Background and Purpose
The cation channel transient receptor potential canonical (TRPC) 6 has been associated with several pathologies including focal segmental glomerulosclerosis, pulmonary ...hypertension and ischaemia reperfusion‐induced lung oedema. We set out to discover novel inhibitors of TRPC6 channels and investigate the therapeutic potential of these agents.
Experimental Approach
A library of potential TRPC channel inhibitors was designed and synthesized. Activity of the compounds was assessed by measuring intracellular Ca2+ levels. The lead compound SAR7334 was further characterized by whole‐cell patch‐clamp techniques. The effects of SAR7334 on acute hypoxic pulmonary vasoconstriction (HPV) and systemic BP were investigated.
Key Results
SAR7334 inhibited TRPC6, TRPC3 and TRPC7‐mediated Ca2+ influx into cells with IC50s of 9.5, 282 and 226 nM, whereas TRPC4 and TRPC5‐mediated Ca2+ entry was not affected. Patch‐clamp experiments confirmed that the compound blocked TRPC6 currents with an IC50 of 7.9 nM. Furthermore, SAR7334 suppressed TRPC6‐dependent acute HPV in isolated perfused lungs from mice. Pharmacokinetic studies of SAR7334 demonstrated that the compound was suitable for chronic oral administration. In an initial short‐term study, SAR7334 did not change mean arterial pressure in spontaneously hypertensive rats (SHR).
Conclusions and Implications
Our results confirm the role of TRPC6 channels in hypoxic pulmonary vasoregulation and indicate that these channels are unlikely to play a major role in BP regulation in SHR. SAR7334 is a novel, highly potent and bioavailable inhibitor of TRPC6 channels that opens new opportunities for the investigation of TRPC channel function in vivo.
Multiple-Object Tracking (MOT) methods are used to detect targets in individual video frames, e.g., vehicles, people, and other objects, and then record each unique target’s path over time. Current ...state-of-the-art approaches are extremely complex because most rely on extracting and comparing visual features at every frame to track each object. These approaches are geared toward high-difficulty-tracking scenarios, e.g., crowded airports, and require expensive dedicated hardware, e.g., Graphics Processing Units. In hardware-constrained applications, researchers are turning to older, less complex MOT methods, which reveals a serious scalability issue within the state-of-the-art. Crowded environments are a niche application for MOT, i.e., there are far more residential areas than there are airports. Given complex approaches are not required for low-difficulty-tracking scenarios, i.e., video showing mainly isolated targets, there is an opportunity to utilize more efficient MOT methods for these environments. Nevertheless, little recent research has focused on developing more efficient MOT methods.This thesis describes a novel MOT method, ClusterTracker, that is built to handle variable-difficulty-tracking environments an order of magnitude faster than the state-of-the-art. It achieves this by avoiding visual features and using quadratic-complexity algorithms instead of the cubic-complexity algorithms found in other trackers. ClusterTracker performs spatial clustering on object detections from short frame sequences, treats clusters as tracklets, and then connects successive tracklets with high bounding-box overlap to form tracks. With recorded video, parallel processing can be applied to several steps of ClusterTracker.This thesis evaluates ClusterTracker’s baseline performance on several benchmark datasets, describes its intended operating environments, and identifies its weaknesses. Subsequent modifications patch these weaknesses while also addressing the scalability concerns of more complex MOT methods. The modified architecture uses clustering feedback to separate isolated targets from non-isolated targets, re-processing the latter with a more complex MOT method. Results show ClusterTracker is uniquely suited for such an approach and allows complex MOT methods to be applied to the challenging tracking situations for which they are intended.
Surface photovoltage is used to study the dynamics of photogenerated carriers which are transported through a highly interconnected three-dimensional network of indium phosphide nanowires. Through ...the nanowire network charge transport is possible over distances far in excess of the nanowire lengths. Surface photovoltage was measured within a region 10.5–14.5 mm from the focus of the illumination, which was chopped at a range of frequencies from 15 Hz to 30 kHz. Carrier dynamics were modeled by approximating the nanowire network as a thin film, then fitted to experiment suggesting diffusion of electrons and holes at approximately 75% of the bulk value in InP but with significantly reduced built-in fields, presumably due to screening by nanowire surfaces.
Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, abdominal obesity, and insulin resistance. However, its ...etiology is unclear, and its management is often unsatisfactory or requires a diversified approach. Here, we describe a new rat PCOS model, the first to exhibit both ovarian and metabolic characteristics of the syndrome. Female rats received the nonaromatizable androgen dihydrotestosterone (DHT) or the aromatase inhibitor letrozole by continuous administration, beginning before puberty, to activate androgen receptors. Adult DHT rats had irregular cycles, polycystic ovaries characterized by cysts formed from atretic follicles, and a diminished granulosa layer. They also displayed metabolic features, including increased body weight, increased body fat, and enlarged mesenteric adipocytes, as well as elevated leptin levels and insulin resistance. All letrozole rats were anovulatory and developed polycystic ovaries with structural changes strikingly similar to those in human PCOS. Our findings suggest that the formation of a “hyperplastic” theca interna reflects the inclusion of luteinized granulosa cells in the cyst wall rather than true hyperplasia. We conclude that the letrozole model is suitable for studies of the ovarian features of human PCOS, while the DHT model is suitable for studies of both ovarian and metabolic features of the syndrome.
GaN-based single-phase bridgeless PFC boost rectifier Jappe, Tiago Kommers; Lohn, Murilo Koerich; Mussa, Samir Ahmad
Journal of engineering (Stevenage, England),
June 2019, Letnik:
2019, Številka:
17
Journal Article
Recenzirano
Odprti dostop
A single-phase GaN-based bridgeless PFC Boost converter design is proposed regarding multi-domain optimisation concepts. A design guideline describing elements losses are presented concerning the ...selected power converter topology. Experimental results are also depicted in 750 W power prototype digitally controlled by an FPGA device using switching frequency up to 500 kHz per active switch.
Ca(2+) sparks are localized intracellular Ca(2+) events released through ryanodine receptors (RyRs) that control excitation-contraction coupling in heart and smooth muscle. Ca(2+) spark triggering ...depends on precise delivery of Ca(2+) ions through dihydropyridine (DHP)-sensitive Ca(2+) channels to RyRs of the sarcoplasmic reticulum (SR), a process requiring a very precise alignment of surface and SR membranes containing Ca(2+) influx channels and RyRs. Because caveolae contain DHP-sensitive Ca(2+) channels and may colocalize with SR, we tested the hypothesis that caveolae are the structural element necessary for the generation of Ca(2+) sparks. Using methyl-ss-cyclodextrin (dextrin) to deplete caveolae, we found that dextrin dose-dependently decreased the frequency, amplitude, and spatial size of Ca(2+) sparks in arterial smooth muscle cells and neonatal cardiomyocytes. However, temporal characteristics of Ca(2+) sparks were not significantly affected. We ruled out the possibility that the decreases in Ca(2+) spark frequency and size are caused by changes in DHP-sensitive L-type channels, SR Ca(2+) load, or changes in membrane potential. Our results suggest a novel signaling model that explains the formation of Ca(2+) sparks in a caveolae microdomain. The transient elevation in Ca(2+)(i) at the inner mouth of a single caveolemmal Ca(2+) channel induces simultaneous activation and thus opens several RyRs to generate a local Ca(2+) release event, a Ca(2+) spark. Alterations in the molecular assembly and ultrastructure of caveolae may lead to pathophysiological changes in Ca(2+) signaling. Thus, caveolae may be intimately involved in cardiovascular cell dysfunction and disease.
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