Characterization and regulation of wild‐type and mutant TASK‐1 two pore domain potassium channels indicated in pulmonary arterial hypertension

Key points The TASK-1 channel gene (KCNK3) has been identified as a possible disease-causing gene in heritable pulmonary arterial hypertension (PAH). In the present study, we show that novel mutated TASK-1 channels, seen in PAH patients, have a substantially reduced current compared to wild-type TASK-1 channels. These mutated TASK-1 channels are located at the plasma membrane to the same degree as wild-type TASK-1 channels. ONO-RS-082 and alkaline pH 8.4 both activate TASK-1 channels but do not recover current through mutant TASK-1 channels. We show that the guanylate cyclase activator, riociguat, a novel treatment for PAH, enhances current through TASK-1 channels but does not recover current through mutant TASK-1 channels. Pulmonary arterial hypertension (PAH) affects ∼15–50 people per million. KCNK3, the gene that encodes the two pore domain potassium channel TASK-1 (K2P3.1), has been identified as a possible disease-causing gene in heritable PAH. Recently, two new mutations have been identified in KCNK3 in PAH patients: G106R and L214R. The present study aimed to characterize the functional properties and regulation of wild-type (WT) and mutated TASK-1 channels and determine how these might contribute to PAH and its treatment. Currents through WT and mutated human TASK-1 channels transiently expressed in tsA201 cells were measured using whole-cell patch clamp electrophysiology. Localization of fluorescence-tagged channels was visualized using confocal microscopy and quantified with in-cell and on-cell westerns. G106R or L214R mutated channels were located at the plasma membrane to the same degree as WT channels; however, their current was markedly reduced compared to WT TASK-1 channels. Functional current through these mutated channels could not be restored using activators of WT TASK-1 channels (pH 8.4, ONO-RS-082). The guanylate cyclase activator, riociguat, enhanced current through WT TASK-1 channels; however, similar to the other activators investigated, riociguat did not have any effect on current through mutated TASK-1 channels. Thus, novel mutations in TASK-1 seen in PAH substantially alter the functional properties of these channels. Current through these channels could not be restored by activators of TASK-1 channels. Riociguat enhancement of current through TASK-1 channels could contribute to its therapeutic benefit in the treatment of PAH

Pseudoartrosis congénita bilateral de la clavícula: a propósito de un caso familiar

Presentamos una paciente de nueve meses con pseudoartrosis congénita bilateral de ambas clavículas, cuya madre presenta el mismo cuadro. Dicho cuadro es una entidad rara, pobremente documentada en la ortopedia pediátrica. La etiología y patogenia aún permanece oscura. La apariencia clínico-radiológica consiste en la ausencia desde el nacimiento de un defecto de unión a nivel del tercio medio clavicular característico. El diagnóstico diferencial debe hacerse con las fracturas perinatales, pseudoartrosis postraumáticas y disostosis cleido-craneales.The case of a female patient of nine months of are and her mother, 41-year-old showing a Congenital Bilateral Pseudoarthrosis of the clavicle are presented. This is a rare entity that has been poorly documented in paediatrics orthopedics literature. The etiology and pathogenesis still remain unclear. The clinical and radiological appearance are characteristic. Differential diagnosis lies between postpartum fractures, postraumatic pseudoarthrosis, and cleidocraneal dysostosis

Sulfide-, fluorite-, barite-bearing siliceous "crusts" related to unconformity surfaces of different ages in Pyrenees and Alps: a new model in carbonate-hosted deposits?

Wumerous stratabound sulfide-, barite-, fluonte-bearing siliceous crusts, from dm to some tens of in thick, occur over large areas of the Alpine belt, ;.e. the Alps and the Pyrenees. They are linked to unconformlty landscapes evolved on various carbonate units of Paieozoic and Triassic sedimentq sequences. Since the study mineralizations constitute the transition between the underlying carbonates and the overlying detrital units, they can be considered as an independent lithostratigraphic units that record a particular metalogenetic process not only in the alpine chains but worldwide. These mineralizations exhibit several morphologies: tabular concordant with the unconfonnities bodies, columnar bodies, karstic cavity-fillings, laminites and veins. In addition, the study deposits are clearly affected by remobilization process occuned during diagenesis or metamorphism. Such processes are responsible for masking the occunence of the breccia/conglomerate typically located at the base of the orebodies.Although the study mineralizations have usually been included in MVT deposit class, constrastirig differences between their diagnostic features and those of MVT mineralizations, suggest that the inclusion of the mineralized crust deposits in the MVT group seem incorrect.These peculiar ore-bearing quartz-crusts, persistent over large areas and showing an independent and distinct character and constituting an important marker for some sedimentary sequences of different ages in Alpine belts, allow the authors to define a new metallogenic model named as "crust-type" (CT) deposits. Comparable mineralization in other geotectonic environments outside Alpine belts point out to CT deposits being a worldwide significant metallogenic event

Optical Properties of Superconducting Nanowire Single-Photon Detectors

We measured the optical absorptance of superconducting nanowire single photon detectors. We found that 200-nm-pitch, 50%-fill-factor devices had an average absorptance of 21% for normally-incident front-illumination of 1.55-um-wavelength light polarized parallel to the nanowires, and only 10% for perpendicularly-polarized light. We also measured devices with lower fill-factors and narrower wires that were five times more sensitive to parallel-polarized photons than perpendicular-polarized photons. We developed a numerical model that predicts the absorptance of our structures. We also used our measurements, coupled with measurements of device detection efficiencies, to determine the probability of photon detection after an absorption event. We found that, remarkably, absorbed parallel-polarized photons were more likely to result in detection events than perpendicular-polarized photons, and we present a hypothesis that qualitatively explains this result. Finally, we also determined the enhancement of device detection efficiency and absorptance due to the inclusion of an integrated optical cavity over a range of wavelengths (700-1700 nm) on a number of devices, and found good agreement with our numerical model.Comment: will appear in optics express with minor revision

Historical Archaeology in the Iberian Peninsula

UID/HIS/04209/2019 DL 57/2016/CP1453/CT0084authorsversionpublishe

An extended chronicle discovery approach to find temporal patterns between sequences

Sequences of events describing the behavior and actions of users or systems can be collected in sev eral domains. An episode is a collection of events that occurs relatively close to each other in a given partial order. Also, chronicles are a special type of temporal patterns, where temporal orders of events are quantified with numerical bounds and reflect the temporal evolution of the system over the time. In this paper, the problem of finding rules for de scribing or predicting the behavior of the sequences with the intention of characterizing some interest ing tasks is considered. Obtaining these patterns is the main objective of this work, where an automatic method to learn relevant and discriminating chron icles is proposed. The method extends existing al gorithms that have been proposed to find frequent episodes/chronicles in a single event sequence to the case of multiple sequences.Ministerio de Economía y Competitividad TIN2009-14378-C02-01 (ARTEMISA)Junta de Andalucía TIC-8052 (Simon

Blocking Complement Factor B Activation Reduces Renal Injury and Inflammation in a Rat Brain Death Model

Introduction: The majority of kidneys used for transplantation are retrieved from brain-dead organ donors. In brain death, the irreversible loss of brain functions results in hemodynamic instability, hormonal changes and immunological activation. Recently, brain death has been shown to cause activation of the complement system, which is adversely associated with renal allograft outcome in recipients. Modulation of the complement system in the brain-dead donor might be a promising strategy to improve organ quality before transplantation. This study investigated the effect of an inhibitory antibody against complement factor B on brain death-induced renal inflammation and injury. Method: Brain death was induced in male Fischer rats by inflating a balloon catheter in the epidural space. Anti-factor B (anti-FB) or saline was administered intravenously 20 min before the induction of brain death (n = 8/group). Sham-operated rats served as controls (n = 4). After 4 h of brain death, renal function, renal injury, and inflammation were assessed. Results: Pretreatment with anti-FB resulted in significantly less systemic and local complement activation than in saline-treated rats after brain death. Moreover, anti-FB treatment preserved renal function, reflected by significantly reduced serum creatinine levels compared to saline-treated rats after 4 h of brain death. Furthermore, anti-FB significantly attenuated histological injury, as seen by reduced tubular injury scores, lower renal gene expression levels (>75%) and renal deposition of kidney injury marker-1. In addition, anti-FB treatment significantly prevented renal macrophage influx and reduced systemic IL-6 levels compared to saline-treated rats after brain death. Lastly, renal gene expression of IL-6, MCP-1, and VCAM-1 were significantly reduced in rats treated with anti-FB. Conclusion: This study shows that donor pretreatment with anti-FB preserved renal function, reduced renal damage and inflammation prior to transplantation. Therefore, inhibition of factor B in organ donors might be a promising strategy to reduce brain death-induced renal injury and inflammation.Nephrolog

How to Improve the Functional Capacity of Frail and Pre-Frail Elderly People? Health, Nutritional Status and Exercise Intervention. The EXERNET-Elder 3.0 Project

Aging is associated with the impairment of health and functional capacity, and physical exercise seems to be an effective tool in frailty prevention and treatment. The purpose of this study was to present the methodology used in the EXERNET-Elder 3.0 project that aims to evaluate the immediate and residual effects and of a multicomponent exercise training program called Elder-fit on frailty, fitness, body composition and quality of life, and also to analyse a possible dietary intake interaction according to health and metabolic status. A total of 110 frail and pre-frail elders participated in this study and were divided into a control group (CG = 52) and an intervention group (IG = 58). The IG performed a supervised multicomponent exercise training program of 6 months and 3 days per week, which included strength, endurance, balance, coordination and flexibility exercises, while the CG continued with their usual daily activities. Both groups received four speeches about healthy habits along the project. Four evaluations were performed: at baseline, after 3 months of training, at the end of the training program (6 months) and 4 months after the program had ended to examine the effects of detraining. Evaluating the efficacy, safety and feasibility of this program will help to develop efficacious physical interventions against frailty. Further, protocols should be described accurately to allow exercise programs to be successfully replicated

Monitoring new long-lasting intravitreal formulation for glaucoma with vitreous images using optical coherence tomography

Intravitreal injection is the gold standard therapeutic option for posterior segment patholo-gies, and long-lasting release is necessary to avoid reinjections. There is no effective intravitreal treatment for glaucoma or other optic neuropathies in daily practice, nor is there a non-invasive method to monitor drug levels in the vitreous. Here we show that a glaucoma treatment combining a hypotensive and neuroprotective intravitreal formulation (IF) of brimonidine–Laponite (BRI/LAP) can be monitored non-invasively using vitreoretinal interface imaging captured with optical coherence tomography (OCT) over 24 weeks of follow-up. Qualitative and quantitative characterisation was achieved by analysing the changes in vitreous (VIT) signal intensity, expressed as a ratio of retinal pigment epithelium (RPE) intensity. Vitreous hyperreflective aggregates mixed in the vitreous and tended to settle on the retinal surface. Relative intensity and aggregate size progressively decreased over 24 weeks in treated rat eyes as the BRI/LAP IF degraded. VIT/RPE relative intensity and total aggregate area correlated with brimonidine levels measured in the eye. The OCT-derived VIT/RPE relative intensity may be a useful and objective marker for non-invasive monitoring of BRI/LAP IF

Characterisation and regulation of wild type and mutant TASK-1 two pore domain potassium channels indicated in pulmonary arterial hypertension

KEY POINTS SUMMARY The TASK-1 channel gene (KCNK3) has been identified as a possible disease-causing gene in heritable pulmonary arterial hypertension (PAH). In this study we show that novel mutated TASK-1 channels, seen in PAH patients, have a substantially reduced current compared to wild type TASK-1 channels. These mutated TASK-1 channels are located at the plasma membrane to the same degree as wild type TASK-1 channels. ONO-RS-082 and alkaline pH 8.4 both activate TASK-1 channels but do not recover current through mutant TASK-1 channels. We show that the guanylate cyclase activator, riociguat, a novel treatment for PAH, enhances current through TASK-1 channels but does not recover current through mutant TASK-1 channels. ABSTRACT Pulmonary arterial hypertension (PAH) affects approximately 15-50 people per million. KCNK3, the gene that encodes the two pore domain potassium channel TASK-1 (K2P3.1), has been identified as a possible disease-causing gene in heritable PAH. Recently two new mutations have been identified in KCNK3, G106R and L214R, in PAH patients. The aim of this study is to characterise the functional properties and regulation of wildtype (WT) and mutated TASK-1 channels and understand how these might contribute to PAH and its treatment. Currents through WT and mutated human TASK-1 channels transiently expressed in tsA201 cells were measured using whole-cell patch-clamp electrophysiology. Localisation of fluorescently-tagged channels was visualised using confocal microscopy and quantified with in-cell and on-cell Westerns. G106R or L214R mutated channels were located at the plasma membrane to the same degree as WT channels, however their current was markedly reduced compared to WT TASK-1 channels. Functional current through these mutated channels could not be restored using activators of WT TASK-1 channels (pH 8.4, ONO-RS-082). The guanylate cyclase activator, riociguat, enhanced current through WT TASK-1 channels, however, like the other activators investigated, riociguat did not have any effect on current through mutated TASK-1 channels. Thus, novel mutations in TASK-1 seen in PAH, substantially alter the functional properties of these channels. Current through these channels could not be restored by activators of TASK-1 channels. Riociguat enhancement of current through TASK-1 channels could contribute to its therapeutic benefit in the treatment of PAH