Differential sensitivity of the cystic fibrosis (CF)-associated mutants G551D and G1349D to potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel.

The genetic disease cystic fibrosis (CF) is caused by loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. Two CF mutants, G551D and G1349D, affect equivalent residues in the highly conserved LSGGQ motifs that are essential components of the ATP-binding sites of CFTR. Both mutants severely disrupt CFTR channel gating by decreasing mean burst duration (MBD) and prolonging greatly the interburst interval (IBI). To identify small molecules that rescue the gating defects of G551D- and G1349D-CFTR and understand better how these agents work, we used the patch clamp technique to study the effects on G551D- and G1349D-CFTR of phloxine B, pyrophosphate (PP(i)), and 2'-deoxy ATP (2'-dATP), three agents that strongly enhance CFTR channel gating. Phloxine B (5 microm) potentiated robustly G551D-CFTR Cl- channels by altering both MBD and IBI. In contrast, phloxine B (5 microm) decreased the IBI of G1349D-CFTR, but this effect was insufficient to rescue G1349D-CFTR channel gating. PP(i) (5 mm) potentiated weakly G551D-CFTR and was without effect on the G1349D-CFTR Cl- channel. However, by altering both MBD and IBI, albeit with different efficacies, 2'-dATP (1 mm) potentiated both G551D- and G1349D-CFTR Cl- channels. Using the ATP-driven nucleotide-binding domain dimerization model of CFTR channel gating, we suggest that phloxine B, PP(i) and 2'-dATP alter channel gating by distinct mechanisms. We conclude that G551D- and G1349D-CFTR have distinct pharmacological profiles and speculate that drug therapy for CF is likely to be mutation-specific

Subtleties on energy calculations in the image method

In this pedagogical work we point out a subtle mistake that can be done by undergraduate or graduate students in the computation of the electrostatic energy of a system containing charges and perfect conductors if they naively use the image method. Specifically, we show that the naive expressions for the electrostatic energy for these systems obtained directly from the image method are wrong by a factor 1/2. We start our discussion with well known examples, namely, point charge-perfectly conducting wall and point charge-perfectly conducting sphere and then proceed to the demonstration of general results, valid for conductors of arbitrary shapes.Comment: 9 pages, 2 figures; Major change in this version: subsection added to Sect.4 (theorem generalization). Minor changes: title replaced; corrections to the English; some explanatory comments adde

Does Giant Magnetoresistance Survive in Presence of Superconducting Contact?

The giant magnetoresistance (GMR) of ferromagnetic bilayers with a superconducting contact (F1/F2/S) is calculated in ballistic and diffusive regimes. As in spin-valve, it is assumed that the magnetization in the two ferromagnetic layers F1 and F2 can be changed from parallel to antiparallel. It is shown that the GMR defined as the change of conductance between the two magnetic configurations is an oscillatory function of the thickness of F2 layer and tends to an asymptotic positive value at large thickness. This is due to the formation of quantum well states in F2 induced by Andreev reflection at the F2/S interface and reflection at F1/F2 interface in antiparallel configuration. In the diffusive regime, if only spin-dependent scattering rates in the magnetic layers are considered (no difference in Fermi wave-vectors between spin up and down electrons) then the GMR is supressed due to the mixing of spin up and down electron-hole channels by Andreev reflection.Comment: 7 pages, 4 figures, submitted to Phys.Rev.Let

Nanoscale Mach-Zehnder interferometer with spin-resolved quantum Hall edge states

We realize a nanoscale-area Mach-Zehnder interferometer with co-propagating quantum Hall spin-resolved edge states and demonstrate the persistence of gate-controlled quantum interference oscillations, as a function of an applied magnetic field, at relatively large temperatures. Arrays of top-gate magnetic nanofingers are used to induce a resonant charge transfer between the pair of spin-resolved edge states. To account for the pattern of oscillations measured as a function of magnetic field and gate voltage, we have developed a simple theoretical model which satisfactorily reproduces the data.Comment: 7 pages, 5 figure

Inclusive University didactics and technological devices: a case study

This paper provides a review of projects related to new technologies used to favour the teaching-learning processes and the inclusive practices in the University context for students with disabilities and with Specific Learning Disorders. Authors present a review of strategies, trajectories and perspectives activated in the national and international scene, aiming to guarantee a significant pedagogical framework of reference. Furthermore, the paper focuses on a meaningful path activated at the University of Macerata, the project Inclusion 3.0, a relevant example of new technologies in support of teaching- learning processes and inclusion practices among all students

Measuring the distribution of current fluctuations through a Josephson junction with very short current pulses

We propose to probe the distribution of current fluctuations by means of the escape probability histogram of a Josephson junction (JJ), obtained using very short bias current pulses in the adiabatic regime, where the low-frequency component of the current fluctuations plays a crucial role. We analyze the effect of the third cumulant on the histogram in the small skewness limit, and address two concrete examples assuming realistic parameters for the JJ. In the first one we study the effects due to fluctuations produced by a tunnel junction, finding that the signature of higher cumulants can be detected by taking the derivative of the escape probability with respect to current. In such a realistic situation, though, the determination of the whole distribution of current fluctuations requires an amplification of the cumulants. As a second example we consider magnetic flux fluctuations acting on a SQUID produced by a random telegraph source of noise.Comment: 6 pages, 6 figures; final versio

Echo-endoscopic appearance of mediastinal metastasis from papillary renal carcinoma.

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Fibroblasts to keratinocytes redox signaling: The possible role of ROS in psoriatic plaque formation

Although the role of reactive oxygen species-mediated (ROS-mediated) signalling in physiologic and pathologic skin conditions has been proven, no data exist on the skin cells ROS-mediated communication. Primary fibroblasts were obtained from lesional and non-lesional skin of psoriatic patients. ROS, superoxide anion, calcium and nitric oxide levels and lipoperoxidation markers and total antioxidant content were measured in fibroblasts. NADPH oxidase activity and NOX1, 2 and 4 expressions were assayed and NOX4 silencing was performed. Fibroblasts and healthy keratinocytes co-culture was performed. MAPK pathways activation was studied in fibroblasts and in co-cultured healthy keratinocytes. Increased intracellular calcium, •NO and ROS levels as well as an enhanced NADPH oxidase 4 (NOX4)–mediated extracellular ROS release was shown in lesional psoriatic vs. control fibroblasts. Upon co-culture with lesional fibroblasts, keratinocytes showed p38 and ERK MAPKs pathways activation, ROS, Ca2+ and •NO increase and cell cycle acceleration. Notably, NOX4 knockdown significantly reduced the observed effects of lesional fibroblasts on keratinocyte cell cycle progression. Co-culture with non-lesional psoriatic and control fibroblasts induced slight cell cycle acceleration, but notable intracellular ROS accumulation and ERK MAPK activation in keratinocytes. Collectively, our data demonstrate that NOX4 expressed in dermal fibroblasts is essential for the redox paracrine regulation of epidermal keratinocytes proliferation