also detected at later ages

Lactoferrin prevents LPS-induced decrease of the iron exporter ferroportin in human monocytes/macrophages.

Iron balance is tightly linked to inflammation and it has been demonstrated that many proteins involved in cellular iron management are up- or down-regulated by inflammatory stimuli, ultimately leading to iron retention in the reticuloendothelial system. Ferroportin is a key player in maintenance of correct iron homeostasis, because it is the only known mammalian cellular iron exporter. In this work we show that incubation of THP-1 monocytes/macrophages with lactoferrin prevents the LPS-induced decrease of ferroportin by reducing secretion of IL-6. © 2014 Springer Science+Business Media New York.Iron balance is tightly linked to inflammation and it has been demonstrated that many proteins involved in cellular iron management are up- or downregulated by inflammatory stimuli, ultimately leading to iron retention in the reticuloendothelial system. Ferroportin is a key player in maintenance of correct iron homeostasis, because it is the only known mammalian cellular iron exporter. In this work we show that incubation of THP-1 monocytes/macrophages with lactoferrin prevents the LPS-induced decrease of ferroportin by reducing secretion of IL-6

Bovine Lactoferrin Counteracts Toll-Like Receptor Mediated Activation Signals in Antigen Presenting Cells

Lactoferrin (LF), a key element in mammalian immune system, plays pivotal roles in host defence against infection and excessive inflammation. Its protective effects range from direct antimicrobial activities against a large panel of microbes, including bacteria, viruses, fungi and parasites, to antinflammatory and anticancer activities. In this study, we show that monocyte-derived dendritic cells (MD-DCs) generated in the presence of bovine LF (bLF) fail to undergo activation by up-modulating CD83, co-stimulatory and major histocompatibility complex molecules, and cytokine/chemokine secretion. Moreover, these cells are weak activators of T cell proliferation and retain antigen uptake activity. Consistent with an impaired maturation, bLF-MD-DC primed T lymphocytes exhibit a functional unresponsiveness characterized by reduced expression of CD154 and impaired expression of IFN-γ and IL-2. The observed imunosuppressive effects correlate with an increased expression of molecules with negative regulatory functions (i.e. immunoglobulin-like transcript 3 and programmed death ligand 1), indoleamine 2,3-dioxygenase, and suppressor of cytokine signaling-3. Interestingly, bLF-MD-DCs produce IL-6 and exhibit constitutive signal transducer and activator of transcription 3 activation. Conversely, bLF exposure of already differentiated MD-DCs completely fails to induce IL-6, and partially inhibits Toll-like receptor (TLR) agonist-induced activation. Cell-specific differences in bLF internalization likely account for the distinct response elicited by bLF in monocytes versus immature DCs, providing a mechanistic base for its multiple effects. These results indicate that bLF exerts a potent anti-inflammatory activity by skewing monocyte differentiation into DCs with impaired capacity to undergo activation and to promote Th1 responses. Overall, these bLF-mediated effects may represent a strategy to block excessive DC activation upon TLR-induced inflammation, adding further evidence for a critical role of bLF in directing host immune function

Search for charginos in e+e- interactions at sqrt(s) = 189 GeV

An update of the searches for charginos and gravitinos is presented, based on a data sample corresponding to the 158 pb^{-1} recorded by the DELPHI detector in 1998, at a centre-of-mass energy of 189 GeV. No evidence for a signal was found. The lower mass limits are 4-5 GeV/c^2 higher than those obtained at a centre-of-mass energy of 183 GeV. The (\mu,M_2) MSSM domain excluded by combining the chargino searches with neutralino searches at the Z resonance implies a limit on the mass of the lightest neutralino which, for a heavy sneutrino, is constrained to be above 31.0 GeV/c^2 for tan(beta) \geq 1.Comment: 22 pages, 8 figure